Author Report for: Zhang ZNo contact information in database for Zhang Z
Ai H, Lee YY, Xie X, Tan CP, Ming Lai O, Li A, Wang Y, Zhang Z Ref: Food Chem, 412:135558, 2023 : PubMed ESTHER: Ai_2023_Food.Chem_412_135558 PubMedSearch: Ai 2023 Food.Chem 412 135558 PubMedID: 36716631 Abstract Palm olein (POL) was modified by enzymatic interesterification with different degrees of acyl migration in a solvent-free packed bed reactor. The fatty acid and acylglycerol composition, isomer content, thermodynamic behavior, and relationship between crystal polymorphism, solid fat content (SFC), crystal microstructure, and texture before and after modification were studied. We found that the increase in sn-2 saturation interesterification was not only due to the generated tripalmitin (PPP) but also caused by acyl migration, and the SFC profiles were changed accordingly. The emergence of high melting point acylglycerols was an important factor accelerating the crystallization rate, further shortening the crystallization induction time, leading to the formation of large crystal spherulites, thereby reducing the hardness. The transformation from the beta' to the beta form occurred during post-hardening during storage. The isomer content also affected the physicochemical properties of the modified POL. Title: Novel Matrine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, and Mechanistic Analysis Ang S, Liang J, Zheng W, Zhang Z, Li J, Yan Z, Wong WL, Zhang K, Chen M, Wu P Ref: Molecules, 28:, 2023 : PubMed ESTHER: Ang_2023_Molecules_28_ PubMedSearch: Ang 2023 Molecules 28 PubMedID: 37049799 Abstract A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC(50) values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 microg/mL, respectively, whereas the LC(50) value of MA was 659.34 microg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 microg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin. Title: Novel Sophoridine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, Acetylcholinesterase Inhibition, and Morphological Study Ang S, Cao N, Zheng W, Zhang Z, Li J, Yan Z, Su K, Wong WL, Zhang K and Wu P <1 more author(s)> Ang S, Cao N, Zheng W, Zhang Z, Li J, Yan Z, Su K, Wong WL, Zhang K, Hong WD, Wu P (- 1) Ref: Insects, 14:, 2023 : PubMed ESTHER: Ang_2023_Insects_14_ PubMedSearch: Ang 2023 Insects 14 PubMedID: 37103214 Abstract Two series of novel sophoridine derivatives were designed, synthesized, and evaluated for their anti-mosquito activity. SOP-2g, SOP-2q, and SOP-2r exhibited potential larvicidal activity against Aedes albopictus larva with LC(50) values of 330.98, 430.53, and 411.09 ppm, respectively. Analysis of structure-activity relationships indicated that the oxime ester group was beneficial for improving the larvicidal biological activity, whereas the long-chain aliphatic group and fused-ring group were introduced. Furthermore, the larvicidal mechanism was also investigated based on the inhibition assay of acetylcholinesterase (AChE) and the morphological observation of dead larva treated with derivatives. Results indicated that the AChE inhibitory activity of the preferred three derivatives were 63.16%, 46.67%, and 35.11%, respectively, at 250 ppm concentration. Additionally, morphological evidence demonstrated that SOP-2q and SOP-2r induced changes in the larva's intestinal cavity, caudal gill, and tail, thereby displaying larvicidal action against Ae. albopictus together with AChE inhibition. Therefore, this study implied that sophoridine and its novel derivatives could be used to control the population of mosquito larva, which may also be effective alkaloids to reduce the mosquito population density. Title: Transcriptional landscape of pathogen-responsive lncRNAs in tomato unveils the role of hydrolase encoding genes in response to Botrytis cinerea invasion Chen D, Zhang Z, Chen Y, Li B, Chen T, Tian S Ref: Plant Cell Environ, :, 2023 : PubMed ESTHER: Chen_2023_Plant.Cell.Environ__ PubMedSearch: Chen 2023 Plant.Cell.Environ PubMedID: 37899711 Abstract LncRNAs have gained increasing attention owing to their important regulatory roles on growth and stress responses of plants. However, the mechanisms underlying the functions of lncRNAs in fruit-pathogen interaction are still largely unknown. In this study, a total of 273 lncRNAs responding to Botrytis cinerea infection were identified in tomato fruit, among which a higher percentage of antisense lncRNAs were targeted to the genes enriched in hydrolase activity. To ascertain the roles of these lncRNAs, seven hydrolase-related transcripts were transiently knocked-down by virus-induced gene silencing. Silencing of lncRNACXE20 reduced the expression level of a carboxylesterase gene, further enhancing the resistance of tomato to B. cinerea. In contrast, silencing of lncRNACHI, lncRNAMMP, lncRNASBT1.9 and lncRNAPME1.9 impaired the resistance to B. cinerea, respectively. Further RT-qPCR assay and enzymatic activity detection displayed that the attenuated resistance of lncRNAMMP and lncRNASBT1.9-silenced plants was associated with the inhibition on the expression of JA-related genes, while the decreased resistance of lncRNACHI-silenced plants resulted in reduced chitinase activity. Collectively, these results may provide references for deciphering the mechanisms underlying specific lncRNAs to interfere with B. cinerea infection by regulating the expression of defence-related genes or affecting hydrolase activity. Title: Dual-Mode Ratiometric Electrochemical and Turn-On Fluorescent Detection of Butyrylcholinesterase Utilizing a Single Probe for the Diagnosis of Alzheimer's Disease Dong H, Zhao L, Wang T, Chen Y, Hao W, Zhang Z, Hao Y, Zhang C, Wei X and Xu M <2 more author(s)> Dong H, Zhao L, Wang T, Chen Y, Hao W, Zhang Z, Hao Y, Zhang C, Wei X, Zhang Y, Zhou Y, Xu M (- 2) Ref: Analytical Chemistry, 95:8340, 2023 : PubMed ESTHER: Dong_2023_Anal.Chem_95_8340 PubMedSearch: Dong 2023 Anal.Chem 95 8340 PubMedID: 37192372 Abstract Biomarkers detection in blood with high accuracy is crucial for the diagnosis and treatment of many diseases. In this study, the proof-of-concept fabrication of a dual-mode sensor based on a single probe (Re-BChE) using a dual-signaling electrochemical ratiometric strategy and a "turn-on" fluorescent method is presented. The probe Re-BChE was synthesized in a single step and demonstrated dual mode response toward butyrylcholinesterase (BChE), a promising biomarker of Alzheimer's disease (AD). Due to the specific hydrolysis reaction, the probe Re-BChE demonstrated a turn-on current response for BChE at -0.28 V, followed by a turn-off current response at -0.18 V, while the fluorescence spectrum demonstrated a turn-on response with an emission wavelength of 600 nm. The developed ratiometric electrochemical sensor and fluorescence detection demonstrated high sensitivity with BChE concentrations with a low detection limit of 0.08 microg mL(-1) and 0.05 microg mL(-1), respectively. Importantly, the dual-mode sensor presents the following advantages: (1) dual-mode readout can correct the impact of systematic or background error, thereby achieving more accurate results; (2) the responses of dual-mode readout originate from two distinct mechanisms and relatively independent signal transduction, in which there is no interference between two signaling routes. Additionally, compared with the reported single-signal electrochemical assays for BChE, both redox potential signals were detected in the absence of biological interference within a negative potential window. Furthermore, it was discovered that the outcomes of direct dual-mode electrochemical and fluorescence quantifications of the level of BChE in serum were in agreement with those obtained from the use of commercially available assay kits for BChE sensing. This method has the potential to serve as a useful point-of-care tool for the early detection of AD. Title: Uptake, accumulation, and degradation of dibutyl phthalate by three wetland plants Fan Y, Li T, Zhang Z, Song X, Cun D, Cui B, Wang Y Ref: Water Sci Technol, 88:1508, 2023 : PubMed ESTHER: Fan_2023_Water.Sci.Technol_88_1508 PubMedSearch: Fan 2023 Water.Sci.Technol 88 1508 PubMedID: 37768752 Abstract The uptake and degradation mechanisms of dibutyl phthalate (DBP) by three wetland plants, namely Lythrum salicaria, Thalia dealbata, and Canna indica, were studied using hydroponics. The results revealed that exposure to DBP at 0.5 mg/L had no significant effect on the growth of L. salicaria and C. indica but inhibited the growth of T. dealbata. After 28 days, DBP concentrations in the roots of L. salicaria, T. dealbata, and C. indica were 8.74, 5.67, and 5.46 mg/kg, respectively, compared to 2.03-3.95 mg/kg in stems and leaves. Mono-n-butyl phthalate concentrations in L. salicaria tissues were significantly higher than those in the other two plants at 23.1, 15.0, and 13.6 mg/kg in roots, stems, and leaves, respectively. The roots of L. salicaria also had the highest concentration of phthalic acid, reaching 2.45 mg/kg. Carboxylesterase, polyphenol oxidase, and superoxide dismutase may be the primary enzymes involved in DBP degradation in wetland plants. The activities of these three enzymes exhibited significant changes in plant tissues. The findings suggest L. salicaria as a potent plant for phytoremediation and use in constructed wetlands for the treatment of DBP-contaminated wastewater. Title: Transcriptomics and Selection Pressure Analysis Reveals the Influence Mechanism of PLIN1 Protein on the Development of Small Size in Min Pigs Liu Q, Yu L, Zhang Z, Chang Y, Liu Z, Xu C Ref: Int J Mol Sci, 24:, 2023 : PubMed ESTHER: Liu_2023_Int.J.Mol.Sci_24_ PubMedSearch: Liu 2023 Int.J.Mol.Sci 24 PubMedID: 36835359 Abstract Body size is an important biological phenotypic trait that has attracted substantial attention. Small domestic pigs can serve as excellent animal models for biomedicine and also help meet sacrificial culture needs in human societies. Although the mechanisms underlying vertebral development regulating body size variation in domestic pigs during the embryonic period have been well described, few studies have examined the genetic basis of body size variation in post embryonic developmental stages. In this study, seven candidate genes-PLIN1, LIPE, PNPLA1, SCD, FABP5, KRT10 and IVL-significantly associated with body size were identified in Min pigs, on the basis of weighted gene co-expression network analysis (WGCNA), and most of their functions were found to be associated with lipid deposition. Six candidate genes except for IVL were found to have been subjected to purifying selection. PLIN1 had the lowest omega value (0.139) and showed heterogeneous selective pressure among domestic pig lineages with different body sizes (p < 0.05). These results suggested that PLIN1 is an important genetic factor regulating lipid deposition and consequently affecting body size variation in pigs. The culture of whole pig sacrifice in Manchu during the Qing Dynasty in China might have contributed to the strong artificial domestication and selection of Hebao pigs. Title: Alteration of gut microbiota after heat acclimation may reduce organ damage by regulating immune factors during heat stress Liu S, Wen D, Feng C, Yu C, Gu Z, Wang L, Zhang Z, Li W, Wu S and Xue L <3 more author(s)> Liu S, Wen D, Feng C, Yu C, Gu Z, Wang L, Zhang Z, Li W, Wu S, Liu Y, Duan C, Zhuang R, Xue L (- 3) Ref: Front Microbiol, 14:1114233, 2023 : PubMed ESTHER: Liu_2023_Front.Microbiol_14_1114233 PubMedSearch: Liu 2023 Front.Microbiol 14 1114233 PubMedID: 36910226 Abstract INTRODUCTION: Heat-related illnesses can lead to morbidity, which are anticipated to increase frequency with predictions of increased global surface temperatures and extreme weather events. Although heat acclimation training (HAT) could prevent heat-related diseases, the mechanisms underlying HAT-promoting beneficial changes in organ function, immunity, and gut microbes remain unclear. METHODS: In the current study, we recruited 32 healthy young soldiers and randomly divided them into 4 teams to conduct HATs for 10 days: the equipment-assisted training team at high temperature (HE); the equipment-assisted training team under normal hot weather (NE); the high-intensity interval training team at high temperature (HIIT), and the control team without training. A standard heat tolerance test (HTT) was conducted before (HTT-1st) and after (HTT-2nd) the training to judge whether the participants met the heat acclimation (HA) criteria. RESULTS: We found that the participants in both HE and NE teams had significantly higher acclimation rates (HA/total population) than whom in the HIIT team. The effects of HAT on the participants of the HE team outperformed that of the NE team. In the HA group, the differences of physiological indicators and plasma organ damage biomarkers (ALT, ALP, creatinine, LDH, alpha-HBDH and cholinesterase) before and after HTT-2nd were significantly reduced to those during HTT-1st, but the differences of immune factors (IL-10, IL-6, CXCL2, CCL4, CCL5, and CCL11) elevated. The composition, metabolism, and pathogenicity of gut microbes changed significantly, with a decreased proportion of potentially pathogenic bacteria (Escherichia-Shigella and Lactococcus) and increased probiotics (Dorea, Blautia, and Lactobacillus) in the HA group. Training for a longer time in a high temperature and humidity showed beneficial effects for intestinal probiotics. CONCLUSION: These findings revealed that pathogenic gut bacteria decrease while probiotics increase following HA, with elevated immune factors and reduced organ damage during heat stress, thereby improving the body's heat adaption. Title: Serum Cholinesterase, C-reactive Protein, Interleukin 6, and Procalcitonin Levels as Predictors of Mortality in Patients in the Intensive Care Unit Liu Q, Fan X, Cui W, Wang X, Zhang Z, Wang N, Qiao L Ref: Turk J Anaesthesiol Reanim, 51:408, 2023 : PubMed ESTHER: Liu_2023_Turk.J.Anaesthesiol.Reanim_51_408 PubMedSearch: Liu 2023 Turk.J.Anaesthesiol.Reanim 51 408 PubMedID: 37876167 Abstract OBJECTIVE: The prognostic utility of inflammatory markers in survival has been suggested in patients with cancer; however, evidence on their prognostic value in severely ill patients is very limited. We aimed to explore the prognostic value of cholinesterase (ChE), C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) in predicting mortality in patients from the intensive care unit (ICU). METHODS: Serum levels of ChE, CRP, IL-6 and PCT were measured in ICU patients from December 13(th), 2019 to June 28(th), 2022. We assessed the predictive power of ChE, CRP, IL-6, and PCT using the receiver operating characteristic (ROC) curves. Furthermore, we evaluated their diagnostic accuracy by comparing the areas under the ROC curve (AUCs) along with their corresponding 95% confidence intervals (CIs). The cut-off values were determined to dichotomise these biomarkers, which were then included in multivariable logistic regression models to examine their relationship with ICU mortality. RESULTS: Among 253 ICU patients included in the study, 66 (26%) died during the ICU stay. The AUCs to predict ICU mortality were 0.643 (95% CI, 0.566-0.719), 0.648 (95% CI, 0.633-0.735), 0.643 (95% CI, 0.563-0.723) and 0.735 (95% CI, 0.664-0.807) for ChE, CRP, IL-6 and PCT, respectively. After adjusting for age, sex and disease severity, lower ChE level (<3.668 x 10(3) U L(-1)) and higher levels of CRP (>10.546 mg dL(-1)), IL-6 (>986.245 pg mL(-1)) and PCT (>0.505 microg L(-1)) were associated with higher mortality risk, with odd ratios of 2.70 (95% CI, 1.32-5.54), 4.99 (95% CI, 2.41-10.38), 3.24 (95% CI, 1.54-6.78) and 3.67 (95% CI, 1.45-9.95), respectively. CONCLUSION: ChE, CRP, IL-6 and PCT were independent ICU mortality risk factors in severely ill patients. Elevated PCT levels exhibited better predictive value than the other three biomarkers that were evaluated. Title: Phosphoproteome reveals long-term potentiation deficit following treatment of ultra-low dose soman exposure in mice Long Q, Zhang Z, Li Y, Zhong Y, Liu H, Chang L, Ying Y, Zuo T, Wang Y, Xu P Ref: J Hazard Mater, 459:132211, 2023 : PubMed ESTHER: Long_2023_J.Hazard.Mater_459_132211 PubMedSearch: Long 2023 J.Hazard.Mater 459 132211 PubMedID: 37572605 Abstract Soman, a warfare nerve agent, poses a significant threat by inducing severe brain damage that often results in death. Nonetheless, our understanding of the biological changes underlying persistent neurocognitive dysfunction caused by low dosage of soman remains limited. This study used mice to examine the effects of different doses of soman over time. Phosphoproteomic analysis of the mouse brain is the first time to be used to detect toxic effects of soman at such low or ultra-low doses, which were undetectable based on measuring the activity of acetylcholinesterase at the whole-animal level. We also found that phosphoproteome alterations could accurately track the soman dose, irrespective of the sampling time. Moreover, phosphoproteome revealed a rapid and adaptive cellular response to soman exposure, with the points of departure 8-38 times lower than that of acetylcholinesterase activity. Impaired long-term potentiation was identified in phosphoproteomic studies, which was further validated by targeted quantitative proteomics, immunohistochemistry, and immunofluorescence analyses, with significantly increased levels of phosphorylation of protein phosphatase 1 in the hippocampus following soman exposure. This increase in phosphorylation inhibits long-term potentiation, ultimately leading to long-term memory dysfunction in mice. Title: Ionic liquid modification reshapes the substrate pockets of lipase to boost its stability and activity in Vitamin E succinate synthesis Ma G, Zhang Z, Chen M, Zhang Y, Nian B, Hu Y Ref: J Sci Food Agric, :, 2023 : PubMed ESTHER: Ma_2023_J.Sci.Food.Agric__ PubMedSearch: Ma 2023 J.Sci.Food.Agric PubMedID: 37994149 Abstract BACKGROUND: The relative low stability, reusability and activity of enzymes made the industrial production of Vitamin E succinate (VES) can only be performed with complex processes and high cost using chemical methods. To address these issues, herein, an ionic liquids (ILs) modification strategy was developed to improve the activity and stability of lipases in VES synthesis in this study. RESULTS: The results showed that the [1-Butyl-3-Methyl Imidazole] [N-Acetyl-L-Proline] ILs modified Candida rugosa lipase (CRL) has the highest modification degree (48.28 %), activity (774 U/g), thermostability, solvent tolerance in three selected modifiers. Additionally, after reaction condition optimization, the highest yield of VES can be improved to 95.18% at 45 degreesC for 15 h, which was significantly improved compared to some previous studies. CONCLUSION: In this study, a high-efficiency VES synthesis strategy was successfully developed via modification of lipase. Moreover, the mechanism in which the ILs modification can enhance the activity and stability of lipase was investigated via both experimental and computational-aided methods. Molecular dynamics simulation suggested that ILs modification changed the geometry of Phe344 from flat to upright, which significantly reshaped and enhanced the size of substrate binding pocket of CRL. It is also agreement with our circular dichroism (CD) and fluorescence spectroscopy results which suggested that the modification changed the secondary structure of CRL to a certain extent. The larger pocket also endowed the suitable binding pose of succinate, which made the hydrogen bonds between succinate and active site Ser209 become stronger, and thus improving the yield of VES. This article is protected by copyright. All rights reserved. Title: Genome-wide identification of CXE and PuCXE15 functions in the catabolism of volatile ester in 'Nanguo' pear fruit Qi L, Li X, Zang N, Zhang Z, Yang Y, Du Y, Sun J, Mostafa I, Yin Z, Wang A Ref: Plant Physiol Biochem, 203:107996, 2023 : PubMed ESTHER: Qi_2023_Plant.Physiol.Biochem_203_107996 PubMedSearch: Qi 2023 Plant.Physiol.Biochem 203 107996 PubMedID: 37688900 Abstract Volatile esters are the main aromatic components that affect consumer sensory preferences. Aroma is a crucial characteristic of the 'Nanguo' pear (Pyrus ussriensis Maxim). Carboxylesterases (CXEs) are positively correlated with the catabolism of volatile esters in peaches; however, the mechanism of action of CXE family members in 'Nanguo' pear is poorly understood. In this study, 40 PuCXEs were identified in the 'Nanguo' pear and assigned into seven groups. In addition, we found that most PuCXEs were relatively conserved and contained cytoplasmic proteins. This hypothesis was supported by phylogenetic analysis, investigation of conserved domains and gene structures, and prediction of subcellular localization. Based on the content of volatile esters and expression levels of PuCXEs analysis, four PuCXEs, including PuCXE7, PuCXE15, PuCXE20, and PuCXE25, had a significant negative correlation with volatile ester accumulation. Particularly, the correlation of PuCXE15 far exceeded that of the other PuCXEs. The results of the transient expression assay showed that PuCXE15 promoted the degradation of ester in vivo. Subcellular localization experiment revealed that PuCXE15 is located in the plasma membrane and nucleus. These results show that PuCXE15 functions in the catabolism of volatile ester in 'Nanguo' pear fruit, and provides a foundation for enhancing aroma quality by artificial control in pear. Title: Identification of a 2-phenylthiazole derivative acetylcholinesterase modulator with in vitro antitumor activity in breast cancer cells Shi X, Liu P, Ma Y, Li M, Zhang Z, Zhang X, Shi D, Si X Ref: Chemical Biology Drug Des, :, 2023 : PubMed ESTHER: Shi_2023_Chem.Biol.Drug.Des__ PubMedSearch: Shi 2023 Chem.Biol.Drug.Des PubMedID: 38009562 Abstract Acetylcholinesterase (AchE) is a serine hydrolase with classical function to degrade acetylcholine and terminate neurotransmission. While "nonclassical" functions of AchE were involved in cell growth, death, invasion, etc. The expression and activity of AchE is changed in tumors, suggesting AChE inhibitors (AchEIs) may serve as potential antitumor drugs. In this study, the antitumor activity of a series of 2-phenylthiazole derivatives originally designed and synthesized as AchEIs were investigated. One compound named A6, was screened out with superior antitumor efficacy, especially against breast cancer MCF-7 cells. A6 significantly disrupted the amino acid metabolism and inhibited migration of MCF-7. In addition, A6 induced apoptosis of MCF-7 cells. To clarify how A6 affected on MCF-7 cells, RNA-seq analysis was conducted to evaluate the whole genome effect of A6 on gene expression. A total of 153 genes were increased, and the expression of 81 genes was decreased. GO and KEGG enrichment analysis showed A6 treatment mainly disrupted sterol/cholesterol pathway, Ras signaling pathway, VEGF signaling pathway, etc. Moreover, bioinformatic analysis and cell viability test showed A6 plays anticancer role by regulating Best1 and HIST1H2BJ. These results indicate that AchEI A6 could be a potential antitumor agent for breast cancer patients and could help the development of novel therapies. Title: Chemoenzymatic Cascade Reaction for the Valorization of the Lignin Depolymerization Product G-C2-Dioxolane Phenol Terholsen H, Meyer JRH, Zhang Z, Deuss PJ, Bornscheuer UT Ref: ChemSusChem, 16:e202300168, 2023 : PubMed ESTHER: Terholsen_2023_ChemSusChem_16_e202300168 PubMedSearch: Terholsen 2023 ChemSusChem 16 e202300168 PubMedID: 36826410 Gene_locus related to this paper: pyrca-PCEST Abstract Combining solid acid catalysts with enzyme reactions in aqueous environments is challenging because either very acidic conditions inactivate the enzymes, or the solid acid catalyst is neutralized. In this study, Amberlyst-15 encapsulated in polydimethylsiloxane (Amb-15@PDMS) is used to deprotect the lignin depolymerization product G-C2 dioxolane phenol in a buffered system at pH 6.0. This reaction is directly coupled with the biocatalytic reduction of the released homovanillin to homovanillyl alcohol by recombinant horse liver alcohol dehydrogenase, which is subsequently acylated by the promiscuous acyltransferase/hydrolase PestE_I208A_L209F_N288A in a one-pot system. The deprotection catalyzed with Amb-15@PDMS attains up to 97 % conversion. Overall, this cascade enables conversions of up to 57 %. Title: Uncovering the interactions between PME and PMEI at the gene and protein levels: Implications for the design of specific PMEI Wang Y, Zhang D, Huang L, Zhang Z, Shi Q, Hu J, He G, Guo X, Shi H, Liang L Ref: J Mol Model, 29:286, 2023 : PubMed ESTHER: Wang_2023_J.Mol.Model_29_286 PubMedSearch: Wang 2023 J.Mol.Model 29 286 PubMedID: 37610510 Abstract CONTEXT: Pectin methylesterase inhibitor (PMEI) can specifically bind and inhibit the activity of pectin methylesterase (PME), which has been widely used in fruit and vegetable juice processing. However, the limited three-dimensional structure, unclear action mechanism, low thermal stability and biological activity of PMEI severely limited its application. In this work, molecular recognition and conformational changes of PME and PMEI were analyzed by various molecular simulation methods. Then suggestions were proposed for improving thermal stability and affinity maturation of PMEI through semi-rational design. METHODS: Phylogenetic trees of PME and PMEI were established using the Maximum likelihood (ML) method. The results show that PME and PMEI have good sequence and structure conservation in various plants, and the simulated data can be widely adopted. In this work, MD simulations were performed using AMBER20 package and ff14SB force field. Protein interaction analysis indicates that H-bonds, van der Waals forces, and the salt bridge formed of K224 with ID116 are the main driving forces for mutual molecular recognition of PME and PMEI. According to the analyses of free energy landscape (FEL), conformational cluster, and motion, the association with PMEI greatly disrupts PME's dispersed functional motion mode and biological function. By monitoring the changes of residue contact number and binding free energy, (I)G35M/ (I)G35R: (I)T93F and (I)T113W/ (I)T113W: (I)D116W mutations contribute to thermal stability and affinity maturation of the PME-PMEI complex system, respectively. This work reveals the interaction between PME and PMEI at the gene and protein levels and provides options for modifying specific PMEI. Title: Ecotoxicological effects of soil lithium on earthworm Eisenia fetida: Lethality, bioaccumulation, biomarker responses, and histopathological changes Xu Z, Zhang Z, Wang X Ref: Environ Pollut, :121748, 2023 : PubMed ESTHER: Xu_2023_Environ.Pollut__121748 PubMedSearch: Xu 2023 Environ.Pollut 121748 PubMedID: 37127236 Abstract Lithium is an emerging environmental contaminant in the current low-carbon economy, but little is known about its influences on soil invertebrates. In this work, earthworm Eisenia fetida was exposed to soils treated with different levels of lithium for 7 d, and multiple ecotoxicological parameters were evaluated. The results showed that mortality was dose-dependent and lithium's median lethal content (LC(50)) to earthworm was respectively 865.08, 361.01, 139.36, and 94.95 mg/kg after 1 d, 2 d, 4 d, and 7 d exposure. The bioaccumulation factor based on measured exogenous lithium content (BF(exog)) respectively reached 0.79, 1.01, 1.57, and 1.27 with the increasing lithium levels, suggesting that lithium accumulation was averagely 1.16-fold to the exogenous content, and 74.42%-81.19%, 14.54%-18.23%, and 2.26%-8.02% of the lithium in exposed earthworms were respectively retained in the cytosol, debris, and granule. Then, lithium stress stimulated the activity of superoxide dismutase, peroxidase, catalase, acetylcholinesterase, and glutathione S-transferase as well as the content of 8-hydroxy-2-deoxyguanosine and metallothionein, indicating the generation of oxidative damage, while the content of reactive oxygen species and malondialdehyde decreased. Finally, lithium introduced histopathological changes, including the degenerated seminal vesicle and muscle hyperplasia, as well as high or extreme nuclear DNA damage. This study confirmed the obvious bioaccumulation and toxic effects caused by soil lithium via ecotoxicological data, providing new theoretical insights into understanding the ecological risks of lithium to soil invertebrates. Title: Chromium exposure altered metabolome and microbiome-associated with neurotoxicity in zebrafish Yan T, Xu Y, Zhu Y, Jiang P, Zhang Z, Li L, Wu Q Ref: J Appl Toxicol, :, 2023 : PubMed ESTHER: Yan_2023_J.Appl.Toxicol__ PubMedSearch: Yan 2023 J.Appl.Toxicol PubMedID: 36727205 Abstract In recent years, chromium (Cr) has been found to induce neurotoxicity. However, the underlying mechanism remains unclear. This study aimed to investigate the effects of chromium exposure on the metabolome and microbiome that may contribute to neurotoxicity in juvenile zebrafish. Zebrafish embryos were exposed to 1mg/L Cr (III) and 1mg/L Cr (VI) for seven days, respectively. Swimming distance and locomotor behavior was decreased, and acetylcholinesterase activity was reduced in Cr-exposed groups. Total cholesterol levels were decreased in Cr-exposed groups. The differential-expressed metabolites due to Cr exposure were mainly enriched in primary bile acid biosynthesis, which indicated that Cr exposure may promote cholesterol conversion. The abundance of Bacteroidetes decreased and the abundance of Actinomycetes increased in Cr- exposed groups, as compared to that in the control group. At the genus level, the abundance of Acinetobacter, Acidophorax, Mycobacterium, Aeromonas, Hydrophagophaga and Brevundimonas increased, whereas Chryseobacterium, Pseudomonas, Delftia and Ancylobacter decreased in the Cr-exposed groups. Analysis of the correlation between gut microbiota and bile acid metabolites showed that changes of gut microbial community due to Cr exposure may be related to secondary bile acid metabolism. Collectively, chromium exposure may disturb cholesterol metabolism, including primary bile acid and microbiota-related secondary bile acid metabolism. This study provides potential mechanism of the effects of chromium on neurotoxicity based on modulation of metabolome and gut microbiota diversity, which needs further verification. Title: Synthesis, Bioactivity and Molecular Docking of Nereistoxin Derivatives Containing Phosphonate Yan Q, Lu X, Zhang Z, Jin Q, Gao R, Li L, Wang H Ref: Molecules, 28:, 2023 : PubMed ESTHER: Yan_2023_Molecules_28_ PubMedSearch: Yan 2023 Molecules 28 PubMedID: 37375402 Abstract Novel nereistoxin derivatives containing phosphonate were synthesized and characterized via (31)P, (1)H and (13)C NMR and HRMS. The anticholinesterase activity of the synthesized compounds was evaluated on human acetylcholinesterase (AChE) using the in vitro Ellman method. Most of the compounds exhibited good inhibition of acetylcholinesterase. All of these compounds were selected to assess their insecticidal activity (in vivo) against Mythimna separata Walker, Myzus persicae Sulzer and Rhopalosiphum padi. Most of the tested compounds displayed potent insecticidal activity against these three species. Compound 7f displayed good activity against all three insect species, showing LC(50) values of 136.86 microg/mL for M. separata, 138.37 microg/mL for M. persicae and 131.64 microg/mL for R. padi. Compound 7b had the highest activity against M. persicae and R. padi, with LC(50) values of 42.93 microg/mL and 58.19 microg/mL, respectively. Docking studies were performed to speculate the possible binding sites of the compounds and explain the reasons for the activity of the compounds. The results showed that the compounds had lower binding energies with AChE than with the acetylcholine receptor (AchR), suggesting that compounds are more easily bound with AChE. Title: Toxicity and Physiological Effects of Nine Lamiaceae Essential Oils and Their Major Compounds on Reticulitermes dabieshanensis Yang X, Jin C, Wu Z, Han H, Zhang Z, Xie Y, Zhang D Ref: Molecules, 28:, 2023 : PubMed ESTHER: Yang_2023_Molecules_28_ PubMedSearch: Yang 2023 Molecules 28 PubMedID: 36903258 Abstract The volatile metabolites of Salvia sclarea, Rosmarinus officinalis, Thymus serpyllum, Mentha spicata, Melissa officinalis, Origanum majorana, Mentha piperita, Ocimum basilicum and Lavandula angustifolia were determined by gas chromatography-mass spectrometry. The vapor insecticidal properties of the analyzed essential oils and their compounds were screened using Reticulitermes dabieshanensis workers. The most effective oils were S. sclarea (major constituent linalyl acetate, 65.93%), R. officinalis (1,8-cineole, 45.56%), T. serpyllum (thymol, 33.59%), M. spicata (carvone, 58.68%), M. officinalis (citronellal, 36.99%), O. majorana (1,8-cineole, 62.29%), M. piperita (menthol, 46.04%), O. basilicum (eugenol, 71.08%) and L. angustifolia (linalool, 39.58%), which exhibited LC(50) values ranging from 0.036 to 1.670 microL/L. The lowest LC(50) values were recorded for eugenol (0.060 microL/L), followed by thymol (0.062 microL/L), carvone (0.074 microL/L), menthol (0.242 microL/L), linalool (0.250 microL/L), citronellal (0.330 microL/L), linalyl acetate (0.712 microL/L) and 1,8-cineole (1.478 microL/L). The increased activity of esterases (ESTs) and glutathione S-transferase (GST) were observed but only alongside the decreased activity of acetylcholinesterase (AChE) in eight main components. Our results indicate that S. sclarea, R. officinalis, T. serpyllum, M. spicata, M. officinalis, O. marjorana, M. piperita, O. basilicum and L. angustifolia essential oils (EOs) and their compounds, linalyl acetate, 1,8-cineole, thymol, carvone, citronellal, menthol, eugenol and linalool could be developed as control agents against termites. Title: Visualization of production and remediation of acetaminophen-induced liver injury by a carboxylesterase-2 enzyme-activatable near-infrared fluorescent probe Yang B, Ding X, Zhang Z, Li J, Fan S, Lai J, Su R, Wang X, Wang B Ref: Talanta, 269:125418, 2023 : PubMed ESTHER: Yang_2023_Talanta_269_125418 PubMedSearch: Yang 2023 Talanta 269 125418 PubMedID: 37988783 Abstract Acetaminophen (APAP) overdose, also known as APAP poisoning, may directly result in hepatic injury, acute liver failure and even death. Nowadays, APAP-induced liver injury (AILI) has become an urgent public health issue in the developing world so the early accurate diagnosis and the revelation of underlying molecular mechanism of AILI are of great significance. As a major detoxifying organ, liver is responsible for metabolizing chemical substances, in which human carboxylesterase-2 (CES2) is present. Hence, we chose CES2 as an effective biomarker for evaluating AILI. By developing a CES2-activatable and water-soluble fluorescent probe PFQ-E with superior affinity (K(m) = 5.9 microM), great sensitivity (limit of detection = 1.05 ng/mL), near-infrared emission (655 nm) and large Stokes shift (135 nm), activity and distribution of CES2 in cells were determined or imaged effectively. More importantly, the APAP-induced hepatotoxicity and the underlying molecular mechanism of pathogenesis of AILI were investigated by measuring the "light-up" response of PFQ-E towards endogenous CES2 in vivo for the first time. Based on the superior performance of the probe PFQ-E for sensing CES2, we believe that it has broad potential in clinical diagnosis and therapy response evaluation of AILI. Title: Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase Yu H, Xu H, Yang X, Zhang Z, Hu J, Lu J, Fu J, Bu M, Zhang H and Wang Y <3 more author(s)> Yu H, Xu H, Yang X, Zhang Z, Hu J, Lu J, Fu J, Bu M, Zhang H, Zhai Z, Wang J, Jiang J, Wang Y (- 3) Ref: J Pharm Anal, 13:1024, 2023 : PubMed ESTHER: Yu_2023_J.Pharm.Anal_13_1024 PubMedSearch: Yu 2023 J.Pharm.Anal 13 1024 PubMedID: 37842660 Abstract Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs. Title: Static Binding and Dynamic Transporting-Based Design of Specific Ring-Chain-Ring Acetylcholinesterase Inhibitor: From Galantamine to Natural Product Zhang Z, Lv J, Wang Y, Yu H, Guo B, Zhai J, Wang C, Zhao Y, Fan F, Luo W Ref: Chemistry, :e202203363, 2023 : PubMed ESTHER: Zhang_2023_Chemistry__e202203363 PubMedSearch: Zhang 2023 Chemistry e202203363 PubMedID: 36826395 Abstract Acetylcholinesterase (AChE) is a key target for the current symptomatic treatment of Alzheimer's disease, and galantamine is a clinical anticholinesterase drug with transiently acting characteristic and good selectivity for AChE. The present theoretical-experimental work improves the drug's residence time without reducing inhibition effect, thus provides crucial breakthrough for modifying the inhibitor of AChE with better-kinetic behavior. The static binding and dynamic delivery properties acquired from atomic view reveal that the galantamine simply occupies catalytic anionic site, and its release from AChE needs only ~ 8.6 kcal/mol. Both of them may cause the short residence time of galantamine. The hotspots and most favorable transport mechanism are identified, and the hydrogen bond and aromatic stacking interactions are observed to play crucial roles for galantamine binding and release in AChE. The typical peripheral anionic site arisen at the delivery process would provide another key occupation to enhance the anti-release ability for inhibitors. The compound with "specific-ring-chain-ring" framework with detail beneficial modify scheme is summarized, which may improve the residence time of inhibitor in AChE. The thermodynamic and dynamic properties of galantamine derivatives are also studied. Based on dictamnine, a natural alkaloid, two novel eligible derivatives are designed, synthesized and evaluated, which verifies our prediction. Multiple computational approaches and experiment combination probably provide a train of thought from static and dynamic view to modify or design appropriate inhibitor on the basis of specific binding and transportation features. Title: Inside Out Computational Redesign of Cavities for Improving Thermostability and Catalytic Activity of Rhizomucor Miehei Lipase Zhang Z, Long M, Zheng N, Lu X, Zhu C, Osire T, Xia X Ref: Applied Environmental Microbiology, :e0217222, 2023 : PubMed ESTHER: Zhang_2023_Appl.Environ.Microbiol__e0217222 PubMedSearch: Zhang 2023 Appl.Environ.Microbiol e0217222 PubMedID: 36912632 Abstract Cavities are created by hydrophobic interactions between residue side chain atoms during the folding of enzymes. Redesigning cavities can improve the thermostability and catalytic activity of the enzyme; however, the synergistic effect of cavities remains unclear. In this study, Rhizomucor miehei lipase (RML) was used as a model to explore volume fluctuation and spatial distribution changes of the internal cavities, which could reveal the roles of internal cavities in the thermostability and catalytic activity. We present an inside out cavity engineering (CE) strategy based on computational techniques to explore how changes in the volumes and spatial distribution of cavities affect the thermostability and catalytic activity of the enzyme. We obtained 12 single-point mutants, among which the melting temperatures (T(m)) of 8 mutants showed an increase of more than 2 degreesC. Sixteen multipoint mutations were further designed by spatial distribution rearrangement of internal cavities. The T(m) of the most stable triple variant, with mutations including T21V (a change of T to V at position 21), S27A, and T198L (T21V/S27A/T198L), was elevated by 11.0 degreesC, together with a 28.7-fold increase in the half-life at 65 degreesC and a specific activity increase of 9.9-fold (up to 5,828 U mg(-1)), one of the highest lipase activities reported. The possible mechanism of decreased volumes and spatial rearrangement of the internal cavities improved the stability of the enzyme, optimizing the outer substrate tunnel to improve the catalytic efficiency. Overall, the inside out computational redesign of cavities method could help to deeply understand the effect of cavities on enzymatic stability and activity, which would be beneficial for protein engineering efforts to optimize natural enzymes. IMPORTANCE In the present study, R. miehei lipase, which is widely used in various industries, provides an opportunity to explore the effects of internal cavities on the thermostability and catalytic activity of enzymes. Here, we execute high hydrostatic pressure molecular dynamics (HP-MD) simulations to screen the critical internal cavity and reshape the internal cavities through site-directed mutation. We show that as the global internal cavity volume decreases, cavity rearrangement can improve the stability of the protein while optimizing the substrate channel to improve the catalytic efficiency. Our results provide significant insights into understanding the mechanism of action of the internal cavity. Our strategy is expected to be applied to other enzymes to promote increases in thermostability and catalytic activity. Title: Efficient decolorization of melanoidin in raw molasses wastewater by thermophilic esterase in actual extreme conditions Zhang Z, Hu W, Xie Q, Shi Y, Zhao Y, Deng Y, He J, Wu X, Zhang Y and Wang W <3 more author(s)> Zhang Z, Hu W, Xie Q, Shi Y, Zhao Y, Deng Y, He J, Wu X, Zhang Y, Zhang W, Liu P, Yang H, Wang W (- 3) Ref: Bioresour Technol, 382:129191, 2023 : PubMed ESTHER: Zhang_2023_Bioresour.Technol_382_129191 PubMedSearch: Zhang 2023 Bioresour.Technol 382 129191 PubMedID: 37196742 Abstract This work was developed to explore the versatility of thermophilic esterase for decolorizing raw molasses wastewater at high temperature and acidic pH. Combining covalent crosslinking method with deep eutectic solvent, a thermophilic esterase from Pyrobaculum calidifontis was immobilized on chitosan/macroporous resin composite carrier. The application of this immobilized thermophilic esterase eliminated 92.35% of colorants in raw molasses wastewater, achieving maximal decolorization efficiency across all the enzymes tested. Strikingly, this immobilized thermophilic esterase was capable of engaging in continuous activity for a 5-day period while removing 76.23% of pigments from samples. It effectively and continuously eliminated BOD(5) and COD, effectively and directly facilitating raw molasses wastewater decolorization under extreme conditions more readily than control group. In addition, this thermophilic esterase was believed to achieve decolorization through an addition reaction that disrupted conjugated system of melanoidins. Together, these results highlight an efficient and practical means of achieving enzyme-based molasses wastewater decolorization. Title: Sulfur-fluoride exchange (SuFEx)-enabled lead discovery of AChE inhibitors by fragment linking strategies Zhang Z, Zhang SL, Wu C, Li HH, Zha L, Shi J, Liu X, Qin HL, Tang W Ref: Eur Journal of Medicinal Chemistry, 257:115502, 2023 : PubMed ESTHER: Zhang_2023_Eur.J.Med.Chem_257_115502 PubMedSearch: Zhang 2023 Eur.J.Med.Chem 257 115502 PubMedID: 37224761 Inhibitor(s) related to this paper: J8-A34 Abstract SuFEx click chemistry has been a method for the rapid synthesis of functional molecules with desirable properties. Here, we demonstrated a workflow that allows for in situ synthesis of sulfonamide inhibitors based on SuFEx reaction for high-throughput testing of their cholinesterase activity. According to fragment-based drug discovery (FBDD), sulfonyl fluorides [R-SO(2)F] with moderate activity were identified as fragment hits, rapidly diversified into 102 analogs in SuFEx reactions, and the sulfonamides were directly screened to yield drug-like inhibitors with 70-fold higher potency (IC(50) = 94 nM). Moreover, the improved molecule J8-A34 can ameliorate cognitive function in Abeta(1-42)-induced mouse model. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, this methodology can accelerate the development of robust biological probes and drug candidates. Title: A High-Density Raman Photometry for Tracking and Quantifying of AchE Activity in The Brain of Freely Moving Animals with Network Zhang Z, Liu Z, Wu P, Guo X, Luo X, Yang Y, Chen J, Tian Y Ref: Adv Sci (Weinh), :e2301004, 2023 : PubMed ESTHER: Zhang_2023_Adv.Sci.(Weinh)__e2301004 PubMedSearch: Zhang 2023 Adv.Sci.(Weinh) e2301004 PubMedID: 37635166 Abstract A high-density Raman photometry based on a dual-recognition strategy is created for accurately quantifying acetylcholinesterase (AchE) activity in 24 brain regions of free-moving animals with network. A series of 5-ethynyl-1,2,3,3-tetramethyl-based molecules with different conjugated structures and substitute groups are designed and synthesized for specific recognition of AchE by Raman spectroscopy. After systematically evaluating the recognition ability toward AchE, 2-(4-((4-(dimethylamino)benzoyl)oxy)styryl)-5-ethynyl-1,3,3-trimethyl-3H-indol-1-ium (ET-5) is finally optimized for AchE determination, which shows the highest selectivity, the greatest sensitivity, and the fastest response time among the investigated seven molecules. More interestingly, using the developed probe for AchE with high accuracy and sensitivity, the optimized AchE regulated by nitric oxide (NO) is discovered for promoting the neurogenesis of neural stem cells (NSCs). Benefiting from the high-density photometry, it is found that the activity and distribution of AchE varied in 24 brain regions, and the levels of AchE activity in 24 brain regions of Alzheimer's mice (AD) are lower than those of normal mice. It is the first time that a functional network of AchE in 24 brain regions is established. It is also found that the loss of AchE functional network in AD mice is restored and reconstructed by the controlled release of AchE regulated by NO. Title: Computational design of highly efficient thermostable MHET hydrolases and dual enzyme system for PET recycling Zhang J, Wang H, Luo Z, Yang Z, Zhang Z, Wang P, Li M, Zhang Y, Feng Y and Zhu Y <1 more author(s)> Zhang J, Wang H, Luo Z, Yang Z, Zhang Z, Wang P, Li M, Zhang Y, Feng Y, Lu D, Zhu Y (- 1) Ref: Commun Biol, 6:1135, 2023 : PubMed ESTHER: Zhang_2023_Commun.Biol_6_1135 PubMedSearch: Zhang 2023 Commun.Biol 6 1135 PubMedID: 37945666 Gene_locus related to this paper: geost-est30 Abstract Recently developed enzymes for the depolymerization of polyethylene terephthalate (PET) such as FAST-PETase and LCC-ICCG are inhibited by the intermediate PET product mono(2-hydroxyethyl) terephthalate (MHET). Consequently, the conversion of PET enzymatically into its constituent monomers terephthalic acid (TPA) and ethylene glycol (EG) is inefficient. In this study, a protein scaffold (1TQH) corresponding to a thermophilic carboxylesterase (Est30) was selected from the structural database and redesigned in silico. Among designs, a double variant KL-MHETase (I171K/G130L) with a similar protein melting temperature (67.58 degreesC) to that of the PET hydrolase FAST-PETase (67.80 degreesC) exhibited a 67-fold higher activity for MHET hydrolysis than FAST-PETase. A fused dual enzyme system comprising KL-MHETase and FAST-PETase exhibited a 2.6-fold faster PET depolymerization rate than FAST-PETase alone. Synergy increased the yield of TPA by 1.64 fold, and its purity in the released aromatic products reached 99.5%. In large reaction systems with 100g/L substrate concentrations, the dual enzyme system KL36F achieved over 90% PET depolymerization into monomers, demonstrating its potential applicability in the industrial recycling of PET plastics. Therefore, a dual enzyme system can greatly reduce the reaction and separation cost for sustainable enzymatic PET recycling. Title: Network pharmacology-based analysis of Jin-Si-Wei on the treatment of Alzheimer's disease Zhi J, Yin L, Zhang Z, Lv Y, Wu F, Yang Y, Zhang E, Li H, Lu N and Hu Q <1 more author(s)> Zhi J, Yin L, Zhang Z, Lv Y, Wu F, Yang Y, Zhang E, Li H, Lu N, Zhou M, Hu Q (- 1) Ref: J Ethnopharmacol, :117291, 2023 : PubMed ESTHER: Zhi_2023_J.Ethnopharmacol__117291 PubMedSearch: Zhi 2023 J.Ethnopharmacol 117291 PubMedID: 37925002 Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Jin-Si-Wei (JSW), a traditional Chinese medicine (TCM) formula, have cognitive enhancing effect and delay the memory decline in an animal model of AD which has been reported. However, the therapeutic mechanism of JSW in the treatment of AD remains unclear. AIM OF THE STUDY: This study aimed to verify the pharmacodynamics of JSW in the treatment of AD, and to explore its potential mechanism based on network pharmacology, molecular docking and experimental validation both in vitro and in vivo. MATERIALS AND METHODS: In this study, the underlying mechanism of JSW against AD was investigated by the integration of network pharmacology. Then, the core pathways and biological process of JSW were verified by experiment, including behavioral test and pathological and biochemical assays with 6-month-old APP(swe)/PS1(deltaE9) transgenic (APP/PS1) mice in vivo and verified with Abeta(1-42)-stimulated SH-SY5Y cells in vitro. At last, molecular docking was used to show the binding activity of each active ingredient to the core genes of JSW treatment in AD. RESULTS: A Drug-Ingredient-Target network was established, which included 363 ingredients and 116 targets related to the JSW treatment of AD. The main metabolic pathway of JSW treatment for AD is neuroactive ligand-receptor interaction pathway, and biological processes are mainly involved in Abeta metabolic process. In vivo experiments, compared with APP/PS1 mice, the cognitive and memory ability of mice was significantly improved after JSW administration. In brain tissue of APP/PS1 mice, JSW could increase the contents of low-density lipoprotein receptor-related protein 1 (LRP-1), enkephalinase (NEP) and Acetyl choline (ACh), and decrease the contents of Abeta(1-42), amyloid precursor protein (APP) and receptor for advanced glycation end products (RAGE), decrease the vitality of cholinesterase (AChE) and choline acetyltransferase (ChAT). Besides, JSW could increase alpha-secretase expression and decrease beta/gamma-secretase expression, and improve the number and morphology of synapses in CA1 region of the hippocampus of APP/PS1 mice. In vitro experiments, Drug-Containing Serum (JSW-serum) has a neuroprotective effect by reducing the apoptosis on Abeta(1-42)-stimulated SH-SY5Y cells. Molecular docking results showed that 2-Isopropyl-8-methylphenanthrene-3,4-dione had strong binding activity with PTGS2, which maybe a potential ingredient for the treatment of AD. CONCLUSIONS: JSW improves AD in APP/PS1 mice, and this therapeutic effect may be achieved in part by altering the neuroactive ligand-receptor interaction pathway. Title: Knockdown of hepatocyte Perilipin-3 mitigates hepatic steatosis and steatohepatitis caused by hepatocyte CGI-58 deletion in mice Bao X, Ma X, Huang R, Chen J, Xin H, Zhou M, Li L, Tong S, Zhang Q and Zhang Z <4 more author(s)> Bao X, Ma X, Huang R, Chen J, Xin H, Zhou M, Li L, Tong S, Zhang Q, Shui G, Deng F, Yu L, Li MD, Zhang Z (- 4) Ref: J Molecular & Cellular Biology, :, 2022 : PubMed ESTHER: Bao_2022_J.Mol.Cell.Biol__ PubMedSearch: Bao 2022 J.Mol.Cell.Biol PubMedID: 36107452 Abstract Comparative gene identification-58 (CGI-58), also known as alpha/beta hydrolase domain containing 5 (ABHD5), is the co-activator of adipose triglyceride lipase that hydrolyzes triglycerides stored in the cytosolic lipid droplets. Mutations in CGI-58 gene cause Chanarin-Dorfman syndrome (CDS), an autosomal recessive neutral lipid storage disease with ichthyosis. The liver pathology of CDS manifests as steatosis and steatohepatitis, which currently has no effective treatments. Perilipin-3 (Plin3) is a member of the Perilipin-ADRP-TIP47 (PAT) protein family that is essential for lipid droplet biogenesis. The objective of this study was to test a hypothesis that deletion of a major lipid droplet protein alleviates fatty liver pathogenesis caused by CGI-58 deficiency in hepatocytes. Adult CGI-58-floxed mice were injected with adeno-associated vectors simultaneously expressing the Cre recombinase and microRNA against Plin3 under the control of a hepatocyte-specific promoter, followed by high-fat diet (HFD) feeding for 6 weeks. Liver and blood samples were then collected from these animals for histological and biochemical analysis. Plin3 knockdown in hepatocytes prevented steatosis, steatohepatitis, and necroptosis caused by hepatocyte CGI-58 deficiency. Our work is the first to show that inhibiting Plin3 in hepatocytes is sufficient to mitigate hepatocyte CGI-58 deficiency-induced hepatic steatosis and steatohepatitis in mice. Title: Soluble Epoxide Hydrolase Inhibition Protected against Diabetic Cardiomyopathy through Inducing Autophagy and Reducing Apoptosis Relying on Nrf2 Upregulation and Transcription Activation Fang Q, Liu X, Ding J, Zhang Z, Chen G, Du T, Wang Y, Xu R Ref: Oxid Med Cell Longev, 2022:3773415, 2022 : PubMed ESTHER: Fang_2022_Oxid.Med.Cell.Longev_2022_3773415 PubMedSearch: Fang 2022 Oxid.Med.Cell.Longev 2022 3773415 PubMedID: 35378826 Abstract BACKGROUND: Many patients with diabetes die from diabetic cardiomyopathy (DCM); however, effective strategies for the prevention or treatment of DCM have not yet been clarified. METHODS: Leptin receptor-deficient (db/db) mice were treated with either the soluble epoxide hydrolase (sEH) inhibitor AUDA or vehicle alone. A virus carrying Nrf2 shRNA was used to manipulate Nrf2 expression in db/db mice. Cardiac structures and functions were analyzed using echocardiography and hemodynamic examinations. Primary cardiomyocytes cultured under high glucose and high fat (HGHF) conditions were used to conduct in vitro loss-of-function assays after culture in the presence or absence of AUDA (1 microM). Fluorescence microscopy-based detection of mCherry-GFP-LC3 was performed to assess autophagic flux. RESULTS: The sEH inhibitor AUDA significantly attenuated ventricular remodeling and ameliorated cardiac dysfunction in db/db mice. Interestingly, AUDA upregulated Nrf2 expression and promoted its nuclear translocation in db/db mice and the HGHF-treated cardiomyocytes. Additionally, AUDA increased autophagy and decreased apoptosis in db/db mice heart. Furthermore, the administration of AUDA promoted autophagic flux and elevated LC3-II protein level in the presence of bafilomycin A1. However, AUDA-induced autophagy was abolished, and the antiapoptotic effect was partially inhibited upon Nrf2 knockdown. CONCLUSION: Our findings suggest that the sEH inhibitor AUDA attenuates cardiac remodeling and dysfunction in DCM via increasing autophagy and reducing apoptosis, which is relevant to activate Nrf2 signaling pathway. Title: Plasma exchange therapy for familial chylomicronemia syndrome in infant: A case report Han L, Qiang G, Yang L, Kou R, Li Q, Xin M, Liu R, Zhang Z Ref: Medicine (Baltimore), 101:e29689, 2022 : PubMed ESTHER: Han_2022_Medicine.(Baltimore)_101_e29689 PubMedSearch: Han 2022 Medicine.(Baltimore) 101 e29689 PubMedID: 35960041 Gene_locus related to this paper: human-LPL Abstract INTRODUCTION: Familial chylomicronemia syndrome (FCS) is a rare genetic disease. FCS usually manifests by the age of 10 years, and 25% of cases of FCS occur during infancy. Here we present a case of FCS in a male infant and summarize our experiences on the diagnosis and therapy of this case. PATIENT CONCERNS: A male infant aged 1 month and 8 days had recurrent hematochezia and hyperchylomicronemia. DIAGNOSIS: FCS based on symptoms and genetic test. INTERVENTIONS: Plasma exchange therapy. OUTCOMES: His development was normal with a good spirit and satisfactory weight gain, and no hematochezia occurred again. CONCLUSION: Genetic test is important for accurate diagnosis of FCS, and we identified a new mutation of lipoprotein lipase gene c.88C>A which conformed to autosomal recessive inheritance. Plasma exchange therapy can be applied to infants with FCS with low risk and good outcomes. Title: An in vitro nerve agent brain poisoning transwell model for convenient and accurate antidote evaluation Huang L, Li Y, Zhang Z, Huang J, Xing H, Wang L, Sui X, Luo Y, Wang Y, Yang J Ref: Toxicol In Vitro, :105541, 2022 : PubMed ESTHER: Huang_2022_Toxicol.In.Vitro__105541 PubMedSearch: Huang 2022 Toxicol.In.Vitro 105541 PubMedID: 36572320 Abstract Nerve agent (NA) can inhibit acetylcholinesterase (AChE) causing seriously injury at extremely low doses. However, the cruel reality is that the lack of effective cerebral antidotes for treatment of NA poisoning. There is an urgent requirement for the large-scale evaluation and screening of antidotes. An effective NA antidote should include two characteristics: a) to permeate the blood-brain barrier (BBB); 2) to reactivate the inhibited AChE in brain. Existing methods for evaluating reactivators in vitro can only examine the reactivation effect, while the current Transwell model can only evaluate the drug penetration performance for crossing the barrier. In this work, brain microvascular endothelial cells (RBMECs) were inoculated to establish a Transwell model. AChE, NAs and antidotes of reactivators were added into the different chambers to simulate central poisoning and peripheral drug administration. This method can evaluate the reactivation ability and brain penetration ability of compounds at same time, which is a rapidly and accurately way for drug preliminary screening. In addition to small-molecule drugs, a liposomal nanoantidote loaded with the reactivator Asoxime chloride (HI-6)was prepared. This nanoantidote show high reactivation rate against the NA (sarin), evaluated by both this modified model in vitro and animal test, gaining the consistence results. Title: Computational design of a cutinase for plastic biodegradation by mining molecular dynamics simulations trajectories Li Q, Zheng Y, Su T, Wang Q, Liang Q, Zhang Z, Qi Q, Tian J Ref: Comput Struct Biotechnol J, 20:459, 2022 : PubMed ESTHER: Li_2022_Comput.Struct.Biotechnol.J_20_459 PubMedSearch: Li 2022 Comput.Struct.Biotechnol.J 20 459 PubMedID: 35070168 Gene_locus related to this paper: thefu-q6a0i3 Abstract Polyethylene terephthalate (PET) has caused serious environmental concerns but could be degraded at high temperature. Previous studies show that cutinase from Thermobifida fusca KW3 (TfCut2) is capable of degrading and upcycling PET but is limited by its thermal stability. Nowadays, Popular protein stability modification methods rely mostly on the crystal structures, but ignore the fact that the actual conformation of protein is complex and constantly changing. To solve these problems, we developed a computational approach to design variants with enhanced protein thermal stability by mining Molecular Dynamics simulation trajectories using Machine Learning methods (MDL). The optimal classification accuracy and the optimal Pearson correlation coefficient of MDL model were 0.780 and 0.716, respectively. And we successfully designed variants with high deltaT (m) values using MDL method. The optimal variant S121P/D174S/D204P had the highest deltaT (m) value of 9.3 degreesC, and the PET degradation ratio increased by 46.42-fold at 70 degC, compared with that of wild type TfCut2. These results deepen our understanding on the complex conformations of proteins and may enhance the plastic recycling and sustainability at glass transition temperature. Title: Association between CES1 rs2244613 and the pharmacokinetics and safety of dabigatran: Meta-analysis and quantitative trait loci analysis Li H, Zhang Z, Weng H, Qiu Y, Zubiaur P, Zhang Y, Fan G, Yang P, Vuorinen AL and Wang C <2 more author(s)> Li H, Zhang Z, Weng H, Qiu Y, Zubiaur P, Zhang Y, Fan G, Yang P, Vuorinen AL, Zuo X, Zhai Z, Wang C (- 2) Ref: Front Cardiovasc Med, 9:959916, 2022 : PubMed ESTHER: Li_2022_Front.Cardiovasc.Med_9_959916 PubMedSearch: Li 2022 Front.Cardiovasc.Med 9 959916 PubMedID: 35990949 Abstract OBJECTIVE: To date, the influence of the carboxylesterase 1 (CES1) rs2244613 genotype on the pharmacokinetics (PKs) and safety of dabigatran remains controversial. Hence, a systematic review was performed to study the association between CES1 rs2244613 genotype and the PKs and safety of dabigatran and CES1 relative expression. METHODS: In addition to the three English databases (Web of Science, PubMed, and Embase), two Chinese databases (CNKI and Wanfang) were thoroughly revised. The mean differences (MD) and corresponding 95% confidence intervals (CI) were applied to evaluate the differences in PKs between the CES1 rs2244613 genotype. Odds ratio (OR) was used to study the risk for bleeding events between the CES1 rs2244613 genotypes. Subsequent expression quantitative trait loci (eQTL) analyses were performed to evaluate genotype-specific expressions in human tissues. RESULTS: Ten studies (n = 2,777) were included. CES1 rs2244613 G allele carriers exhibited significantly lower dabigatran trough concentrations compared to T allele carriers (MD: -8.00 ng/mL; 95% CI: -15.08 to -0.92; p = 0.03). The risk for bleeding events was significantly lower in carriers of the G allele compared to T allele carriers (OR: 0.65; 95% CI: 0.44-0.96; p = 0.03). Subsequent eQTL analysis showed significant genome-wide expressions in two human tissues, whole blood (p = 5.1 x 10(-10)) and liver (p = 6.2 x 10(-43)). CONCLUSION: Our meta-analysis indicated a definite relation between the CES1 rs2244613 genotype and tolerability variations or pharmacokinetic fluctuations. The carriers of T allele showed higher dabigatran concentrations; therefore, they would benefit from a dose reduction. SYSTEMATIC REVIEW REGISTRATION: [https://inplasy.com/inplasy-2022-6-0027/], identifier [NPLASY202260027]. Title: Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction Liu Z, Yang N, Dong J, Tian W, Chang L, Ma J, Guo J, Tan J, Dong A and Tang B <27 more author(s)> Liu Z, Yang N, Dong J, Tian W, Chang L, Ma J, Guo J, Tan J, Dong A, He K, Zhou J, Cinar R, Wu J, Salinas AG, Sun L, Kumar M, Sullivan BT, Oldham BB, Pitz V, Makarious MB, Ding J, Kung J, Xie C, Hawes SL, Wang L, Wang T, Chan P, Zhang Z, Le W, Chen S, Lovinger DM, Blauwendraat C, Singleton AB, Cui G, Li Y, Cai H, Tang B (- 27) Ref: Nat Commun, 13:3490, 2022 : PubMed ESTHER: Liu_2022_Nat.Commun_13_3490 PubMedSearch: Liu 2022 Nat.Commun 13 3490 PubMedID: 35715418 Gene_locus related to this paper: human-DAGLB, mouse-DGLB Abstract Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase beta (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism. Title: Genes, Structural, and Biochemical Characterization of Four Chlorophyllases from Solanum lycopersicum Liu G, Meng X, Ren Y, Zhang M, Chen Z, Zhang Z, Pang X, Zhang X Ref: Int J Mol Sci, 23:11716, 2022 : PubMed ESTHER: Liu_2022_Int.J.Mol.Sci_23_11716 PubMedSearch: Liu 2022 Int.J.Mol.Sci 23 11716 PubMedID: 36233017 Abstract Recent studies have confirmed that chlorophyllase (CLH), a long-found chlorophyll (Chl) dephytylation enzyme for initiating Chl catabolism, has no function in leaf senescence-related Chl breakdown. Yet, CLH is considered to be involved in fruit degreening and responds to external and hormonal stimuli. The purpose of this work was to elucidate in detail the biochemical, structural properties, and gene expression of four CLHs from the Solanum lycopersicum genome so as to understand the roles of Solanum lycopersicum chlorophyllases (SlCLHs). SlCLH1/4 were the predominantly expressed CLH genes during leaf and fruit development/ripening stages, and SlCLH1 in mature green fruit was modulated by light. SlCLH1/2/3/4 contained a highly conserved GHSXG lipase motif and a Ser-Asp-His catalytic triad. We identified Ser159, Asp226, and His258 as the essential catalytic triad by site-directed mutagenesis in recombinant SlCLH1. Kinetic analysis of the recombinant enzymes revealed that SlCLH1 had high hydrolysis activities against Chl a, Chl b, and pheophytin a (Phein a), but preferred Chl a and Chl b over Phein a; SlCLH2/3 only showed very low activity to Chl a and Chl b, while SlCLH4 showed no Chl dephytylation activity. The recombinant SlCLH1/2/3 had different pH stability and temperature optimum. Removal of the predicted N-terminal processing peptide caused a partial loss of activity in recombinant SlCLH1/2 but did not compromise SlCLH3 activity. These different characteristics among SlCLHs imply that they may have different physiological functions in tomato. Title: Genome-wide expression analysis of carboxylesterase (CXE) gene family implies GBCXE49 functional responding to alkaline stress in cotton Rui C, Peng F, Fan Y, Zhang Y, Zhang Z, Xu N, Zhang H, Wang J, Li S and Ye W <7 more author(s)> Rui C, Peng F, Fan Y, Zhang Y, Zhang Z, Xu N, Zhang H, Wang J, Li S, Yang T, Malik WA, Lu X, Chen X, Wang D, Chen C, Gao W, Ye W (- 7) Ref: BMC Plant Biol, 22:194, 2022 : PubMed ESTHER: Rui_2022_BMC.Plant.Biol_22_194 PubMedSearch: Rui 2022 BMC.Plant.Biol 22 194 PubMedID: 35413814 Abstract BACKGROUND: Carboxylesterase (CXE) is a type of hydrolase with alpha/beta sheet hydrolase activity widely found in animals, plants and microorganisms, which plays an important role in plant growth, development and resistance to stress. RESULTS: A total of 72, 74, 39, 38 CXE genes were identified in Gossypium barbadense, Gossypium hirsutum, Gossypium raimondii and Gossypium arboreum, respectively. The gene structure and expression pattern were analyzed. The GBCXE genes were divided into 6 subgroups, and the chromosome distribution of members of the family were mapped. Analysis of promoter cis-acting elements showed that most GBCXE genes contain cis-elements related to plant hormones (GA, IAA) or abiotic stress. These 6 genes we screened out were expressed in the root, stem and leaf tissues. Combined with the heat map, GBCXE49 gene was selected for subcellular locate and confirmed that the protein was expressed in the cytoplasm. CONCLUSIONS: The collinearity analysis of the CXE genes of the four cotton species in this family indicated that tandem replication played an indispensable role in the evolution of the CXE gene family. The expression patterns of GBCXE gene under different stress treatments indicated that GBCXE gene may significantly participate in the response to salt and alkaline stress through different mechanisms. Through the virus-induced gene silencing technology (VIGS), it was speculated that GBCXE49 gene was involved in the response to alkaline stress in G. barbadense. Title: Development of indole-2-carbonyl piperazine urea derivatives as selective FAAH inhibitors for efficient treatment of depression and pain Shang Y, Wang M, Hao Q, Meng T, Li L, Shi J, Yang G, Zhang Z, Yang K, Wang J Ref: Bioorg Chem, 128:106031, 2022 : PubMed ESTHER: Shang_2022_Bioorg.Chem_128_106031 PubMedSearch: Shang 2022 Bioorg.Chem 128 106031 PubMedID: 36037600 Abstract Fatty acid amide hydrolase (FAAH), aserinehydrolase with significant role in thehydrolysis of endocannabinoids, is a promising therapeutic target for peripheral and central nervous system related disorders, including pain, neuroinflammation and depression. Employing a structure-based approach, a novel series of indole-2-carbonyl piperazine urea derivatives were designed and synthesized as FAAH inhibitors for the treatment of pain-depression comorbidity. Among them, compound 4i emerged as the most potent inhibitor (IC(50) = 0.12 microM) with fine selectivity versus CES2, ABHD6, MAGL and the cannabinoid receptor, which also displayed superior metabolic stability in human liver microsome and an adequate pharmacokinetic profile in rodents. Treatment of depressed rats with 4i demonstrated favorable antidepressant-like effects not only by increasing the level of BDNF in the hippocampus but also by restraining the apoptosis of hippocampal neurons. Also, 4i effectively suppressed the LPS-induced neuroinflammation in vitro. Moreover, 4i exhibited potent analgesic activity, which indicated its promising therapeutical application for pain and depression. These meaningful results shed light on FAAH inhibitors as promising pain-depression comorbidity therapeutics. Title: Label-Free and Ultrasensitive Detection of Butyrylcholinesterase and Organophosphorus Pesticides by Mn(II)-Based Electron Spin Resonance Spectroscopy with a Zero Background Signal Tang L, Wang C, Tian S, Zhang Z, Yu Y, Song D Ref: Analytical Chemistry, :, 2022 : PubMed ESTHER: Tang_2022_Anal.Chem__ PubMedSearch: Tang 2022 Anal.Chem PubMedID: 36332200 Abstract Mn(II)-based electron spin resonance (ESR) spectroscopy was used for detecting butyrylcholinesterase (BChE) and organophosphorus pesticides (OPs). MnO(2) nanosheets were synthesized with manganese chloride and hydrogen peroxide. With the catalysis of BChE, S-butyrylthiocholine iodide (BTCh) was hydrolyzed into thiocholine which has a reducing -SH group. In the presence of thiocholine, MnO(2) nanosheets were broken down and Mn(IV) in MnO(2) nanosheets was reduced into Mn(II). Mn(2+) is a paramagnetic ion and gives a good ESR signal. In contrast, MnO(2) nanosheets have no ESR signal and need not be separated from Mn(2+). Mn(2+) can be determined directly by ESR spectroscopy, and no further sensing probe is needed. ESR spectroscopy based on directly detecting Mn(2+) is much simpler than those using other probes besides MnO(2). The ESR signal of Mn(2+) is proportional to the catalytic activity of BChE. OPs which inhibit the activity of BChE can also be detected by probing the ESR signal of Mn(2+). Since there is no ESR signal of MnO(2) nanosheets, the background signal in the absence of BChE was close to zero. The limit of detection (LOD) of BChE was as low as 0.042 U L(-1). The standard curve for determining the OP paraoxon was established by measuring the inhibition of BChE by paraoxon, and the LOD of paraoxon was found to be 0.076 ng mL(-1). The spiked Chinese cabbage extract samples were analyzed, and the experimental results indicated that the recoveries were from 96.5 to 102.8%. The planted Chinese cabbage was sprayed with the paraoxon solution, and the residue amount of paraoxon in the extract was estimated by the method. The result obtained by the present method was consistent with that obtained by HPLC, which proved the practicability of this new method. Title: Role of lncRNA LIPE-AS1 in adipogenesis Thunen A, La Placa D, Zhang Z, Shively JE Ref: Adipocyte, 11:11, 2022 : PubMed ESTHER: Thunen_2022_Adipocyte_11_11 PubMedSearch: Thunen 2022 Adipocyte 11 11 PubMedID: 34957921 Abstract Recent studies have identified long non-coding RNAs (lncRNAs) as potential regulators of adipogenesis. In this study, we have characterized a lncRNA, LIPE-AS1, that spans genes CEACAM1 to LIPE in man with conservation of genomic organization and tissue expression between mouse and man. Tissue-specific expression of isoforms of the murine lncRNA were found in liver and adipose tissue, one of which, designated mLas-V3, overlapped the Lipe gene encoding hormone-sensitive lipase in both mouse and man suggesting that it may have a functional role in adipose tissue. Knock down of expression of mLas-V3 using anti-sense oligos (ASOs) led to a significant decrease in the differentiation of the OP9 pre-adipocyte cell line through the down regulation of the major adipogenic transcription factors Pparg and Cebpa. Knock down of mLas-V3 induced apoptosis during the differentiation of OP9 cells as shown by expression of active caspase-3, a change in the localization of LIP/LAP isoforms of C/EBPbeta, and expression of the cellular stress induced factors CHOP, p53, PUMA, and NOXA. We conclude that mLas-V3 may play a role in protecting against stress associated with adipogenesis, and its absence leads to apoptosis. Title: Encapsulating gold nanoclusters into metal-organic frameworks to boost luminescence for sensitive detection of copper ions and organophosphorus pesticides Wei D, Li M, Wang Y, Zhu N, Hu X, Zhao B, Zhang Z, Yin D Ref: J Hazard Mater, 441:129890, 2022 : PubMed ESTHER: Wei_2022_J.Hazard.Mater_441_129890 PubMedSearch: Wei 2022 J.Hazard.Mater 441 129890 PubMedID: 36084467 Abstract Gold nanoclusters (Au NCs) with luminescence property are emerging as promising candidates in fluorescent methods for monitoring contaminants, but low luminescence efficiency hampers their extensive applications. Herein, GSH-Au NCs@ZIF-8 was designed by encapsulating GSH-Au NCs with AIE effect into metal-organic frameworks, achieving high luminescence efficiency and good stability through the confinement effect of ZIF-8. Accordingly, a fluorescent sensing platform was constructed for the sensitive detection of copper ions (Cu(2+)) and organophosphorus pesticides (OPs). Firstly, the as-prepared GSH-Au NCs@ZIF-8 could strongly accumulate Cu(2+) due to the adsorption property of MOFs, accompanied by a significant fluorescence quenching effect with a low detection limit of 0.016 microM for Cu(2+). Besides, thiocholine (Tch), the hydrolysis product of acetylthiocholine (ATch) by acetylcholinesterase (AchE), could coordinate with Cu(2+) by sulfhydryl groups (-SH), leading to a significant fluorescence recovery, which was further used for the quantification of OPs owing to its inhibition to AChE activity. Furthermore, a hydrogel sensor was explored to accomplish equipment-free, visual, and quantitative monitoring of Cu(2+) and OPs by a smartphone sensing platform. Overall, this work provides an effective and universal strategy for enhancing the luminescence efficiency and stability of Au NCs, which would greatly promote their applications in contaminants monitoring. Title: Isolation and acetylcholinesterase inhibitory activity of asterric acid derivatives produced by Talaromyces aurantiacus FL15, an endophytic fungus from Huperzia serrata Xiao Y, Liang W, Liu D, Zhang Z, Chang J, Zhu D Ref: 3 Biotech, 12:60, 2022 : PubMed ESTHER: Xiao_2022_3.Biotech_12_60 PubMedSearch: Xiao 2022 3.Biotech 12 60 PubMedID: 35186657 Abstract Alzheimer's disease (AD) is a neurodegenerative disease and the fourth leading cause of death after cardiovascular disease, tumors, and stroke. Acetylcholinesterase (AChE) inhibitors, which are based on cholinergic damage, remain the mainstream drugs to alleviate AD-related symptoms. This study aimed to explore novel AChE inhibitors produced by the endophytic fungus FL15 from Huperzia serrata. The fungus was identified as Talaromyces aurantiacus FL15 according to its morphological characteristics and ITS, 18S rDNA, and 28S rDNA sequence analysis. Subsequently, seven natural metabolites were isolated from strain FL15, and identified as asterric acid (1), methyl asterrate (2), ethyl asterrate (3), emodin (4), physcion (5), chrysophanol (6), and sulochrin (7). Compounds 1-3, which possess a diphenyl ether structure, exhibited highly selective and moderate AChE inhibitory activities with IC(50) values of 66.7, 23.3, and 20.1 microM, respectively. The molecular docking analysis showed that compounds 1-3 interacted with the active catalytic site and peripheral anionic site of AChE, and the esterification substitution groups at position 8 of asterric acid may contribute to its bioactivity. The asterric acid derivatives showed highly selective and moderate AChE inhibitory activities, probably via interaction with the peripheral anionic site and catalytic site of AChE. To the best of our knowledge, this study was the first report of the AChE inhibitory activity of asterric acid derivatives, which opens new perspectives for the design of more effective derivatives that could serve as a drug carrier for new chemotherapeutic agents to treat AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03125-2. Title: Polyketide Derivatives from the Endophytic Fungus Phaeosphaeria sp. LF5 Isolated from Huperzia serrata and Their Acetylcholinesterase Inhibitory Activities Xiao Y, Liang W, Zhang Z, Wang Y, Zhang S, Liu J, Chang J, Ji C, Zhu D Ref: J Fungi (Basel), 8:, 2022 : PubMed ESTHER: Xiao_2022_J.Fungi.(Basel)_8_ PubMedSearch: Xiao 2022 J.Fungi.(Basel) 8 PubMedID: 35330234 Abstract The secondary metabolites of Phaeosphaeria sp. LF5, an endophytic fungus with acetylcholinesterase (AChE) inhibitory activity isolated from Huperzia serrata, were investigated. Their structures and absolute configurations were elucidated by means of extensive spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses, and calculations of electronic circular dichroism (ECD). A chemical study on the solid-cultured fungus LF5 resulted in 11 polyketide derivatives, which included three previously undescribed derivatives: aspilactonol I (4), 2-(1-hydroxyethyl)-6-methylisonicotinic acid (7), and 6,8-dihydroxy-3-(1'R, 2'R-dihydroxypropyl)-isocoumarin (9), and two new natural-source-derived aspilactonols (G, H) (2, 3). Moreover, the absolute configuration of de-O-methyldiaporthin (11) was identified for the first time. Compounds 4 and 11 exhibited inhibitory activity against AChE with half maximal inhibitory concentration (IC(50)) values of 6.26 and 21.18 microM, respectively. Aspilactonol I (4) is the first reported furanone AChE inhibitor (AChEI). The results indicated that Phaeosphaeria is a good source of polyketide derivatives. This study identified intriguing lead compounds for further research and development of new AChEIs. Title: Anoectochilus roxburghii flavonoids extract ameliorated the memory decline and reduced neuron apoptosis via modulating SIRT1 signaling pathway in senescent mice Zeng Z, Chen C, Situ Y, Shen Z, Chen Y, Zhang Z, Tang C, Jiang T Ref: J Ethnopharmacol, :115361, 2022 : PubMed ESTHER: Zeng_2022_J.Ethnopharmacol__115361 PubMedSearch: Zeng 2022 J.Ethnopharmacol 115361 PubMedID: 35609756 Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus roxburghii (A. roxburghii) is a precious herb and folk medicine in many Asian countries. It has been used traditionally to treat diabetes, etc., and also used as a dietary therapy to delay senescence. AIM OF THE STUDY: This study was to evaluate the neuroprotective effects of A. roxburghii flavonoids extract (ARF) and whether its effects were due to the regulation of SIRT1 signaling pathway in senescent mice and in D-galactose (D-gal) induced aging in SH-SY5Y cells. MATERIALS AND METHODS: 18-month-old mice were randomly divided into senescent model, low-dose ARF, high-dose ARF and vitamin E group. 2-Month-old mice were as a control group. After 8 weeks treatment, Morris water maze (MWM) was performed. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), monoamine oxidase (MAO) and acetylcholinesterase (AChE) in the cortex were determined. Hippocampus morphologic changes were observed with haematoxylin and eosin (H&E), Nissl, senescence-associated-galactosidase (SA-beta-gal) and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining. Apoptosis-related molecular expressions in the hippocampus were performed by western blotting. Furthermore, after stimulated by EX527 (a SIRT1 inhibitor), the SIRT1-dependent neuroprotective effects of ARF were determined by measuring SRIT1 and p53 expression in SH-SY5Y aging cells induced by D-gal. RESULTS: ARF could significantly ameliorated memory decline in senescent mice and reduced the generations of ROS, MDA and the activities of MAO and ACh-E, while increasing SOD activities in the cortex of aging mice. ARF obviously improved hippocampus pathological alterations, increased the number of Nissl bodies, while reducing senescent and apoptotic cells in senescent mice hippocampus. Further, ARF positively regulated SIRT1 expression, and reduced apoptosis-related molecules p53, p21 and Caspase-3 expression, while increasing the ratio of Bcl-2/Bax. In D-gal-induced SH-SY5Y cells, the effects of ARF on SIRT1 and p53, and the ability of scavenging ROS were mostly abolished after incubation with the EX527. CONCLUSIONS: ARF, in a SIRT1-dependent manner, exerted neuroprotection via modulating SIRT1/p53 signaling pathway against memory decline and apoptosis due to age-induced oxidative stress damage in senescent mice. Title: Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders Zhang Z, Hou M, Ou H, Wang D, Li Z, Zhang H, Lu J Ref: Front Endocrinol (Lausanne), 13:1067529, 2022 : PubMed ESTHER: Zhang_2022_Front.Endocrinol.(Lausanne)_13_1067529 PubMedSearch: Zhang 2022 Front.Endocrinol.(Lausanne) 13 1067529 PubMedID: 36479216 Gene_locus related to this paper: human-NLGN2, human-NLGN3 Abstract The development of autism spectrum disorders (ASDs) involves both environmental factors such as maternal diabetes and genetic factors such as neuroligins (NLGNs). NLGN2 and NLGN3 are two members of NLGNs with distinct distributions and functions in synapse development and plasticity. The relationship between maternal diabetes and NLGNs, and the distinct working mechanisms of different NLGNs currently remain unclear. Here, we first analyzed the expression levels of NLGN2 and NLGN3 in a streptozotocin-induced ASD mouse model and different brain regions to reveal their differences and similarities. Then, cryogenic electron microscopy (cryo-EM) structures of human NLGN2 and NLGN3 were determined. The overall structures are similar to their homologs in previous reports. However, structural comparisons revealed the relative rotations of two protomers in the homodimers of NLGN2 and NLGN3. Taken together with the previously reported NLGN2-MDGA1 complex, we speculate that the distinct assembly adopted by NLGN2 and NLGN3 may affect their interactions with MDGAs. Our results provide structural insights into the potential distinct mechanisms of NLGN2 and NLGN3 implicated in the development of ASD. Title: 5-Methyltetrahydrofolate Alleviates Memory Impairment in a Rat Model of Alzheimer's Disease Induced by D-Galactose and Aluminum Chloride Zhang Z, Wu H, Qi S, Tang Y, Qin C, Liu R, Zhang J, Cao Y, Gao X Ref: Int J Environ Research Public Health, 19:, 2022 : PubMed ESTHER: Zhang_2022_Int.J.Environ.Res.Public.Health_19_ PubMedSearch: Zhang 2022 Int.J.Environ.Res.Public.Health 19 PubMedID: 36554305 Abstract The effects of 5-methyltetrahydrofolate (5-MTHF) on a rat model of Alzheimer's disease (AD) induced by D-galactose (D-gal) and aluminum chloride (AlCl(3)) were investigated. Wistar rats were given an i.p. injection of 60 mg/kg D-gal and 10 mg/kg AlCl(3) to induce AD and three doses of 1 mg/kg, 5 mg/kg or 10 mg/kg 5-MTHF by oral gavage. A positive control group was treated with 1 mg/kg donepezil by gavage. Morris water maze performance showed that 5 and 10 mg/kg 5-MTHF significantly decreased escape latency and increased the number of platform crossings and time spent in the target quadrant for AD rats. The administration of 10 mg/kg 5-MTHF decreased the brain content of amyloid beta-protein 1-42 (Abeta(1-42)) and phosphorylated Tau protein (p-Tau) and decreased acetylcholinesterase and nitric oxide synthase activities. Superoxide dismutase activity, vascular endothelial growth factor level and glutamate concentration were increased, and malondialdehyde, endothelin-1, interleukin-6, tumor necrosis factor-alpha and nitric oxide decreased. The administration of 10 mg/kg 5-MTHF also increased the expression of disintegrin and metallopeptidase domain 10 mRNA and decreased the expression of beta-site amyloid precursor protein cleavage enzyme 1 mRNA. In summary, 5-MTHF alleviates memory impairment in a D-gal- and AlCl(3)-exposed rat model of AD. The inhibition of Abeta(1-42) and p-Tau release, reduced oxidative stress, the regulation of amyloid precursor protein processing and the release of excitatory amino acids and cytokines may be responsible. Title: Future of Structured Lipids: Enzymatic Synthesis and Their New Applications in Food Systems Zhou J, Lee YY, Mao Y, Wang Y, Zhang Z Ref: Foods, 11:, 2022 : PubMed ESTHER: Zhou_2022_Foods_11_ PubMedSearch: Zhou 2022 Foods 11 PubMedID: 36010399 Abstract Structured lipids (SLs) refer to a new type of functional lipid obtained by modifying natural triacylglycerol (TAG) through the restructuring of fatty acids, thereby altering the composition, structure, and distribution of fatty acids attached to the glycerol backbones. Due to the unique functional characteristics of SLs (easy to absorb, low in calories, reduced serum TAG, etc.), there is increasing interest in the research and application of SLs. SLs were initially prepared using chemical methods. With the wide application of enzymes in industries and the advantages of enzymatic synthesis (mild reaction conditions, high catalytic efficiency, environmental friendliness, etc.), synthesis of SLs using lipase has aroused great interest. This review summarizes the reaction system of SL production and introduces the enzymatic synthesis and application of some of the latest SLs discussed/developed in recent years, including medium- to long-chain triacylglycerol (MLCT), diacylglycerol (DAG), EPA- and DHA-enriched TAG, human milk fat substitutes, and esterified propoxylated glycerol (EPG). Lastly, several new ways of applying SLs (powdered oil, DAG plastic fat, inert gas spray oil, and emulsion) in the future food industry are also highlighted. Title: Treatment efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization versus regorafenib monotherapy in colorectal cancer liver metastasis patients who fail standard treatment regimens Cao F, Zheng J, Luo J, Zhang Z, Shao G Ref: J Cancer Research Clin Oncol, :, 2021 : PubMed ESTHER: Cao_2021_J.Cancer.Res.Clin.Oncol__ PubMedSearch: Cao 2021 J.Cancer.Res.Clin.Oncol PubMedID: 34302208 Abstract OBJECTIVE: This study aimed to evaluate the efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization (DEB-TACE) versus regorafenib monotherapy in colorectal cancer liver metastases (CRLM) patients who failed standard treatment regimens. METHODS: Totally, 76 eligible CRLM patients were analyzed, among which 42 patients received regorafenib monotherapy (as regorafenib group) and 34 patients received regorafenib plus DEB-TACE (as regorafenib plus DEB-TACE group). RESULTS: Objective response rate (35.3% versus 7.1%, P = 0.002) and disease control rate (76.5% versus 47.6%, P = 0.011) were both increased in regorafenib plus DEB-TACE group compared with regorafenib group; meanwhile, negative conversion rate of carcinoembryonic antigen (66.7% versus 28.6%, P = 0.008) after treatment was elevated in regorafenib plus DEB-TACE group compared with regorafenib group. Notably, progression-free survival (PFS) (median value: 7.6 versus 4.1 months, P < 0.001) and overall survival (OS) (median value: 15.7 versus 9.2 months, P < 0.001) were both higher in regorafenib plus DEB-TACE group compared with regorafenib group. Furthermore, liver function indexes (alanine transaminase, aspartate aminotransferase, and cholinesterase levels) after treatment were all similar between the two groups (all P > 0.05). In addition, the occurrences of upper abdominal distending pain (P < 0.001), nausea and vomiting (P = 0.002) and fever (P = 0.002) were higher in regorafenib plus DEB-TACE group compared with regorafenib group, while the majority of these adverse events were mild and tolerable. CONCLUSIONS: Regorafenib plus DEB-TACE is superior to regorafenib monotherapy regarding treatment response, PFS and OS, while induces tolerable post-embolization syndrome in CRLM patients who fail standard treatment regimens. Title: Preparation of MED1(transcription mediator subunit) gene nanocarrier and its mechanism of action on liver cell regeneration in chronic acute liver failure Guo J, Zhang Z, Zhu J Ref: Bioengineered, 12:7600, 2021 : PubMed ESTHER: Guo_2021_Bioengineered_12_7600 PubMedSearch: Guo 2021 Bioengineered 12 7600 PubMedID: 34612778 Abstract Liver failure has attracted attention in clinical work due to its high mortality, and the development of liver transplantation is restricted by various factors. Therefore, it is very important to carry out research on the mechanism of liver cell regeneration. This article has studied in depth the preparation of MED1 gene nanocarriers, collected human plasmids and cells through experimental materials and experimental instruments, and conducted comparative research on conventional culture. This question conducts a regeneration experiment on liver cells in chronic-onset acute liver failure, divides patients into an experimental group and a control group, and understands the recovery of liver function according to the screening of their plasma samples and separation of plasma. This article selects the commonly used clinical biological markers, such as Na+, AFP, Alb, CHE (serum cholinesterase) and other indicators to reflect the regeneration ability of liver function. The incidence of surgical complications in the control group, such as ascites, infection, bleeding, HE, hepatorenal syndrome, and hyponatremia were 71.3%, 87.4%, 16.1%, 41.4%, 19.5%, and 33.3%, respectively. Significantly higher than the experimental group, the difference was statistically significant (P < 0.05); while gender, age, PLT level and whether to use hormones, artificial liver or not there was no significant difference between the two groups (P > 0.05). Title: Novel cannabidiol-carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease Jiang X, Zhang Z, Zuo J, Wu C, Zha L, Xu Y, Wang S, Shi J, Liu XH and Tang W <1 more author(s)> Jiang X, Zhang Z, Zuo J, Wu C, Zha L, Xu Y, Wang S, Shi J, Liu XH, Zhang J, Tang W (- 1) Ref: Eur Journal of Medicinal Chemistry, 223:113735, 2021 : PubMed ESTHER: Jiang_2021_Eur.J.Med.Chem_223_113735 PubMedSearch: Jiang 2021 Eur.J.Med.Chem 223 113735 PubMedID: 34371367 Inhibitor(s) related to this paper: CBD-carbamate-C16 Abstract Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC(50) = 5.3 nM, SI > 4000), superior to CBD (IC(50) = 0.67 microM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (K(d) = 13 nM, k(2) = 0.26 min(-1)), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Abeta(1-42) (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD. Title: Association of TaD14-4D, a Gene Involved in Strigolactone Signaling, with Yield Contributing Traits in Wheat Liu R, Hou J, Li H, Xu P, Zhang Z, Zhang X Ref: Int J Mol Sci, 22:, 2021 : PubMed ESTHER: Liu_2021_Int.J.Mol.Sci_22_ PubMedSearch: Liu 2021 Int.J.Mol.Sci 22 PubMedID: 33916852 Abstract Tillering is a crucial agronomic trait of wheat; it determines yield and plant architecture. Strigolactones (SLs) have been reported to inhibit plant branching. D14, a receptor of SLs, has been described to affect tillering in rice, yet it has seldomly been studied in wheat. In this study, three TaD14 homoeologous genes, TaD14-4A, TaD14-4B, and TaD14-4D, were identified. TaD14-4A, TaD14-4B, and TaD14-4D were constitutively expressed, and TaD14-4D had a higher expression level in most tissues. TaD14 proteins were localized in both cytoplasm and nucleus. An SNP and a 22 bp insertion/deletion (Indel) at the exon regions of TaD14-4D were detected, forming three haplotypes, namely 4D-HapI, 4D-HapII, and 4D-HapIII. Due to the frameshift mutation in the coding region of 4D-HapII, the interaction of 4D-HapII with TaMAX2 and TaD53 was blocked, which led to the blocking of SL signal transduction. Based on the two variation sites, two molecular markers, namely dCAPS-250 and Indel-747, were developed. Association analysis suggested that haplotypes of TaD14-4D were associated with effective tillering number (ETN) and thousand kernel weight (TKW) simultaneously in four environments. The favorable haplotype 4D-HapIII underwent positive selection in global wheat breeding. This study provides insights into understanding the function of natural variations of TaD14-4D and develops two useful molecular markers for wheat breeding. Title: Elsholtzia rugulosa: Phytochemical Profile and Antioxidant, Anti-Alzheimer's Disease, Antidiabetic, Antibacterial, Cytotoxic and Hepatoprotective Activities Liu L, Gao Q, Zhang Z, Zhang X Ref: Plant Foods Hum Nutr, :, 2021 : PubMed ESTHER: Liu_2021_Plant.Foods.Hum.Nutr__ PubMedSearch: Liu 2021 Plant.Foods.Hum.Nutr PubMedID: 34853948 Abstract Elsholtzia rugulosa Hemsl., a species of the Labiatae family, has a long history of use as a honey plant, herbal tea, and folk medicine in China. However, little is known about its composition and biological activities. The present study aimed to investigate the total phenol and flavonoid contents, phytochemical composition, and multiple biological activities of this plant. The total flavonoid content of the ethyl acetate fraction (EAF) was higher than those of the petroleum ether fraction (PEF), n-butanol fraction (NBF), and water fraction (WF). The EAF also had much stronger antioxidant, cytotoxic, hepatoprotective, and acetylcholinesterase (AChE) and alpha-glucosidase inhibitory activities than the PEF, NBF, and WF. More importantly, the IC(50) values of the EAF and NBF against alpha-glucosidase were much lower than that of the positive control acarbose, indicating their potent alpha-glucosidase inhibitory activities. The isolation of the EAF led to the acquisition of 9 compounds, four of which (beta-daucosterol, methyl rosmarinate, betulinic acid, and oleanolic acid) possessed significant alpha-glucosidase inhibitory activities. Maltol 6'-O-(5-O-p-coumaroyl)-beta-D-apiofuranosyl-beta-D-glucopyranoside and rosmarinic acid were the major phenolic compounds in the EAF according to the HPLC-DAD analysis. All these findings indicate that the EAF, NBF, and some isolated compounds have the potential to be developed as antidiabetic drugs. Moreover, the dual inhibition of AChE and butyrylcholinesterase (BChE) of certain fractions indicates their potential in the development of anti-Alzheimer's disease drugs. The present study provides a new understanding of the phytochemistry and bioactivity of E. rugulosa. Title: Combined use of GABA and sitagliptin promotes human beta-cell proliferation and reduces apoptosis Liu W, Lau HK, Son DO, Jin T, Yang Y, Zhang Z, Li Y, Prud'homme GJ, Wang Q Ref: J Endocrinol, 248:133, 2021 : PubMed ESTHER: Liu_2021_J.Endocrinol_248_133 PubMedSearch: Liu 2021 J.Endocrinol 248 133 PubMedID: 33258801 Inhibitor(s) related to this paper: Sitagliptin Abstract gamma-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent beta-cell survival and function. In human beta-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic beta-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human beta-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human beta-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ beta-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of alpha-Klotho, a protein with protective and stimulatory effects on beta cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of beta-cell proliferation and a decrease in apoptosis. Title: Early enteral nutrition combined with PSS-based nursing in the treatment of organophosphorus pesticide poisoning Sun Y, Yang Y, Zhang Z, Li Y, Hu Y, Wang N Ref: Am J Transl Res, 13:9315, 2021 : PubMed ESTHER: Sun_2021_Am.J.Transl.Res_13_9315 PubMedSearch: Sun 2021 Am.J.Transl.Res 13 9315 PubMedID: 34540048 Abstract OBJECTIVE: To investigate the administration of early enteral nutrition combined with poisoning severity score (PSS)-based nursing in the treatment of organophosphorus pesticide poisoning (OPP). METHODS: A total of 99 OPP patients treated in our hospital between June 2019 and June 2020 were enrolled in this study and were divided into the conventional group (n=46, early enteral nutrition support + routine care) and the combined group (n=53, PSS-based nursing + early enteral nutrition support + routine care). The nutritional status indicators, the hemoglobin (Hb) and blood glucose levels, the Glasgow coma scale (GCS) scores, and the complications were compared between the two groups. RESULTS: The total protein (TP), albumin (ALB), and prealbumin (PAB) levels were reduced in the conventional group after the intervention (P<0.05) but were significantly lower than they were in the combined group (P<0.05). The Hb and blood glucose levels were decreased in the conventional group after the intervention (P<0.05) and were significantly higher than they were in the combined group (P<0.05). The GCS scores increased significantly as the treatment progressed (P<0.05), and the GCS scores in the combined group were significantly higher than the GCS scores in the conventional group at 3 and 5 days after the treatment (P<0.05). The time to the recovery of 60% cholinesterase (CHE) activity, the durations of the mechanical ventilation, the lengths of the hospital stays, and the hospital costs in the combined group were significantly lower than they were in the conventional group (P<0.05). The complication rate in the combined group (9.43%) was significantly lower than the complication rate in the conventional group (32.61%) (P<0.05). CONCLUSION: Early enteral nutrition combined with PSS-based nursing can effectively control the blood glucose, improve the nutritional disorders, promote recovery, and reduce complications in OPP patients. Title: Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease Tang W, Zhang H, Wu C, Chen X, Zhang Z, Jiang X, Qin HL Ref: ChemMedChem, :, 2021 : PubMed ESTHER: Tang_2021_ChemMedChem__ PubMedSearch: Tang 2021 ChemMedChem PubMedID: 34036731 Abstract Novel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B > series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 microM), which was nicely fallen into Tc AChE via hydrogen interactions between delta-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive ( K i = 7.67 microM) AChE inhibition, nontoxicity and remarkable neuro-protective activity. In vivo studies confirmed that compound B4 significantly ameliorates performances of scopolamine-treated C57BL/6J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD. Title: A Lab-in-a-Syringe Device Integrated with a Smartphone Platform: Colorimetric and Fluorescent Dual-Mode Signals for On-Site Detection of Organophosphorus Pesticides Wei D, Wang Y, Zhu N, Xiao J, Li X, Xu T, Hu X, Zhang Z, Yin D Ref: ACS Appl Mater Interfaces, :, 2021 : PubMed ESTHER: Wei_2021_ACS.Appl.Mater.Interfaces__ PubMedSearch: Wei 2021 ACS.Appl.Mater.Interfaces PubMedID: 34623807 Abstract Herein, a portable lab-in-a-syringe device integrated with a smartphone sensing platform was designed for rapid, visual quantitative determination of organophosphorus pesticides (OPs) via colorimetric and fluorescent signals. The device was chiefly made up of a conjugate pad labeled with cetyltrimethylammonium bromide-coated gold nanoparticles (CTAB-Au NPs) and a sensing pad modified by ratiometric probes (red-emission quantum dots@SiO(2) nanoparticles@green-emission quantum dots, rQDs@SiO(2)@gQDs probe), which was assembled through a disposable syringe and reusable plastic filter. In the detection system, thiocholine (Tch), the hydrolysis product of thioacetylcholine (ATch) by acetylcholinesterase (AchE), could trigger the aggregation of CTAB-Au NPs, resulting in a significant color change from red to purple. Then, CTAB-Au NPs flowed vertically upward and bound to the rQDs@SiO(2)@gQDs probe on the sensing pad, reducing the fluorescence resonance energy transfer effect between CTAB-Au NPs and gQDs. Meanwhile, rQDs embedded in SiO(2) NPs remained stable as internal reference fluorescence, achieving a color transition from red to green. Thus, based on the inhibition of AChE activity by OPs, a colorimetric and fluorescent dual-mode platform was constructed for on-site detection of OPs. Using glyphosate as a model, with the support of a color recognizer application (APP) on a smartphone, the ratio of red and green channel values could be utilized for accurate OP quantitative analysis ranging from 0 to 10 microM with a detection limit of 2.81 nM (recoveries, 90.8-122.4%; CV, 1.2-3.4%). Overall, the portable lab-in-a-syringe device based on a smartphone sensing platform integrated sample monitoring and result analysis in the field, implying great potential for on-site detection of OPs. Title: Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease Wu C, Zhang G, Zhang ZW, Jiang X, Zhang Z, Li H, Qin HL, Tang W Ref: J Enzyme Inhib Med Chem, 36:1860, 2021 : PubMed ESTHER: Wu_2021_J.Enzyme.Inhib.Med.Chem_36_1860 PubMedSearch: Wu 2021 J.Enzyme.Inhib.Med.Chem 36 1860 PubMedID: 34425715 Abstract To discover novel scaffolds as leads against dementia, a series of delta-aryl-1,3-dienesulfonyl fluorides with alpha-halo, alpha-aryl and alpha-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC(50) = 0.021 microM for eqBChE, 3.62 microM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH(3) > -CH(3) > -Cl (-Br) for delta-aryl; (ii) alpha-Br > alpha-Cl, alpha-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (K(i) = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Abeta(1-42)-induced cognitive dysfunction to the normal level, and the assessment of total amount of Abeta(1-42) confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD. Title: Comparative transcriptome analysis of Chinese grass shrimp (Palaemonetes sinensis) hepatopancreas under ectoparasitic isopod (Tachaea chinensis) infection Yu C, Xu W, Li X, Jin J, Zhao X, Wang S, Zhang Z, Wei Y, Chen Q, Li Y Ref: Fish Shellfish Immunol, :, 2021 : PubMed ESTHER: Yu_2021_Fish.Shellfish.Immunol__ PubMedSearch: Yu 2021 Fish.Shellfish.Immunol PubMedID: 34303835 Abstract Tachaea chinensis, a parasitic isopod, negatively affects the production of several commercially important shrimp species. To better understand the interaction between shrimp immunity and isopod infection, we performed a transcriptome analysis of the hepatopancreas of Palaemonetes sinensis challenged with T. chinensis. After assembly and annotation, 75,980 high-quality unigenes were obtained using RNA-seq data. Dierential gene expression analysis revealed 896 signicantly dierently expressed genes (DEGs) after infection, with 452 and 444 upregulated and downregulated genes, respectively. Specifically, expression levels of genes involved in detoxification, such as the interferon regulatory factor, venom carboxylesterase-6, serine proteinase inhibitor, and cytochrome P450, were upregulated. Furthermore, expression levels of genes corresponding to retinol dehydrogenase, triosephosphate isomerase, variant ionotropic glutamate receptor, and phosphoenolpyruvate carboxykinase were significantly upregulated after isopod parasitization, indicating that the shrimp's visual system was influenced by isopod parasitization. Moreover, quantitative real-time PCR of 10 DEGs helped validate the RNA-seq findings. These results provide a valuable basis for future studies on the elucidation of immune responses of P. sinensis to T. chinensis infection. Title: Functional Characterization and Crystal Structure of the Bifunctional Thioesterase Catalyzing Epimerization and Cyclization in Skyllamycin Biosynthesis Yu J, Juan S, Chi C, Liu T, Geng T, Cai Z, Dong W, Shi C, Ma X and Ma M <6 more author(s)> Yu J, Juan S, Chi C, Liu T, Geng T, Cai Z, Dong W, Shi C, Ma X, Zhang Z, Xing B, Jin H, Zhang L, Dong S, Yang D, Ma M (- 6) Ref: ACS Catal, 11:11733, 2021 : PubMed ESTHER: Yu_2021_ACS.Catalysis_11_11733 PubMedSearch: Yu 2021 ACS.Catalysis 11 11733 Gene_locus related to this paper: strsq-a0a1j0r317 Abstract The d-amino acid residues are hallmark building blocks of nonribosomal peptides. Here, we report the bifunctional thioesterase domain (TE domain) Skyxy-TE that catalyzes both epimerization and cyclization in skyllamycin biosynthesis. Skyxy-TE specifically catalyzes the epimerization of the C-terminal l-amino acid residue of the linear substrate, then catalyzes regioselective intramolecular cyclization. The crystal structure of Skyxy-TE was solved at 2.25 and site-directed mutagenesis was performed, revealing key residues involved in the epimerization and cyclization. This study expands the understanding of the versatile TE domains and facilitates chemoenzymatic synthesis or combinatorial biosynthesis in the future. Title: Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer's disease Zhang Z, Guo J, Cheng M, Zhou W, Wan Y, Wang R, Fang Y, Jin Y, Liu J, Xie SS Ref: Eur Journal of Medicinal Chemistry, 213:113154, 2021 : PubMed ESTHER: Zhang_2021_Eur.J.Med.Chem_213_113154 PubMedSearch: Zhang 2021 Eur.J.Med.Chem 213 113154 PubMedID: 33476932 Abstract In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC(50) values 0.85 microM and 0.59 microM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound 4j was a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu(2+) and Al(3+) at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound 4j could improve memory function of scopolamine-induced amnesia mice. Hence, the compound 4j can be considered as a promising lead compound for further investigation in the treatment of AD. Title: Neuroprotective effects of maize tetrapeptide-anchored gold nanoparticles in Alzheimer's disease Zhang J, Liu R, Zhang D, Zhang Z, Zhu J, Xu L, Guo Y Ref: Colloids Surf B Biointerfaces, 200:111584, 2021 : PubMed ESTHER: Zhang_2021_Colloids.Surf.B.Biointerfaces_200_111584 PubMedSearch: Zhang 2021 Colloids.Surf.B.Biointerfaces 200 111584 PubMedID: 33508658 Abstract Nanopeptide assembled from peptide-anchored nanoparticles possess an enormous research potential in the field of cellular medicine and disease treatment. The aim of this study was to explore the neuroprotective effects of maize tetrapeptide anchored gold nanoparticles against l-glutamic acid-induced PC12 cell apoptosis and a murine Alzheimer's disease model induced by aluminum chloride and d-galactose. The results revealed that the nanopeptide antioxidant inhibited intracellular ROS accumulation and promoted cell differentiation than that of maize bioactive tetrapeptide. Compared with untreated Alzheimer's disease model mice, nanopeptide administration shortened the escape latency time in a water maze test and improved the movements in the autonomic activity test. After 16 days of nanopeptide administration, the central cholinergic system function of acetylcholine and cholineacetyltransferase were enhanced, and the level of acetylcholinesterase was reduced. It also increased superoxide dismutase and glutathione peroxidase activity in sera and hypothalami. Moreover, nanopeptide treatment upregulated cerebral nuclear factor erythroid 2-related factor 2 and heme-oxygenase-1 and downregulated kelch-like ECH-associated protein 1 relative to untreated Alzheimer's disease model mice. Thus, the novel nanopeptide is expected to be used as the neuroprotective agent to prevent Alzheimer's disease. Title: Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer's disease Fu J, Bao F, Gu M, Liu J, Zhang Z, Ding J, Xie SS Ref: J Enzyme Inhib Med Chem, 35:118, 2020 : PubMed ESTHER: Fu_2020_J.Enzyme.Inhib.Med.Chem_35_118 PubMedSearch: Fu 2020 J.Enzyme.Inhib.Med.Chem 35 118 PubMedID: 31694418 Abstract A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 muM for eeAChE; IC50 = 0.16 muM for hAChE), and it was also the best inhibitor to AChE-induced Abeta aggregation (29.02% at 100 muM) and an efficient inhibitor to self-induced Abeta aggregation (30.67% at 25 muM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po). Title: Enantioselective disposition and metabolic products of isofenphos-methyl in rats and the hepatotoxic effects Gao B, Zhao S, Shi H, Zhang Z, Li L, He Z, Wen Y, Covaci A, Wang M Ref: Environ Int, 143:105940, 2020 : PubMed ESTHER: Gao_2020_Environ.Int_143_105940 PubMedSearch: Gao 2020 Environ.Int 143 105940 PubMedID: 32663714 Abstract Isofenphos-methyl (IFP), a chiral organophosphorus pesticide, is one of the main chemicals used to control underground insects and nematodes. Recently, the use of IFP on vegetables and fruits has been prohibited due to its high toxicity. In this study, we investigated the enantioselective distribution and metabolism of IFP and its metabolites, namely, isofenphos-methyl oxon (IFPO) and isocarbophos oxon (ICPO), in male Sprague Dawley (SD) rats. Forty eight hours (48 h) after exposure, ICPO was the main detectable compound in blood (up to 75%) and urine (up to 77%), and we found that (S)-ICPO was significantly more stable than (R)-ICPO (p < 0.05). Therefore, (S)-ICPO was proposed as a suitable candidate biomarker for the biomonitoring of IFP in human urine and blood. After 48 h exposure, 21.2-41.0%, 4.1-15.1%, and 8.6-18.7% of dosed IFP was detected in the liver of racemic, R and S enantiomer-exposed rats, respectively, and R-IFP and R-IFPO showed a faster degradation (p < 0.05). Our results showed that after one week of consecutive exposure to IFP, ICPO was accumulated in the liver of rats in both racemic and enantiopure groups (no difference between the groups, p > 0.05). We found that cytochrome P450 (CYP) (i.e. CYP2C11, CYP2D2 and CYP3A2 enzymes and carboxylesterases) is responsible for the enantioselective metabolism of IFP in liver. In addition, rats exposed to (S)-IFP exhibited hepatic lipid peroxidation, liver inflammation and hepatic fibrosis. This study provides useful information and a reference for the biomonitoring and risk assessment of IFP and organophosphorus pesticide exposure. Title: Directed Evolution of Pseudomonas fluorescens Lipase Variants With Improved Thermostability Using Error-Prone PCR Guan L, Gao Y, Li J, Wang K, Zhang Z, Yan S, Ji N, Zhou Y, Lu S Ref: Front Bioeng Biotechnol, 8:1034, 2020 : PubMed ESTHER: Guan_2020_Front.Bioeng.Biotechnol_8_1034 PubMedSearch: Guan 2020 Front.Bioeng.Biotechnol 8 1034 PubMedID: 32984290 Gene_locus related to this paper: psefl-lipa Abstract Lipases catalyze the hydrolysis of fats and oils, and have been widely used in various industrial fields. However, bacterial lipases have a lower thermostability in industrial processes, which was a limiting factor in their industrial application. In this study, we obtained an improve variant of Pseudomonas fluorescens lipase (PFL) with enhanced thermostability using classical error-prone PCR. Wild-type PFL showed an optimal temperature and pH of 50degC and pH 7.5, respectively. Due to the low thermostability of PFL, a library containing over 3000 individual mutants as constructed using error-prone PCR. Screening for thermotolerance yielded the mutants L218P and P184C/M243C with T (m) values of 62.5 and 66.0degC, which was 2.5 and 6degC higher than that of the WT, respectively. The combination of the two mutants (P184C/M243C/L218P) resulted in an approximately additive effect with a T (m) value of 68.0degC. Although the increase of T (m) was not substantial, the mutant also had dramatically increased methanol tolerance. Structural analysis revealed that the introduction of a disulfide bond between P184C and M243C and the substitution of Pro to reduce the flexibility of a loop increased the thermostability of PFL, which provides a theoretical foundation for improving the thermostability and methanol tolerance of lipase family I.1 to resist the harsh conditions of industrial processes. Title: Sublethal concentrations of triclosan elicited oxidative stress, DNA damage, and histological alterations in the liver and brain of adult zebrafish Gyimah E, Dong X, Qiu W, Zhang Z, Xu H Ref: Environ Sci Pollut Res Int, :, 2020 : PubMed ESTHER: Gyimah_2020_Environ.Sci.Pollut.Res.Int__ PubMedSearch: Gyimah 2020 Environ.Sci.Pollut.Res.Int PubMedID: 32157542 Abstract Triclosan (TCS), an antimicrobial agent, has been a pollutant of increasing concern owing to its potential health risk on humans and aquatic animals. The present study seeks to test the hypothesis that TCS could alter the oxidative stress-related parameters in the brain and liver, as well as eliciting DNA damage in hepatocytes of adult zebrafish. On the basis of the 96 h LC50 (398.9 mug/L), adult zebrafish were separately exposed to 50, 100, and 150 mug/L TCS for 30 days. The brain and liver tissues from adult zebrafish were excised and assayed for a suite of antioxidant parameters and oxidative stress biomarkers including DNA damage in the liver. The induced effect by TCS on the activity of acetylcholinesterase (AChE) was also analyzed in the brain. Results showed a significant decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the brain and liver of adult zebrafish. Also, the contents of the glutathione system (GSH and GSSH), as well as the activity of the glutathione reductase (GR), assayed in the liver, were reduced while the contents of malondialdehyde (MDA) were elevated in the liver. A comet assay revealed dose-dependent DNA damage in zebrafish hepatocytes. The 8-hydroxy-2'-deoxyguanosine (8-OHdG), MDA, and carbonyl protein contents in brain tissues significantly increased. Moreover, the AChE in the zebrafish brain was induced. Apparently, no obvious histological changes in brain tissues of zebrafish were observed compared with those of the control whereas atrophy and necrosis of hepatocytes and increased hepatic plate gap were observed in zebrafish hepatocytes after TCS exposure. The obtained results highlight that sublethal concentrations of TCS may be deleterious to the liver and brain of adult zebrafish upon subchronic exposure. Title: IRREGULAR POLLEN EXINE2 Encodes a GDSL Lipase Essential for Male Fertility in Maize Huo Y, Pei Y, Tian Y, Zhang Z, Li K, Liu J, Xiao S, Chen H Ref: Plant Physiol, 184:1438, 2020 : PubMed ESTHER: Huo_2020_Plant.Physiol_184_1438 PubMedSearch: Huo 2020 Plant.Physiol 184 1438 PubMedID: 32913046 Abstract Anther cuticle and pollen exine are two physical barriers protecting plant reproductive cells against environmental stresses; defects in either often cause male sterility. Here, we report the characterization of a male-sterile mutant irregular pollen exine2 (ipe2) of maize (Zea mays), which displays shrunken anthers and no starch accumulation in mature pollen grains. We cloned the causal gene IPE2 and confirmed its role in male fertility in maize with a set of complementary experiments. IPE2 is specifically expressed in maize developing anthers during stages 8 to 9 and encodes an endoplasmic-reticulum-localized GDSL lipase. Dysfunction of IPE2 resulted in delayed degeneration of tapetum and middle layer, leading to defective formation of anther cuticle and pollen exine, and complete male sterility. Aliphatic metabolism was greatly altered, with the contents of lipid constituents, especially C16/C18 fatty acids and their derivatives, significantly reduced in ipe2 developing anthers. Our study elucidates GDSL function in anther and pollen development and provides a promising genetic resource for breeding hybrid maize. Title: The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 spike Li Y, Zhang Z, Yang L, Lian X, Xie Y, Li S, Xin S, Cao P, Lu J Ref: iScience, :101160, 2020 : PubMed ESTHER: Li_2020_iScience__101160 PubMedSearch: Li 2020 iScience 101160 PubMedID: 32405622 Abstract The ongoing outbreak of the novel coronavirus pneumonia COVID-19 has caused great number of cases and deaths, but our understanding about the pathogen SARS-CoV-2 remains largely unclear. The attachment of the virus with the cell-surface receptor and a co-factor is the first step for the infection. Here, bioinformatics approaches combining human-virus protein interaction prediction and protein docking based on crystal structures have revealed the high affinity between human dipeptidyl peptidase 4 (DPP4) and the spike (S) receptor-binding domain of SARS-CoV-2. Intriguingly, the crucial binding residues of DPP4 are identical to those as bound to the MERS-CoV-S. Moreover, E484 insertion and adjacent substitutions should be most essential for this DPP4-binding ability acquirement of SARS-CoV-2-S compared with SARS-CoV-S. This potential utilization of DPP4 as a binding target for SARS-CoV-2 may offer novel insight into the viral pathogenesis, and help the surveillance and therapeutics strategy for meeting the challenge of COVID-19. Title: Nos2 deficiency enhances carbon tetrachloride-induced liver injury in aged mice Li D, Song Y, Wang Y, Guo Y, Zhang Z, Yang G, Wang G, Xu C Ref: Iran J Basic Med Sci, 23:600, 2020 : PubMed ESTHER: Li_2020_Iran.J.Basic.Med.Sci_23_600 PubMedSearch: Li 2020 Iran.J.Basic.Med.Sci 23 600 PubMedID: 32742597 Abstract OBJECTIVES: As a multifunctional molecule, NO has different effects on liver injury. The present work aimed to investigate the effects of Nos2 knockout (KO) on acute liver injury in aged mice treated with carbon tetrachloride (CCl(4)). MATERIALS AND METHODS: The acute liver injury model was produced by CCl(4) at 10 ml/kg body weight in 24-month-old Nos2 KO mice and wild type (WT) mice groups. The histological changes, transaminase and glutathione (GSH) contents, and the expressions of liver function genes superoxide dismutase (SOD2) and butyrylcholinesterase (BCHE), as well as apoptosis- and inflammation-associated genes were detected at 0, 6, 16, 20, 28, and 48 hr, respectively. RESULTS: Compared with WT aged mice, there are more fat droplets in liver tissues of Nos2 KO aged mice, and the serum levels of ALT and AST were elevated in the KO group; in addition, there was a decrease in the expression of SOD2 and BCHE and GSH content at multiple time-points. Furthermore, the expression of apoptosis protein CASPASE-3 was elevated from 20 to 48 hr, the same as CASPASE-9 at 28 and 48 hr and pro-apoptotic protein BAX at 6 and 28 hr, while the expression of apoptosis inhibitory protein BCL2 declined at 6 and 28 hr; at the same time the mRNA expressions of genes related to inflammation were increased at different extents in liver extracts of Nos2 KO aged mice. CONCLUSION: Nos2 KO exacerbated liver injury probably by elevated oxidative stress, apoptosis and inammation response in CCl(4)-induced aged mice liver intoxication model. Title: Hydroxylated polychlorinated biphenyls (OH-PCBs) exert strong inhibitory effects towards human carboxylesterases (CESs) Sun HZ, Qin GQ, Wang FG, Bai Y, Zhang Z, Fang ZZ Ref: Sci Total Environ, 745:141140, 2020 : PubMed ESTHER: Sun_2020_Sci.Total.Environ_745_141140 PubMedSearch: Sun 2020 Sci.Total.Environ 745 141140 PubMedID: 32736114 Abstract Polychlorinated biphenyls (PCBs) have been reported to pose a severe risk towards human health, and hydroxylated polychlorinated biphenyls (OH-PCBs) were potential substances basis for PCBs' toxicity. This study aims to determine the inhibition of OH-PCBs towards human carboxylesterases (CESs), including CES1 and CES2. For phenotypic analysis of CES1 and CES2 activity, we used the hydrolysis metabolism of 2-(2-benzoyl3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) catalyzed by human liver microsomes (HLMs) as the probe reactions. Preliminary inhibition screening showed that the inhibition potential of OH-PCBs towards CES1 and CES2 increased with the increased numbers of chlorine atoms in OH-PCBs. Both 2'-OH-PCB61 and 2'-OH-PCB65 showed concentration-dependent inhibition towards both CES1 and CES2. Lineweaver-Burk plots showed that 2'-OH-PCB61 and 2'-OH-PCB65 exerted non-competitive inhibition towards CES1 and competitive inhibition towards CES2. The inhibition kinetics parameters (Ki) were 6.8 muM and 7.0 muM for 2'-OH-PCB61 and 2'-OH-PCB65 towards CES1, respectively. The inhibition kinetics parameters (Ki) were 1.4 muM and 1.0 muM for 2'-OH-PCB61 and 2'-OH-PCB65 towards CES2, respectively. In silico docking methods elucidate the contribution of hydrogen bonds and hydrophobic contacts towards the binding of 2'-OH-PCB61 and 2'-OH-PCB65 with CES1 and CES2. All these results will provide a new perspective for elucidation of toxicity mechanism of PCBs and OH-PCBs. Title: Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis Tu L, Su P, Zhang Z, Gao L, Wang J, Hu T, Zhou J, Zhang Y, Zhao Y and Gao W <9 more author(s)> Tu L, Su P, Zhang Z, Gao L, Wang J, Hu T, Zhou J, Zhang Y, Zhao Y, Liu Y, Song Y, Tong Y, Lu Y, Yang J, Xu C, Jia M, Peters RJ, Huang L, Gao W (- 9) Ref: Nat Commun, 11:971, 2020 : PubMed ESTHER: Tu_2020_Nat.Commun_11_971 PubMedSearch: Tu 2020 Nat.Commun 11 971 PubMedID: 32080175 Gene_locus related to this paper: triwf-a0a7j7c8l4 Abstract Triptolide is a trace natural product of Tripterygium wilfordii. It has antitumor activities, particularly against pancreatic cancer cells. Identification of genes and elucidation of the biosynthetic pathway leading to triptolide are the prerequisite for heterologous bioproduction. Here, we report a reference-grade genome of T. wilfordii with a contig N50 of 4.36 Mb. We show that copy numbers of triptolide biosynthetic pathway genes are impacted by a recent whole-genome triplication event. We further integrate genomic, transcriptomic, and metabolomic data to map a gene-to-metabolite network. This leads to the identification of a cytochrome P450 (CYP728B70) that can catalyze oxidation of a methyl to the acid moiety of dehydroabietic acid in triptolide biosynthesis. We think the genomic resource and the candidate genes reported here set the foundation to fully reveal triptolide biosynthetic pathway and consequently the heterologous bioproduction. Title: Growth Performance and Enzymatic Response of the Grasshopper, Calliptamus abbreviatus (Orthoptera: Acrididae), to Six Plant-Derived Compounds Wang Y, Huang X, Chang BH, Zhang Z Ref: J Insect Sci, 20:, 2020 : PubMed ESTHER: Wang_2020_J.Insect.Sci_20_ PubMedSearch: Wang 2020 J.Insect.Sci 20 PubMedID: 32501501 Abstract Plant-derived compounds are sources of biopesticides for the control of insect pests. We compared the growth performance and enzymatic response of the grasshopper Calliptamus abbreviatus Ikonn to six plant-derived compounds (rutin, quercetin, nicotine, matrine, azadirachtin, and rotenone) in laboratory and field trials. When exposed to the six compounds, C. abbreviatus had significantly reduced growth and survival. All the compounds significantly induced an elevated level of reactive oxygen species, indicating oxidative damage. The activity of detoxifying enzymes, including cytochrome P450s, carboxylesterase, glutathione-S-transferase, and UDP-glucuronosyltransferase, and the antioxidant enzymes, including superoxide dismutase, catalase, and peroxidase, all significantly increased after exposure to the six compounds. These data suggest that the six plant-derived compounds had negative effects on C. abbreviatus. Of the six compounds, matrine, azadirachtin, and rotenone were more toxic to C. abbreviatus, followed by nicotine, quercetin, and rutin. These results show the potential of these compounds as botanical pesticides, which can be applied for the biological control of the grasshopper C. abbreviatus. Title: Identification of genes involved in sex pheromone biosynthesis and metabolic pathway in the Chinese oak silkworm, Antheraea pernyi Wang QH, Gong Q, Fang SM, Liu YQ, Zhang Z, Yu QY Ref: Int J Biol Macromol, 163:1487, 2020 : PubMed ESTHER: Wang_2020_Int.J.Biol.Macromol_163_1487 PubMedSearch: Wang 2020 Int.J.Biol.Macromol 163 1487 PubMedID: 32755713 Abstract The Chinese oak silkworm, Antheraea pernyi, has not only been semi-domesticated as an important economical insect but also used for genetic research. The female moths of A. pernyi employ a pheromone blend containing (E,Z)-6,11-hexadecadienal (E6,Z11-16:Ald), (E,Z)-6,11-hexadecadienyl acetate (E6,Z11-16:OAc), and (E,Z)-4,9-tetradecadienyl acetate (E4,Z9-14:OAc). While its biosynthesis pathway is largely unknown. By deep sequencing and de novo assembly of sex pheromone gland (PG) transcriptome, we identified 141 candidate genes that are putatively related to pheromone biosynthesis, degradation, and chemoreception in A. pernyi. Gene expression patterns and phylogenetic analysis revealed that two desaturases (AperDES1 and 2), two fatty acid reductase (AperFAR1 and 2), and three acetyltransferase genes (AperACT1, 2 and 3) showed PG-biased or specific expression and were phylogenetically related to genes known to be involved in pheromone synthesis in other species. Furthermore, two carboxylesterases (AperCOE6 and 11) and two chemosensory protein (AperCSP1 and 6) were also expressed specifically or predominantly in the PGs, which might be related to sex pheromone degradation and transportation, respectively. Based on these results, the sex pheromone biosynthesis and metabolic pathway was proposed in A. pernyi. This study provides some crucial candidates for further functional elucidation, and may be used for interfering sexual communication in other Saturniidae pests. Title: A Network-Based Approach to Explore the Mechanisms of Uncaria Alkaloids in Treating Hypertension and Alleviating Alzheimer's Disease Wu W, Zhang Z, Li F, Deng Y, Lei M, Long H, Hou J Ref: Int J Mol Sci, 21:, 2020 : PubMed ESTHER: Wu_2020_Int.J.Mol.Sci_21_ PubMedSearch: Wu 2020 Int.J.Mol.Sci 21 PubMedID: 32143538 Abstract Uncaria alkaloids are the major bioactive chemicals found in the Uncaria genus, which have a long history of clinical application in treating cardiovascular and mental diseases in traditional Chinese medicine (TCM). However, there are gaps in understanding the multiple targets, pathways, and biological activities of Uncaria alkaloids. By constructing the interactions among drug-targets-diseases, network pharmacology provides a systemic methodology and a novel perspective to present the intricate connections among drugs, potential targets, and related pathways. It is a valuable tool for studying TCM drugs with multiple indications, and how these multi-indication drugs are affected by complex interactions in the biological system. To better understand the mechanisms and targets of Uncaria alkaloids, we built an integrated analytical platform based on network pharmacology, including target prediction, protein-protein interaction (PPI) network, topology analysis, gene enrichment analysis, and molecular docking. Using this platform, we revealed the underlying mechanisms of Uncaria alkaloids' anti-hypertensive effects and explored the possible application of Uncaria alkaloids in preventing Alzheimer's disease. These results were further evaluated and refined using biological experiments. Our study provides a novel strategy for understanding the holistic pharmacology of TCM, as well as for exploring the multi-indication properties of TCM beyond its traditional applications. Title: Improving the production of AHL lactonase AiiO-AIO6 from Ochrobactrum sp. M231 in intracellular protease-deficient Bacillus subtilis Xia R, Yang Y, Pan X, Gao C, Yao Y, Liu X, Teame T, Zhang F, Hu J and Zhou Z <3 more author(s)> Xia R, Yang Y, Pan X, Gao C, Yao Y, Liu X, Teame T, Zhang F, Hu J, Ran C, Zhang Z, Liu-Clarke J, Zhou Z (- 3) Ref: AMB Express, 10:138, 2020 : PubMed ESTHER: Xia_2020_AMB.Express_10_138 PubMedSearch: Xia 2020 AMB.Express 10 138 PubMedID: 32757095 Gene_locus related to this paper: ocha4-a6wx49 Abstract Quorum quenching (QQ) blocks bacterial cell-to-cell communication (i.e., quorum sensing), and is a promising antipathogenic strategy to control bacterial infection via inhibition of virulence factor expression and biofilm formation. QQ enzyme AiiO-AIO6 from Ochrobactrum sp. M231 has several excellent properties and shows biotherapeutic potential against important bacterial pathogens of aquatic species. AiiO-AIO6 can be secretory expressed in Bacillus subtilis via a non-classical secretion pathway. To improve AiiO-AIO6 production, four intracellular protease-deletion mutants of B. subtilis 1A751 were constructed by individually knocking out the intracellular protease-encoding genes (tepA, ymfH, yrrN and ywpE). The AiiO-AIO6 expression plasmid pWB-AIO6BS was transformed into the B. subtilis 1A751 and its four intracellular protease-deletion derivatives. Results showed that all recombinant intracellular protease-deletion derivatives (BStepA, BSymfH, BSyrrN and BSywpE) had a positive impact on AiiO-AIO6 production. The highest amount of AiiO-AIO6 extracellular production of BSywpE in shake flask reached 1416.47 U/mL/OD(600), which was about 121% higher than that of the wild-type strain. Furthermore, LC-MS/MS analysis of the degrading products of 3-oxo-C8-HSL by purification of AiiO-AIO6 indicated that AiiO-AIO6 was an AHL-lactonase which hydrolyzes the lactone ring of AHLs. Phylogenetic analysis showed that AiiO-AIO6 was classified as a member of the alpha/beta hydrolase family with a conserved "nucleophile-acid-histidine" catalytic triad. In summary, this study showed that intracellular proteases were responsible for the reduced yields of heterologous proteins and provided an efficient strategy to enhance the extracellular production of AHL lactonase AiiO-AIO6. Title: Cell Wall Polysaccharide-Mediated Cadmium Tolerance Between Two Arabidopsis thaliana Ecotypes Xiao Y, Wu X, Liu D, Yao J, Liang G, Song H, Ismail AM, Luo JS, Zhang Z Ref: Front Plant Sci, 11:473, 2020 : PubMed ESTHER: Xiao_2020_Front.Plant.Sci_11_473 PubMedSearch: Xiao 2020 Front.Plant.Sci 11 473 PubMedID: 32477379 Abstract Cadmium (Cd) is a toxic metal element and the mechanism(s) underlying Cd tolerance in plants are still unclear. Increasingly more studies have been conducted on Cd binding to plant cell walls (CW) but most of them have focused on Cd fixation by CW pectin, and few studies have examined Cd binding to cellulose and hemicellulose. Here we found that Cd binding to CW pectin, cellulose, and hemicellulose was significantly higher in Tor-1, a Cd tolerant A. thaliana ecotype, than in Ph2-23, a sensitive ecotype, as were the concentrations of pectin, cellulose, and hemicellulose. Transcriptome analysis revealed that the genes regulating CW pectin, cellulose, and hemicellulose polysaccharide concentrations in Tor-1 differed significantly from those in Ph2-23. The expressions of most genes such as pectin methyl esterase inhibitors (PMEIs), pectin lyases, xyloglucan endotransglucosylase/hydrolase, expansins (EXPAs), and cellulose hydrolase were higher in Ph2-23, while the expressions of cellulose synthase-like glycosyltransferase 3 (CSLG3) and pectin ethyl esterase 4 (PAE4) were higher in Tor-1. The candidate genes identified here seem to regulate CW Cd fixation by polysaccharides. In conclusion, an increase in pectin demethylation activity, the higher concentration of cellulose and hemicellulose, regulated by related genes, in Tor-1 than in Ph2-23 are likely involved in enhanced Cd CW retention and reduce Cd toxicity. Title: Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II) Ye Q, Wang H, Xia X, Zhou C, Liu Z, Xia ZE, Zhang Z, Zhao Y, Yehenala J and He Y <5 more author(s)> Ye Q, Wang H, Xia X, Zhou C, Liu Z, Xia ZE, Zhang Z, Zhao Y, Yehenala J, Wang S, Zhou G, Hu K, Wu B, Wu CT, He Y (- 5) Ref: Trials, 21:520, 2020 : PubMed ESTHER: Ye_2020_Trials_21_520 PubMedSearch: Ye 2020 Trials 21 520 PubMedID: 32532356 Abstract OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. INCLUSION CRITERIA: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: 1)Adults aged 18-65 years;2)Voluntarily participate in this clinical trial and sign the "informed consent form" or have consent from a legal representative.3)Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg).4)COVID-19 featured lung lesions in chest X-ray image. EXCLUSION CRITERIA: Patients will be excluded from the study if they meet any of the following criteria. 1.Patients have received other experimental treatment for COVID-19 within the last 30 days;2.Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit);3.Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m(2)) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis;4.Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses;5.Female patients who have no sexual protection in the last 30 days prior to the screening assessment;6.Pregnant or lactating women or women using estrogen contraception;7.Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period;8.Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: GradeDescriptionGrade 1:Discharged of patient;Grade 2:Hospitalized without oxygen supplement;Grade 3:Hospitalized, oxygen supplement is required, but NIV / HFNC is not required;Grade 4:Hospitalized in intensive care unit, and NIV / HFNC treatment is required;Grade 5:Hospitalized in intensive care unit, requiring ECMO and/or IMV;Grade 6:Death. ABBREVIATIONS: NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h +/- 30min, 24h +/- 30min after the injection) and follow-up period D90 +/- 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h +/- 30min, 24h +/- 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 +/- 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 +/- 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 beta, IL-2, TNF-a, ITN-gamma), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood beta-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 +/- 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h +/- 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient's randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16(th) April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. Title: The degraded polysaccharide from Pyropia haitanensis represses amyloid beta peptide-induced neurotoxicity and memory in vivo Zhang Z, Wang X, Pan Y, Wang G, Mao G Ref: Int J Biol Macromol, 146:725, 2020 : PubMed ESTHER: Zhang_2020_Int.J.Biol.Macromol_146_725 PubMedSearch: Zhang 2020 Int.J.Biol.Macromol 146 725 PubMedID: 31739053 Abstract An antioxidant polysaccharide, porphyran, from red algae Pyropia haitanensis, is introduced as a protective agent against neurotoxicity-induced amyloid beta peptide (Abeta) of Alzheimer's disease (AD) mice. Then the activity of acetylcholinesterase (AChE) and choline acetyltransferase (CHAT) in the cortical and hippocampal tissue were examined by colorimetric method. Results showed that porphyran significantly ameliorated the learning and memory impairment induced by Abeta1-40. Biochemical analysis showed that porphyran increased ChAT activity and decreased AChE activity in the cortical and hippocampal tissue. The mechanism may be related with the increase of cerebral acetylcholine content. Porphyran has a potential of developing anti-aging drug. Title: The structure-based optimization of delta-sultone-fused pyrazoles as selective BuChE inhibitors Zhang Z, Min J, Chen M, Jiang X, Xu Y, Qin H, Tang W Ref: Eur Journal of Medicinal Chemistry, 201:112273, 2020 : PubMed ESTHER: Zhang_2020_Eur.J.Med.Chem_201_112273 PubMedSearch: Zhang 2020 Eur.J.Med.Chem 201 112273 PubMedID: 32569925 Abstract Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with delta-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC50 = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (Ki = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis. Title: Total flavonoids of Selaginella pulvinata alleviates cognitive impairment in mice Zhang L, Zhang Y, Hou Y, Li H, Li C, Xin J, Zhou N, Li Q, Song Y, Zhang Z Ref: Biomed Rep, 13:8, 2020 : PubMed ESTHER: Zhang_2020_Biomed.Rep_13_8 PubMedSearch: Zhang 2020 Biomed.Rep 13 8 PubMedID: 32607237 Abstract Cognitive impairment (CI) refers to dysfunctional cognition, which encompasses a spectrum of disorders, ranging from mild cognitive impairment to dementia. Any factor that results in cortical damage may cause CI. Total flavonoids of Selaginella pulvinata (TFSP), have shown promising antioxidant and protective effects in animal models. In the present study, mice were intraperitoneally treated with scopolamine, sodium nitrite or 45% ethanol to induce memory impairment, and the effects were assessed using a step-down test. After performing the behavioural test, hippocampal sections were collected for anatomical analysis, and the brain and serum levels of memory-related molecules were evaluated. The results showed that TFSP improved memory in a mouse model of CI significantly. Serum data were consistent with the behavioural results: TFSP increased blood acetylcholine levels through modulation of the acetylcholinesterase and choline acetyltransferase levels. It also ameliorated oxidative stress in neurons, increasing superoxide dismutase, glutathione peroxidase and inhibiting nitric oxide synthase levels in the brain. These results suggest that TFSP may exhibit potential as a clinical treatment for neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and senile dementia. Title: Co-expression of Pseudomonas alcaligenes Lipase and Its Specific Foldase in Pichia pastoris by a Dual Expression Cassette Strategy Zhang Z, Zhang X, Hao H, Gong X, Gu X Ref: Protein Expr Purif, :105721, 2020 : PubMed ESTHER: Zhang_2020_Protein.Expr.Purif__105721 PubMedSearch: Zhang 2020 Protein.Expr.Purif 105721 PubMedID: 32763465 Abstract Lipomax is a commercialized foldase-dependent Pseudomonas lipase that was previously expressed only in Pseudomonas strains. Here, using Pichia pastoris as the host, we report a new co-expression method that leads to the successful production of Lipomax. The active Lipomax is extracellularly co-expressed with its cognate foldase (LIM); and the purified enzyme mix has the optimum pH at pH 8.0 and an optimal temperature around 40degC. N-glycosylation was observed for Pichia produced Lipomax, and its reduction was shown to increase the lipolytic activity. With different p-nitrophenyl esters as the substrates, the substrate profiling analyses further indicate that Lipomax prefers esters with middle-long chain fatty acids, showing the highest specific activity to p-nitrophenyl caprylate (C8). The extracellular co-expression of Lipomax and LIM in Pichia will not only increase our ability to investigate additional eukaryotic hosts for lipase expression, but also be of considerable value in analyzing other foldase-dependent lipases. Title: Characterization of enzymatically interesterified palm oil-based fats and its potential application as cocoa butter substitute Zhang Z, Song J, Lee WJ, Xie X, Wang Y Ref: Food Chem, 318:126518, 2020 : PubMed ESTHER: Zhang_2020_Food.Chem_318_126518 PubMedSearch: Zhang 2020 Food.Chem 318 126518 PubMedID: 32151925 Abstract Cocoa butter substitutes (CBS) used for chocolate preparation was produced using a mixture of palm kernel oil (PKO) and enzymatically interesterified fats. The interesterified fats consisted of palm olein (POL), fully hydrogenated palm oil (FHPO) and PKO that were catalyzed using Lipozyme TL IM at 65 degreeC in a solvent-free packed bed reactor. An interesterification degree of 97.10% was obtained using feed flow rate of 70 mL/min and the interesterified fats showed steep solid fat content (SFC) curve characteristics with low SFC at high temperature. In the binary system, PKO and the interesterified fats showed good compatibility at 5-10 degreeC, while eutectic effects were observed at 15-35 degreeC. CBS produced from PKO and the interesterified fats in a mass ratio of 4:6 (CBS-46) and 3:7 (CBS-37) had crystals formed prominently in the beta' form. Without the need of a tempering process, chocolate made using CBS-46 as the base oil exhibited the desired properties in terms of hardness and fracturability. Title: Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase Zhang Z, Fan F, Luo W, Zhao Y, Wang C Ref: Front Chem, 8:730, 2020 : PubMed ESTHER: Zhang_2020_Front.Chem_8_730 PubMedSearch: Zhang 2020 Front.Chem 8 730 PubMedID: 33195011 Abstract Butyrylcholinesterase (BChE) is a non-specific enzyme with clinical pharmacological and toxicological significance, which was a renewed interest as therapeutic target in Alzheimer's disease (AD) nowadays. Here, all-atom molecular dynamics simulations of butyrylcholinesterase with tacrine complex were designed to characterize inhibitor binding modes, strengths, and the hydrogen-bond dependent non-covalent release mechanism. Four possible release channels were identified, and the most favorable channel was determined by random acceleration molecular dynamics molecular dynamics (RAMD MD) simulations. The thermodynamic and dynamic properties as well as the corresponding Detour-forward delivery mechanism were determined according to the classical molecular dynamics (MD) simulations accompanied with umbrella sampling. The free energy barrier of the tacrine release process for the most beneficial pathway is about 10.95 kcal/mol, which is related to the non-covalent interactions from the surrounding residues, revealing the specific binding characteristics in the active site. The residues including Asp70, Ser79, Trp82, Gly116, Thr120, Tyr332, and His438 were identified to play major roles in the stabilization of tacrine in the pocket of BChE, where hydrogen bonding and Pi-Pi interactions are significant factors. Tyr332 and Asp70, which act as gate keepers, play crucial roles in the substrate delivery. The present results provide a basic understanding for the ligand transport mechanism depending on the BChE enzymatic environment, which is useful for the design of BChE inhibitors in the future. Title: Electrostatic Effect of Functional Surfaces on the Activity of Adsorbed Enzymes: Simulations and Experiments Zheng H, Yang SJ, Zheng YC, Cui Y, Zhang Z, Zhong JY, Zhou J Ref: ACS Appl Mater Interfaces, 12:35676, 2020 : PubMed ESTHER: Zheng_2020_ACS.Appl.Mater.Interfaces_12_35676 PubMedSearch: Zheng 2020 ACS.Appl.Mater.Interfaces 12 35676 PubMedID: 32649833 Abstract The efficient immobilization of haloalkane dehalogenase (DhaA) on carriers with retaining of its catalytic activity is essential for its application in environmental remediation. In this work, adsorption orientation and conformation of DhaA on different functional surfaces were investigated by computer simulations; meanwhile, the mechanism of varying the catalytic activity was also probed. The corresponding experiments were then carried out to verify the simulation results. (The simulations of DhaA on SAMs provided parallel insights into DhaA adsorption in carriers. Then, the theory-guided experiments were carried out to screen the best surface functional groups for DhaA immobilization.) The electrostatic interaction was considered as the main impact factor for the regulation of enzyme orientation, conformation, and enzyme bioactivity during DhaA adsorption. The synergy of overall conformation, enzyme substrate tunnel structural parameters, and distance between catalytic active sites and surfaces codetermined the catalytic activity of DhaA. Specifically, it was found that the positively charged surface with suitable surface charge density was helpful for the adsorption of DhaA and retaining its conformation and catalytic activity and was favorable for higher enzymatic catalysis efficiency in haloalkane decomposition and environmental remediation. The neutral, negatively charged surfaces and positively charged surfaces with high surface charge density always caused relatively larger DhaA conformation change and decreased catalytic activity. This study develops a strategy using a combination of simulation and experiment, which can be essential for guiding the rational design of the functionalization of carriers for enzyme adsorption, and provides a practical tool to rationally screen functional groups for the optimization of adsorbed enzyme functions on carriers. More importantly, the strategy is general and can be applied to control behaviors of different enzymes on functional carrier materials. Title: Spectroscopic and molecular modeling investigation on inhibition effect of nitroaromatic compounds on acetylcholinesterase activity Chen Y, Wang M, Fu H, Qu X, Zhang Z, Kang F, Zhu D Ref: Chemosphere, 236:124365, 2019 : PubMed ESTHER: Chen_2019_Chemosphere_236_124365 PubMedSearch: Chen 2019 Chemosphere 236 124365 PubMedID: 31325829 Abstract Nitroaromatic compounds (NACs) are widely distributed in the environment and are considered toxic or carcinogenic. However, little attention has been paid to the binding interactions between NACs and biomacromolecules (e.g., proteins). Here we investigated the effects of three model NACs, nitrobenzene (NB), 1,3-dinitrobenzene (DNB), and 1,3,5-trinitrobenzene (TNB), on the activity of acetylcholinesterase (AChE). The presence of NACs (up to 0.5mM) effectively suppressed the AChE-catalyzed hydrolysis of acetylthiocholine iodide, with the suppression effect increasing with the nitro-group substitution (TNB>DNB>NB). Consistently, the UV absorption of AChE at 206nm arising from the skeleton structure decreased by the addition NACs, and the decrease exhibited the same compound sequence, reflecting the perturbing interactions with the skeleton enzyme structure. However, no changes were made on the secondary structure of AChE, as evidenced by the circular dichroism analysis. The fluorescence quenching analysis of AChE demonstrated that NB and DNB interacted with both tryptophan (Trp) and tyrosine (Tyr) residues, whereas TNB interacted only with Trp. The UV absorption and fluorescence quenching analyses both reflected that the interactions with the non-skeleton aromatic amino acids were weak. (1)H NMR analysis confirmed the strong pi-pi coupling interactions between TNB and model Trp. Molecular simulation indicated that the DNB or TNB molecule was sandwiched between Trp84 and Phe330 at the catalytic site via pi-pi coupling interactions. The findings highlight the importance of specific interactions of NACs with proteins to cause them to malfunction. Title: A potential biomarker of isofenphos-methyl in humans: A chiral view Gao B, Zhao S, Zhang Z, Li L, Hu K, Kaziem AE, He Z, Hua X, Shi H, Wang M Ref: Environ Int, 127:694, 2019 : PubMed ESTHER: Gao_2019_Environ.Int_127_694 PubMedSearch: Gao 2019 Environ.Int 127 694 PubMedID: 30991225 Inhibitor(s) related to this paper: Isocarbophos, Isofenphos-methyl Abstract Isofenphos-methyl (IFP) is a very active and persistent chiral insecticide. However, IFP has lower activity against acetylcholinesterases (AChEs). Previously, it was confirmed that phosphorothioate organophosphorus pesticides with N-alkyl (POPN) require activation by oxidative desulfuration and N-dealkylation. In this work, we demonstrated that IFP could be metabolized in human liver microsomes to isofenphos-methyl oxon (IFPO, 52.7%), isocarbophos (ICP, 14.2%) and isocarbophos oxon (ICPO, 11.2%). It was found that (R)-IFP was preferentially degraded compared to the (S)-enantiomer, and the enantiomeric fraction (EF) value reached 0.61 at 60min. However, (S)-enantiomers of the three metabolites, were degraded preferentially, and the EF values ranged from 0.34 to 0.45. Cytochrome P450 (CYP) isoforms CYP3A4, CYP2E1, and CYP1A2 and carboxylesterase enzyme have an essential role in the enantioselective metabolism of IFP; but, the enzymes that participate in the degradation of IFP metabolites are different. The AChE inhibition bioassay indicated that ICPO is the only effective inhibitor of AChE. The covalent molecular docking has proposed that the metabolites of IFP and its analogs after N-dealkylation and oxidative desulfuration will possess the highest inhibitory activity against AChE. This study is the first to demonstrate that ICPO can be regarded as a potential biomarker for the biomonitoring of IFP and ICP exposure in humans. Title: Study on the Multitarget Synergistic Effects of Kai-Xin-San against Alzheimer's Disease Based on Systems Biology Guo S, Wang J, Wang Y, Zhang Y, Bi K, Zhang Z, Li Q Ref: Oxid Med Cell Longev, 2019:1707218, 2019 : PubMed ESTHER: Guo_2019_Oxid.Med.Cell.Longev_2019_1707218 PubMedSearch: Guo 2019 Oxid.Med.Cell.Longev 2019 1707218 PubMedID: 31976026 Abstract Kai-Xin-San (KXS), a classical Chinese traditional prescription, was widely applied in the treatment of Alzheimer's disease (AD), while its functional mechanisms still remain unclear. By using systems biology approaches at animal, cellular, and molecular levels, the improvement of KXS on cognitive impairment was achieved by inhibiting abnormal acetylcholinesterase. The function on the nerve skeleton was performed by regulating the Tau phosphorylation pathway. Its antioxidant, anti-inflammatory, and antiapoptotic effects by modulating the aberrant upregulation of ROS, proinflammatory factors, and apoptosis-related proteins in the brain were studied to reveal the synergistic therapeutic efficacy of KXS. Then, formula dismantling in vitro indicated that ginseng was the principal herb, whereas three other herbs served adjuvant roles to achieve the best effect. After that, the in vivo analysis of components into plasma and brain of AD rats showed that 8 of 23 components in blood and 4 of 10 components in brain were from ginseng, respectively, further verifying the principal status of ginseng and the synergistic effects of the formula. Thus, the anti-AD effects of KXS were achieved by multitargets and multichannels. The systems biology approaches presented here provide a novel way in traditional herbal medicine research. Title: Development of the hidden multifunctional agents for Alzheimer's disease Huang W, Liang M, Li Q, Zheng X, Zhang C, Wang Q, Tang L, Zhang Z, Wang B, Shen Z Ref: Eur Journal of Medicinal Chemistry, 177:247, 2019 : PubMed ESTHER: Huang_2019_Eur.J.Med.Chem_177_247 PubMedSearch: Huang 2019 Eur.J.Med.Chem 177 247 PubMedID: 31158742 Abstract Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-beta (Abeta) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Abeta aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models. Title: Novel chromanone-dithiocarbamate hybrids as multifunctional AChE inhibitors with beta-amyloid anti-aggregation properties for the treatment of Alzheimer's disease Jiang N, Ding J, Liu J, Sun X, Zhang Z, Mo Z, Li X, Yin H, Tang W, Xie SS Ref: Bioorg Chem, 89:103027, 2019 : PubMed ESTHER: Jiang_2019_Bioorg.Chem_89_103027 PubMedSearch: Jiang 2019 Bioorg.Chem 89 103027 PubMedID: 31176237 Abstract By connecting chromanone with dithiocarbamate moieties through flexible linkers, a series of hybrids as novel multifunctional AChE inhibitors have been designed and synthesized. Most of these compounds displayed strong and excellently selective inhibition to eeAChE as well as potent inhibition to self- and AChE-induced Abeta aggregation. Among them, compound 6c showed the best activity to inhibit eeAChE (IC50=0.10muM) and AChE-induced Abeta aggregation (33.02% at 100muM), and could effectively inhibit self-induced Abeta aggregation (38.25% at 25muM). Kinetic analysis and docking study indicated that compound 6c could target both the CAS and PAS, suggesting that it was a dual binding site inhibitor for AChE. Besides, it exhibited good ability to penetrate the BBB and low neurotoxicity in SH-SY5Y cells. More importantly, compound 6c was well tolerated in mice (2500mg/kg, po) and could attenuate the memory impairment in a scopolamine-induced mouse model. Overall, these results highlight 6c as a promising multifunctional agent for treating AD and also demonstrate that the dithiocarbamate is a valid scaffold for design of multifunctional AChE inhibitors. Title: Gamma-glutamyl transpeptidase to cholinesterase and platelet ratio in predicting significant liver fibrosis and cirrhosis of chronic hepatitis B Liu D, Li J, Lu W, Wang Y, Zhou X, Huang D, Li X, Ding R, Zhang Z Ref: Clin Microbiol Infect, 25:514 e1, 2019 : PubMed ESTHER: Liu_2019_Clin.Microbiol.Infect_25_514 e1 PubMedSearch: Liu 2019 Clin.Microbiol.Infect 25 514 e1 PubMedID: 29906588 Abstract OBJECTIVES: To evaluate the performance of a new mathematical model gamma-glutamyl transpeptidase to cholinesterase and platelet ratio (GCPR) versus gamma-glutamyl transpeptidase to platelet ratio (GPR) in predicting significant fibrosis and cirrhosis of chronic hepatitis B. METHODS: A complete cohort of 2343 patients was divided into early and late cohort depending on the time of liver biopsy. With reference to the Scheuer standard, liver pathologic stage 2 or higher and stage 4 or higher were defined as significant fibrosis and cirrhosis, respectively. Receiver operating characteristic (ROC) curve was used to evaluate the performance of investigated models. RESULTS: In the early cohort, the areas under ROC curves (AUROCs) of GCPR in predicting significant fibrosis of hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients (0.782 and 0.775) were both significantly greater than those of GPR (0.748 and 0.747) (Z = 8.198 and Z = 6.023, both p <0.0001); the AUROCs of GCPR in predicting cirrhosis of HBeAg-positive and HBeAg-negative patients (0.842 and 0.861) were both significantly greater than those of GPR (0.802 and 0.823) (Z = 6.686 and Z = 6.116, both p <0.0001). In early, late and complete cohorts, using a single cutoff of GCPR > 0.080, the specificities of GCPR in predicting significant fibrosis of HBeAg-positive patients were 83.3%, 88.2% and 85.0% and of HBeAg-negative patients were 87.6%, 87.4% and 87.6%, respectively; and the sensitivities of GCPR in predicting cirrhosis of HBeAg-positive patients were 81.9%, 88.7% and 84.2% and of HBeAg-negative patients were 83.1%, 82.1% and 82.7%, respectively. CONCLUSIONS: GCPR has higher performance than GPR in predicting significant fibrosis and cirrhosis of chronic hepatitis B. Title: Identifying the Potential Substrates of the Depalmitoylation Enzyme Acyl-protein Thioesterase 1 Liu H, Yan P, Ren J, Wu C, Yuan W, Rao M, Zhang Z, Kong E Ref: Curr Mol Med, 19:364, 2019 : PubMed ESTHER: Liu_2019_Curr.Mol.Med_19_364 PubMedSearch: Liu 2019 Curr.Mol.Med 19 364 PubMedID: 30914023 Abstract BACKGROUND: The homeostasis of palmitoylation and depalmitoylation is involved in various cellular processes, the disruption of which induces severe physiological consequences. Acyl-protein thioesterase (APT) and palmitoyl-protein thioesterases (PPT) catalyze the depalmitoylation process. The natural mutation in human PPT1 caused neurodegenerative disease, yet the understanding of APT1 remains to be elucidated. While the deletion of APT1 in mice turned out to be potentially embryonically lethal, the decoding of its function strictly relied on the identification of its substrates. OBJECTIVE: To determine the potential substrates of APT1 by using the generated human APT1 knockout cell line. METHODS: The combined techniques of palmitoyl-protein enrichment and massspectrometry were used to analyze the different proteins. Palmitoyl-proteins both in HEK293T and APT1-KO cells were extracted by resin-assisted capture (RAC) and data independent acquisition (DIA) quantitative method of proteomics for data collection. RESULTS: In total, 382 proteins were identified. The gene ontology classification segregated these proteins into diverse biological pathways e.g. endoplasmic reticulum process and ubiquitin-mediated proteolysis. A few potential substrates were selected for verification; indeed, major proteins were palmitoylated. Importantly, their levels of palmitoylation were clearly changed in APT1-KO cells. Interestingly, the proliferation of APT1-KO cells escalated dramatically as compared to that of the WT cells, which could be rescued by APT1 overexpression. CONCLUSION: Our study provides a large scale of potential substrates of APT1, thus facilitating the understanding of its intervened molecular functions. Title: Thioesterase-Catalyzed Aminoacylation and Thiolation of Polyketides in Fungi Tang MC, Fischer CR, Chari JV, Tan D, Suresh S, Chu A, Miranda M, Smith J, Zhang Z and Tang Y <2 more author(s)> Tang MC, Fischer CR, Chari JV, Tan D, Suresh S, Chu A, Miranda M, Smith J, Zhang Z, Garg NK, St Onge RP, Tang Y (- 2) Ref: Journal of the American Chemical Society, 141:8198, 2019 : PubMed ESTHER: Tang_2019_J.Am.Chem.Soc_141_8198 PubMedSearch: Tang 2019 J.Am.Chem.Soc 141 8198 PubMedID: 31051070 Gene_locus related to this paper: punst-KU42 Abstract Fungal highly reducing polyketide synthases (HRPKSs) biosynthesize polyketides using a single set of domains iteratively. Product release is a critical step in HRPKS function to ensure timely termination and enzyme turnover. Nearly all of the HRPKSs characterized to date employ a separate thioesterase (TE) or acyltransferase enzyme for product release. In this study, we characterized two fungal HRPKSs that have fused C-terminal TE domains, a new domain architecture for fungal HRPKSs. We showed that both HRPKS-TEs synthesize aminoacylated polyketides in an ATP-independent fashion. The KU42 TE domain selects cysteine and homocysteine and catalyzes transthioesterification using the side-chain thiol group as the nucleophile. In contrast, the KU43 TE domain selects leucine methyl ester and performs a direct amidation of the polyketide, a reaction typically catalyzed by nonribosomal peptide synthetase (NRPS) domains. The characterization of these HRPKS-TE enzymes showcases the functional diversity of HRPKS enzymes and provides potential TE domains as biocatalytic tools to diversify HRPKS structures. Title: Neuroprotective potential of ketamine prevents developing brain structure impairment and alteration of neurocognitive function induced via isoflurane through the PI3K/AKT/GSK-3beta pathway Wang R, Zhang Z, Kumar M, Xu G, Zhang M Ref: Drug Des Devel Ther, 13:501, 2019 : PubMed ESTHER: Wang_2019_Drug.Des.Devel.Ther_13_501 PubMedSearch: Wang 2019 Drug.Des.Devel.Ther 13 501 PubMedID: 30787593 Abstract Background: The aim of the current experimental study was to scrutinize the neuroprotective effect of ketamine on the isoflurane (iso)-induced cognitive dysfunction in rats via phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3beta (GSK-3beta) pathway. Materials and methods: Sprague-Dawley rats were used for the current experimental study. The rats were divided into six groups and rats were treated with ketamine and memantine. For the estimation of cognitive function study, we used the Morris water test. Pro-inflammatory cytokines such as IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), and caspase-6; the antioxidant parameters malondialdehyde, glutathione, superoxide dismutase, catalase, and protein carbonyl; acetylcholinesterase, amyloid beta, and brain-derived neurotrophic factor were estimated, respectively. The protein expression of AKT, GSK-3beta, p21WAF1/CIP1, and p53 was also estimated, respectively. Results: Ketamine significantly enhanced cognitive function and showed anti-inflammatory and antioxidant effects, and exhibited the neuroprotective effect of ketamine against the isoflurane-induced cognitive impairment. Additionally, ketamine significantly (P<0.005) suppressed IL-1beta, TNF-alpha, IL-6, caspase-6 and p21WAF1/CIP1, p53 expression and up-regulated the PI3K/AKT/GSK-3beta expression in the group of iso-induced rats. Conclusion: We can conclude that ketamine prevented the cognitive impairment induced by isoflurane anesthesia through anti-apoptotic, anti-inflammatory, and antioxidant effects via the PI3K/AKT/GSK-3beta pathway. Title: Discovery of delta-sultone-fused pyrazoles for treating Alzheimer's disease: Design, synthesis, biological evaluation and SAR studies Xu Y, Zhang Z, Jiang X, Chen X, Wang Z, Alsulami H, Qin HL, Tang W Ref: Eur Journal of Medicinal Chemistry, 181:111598, 2019 : PubMed ESTHER: Xu_2019_Eur.J.Med.Chem_181_111598 PubMedSearch: Xu 2019 Eur.J.Med.Chem 181 111598 PubMedID: 31415981 Abstract A class of novel delta-sulfonolactone-fused pyrazole scaffold was prepared via sulfur (VI) fluoride exchange (SuFEx) chemistry using aryl sulfonyl fluorides and pyrazolones. Enzyme screening revealed their cholinesterase inhibitory activity, among them, compounds 4a, 5a and 5d were identified as highly selective submicromolar BuChE inhibitors (IC50=0.20, 0.46 and 0.42muM, respectively), which exhibited nontoxicity, lipophilicity and remarkable neuroprotective activity. Kinetic studies showed that BuChE inhibition of compounds 5a and 5d was reversible, mixed-type and non-competitive inhibition against BuChE (Ki=145nM and 60nM, respectively). Compound 5d can be accommodated into hBuChE via pi-S interaction and hydrophobic interactions. The title compounds are potentially symptomatic treatment in progressive Alzheimer's disease. Title: Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction Yan M, Zhang Z, Liu Z, Zhang C, Zhang J, Fan S, Yang Z Ref: Molecules, 24:, 2019 : PubMed ESTHER: Yan_2019_Molecules_24_ PubMedSearch: Yan 2019 Molecules 24 PubMedID: 31717501 Gene_locus related to this paper: human-CES1 Abstract Human carboxylesterase 1 (hCES1) is a major carboxylesterase in the human body and plays important roles in the metabolism of a wide variety of substances, including lipids and drugs, and therefore is attracting more and more attention from areas including lipid metabolism, pharmacokinetics, drug-drug interactions, and prodrug activation. In this work, we studied the catalytic hydrolysis mechanism of hCES1 by the quantum mechanics computation method, using cocaine as a model substrate. Our results support the four-step theory of the esterase catalytic hydrolysis mechanism, in which both the acylation stage and the deacylation stage include two transition states and a tetrahedral intermediate. The roles and cooperation of the catalytic triad, S221, H468, and E354, were also analyzed in this study. Moreover, orthoester intermediates were found in hCES1-catalyzed cocaine hydrolysis reaction, which significantly elevate the free energy barrier and slow down the reaction. Based on this finding, we propose that hCES1 substrates with beta-aminocarboxylester structure might form orthoester intermediates in hCES1-catalyzed hydrolysis, and therefore prolong their in vivo half-life. Thus, this study helps to clarify the catalytic mechanism of hCES1 and elucidates important details of its catalytic process, and furthermore, provides important insights into the metabolism of hCES1 substrates and drug designing. Title: A sensitive amperometric AChE-biosensor for organophosphate pesticides detection based on conjugated polymer and Ag-rGO-NH2 nanocomposite Zhang P, Sun T, Rong S, Zeng D, Yu H, Zhang Z, Chang D, Pan H Ref: Bioelectrochemistry, 127:163, 2019 : PubMed ESTHER: Zhang_2019_Bioelectrochemistry_127_163 PubMedSearch: Zhang 2019 Bioelectrochemistry 127 163 PubMedID: 30831354 Abstract Long-term accumulation of organophosphate pesticides in environment presents a potential hazard to human and animal health. Towards this, a highly sensitive amperometric AChE-biosensor based on conjugated polymer and Ag-rGO-NH2 nanocomposite has been successfully developed. First, 4, 7-di (furan-2-yl) benzo thiadiazole (FBThF) was electrochemically polymerized on the electrode surface. Then, Ag-rGO-NH2 nanocomposite and acetylcholinesterase (AChE) are modified on the polymer membrane surface. In this way, a novel amperometric AChE-biosensor was successfully prepared. The as-prepared biosensor possessed excellent conductivity, catalytic activity, and biocompatibility which were attributed to the synergistic effects of poly(FBThF) and Ag-rGO-NH2 and provided a hydrophilic surface for AChE adhesion. Under optimized conductions, the linear range was 0.099-9.9mugL(-1) with a regression coefficient of 0.9947 for malathion, 0.0206-2.06mugL(-1) with a regression coefficient of 0.9969 for trichlorfon. The detection limit is calculated to be about 0.032mugL(-1) for malathion and 0.001mugL(-1) for trichlorfon (S/N=3). Moreover, the biosensor exhibited acceptable reproducibility and long-term stability, which makes it possible to provide a novel and promising tool for analysis of organophosphate pesticides. Title: A Review of Danshen Combined with Clopidogrel in the Treatment of Coronary Heart Disease Zhang Z, Wang Y, Tan W, Wang S, Liu J, Liu X, Wang X, Gao X Ref: Evid Based Complement Alternat Med, 2019:2721413, 2019 : PubMed ESTHER: Zhang_2019_Evid.Based.Complement.Alternat.Med_2019_2721413 PubMedSearch: Zhang 2019 Evid.Based.Complement.Alternat.Med 2019 2721413 PubMedID: 30911318 Abstract Objective: Danshen, the root of Salvia miltiorrhiza Bunge, is a traditional herbal medicine in China, which has been used to treat irregular menstruation, cold hernia, and abdominal pain for thousands of years. Danshen is frequently used in combination with drugs to treat cardiovascular diseases. Clopidogrel is a commonly used drug for treating coronary heart disease, but clopidogrel resistance restricts its development. Therefore, the clinical efficacy of Danshen combined with clopidogrel treats coronary heart disease and the relationship between Danshen and clopidogrel metabolism enzymes is suggested for future investigations. Materials and Methods: The information was collected by searching online databases, and the RevMan 5.3 software was used to perform meta-analysis. Results: Twenty-two articles, including 2587 patients, were enrolled after the evaluation. Meta-analysis showed that Danshen combined with clopidogrel was more effective than clopidogrel alone in treating coronary heart disease by improving clinical curative effect, reducing the frequency of angina pectoris, improving electrocardiogram results, shortening the duration of angina pectoris, and easing adverse reactions. Danshen inhibited carboxylesterase 1 and most enzyme of cytochrome P450, especially cytochrome P450 1A2, which may affect the metabolism of clopidogrel. Conclusion: Danshen combined with clopidogrel may compensate for individual differences of clopidogrel resistance among individuals in the treatment of coronary heart disease. Meanwhile, the inhibitory effect of Danshen on cytochrome P450 and carboxylesterase 1 could be partly responsible for the synergistic and attenuating effects of Danshen combined with clopidogrel. Title: Transcriptomic analysis of Chlorimuron-ethyl degrading bacterial strain Klebsiella jilinsis 2N3 Zhang C, Hao Q, Zhang S, Zhang Z, Zhang X, Sun P, Pan H, Zhang H, Sun F Ref: Ecotoxicology & Environmental Safety, 183:109581, 2019 : PubMed ESTHER: Zhang_2019_Ecotoxicol.Environ.Saf_183_109581 PubMedSearch: Zhang 2019 Ecotoxicol.Environ.Saf 183 109581 PubMedID: 31446172 Abstract Chlorimuron-ethyl is a sulfonylurea herbicide with a long residual period in the field and is toxic to rotational crops. Klebsiella jilinsis 2N3 is a gram-negative bacterium that can rapidly degrade Chlorimuron-ethyl. In this study, the gene expression changes in strain 2N3 during degradation of Chlorimuron-ethyl was analyzed by RNA-Seq. Results showed that 386 genes were up-regulated and 453 genes were down-regulated. KEGG pathway enrichment analysis revealed the highest enrichment ratio in the pathway of sulfur metabolism. On the basis of the functional annotation and gene expression, we predicted that carboxylesterase, monooxygenase, glycosyltransferase, and cytochrome P450 were involved in the metabolism of Chlorimuron-ethyl biodegradation. Results of qRT-PCR showed that the relative mRNA expression levels of these genes were higher in treatment group than those in control group. The cytochrome P450 encoded by Kj-CysJ and the alkanesulfonate monooxygenase encoded by Kj-SsuD were predicted and further experimentally confirmed by gene knockout as the key enzymes in the biodegradation process. Cultured in basal medium containing Chlorimuron-ethyl (5mgL(-1)) in 36h, the strains of DeltaKj-CysJ, DeltaKj-SsuD, and WT reached the highest OD600 values of 0.308, 0.873, and 1.085, and the highest degradation rates of Chlorimuron-ethyl of 11.83%, 96.21%, and 95.62%, respectively. Title: Whole Genome Sequencing and Analysis of Chlorimuron-Ethyl Degrading Bacteria Klebsiella pneumoniae 2N3 Zhang C, Hao Q, Zhang Z, Zhang X, Pan H, Zhang J, Zhang H, Sun F Ref: Int J Mol Sci, 20:, 2019 : PubMed ESTHER: Zhang_2019_Int.J.Mol.Sci_20_ PubMedSearch: Zhang 2019 Int.J.Mol.Sci 20 PubMedID: 31234527 Gene_locus related to this paper: klep7-a6tb98, klep7-mhpc Abstract Klebsiella pneumoniae 2N3 is a strain of gram-negative bacteria that can degrade chlorimuron-ethyl and grow with chlorimuron-ethyl as the sole nitrogen source. The complete genome of Klebsiella pneumoniae 2N3 was sequenced using third generation high-throughput DNA sequencing technology. The genomic size of strain 2N3 was 5.32 Mb with a GC content of 57.33% and a total of 5156 coding genes and 112 non-coding RNAs predicted. Two hydrolases expressed by open reading frames (ORFs) 0934 and 0492 were predicted and experimentally confirmed by gene knockout to be involved in the degradation of chlorimuron-ethyl. Strains of DeltaORF 0934, DeltaORF 0492, and wild type (WT) reached their highest growth rates after 8-10 hours in incubation. The degradation rates of chlorimuron-ethyl by both DeltaORF 0934 and DeltaORF 0492 decreased in comparison to the WT during the first 8 hours in culture by 25.60% and 24.74%, respectively, while strains DeltaORF 0934, DeltaORF 0492, and the WT reached the highest degradation rates of chlorimuron-ethyl in 36 hours of 74.56%, 90.53%, and 95.06%, respectively. This study provides scientific evidence to support the application of Klebsiella pneumoniae 2N3 in bioremediation to control environmental pollution. Title: Interesterification of rice bran wax and palm olein catalyzed by lipase: Crystallization behaviours and characterization Zhang Z, Ye J, Fei T, Ma X, Xie X, Huang H, Wang Y Ref: Food Chem, 286:29, 2019 : PubMed ESTHER: Zhang_2019_Food.Chem_286_29 PubMedSearch: Zhang 2019 Food.Chem 286 29 PubMedID: 30827609 Abstract Rice bran wax (RBW) is a traditional plant based natural wax and an increasingly popular component in textiles, fruit coatings and cosmetics. Properties of RBW can be modified by acyglycerols, and the resulting products can possess features with great potential in different applications. In this study, RBW was interesterified with palm olein (POL) catalyzed by Lipozyme TL IM, and the effects of RBW on the crystallization rate, solid fat content (SFC) and thermodynamic properties were investigated. The crystallization rates of RBW-based enzymatically interesterified (EIE) products were significantly higher than both the starting mixture and fully hydrogenated rapeseed oil (FHRSO). The EIE RBW-based samples were predominantly crystallized in beta' form, and presented a much smoother SFC profile as compared to physically blended raw materials. The SFC values were significantly decreased, conversely increased, and remained constant, and at 10 degreeC, 20-30 degreeC, and 35-40 degreeC as the wax ester and acylglycerols compositions changes. Overall, RBW-based samples after EIE showed an increased hardness and good surface properties, which make it a potential plastic fats substitute. Title: Association between EPHX1 polymorphisms and carbamazepine metabolism in epilepsy: a meta-analysis Zhao GX, Shen ML, Zhang Z, Wang P, Xie CX, He GH Ref: Int J Clin Pharm, 41:1414, 2019 : PubMed ESTHER: Zhao_2019_Int.J.Clin.Pharm_41_1414 PubMedSearch: Zhao 2019 Int.J.Clin.Pharm 41 1414 PubMedID: 31650507 Abstract Background: EPHX1 gene polymorphisms were recently acknowledged as an important source of individual variability in carbamazepine metabolism, but the result of that association still remains controversial. Aim of the review To obtain a more precise estimation of the associations between EPHX1 polymorphisms and carbamazepine metabolism and resistance. Methods: The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched for appropriate studies regarding the rs1051740 and rs2234922 polymorphisms of EPHX1 up to September 2019. The meta-analysis was carried out using the Review Manager 5.3 software. The mean difference and 95% confidence interval were applied to assess the strength of the relationship. Results: A total of 7 studies involving 1118 related epilepsy patients were included. EPHX1 rs1051740 polymorphism was significantly associated with adjusted concentrations of both carbamazepine (CC vs. TT: P = 0.02; CC vs. CT + TT: P = 0.005) and carbamazepine-10,11-epoxide (CC vs. CT + TT: P = 0.03). Furthermore, EPHX1 rs2234922 polymorphism was also observed to be significantly associated with decreased adjusted concentrations of carbamazepine-10,11-trans dihydrodiol (GG vs. GA + AA: P = 0.04) and CBZD:CBZE ratio (GG vs. AA: P = 0.008; GG vs. GA + AA: P = 0.0008). Nevertheless, the pooled analysis showed that the EPHX1 polymorphisms had no significant effect on CBZ resistance. Conclusion EPHX1 rs1051740 and rs2234922 polymorphisms may affect the carbamazepine metabolism; but carbamazepine resistance was not related to any of the single nucleotide polymorphisms investigated. These findings provided further evidence for individualized therapy of epilepsy patients in clinics. Title: Hippocampal Proteomic Alteration in Triple Transgenic Mouse Model of Alzheimer's Disease and Implication of PINK 1 Regulation in Donepezil Treatment Zhou X, Xiao W, Su Z, Cheng J, Zheng C, Zhang Z, Wang Y, Wang L, Xu B and Pui Man Hoi M <2 more author(s)> Zhou X, Xiao W, Su Z, Cheng J, Zheng C, Zhang Z, Wang Y, Wang L, Xu B, Li S, Yang X, Pui Man Hoi M (- 2) Ref: J Proteome Res, 18:1542, 2019 : PubMed ESTHER: Zhou_2019_J.Proteome.Res_18_1542 PubMedSearch: Zhou 2019 J.Proteome.Res 18 1542 PubMedID: 30484658 Abstract Donepezil is a clinically approved acetylcholinesterase inhibitor (AChEI) for cognitive improvement in Alzheimer's disease (AD). Donepezil has been used as a first-line agent for the symptomatic treatment of AD, but its ability to modify disease pathology and underlying mechanisms is not clear. We investigated the protective effects and underlying mechanisms of donepezil in AD-related triple transgenic (APPSwe/PSEN1M146V/MAPTP301L) mouse model (3xTg-AD). Mice (8-month old) were treated with donepezil (1.3 mg/kg) for 4 months and evaluated by behavioral tests for assessment of cognitive functions, and the hippocampal tissues were examined by protein analysis and quantitative proteomics. Behavioral tests showed that donepezil significantly improved the cognitive capabilities of 3xTg-AD mice. The levels of soluble and insoluble amyloid beta proteins (Abeta1-40 and Abeta1-42) and senile plaques were reduced in the hippocampus. Golgi staining of the hippocampus showed that donepezil prevented dendritic spine loss in hippocampal neurons of 3xTg-AD mice. Proteomic studies of the hippocampal tissues identified 3131 proteins with altered expression related to AD pathology, of which 262 could be significantly reversed with donepezil treatment. Bioinformatics with functional analysis and protein-protein interaction (PPI) network mapping showed that donepezil significantly elevated the protein levels of PINK 1, NFASC, MYLK2, and NRAS in the hippocampus, and modulated the biological pathways of axon guidance, mitophagy, mTOR, and MAPK signaling. The substantial upregulation of PINK 1 with donepezil was further verified by Western blotting. Donepezil exhibited neuroprotective effects via multiple mechanisms. In particular, PINK 1 is related to mitophagy and cellular protection from mitochondrial dysfunction, which might play important roles in AD pathogenesis and represent a potential therapeutic target. Title: The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease Zhu G, Wang K, Shi J, Zhang P, Yang D, Fan X, Zhang Z, Liu W, Sang Z Ref: Bioorganic & Medicinal Chemistry Lett, 29:126625, 2019 : PubMed ESTHER: Zhu_2019_Bioorg.Med.Chem.Lett_29_126625 PubMedSearch: Zhu 2019 Bioorg.Med.Chem.Lett 29 126625 PubMedID: 31444085 Abstract A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC(50) value of 2.9 microM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu(2+) complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC(50) = 6.8 microM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease. Title: A novel homozygous NDRG1 mutation in a Chinese patient with Charcot-Marie-Tooth disease 4D Chen B, Niu S, Chen N, Pan H, Wang X, Zhang Z Ref: J Clin Neurosci, 53:231, 2018 : PubMed ESTHER: Chen_2018_J.Clin.Neurosci_53_231 PubMedSearch: Chen 2018 J.Clin.Neurosci 53 231 PubMedID: 29724652 Gene_locus related to this paper: human-NDRG1 Abstract Charcot-Marie-Tooth disease 4D (CMT4D) is characterized by severe peripheral neuropathy and deafness. It is caused by mutations in the N-myc downstream-regulated gene 1 (NDRG1). We report a Chinese man with a homozygous mutation c.675C > T of NDRG1 that resulted in Q185X, representing the third known CMT4D patient of non-European ancestry. The patient presented with a 15-year-long history of progressive limb weakness accompanied by hearing loss and dysarthria. There was abnormal differentiation and increased interpeak latencies in brainstem auditory evoked potentials. Compound muscle action potentials (CMAP) of the peripheral nerves were not elicited in distal segments, while prolonged distal latencies and decreased CMAP were present in proximal nerves. A mild enlargement of the lateral ventricles showed in brain magnetic resonance imaging studies. Q185X of NDRG1 is a novel mutation with CMT4D, which are demonstrated in Asian population. Q185X of the NDRG1 expands the clinical and mutational spectrum of CMT4D. Title: CXCL5, the upregulated chemokine in patients with uterine cervix cancer, in vivo and in vitro contributes to oncogenic potential of Hela uterine cervix cancer cells Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P and Wang W <7 more author(s)> Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P, Qu Y, Zhang Z, Yang Z, Xiang Y, Zhang W, Wang S, Shao W, Wang W (- 7) Ref: Biomed Pharmacother, 107:1496, 2018 : PubMed ESTHER: Feng_2018_Biomed.Pharmacother_107_1496 PubMedSearch: Feng 2018 Biomed.Pharmacother 107 1496 PubMedID: 30257367 Abstract CXCL5 is showed a surprisingly elevated profile and implicated in tumorigenesis in several tumors. However, the expression and function of CXCL5 in uterine cervix cancer (UCC) remain largely unknown. The current study aimed to elucidate the expression pattern of CXCL5 in human UCC tissues and Hela cervix cancer cell, as well as its functions in Hela cells. Our data showed that CXCL5 and its receptor CXCR2 were expressed by Hela uterine cervix cancer cells. CXCL5 was upregulated in UCC tissues, and its overexpression was positively correlated with age, but did not correlate with clinical stages and tumor infiltration. Exogenous administration of CXCL5 and CXCL5 overexpression contributed to proliferation and migration activities of Hela cells in vitro, consistent with this, CXCL5 overexpression also promoted growth of Hela cells in a nude mouse xenograft model. At the gene level, CXCL5 overexpression regulated the expression of tumor-related genes including ERK, p-ERK, AKT, p-AKT, DIABOL, NUMB, NDRG3 and CXCR2. Taken together, CXCL5 may contribute to a dominant role in UCC progression and sever as a potential molecular therapeutic target for UCC. Title: Enhancement of brain-targeting delivery of danshensu in rat through conjugation with pyrazine moiety to form danshensu-pyrazine ester Hui A, Yin H, Zhang Z, Zhou A, Chen J, Yang L, Wu Z, Zhang W Ref: Drug Deliv Transl Res, 8:787, 2018 : PubMed ESTHER: Hui_2018_Drug.Deliv.Transl.Res_8_787 PubMedSearch: Hui 2018 Drug.Deliv.Transl.Res 8 787 PubMedID: 29524164 Abstract Tetramethylpyrazine was introduced to the structure of danshensu (DSS) as P-glycoprotein (P-gp)-inhibiting carrier, designing some novel brain-targeting DSS-pyrazine derivatives via prodrug delivery strategy. Following the virtual screening, three DSS-pyrazine esters (DT1, DT2, DT3) were selected because of their better prediction parameters related to brain-targeting. Among them, DT3 was thought to be a promising candidate due to its appropriate bioreversible property in vitro release assay. Further investigation with regard to DT3's brain-targeting effects in vivo was also reported in this study. High-performance liquid chromatography-diode array detection (HPLC-DAD) method was established for the quantitative determination of DT3 and DSS in rat plasma, brain homogenate after intravenous injection. In vivo metabolism of DT3 indicated that it was first converted into DT1, DT2, then the generation of DSS, which could be the result of carboxylesterase activity in rat blood and brain tissue. Moreover, the brain pharmacokinetics of DT3 was significantly altered with 2.16 times increase in half-life compared with that of DSS, and its drug targeting index (DTI) was up to 16.95. Above these data demonstrated that DT3 had better tendency of brain-targeting delivery, which would be positive for the treatment of brain-related disorders. Title: A low trans margarine fat analog to beef tallow for healthier formulations: Optimization of enzymatic interesterification using soybean oil and fully hydrogenated palm oil Li Y, Zhao J, Xie X, Zhang Z, Zhang N, Wang Y Ref: Food Chem, 255:405, 2018 : PubMed ESTHER: Li_2018_Food.Chem_255_405 PubMedSearch: Li 2018 Food.Chem 255 405 PubMedID: 29571493 Abstract The health hazard of tallow and partial hydrogenated oils is well known in margarine productions. For this, food manufactures are urged to develop novel alternatives for healthier margarine formulations. The highest interesterification degree acquired with lipase Lipozyme 435 standing out from other catalysts (solid acid, sodium hydroxide and methoxide) was applied to produce low trans margarine fat analogs to beef tallow (BT) with the blend of soybean oil (SO) and fully hydrogenated palm oil (FHPO) in a mass ratio of 4:3. Reaction parameters like enzyme dosage (4.2 wt%), temperature (95 degreeC) and time (245 min) were optimized using the Box-Behnken design. Regarding fatty acid profiles, triacylglycerol species, solid fat content, polymorphism, melting and crystallization behaviors, the resulting interesterified oil was characterized in comparison with BT, FHPO and the SO-FHPO blend so as to prove its potential in formulating low trans fat margarines because of desirable physicochemical properties and polymorphs. Title: Theoretical Study on Zearalenol Compounds Binding with Wild Type Zearalenone Hydrolase and V153H Mutant Liu Y, Wan Y, Zhu J, Yu Z, Tian X, Han J, Zhang Z, Han W Ref: Int J Mol Sci, 19:, 2018 : PubMed ESTHER: Liu_2018_Int.J.Mol.Sci_19_ PubMedSearch: Liu 2018 Int.J.Mol.Sci 19 PubMedID: 30231501 Gene_locus related to this paper: biooc-ZHD101 Abstract Zearalenone hydrolase (ZHD) is the only reported alpha/beta-hydrolase that can detoxify zearalenone (ZEN). ZHD has demonstrated its potential as a treatment for ZEN contamination that will not result in damage to cereal crops. Recent researches have shown that the V153H mutant ZHD increased the specific activity against alpha-ZOL, but decreased its specific activity to beta-ZOL. To understand whyV153H mutation showed catalytic specificity for alpha-ZOL, four molecular dynamics simulations combining with protein network analysis for wild type ZHD alpha-ZOL, ZHD beta-ZOL, V153H alpha-ZOL, and V153H beta-ZOL complexes were performed using Gromacs software. Our theoretical results indicated that the V153H mutant could cause a conformational switch at the cap domain (residues Gly161(-)Thr190) to affect the relative position catalytic residue (H242). Protein network analysis illustrated that the V153H mutation enhanced the communication with the whole protein and residues with high betweenness in the four complexes, which were primarily assembled in the cap domain and residues Met241 to Tyr245 regions. In addition, the existence of alpha-ZOL binding to V153H mutation enlarged the distance from the OAE atom in alpha-ZOL to the NE2 atom in His242, which prompted the side chain of H242 to the position with catalytic activity, thereby increasing the activity of V153H on the alpha-ZOL. Furthermore, alpha-ZOL could easily form a right attack angle and attack distance in the ZHD and alpha-ZOL complex to guarantee catalytic reaction. The alanine scanning results indicated that modifications of the residues in the cap domain produced significant changes in the binding affinity for alpha-ZOL and beta-ZOL. Our results may provide useful theoretical evidence for the mechanism underlying the catalytic specificity of ZHD. Title: Genome-Wide Identification and Expression Analysis of Cutinase Gene Family in Rhizoctonia cerealis and Functional Study of an Active Cutinase RcCUT1 in the Fungal-Wheat Interaction Lu L, Rong W, Massart S, Zhang Z Ref: Front Microbiol, 9:1813, 2018 : PubMed ESTHER: Lu_2018_Front.Microbiol_9_1813 PubMedSearch: Lu 2018 Front.Microbiol 9 1813 PubMedID: 30131789 Abstract Wheat (Triticum aestivum L.) is a staple food of more than 50% of global population. Rhizoctonia cerealis is the causal agent of sharp eyespot, a devastating disease of cereal crops including wheat. Cutinases produced by fungal pathogens play important roles in host-pathogen compatible interactions, but little is known about cutinases in R. cerealis. In this study, we identified a total of six cutinase encoding genes from R. cerealis genome, designated as RcCUT1-RcCUT6, analyzed their expression patterns during the infection, and determined virulence role for RcCUT1. All the proteins, RcCUT1-RcCUT6, contain a highly conserved GYSKG motif and another conserved C-x(3)-D-x(2)-C-x(2)-[GS]-[GSD]-x(4)-[AP]-H motif in the carbohydrate esterase 5 domain. The RcCUT1, RcCUT2, RcCUT4, and RcCUT5 are predicted to be secreted proteins containing four cysteine residues. These six cutinase genes had different expression patterns during the fungal infection process to wheat, among which RcCUT1 was highly expressed across all the infection time points but RcCUT6 was not expressed at all and the others were expressed only at certain time points. Further, RcCUT1 was heterologously expressed in Escherichia coli to obtain a purified protein. The purified RcCUT1 was shown to possess the cutinase activity and be able to induce necrosis, H2O2 accumulation, and expression of defense-related genes when infiltrated into wheat and Nicotiana benthamiana leaves. In contrast, RcCUT1 protein with serine mutation at the first motif had no cutinase activity, consequently lost the ability to induce necrosis. Noticeably, application of the purified RcCUT1 with R. cerealis led to significantly higher levels of the disease in wheat leaves than application of the fungus alone. These results strongly suggest that RcCUT1 serves as a virulence factor for the fungus. This is the first investigation of the cutinase genes in R. cerealis and the findings provide an important insight into pathogenesis mechanisms of R. cerealis on wheat. Title: Draft genome sequence of Camellia sinensis var. sinensis provides insights into the evolution of the tea genome and tea quality Wei C, Yang H, Wang S, Zhao J, Liu C, Gao L, Xia E, Lu Y, Tai Y and Wan X <33 more author(s)> Wei C, Yang H, Wang S, Zhao J, Liu C, Gao L, Xia E, Lu Y, Tai Y, She G, Sun J, Cao H, Tong W, Gao Q, Li Y, Deng W, Jiang X, Wang W, Chen Q, Zhang S, Li H, Wu J, Wang P, Li P, Shi C, Zheng F, Jian J, Huang B, Shan D, Shi M, Fang C, Yue Y, Li F, Li D, Wei S, Han B, Jiang C, Yin Y, Xia T, Zhang Z, Bennetzen JL, Zhao S, Wan X (- 33) Ref: Proc Natl Acad Sci U S A, 115:E4151, 2018 : PubMed ESTHER: Wei_2018_Proc.Natl.Acad.Sci.U.S.A_115_E4151 PubMedSearch: Wei 2018 Proc.Natl.Acad.Sci.U.S.A 115 E4151 PubMedID: 29678829 Gene_locus related to this paper: camsi-a0a4s4dr18, camsi-a0a4s4etg9, camsi-a0a4s4e3j5, camsi-a0a4s4d2s5, camsi-a0a4s4duc4, camsi-a0a4v3wr80, camsi-a0a4v3wpu4 Abstract Tea, one of the world's most important beverage crops, provides numerous secondary metabolites that account for its rich taste and health benefits. Here we present a high-quality sequence of the genome of tea, Camellia sinensis var. sinensis (CSS), using both Illumina and PacBio sequencing technologies. At least 64% of the 3.1-Gb genome assembly consists of repetitive sequences, and the rest yields 33,932 high-confidence predictions of encoded proteins. Divergence between two major lineages, CSS and Camellia sinensis var. assamica (CSA), is calculated to approximately 0.38 to 1.54 million years ago (Mya). Analysis of genic collinearity reveals that the tea genome is the product of two rounds of whole-genome duplications (WGDs) that occurred approximately 30 to 40 and approximately 90 to 100 Mya. We provide evidence that these WGD events, and subsequent paralogous duplications, had major impacts on the copy numbers of secondary metabolite genes, particularly genes critical to producing three key quality compounds: catechins, theanine, and caffeine. Analyses of transcriptome and phytochemistry data show that amplification and transcriptional divergence of genes encoding a large acyltransferase family and leucoanthocyanidin reductases are associated with the characteristic young leaf accumulation of monomeric galloylated catechins in tea, while functional divergence of a single member of the glutamine synthetase gene family yielded theanine synthetase. This genome sequence will facilitate understanding of tea genome evolution and tea metabolite pathways, and will promote germplasm utilization for breeding improved tea varieties. Title: Cholinesterase inhibitors for the treatment of delirium in non-ICU settings Yu A, Wu S, Zhang Z, Dening T, Zhao S, Pinner G, Xia J, Yang D Ref: Cochrane Database Syst Rev, 6:CD012494, 2018 : PubMed ESTHER: Yu_2018_Cochrane.Database.Syst.Rev_6_CD012494 PubMedSearch: Yu 2018 Cochrane.Database.Syst.Rev 6 CD012494 PubMedID: 29952000 Abstract BACKGROUND: Delirium is a common clinical syndrome defined as alterations in attention with an additional disturbance in cognition or perception, which develop over a short period of time and tend to fluctuate during the course of the episode. Delirium is commonly treated in hospitals or community settings and is often associated with multiple adverse outcomes such as increased cost, morbidity, and even mortality. The first-line intervention involves a multicomponent non-pharmacological approach that includes ensuring effective communication and reorientation in addition to providing reassurance or a suitable care environment. There are currently no drugs approved specifically for the treatment of delirium. Clinically, however, various medications are employed to provide symptomatic relief, such as antipsychotic medications and cholinesterase inhibitors, among others. OBJECTIVES: To evaluate the effectiveness and safety of cholinesterase inhibitors for treating people with established delirium in a non-intensive care unit (ICU) setting. SEARCH METHODS: We searched ALOIS, which is the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, on 26 October 2017. We also cross-checked the reference lists of included studies to identify any potentially eligible trials. SELECTION CRITERIA: We included randomised controlled trials, published or unpublished, reported in English or Chinese, which compared cholinesterase inhibitors to placebo or other drugs intended to treat people with established delirium in a non-ICU setting. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were duration of delirium, severity of delirium, and adverse events. The secondary outcomes were use of rescue medications, persistent cognitive impairment, length of hospitalisation, institutionalisation, mortality, cost of intervention, leaving the study early, and quality of life. For dichotomous outcomes, we calculated the risk ratio (RR) with 95% confidence intervals (CIs); for continuous outcomes we calculated the mean difference (MD) with 95% CIs. We assessed the quality of evidence using GRADE to generate a 'Summary of findings' table. MAIN RESULTS: We included one study involving 15 participants from the UK. The included participants were diagnosed with delirium based on the Confusion Assessment Method (CAM) criteria. Eight males and seven females were included, with a mean age of 82.5 years. Seven of the 15 participants had comorbid dementia at baseline. The risk of bias was low in all domains.The study compared rivastigmine with placebo. We did not find any clear differences between the two groups in terms of duration of delirium (MD -3.6, 95% CI -15.6 to 8.4), adverse events (nausea, RR 0.30, 95% CI 0.01 to 6.29), use of rescue medications (RR 0.13, 95% CI 0.01 to 2.1), mortality (RR 0.10, 95% CI 0.01 to 1.56), and leaving the study early (RR 0.88, 95% CI 0.07 to 11.54). Evidence was not available regarding the severity of delirium, persistent cognitive impairment, length of hospitalisation, cost of intervention, or other predefined secondary outcomes.The quality of evidence is low due to the very small sample size. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of cholinesterase inhibitors for the treatment of delirium in non-ICU settings. No clear benefits or harms associated with cholinesterase inhibitors were observed when compared with placebo due to the lack of data. More trials are required. Title: Neurotrophins and cholinergic enzyme regulated by calpain-2: New insights into neuronal apoptosis induced by polybrominated diphenyl ether-153 Zhang H, Yang X, Li X, Zhang Z, Hou L, Wang Z, Niu Q, Wang T Ref: Toxicol Lett, 291:29, 2018 : PubMed ESTHER: Zhang_2018_Toxicol.Lett_291_29 PubMedSearch: Zhang 2018 Toxicol.Lett 291 29 PubMedID: 29621559 Abstract Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons. Neurotrophins and cholinergic enzymes play critical roles in the neuronal survival, maintenance, synaptic plasticity and learning memory, however, their roles in neuronal apoptosis following the BDE-153 treatment remain unclear. In this study, we firstly explored the possible predominant pathway underlying the neuronal apoptotic induced by the BDE-153 treatment in rat cerebral cortex, by measuring expression levels (mRNA and protein) of p53, caspase-3, 8, 9, calpain-1, and calpain-2, detected the levels (protein contents and mRNA) of neurotrophins including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), and measured acetylcholinesterase (AchE) and choline acetyltransferase (ChaT) activities in rat cerebral cortex and primary neurons following BDE-153 treatment with or without pretreatment with inhibitors. Results showed that the neuronal apoptosis induced by BDE-153 was dependent on p53, and dependent on more calpain-2 than caspase-3 in the cerebral cortex of rats. Following the BDE-153 treatment, the protein contents and mRNA levels of BDNF, GDNF, NGF, NT-3, and NT-4, as well as the AchE and ChaT activities were significantly decreased in the cerebral cortex and primary neurons when compared to the untreated group. When pretreated primary neurons with calpain inhibitor PD150606 or cyclin-dependent kinase (cdk5, the downstream complex of calpain) inhibitor Roscovitine, the neurotrophins contents and activities of ChaT and AchE were reverted, along with the improvement of neuron survival compared with BDE-153 treatment alone. We conclude that neurotrophins and cholinergic enzymes were regulated by the calpain-2 activation and its downstream cdk5 pathway, and which was involved in the neuronal apoptosis induced by the BDE-153 treatment. Title: Association between the PON1 Q192R polymorphism and coronary heart disease in Chinese: A meta-analysis Zhang Z, Ou J, Cai P, Niu B, Li J Ref: Medicine (Baltimore), 97:e11151, 2018 : PubMed ESTHER: Zhang_2018_Medicine.(Baltimore)_97_e11151 PubMedSearch: Zhang 2018 Medicine.(Baltimore) 97 e11151 PubMedID: 29952962 Abstract BACKGROUND: The relation has not been reported consistently between the PON1 Q192R polymorphism and coronary heart disease (CHD). To clarify the discrepancy, we performed the present meta-analysis to evaluate the association between the PON1 gene Q192R polymorphism and CHD risk in Chinese population. METHODS: We conducted a comprehensive search of the PubMed, EMBASE, and China National Knowledge Infrastructure databases for all available case-control studies. Two reviewers independently selected studies. Data were analyzed by STATA software package v 12.0. RESULTS: Thirteen studies investigating the association between the PON1 Q192R polymorphism and risk of CHD were selected in this meta-analysis with 4353 cases and 4882 controls. The association between the PON1 Q192R polymorphism and CHD is statistically significant under the recessive genetic model (R/R vs Q/R + Q/Q, odds ratio [OR] = 1.111, 95% confidence interval [CI] = 1.017-1.214). We observed no statistical association between PON1 Q192R polymorphism and risk of CHD under allele model (R vs Q, OR = 1.087, 95% CI = 0.976-1.209), homozygous model (RR vs QQ, OR = 1.192, 95% CI = 0.949-1.496), and dominant genetic model (Q/R + R/R vs Q/Q, OR = 1.127, 95% CI = 0.938-1.354). CONCLUSION: This meta-analysis suggests that the PON1 Q192R polymorphism has a weak association with CHD risk in Chinese. Title: Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits Zhang X, Zhang Z, Yang Y, Suo Y, Liu R, Qiu J, Zhao Y, Jiang N, Liu C and Liu T <2 more author(s)> Zhang X, Zhang Z, Yang Y, Suo Y, Liu R, Qiu J, Zhao Y, Jiang N, Liu C, Tse G, Li G, Liu T (- 2) Ref: Cardiovasc Diabetol, 17:160, 2018 : PubMed ESTHER: Zhang_2018_Cardiovasc.Diabetol_17_160 PubMedSearch: Zhang 2018 Cardiovasc.Diabetol 17 160 PubMedID: 30591063 Inhibitor(s) related to this paper: Alogliptin Abstract BACKGROUND: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. METHODS: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-beta1, NF-kappaB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. RESULTS: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1alpha/NRF1/Tfam signaling pathway. CONCLUSIONS: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis. Title: Sublethal effects of chlorfenapyr on the life table parameters, nutritional physiology and enzymatic properties of Bradysia odoriphaga (Diptera: Sciaridae) Zhao Y, Wang Q, Ding J, Wang Y, Zhang Z, Liu F, Mu W Ref: Pestic Biochem Physiol, 148:93, 2018 : PubMed ESTHER: Zhao_2018_Pestic.Biochem.Physiol_148_93 PubMedSearch: Zhao 2018 Pestic.Biochem.Physiol 148 93 PubMedID: 29891384 Abstract Bradysia odoriphaga (Diptera: Sciaridae) is the major pest affecting Chinese chive production. Chlorfenapyr is a halogenated pyrrole-based pro-insecticide that is currently used to control insects and mites on a variety of crops. In the present study, fourth-instar larvae of B. odoriphaga were exposed to chlorfenapyr at LC1, LC20 and LC50 concentrations. The developmental duration of the treated larvae was not significantly different, but fecundity was significantly increased in the LC1 and LC20 treatment groups compared with the control group. The population parameters of the LC1 treatment group were increased significantly, whereas those of the LC50 treatment group were reduced significantly compared with the control. The food consumption by larvae and pupal weight were significantly increased under the LC1 treatment and decreased under the LC50 treatment compared with the control. Moreover, chlorfenapyr decreased the lipid, carbohydrate and trehalose contents significantly, whereas the total protein content was increased compared with the control. Additionally, the activities of protease, lipase and trehalase were significantly decreased. Chlorfenapyr treatment for 24h also induced the activities of glutathione S-transferase (GST), carboxylesterase (CarE) and O-demethylation. The results of this study suggest that low lethal concentrations of chlorfenapyr can affect oviposition, population development, the activities of digestion and detoxification enzymes, and nutrient accumulation in B. odoriphaga. This study provides valuable information for the assessment and rational application of chlorfenapyr for effective control of this pest. Title: Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells Fu G, Dai J, Zhang D, Zhu L, Tang X, Zhang L, Zhou T, Duan P, Quan C and Shi Y <2 more author(s)> Fu G, Dai J, Zhang D, Zhu L, Tang X, Zhang L, Zhou T, Duan P, Quan C, Zhang Z, Song S, Shi Y (- 2) Ref: Environ Toxicol, 32:1055, 2017 : PubMed ESTHER: Fu_2017_Environ.Toxicol_32_1055 PubMedSearch: Fu 2017 Environ.Toxicol 32 1055 PubMedID: 27416487 Abstract Di(2-ethylhexyl) phthalate (DEHP), a plasticizer of synthetic polymers, is a well-known endocrine disrupting chemical (EDC) and reproductive toxicant. Addressing the unclear mechanism of DEHP-induced reproductive dysfunction, this study used GC-2spd cells to investigate the molecular mechanism involved in the DEHP-induced toxicity in the male reproductive system. The results indicated that the apoptotic cell death was significantly induced by DEHP exposure over 100 muM. Furthermore, DEHP treatment could induce oxidative stress in GC-2spd cells involving in the decrease of superoxide dismutase (SOD) activity (200 muM) and glutathione peroxidase (GSH-Px) activity (50 and 100 muM). In addition, DEHP induction also caused the elevated ratios of Bax/Bcl-2, release of cytochrome c and decomposition of procaspase-3 and procaspase-9 in GC-2spd cells. Taken together, our work provided the evidence that DEHP exposure might induce apoptosis of GC-2spd cells via mitochondria pathway mediated by oxidative stress. Title: Biology, physiology and gene expression of grasshopper Oedaleus asiaticus exposed to diet stress from plant secondary compounds Huang X, Ma J, Qin X, Tu X, Cao G, Wang G, Nong X, Zhang Z Ref: Sci Rep, 7:8655, 2017 : PubMed ESTHER: Huang_2017_Sci.Rep_7_8655 PubMedSearch: Huang 2017 Sci.Rep 7 8655 PubMedID: 28819233 Abstract We studied the role of plant primary and secondary metabolites in mediating plant-insect interactions by conducting a no-choice single-plant species field experiment to compare the suitability, enzyme activities, and gene expression of Oedaleus asiaticus grasshoppers feeding on four host and non-host plants with different chemical traits. O. asiaticus growth showed a positive relationship to food nutrition content and a negative relationship to secondary compounds content. Grasshopper amylase, chymotrypsin, and lipase activities were positively related to food starch, crude protein, and lipid content, respectively. Activity of cytochrome P450s, glutathione-S-transferase, and carboxylesterase were positively related to levels of secondary plant compounds. Gene expression of UDP-glucuronosyltransferase 2C1, cytochrome P450 6K1 were also positively related to secondary compounds content in the diet. Grasshoppers feeding on Artemisia frigida, a species with low nutrient content and a high level of secondary compounds, had reduced growth and digestive enzyme activity. They also had higher detoxification enzyme activity and gene expression compared to grasshoppers feeding on the grasses Cleistogenes squarrosa, Leymus chinensis, or Stipa krylovii. These results illustrated Oedaleus asiaticus adaptive responses to diet stress resulting from toxic chemicals, and support the hypothesis that nutritious food benefits insect growth, but plant secondary compounds are detrimental for insect growth. Title: Neuroprotective Effects and Mechanisms of Action of Multifunctional Agents Targeting Free Radicals, Monoamine Oxidase B and Cholinesterase in Parkinson's Disease Model Liu Z, Cai W, Lang M, Yan R, Li Z, Zhang G, Yu P, Wang Y, Sun Y, Zhang Z Ref: Journal of Molecular Neuroscience, 61:498, 2017 : PubMed ESTHER: Liu_2017_J.Mol.Neurosci_61_498 PubMedSearch: Liu 2017 J.Mol.Neurosci 61 498 PubMedID: 28144826 Abstract Parkinson's disease (PD) is a complex neurodegenerative disorder with multifactorial pathologies, including progressive loss of dopaminergic (DA) neurons, oxidative stress, mitochondrial dysfunction, and increased monoamine oxidase (MAO) enzyme activity. There are currently only a few agents approved to ameliorate the symptoms of PD; however, no agent is able to reverse the progression of the disease. Due to the multifactorial pathologies, it is necessary to develop multifunctional agents that can affect more than one target involved in the disease pathology. We have designed and synthesized a series of new multifunctional anti-Parkinson's compounds which can protect cerebral granular neurons from 1-methyl-4-phenylpyridinium (MPP+) insult, scavenge free radicals, and inhibit monoamine oxidase (MAO)/cholinesterase (ChE) activities. Among them, MT-20R exhibited the most potent MAO-B inhibition both in vitro and in vivo. We further investigated the neuroprotective effects of MT-20R using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. In vivo, MT-20R alleviated MPTP-induced motor deficits, raised the striatal contents of dopamine and its metabolites, and restored the expression of tyrosine hydroxylase (TH) and the number of TH-positive DA neurons in the substantia nigra. Additionally, MT-20R enhanced the expression of Bcl-2, decreased the expression of Bax and Caspase 3, and activated the AKT/Nrf2/HO-1 signaling pathway. These findings suggest that MT-20R may be a novel therapeutic candidate for treatment of PD. Title: The Genome of Medicinal Plant Macleaya cordata Provides New Insights into Benzylisoquinoline Alkaloids Metabolism Liu X, Liu Y, Huang P, Ma Y, Qing Z, Tang Q, Cao H, Cheng P, Zheng Y and Zeng J <19 more author(s)> Liu X, Liu Y, Huang P, Ma Y, Qing Z, Tang Q, Cao H, Cheng P, Zheng Y, Yuan Z, Zhou Y, Liu J, Tang Z, Zhuo Y, Zhang Y, Yu L, Huang J, Yang P, Peng Q, Zhang J, Jiang W, Zhang Z, Lin K, Ro DK, Chen X, Xiong X, Shang Y, Huang S, Zeng J (- 19) Ref: Mol Plant, 10:975, 2017 : PubMed ESTHER: Liu_2017_Mol.Plant_10_975 PubMedSearch: Liu 2017 Mol.Plant 10 975 PubMedID: 28552780 Gene_locus related to this paper: 9magn-a0a200rdw7, 9magn-a0a200qd12, 9magn-a0a200pqd0, 9magn-a0a200q3h1, 9magn-a0a200r223, 9magn-a0a200qv20 Abstract The overuse of antibiotics in animal agriculture and medicine has caused a series of potential threats to public health. Macleaya cordata is a medicinal plant species from the Papaveraceae family, providing a safe resource for the manufacture of antimicrobial feed additive for livestock. The active constituents from M. cordata are known to include benzylisoquinoline alkaloids (BIAs) such as sanguinarine (SAN) and chelerythrine (CHE), but their metabolic pathways have yet to be studied in this non-model plant. The active biosynthesis of SAN and CHE in M. cordata was first examined and confirmed by feeding (13)C-labeled tyrosine. To gain further insights, we de novo sequenced the whole genome of M. cordata, the first to be sequenced from the Papaveraceae family. The M. cordata genome covering 378 Mb encodes 22,328 predicted protein-coding genes with 43.5% being transposable elements. As a member of basal eudicot, M. cordata genome lacks the paleohexaploidy event that occurred in almost all eudicots. From the genomics data, a complete set of 16 metabolic genes for SAN and CHE biosynthesis was retrieved, and 14 of their biochemical activities were validated. These genomics and metabolic data show the conserved BIA metabolic pathways in M. cordata and provide the knowledge foundation for future productions of SAN and CHE by crop improvement or microbial pathway reconstruction. Title: Expression of family with sequence similarity 172 member A and nucleotide-binding protein 1 is associated with the poor prognosis of colorectal carcinoma Liu W, Wang S, Qian K, Zhang J, Zhang Z, Liu H Ref: Oncol Lett, 14:3587, 2017 : PubMed ESTHER: Liu_2017_Oncol.Lett_14_3587 PubMedSearch: Liu 2017 Oncol.Lett 14 3587 PubMedID: 28927116 Abstract In our previous studies, a functionally unknown gene, family with sequence similarity 172, member A (FAM172A), was identified. High levels of FAM172A suppressed the cell cycle process, arresting HepG2 cells in G1/S and inhibiting cell proliferation. The present study aimed to confirm the expression levels of FAM172A and nucleotide-binding protein 1 (NUBP1) in colorectal cancer (CRC) tissues and normal colorectal tissues. The impact of FAM172A and NUBP1 on the prognosis of patients with CRC was also analyzed. Immunohistochemical staining for FAM172A and NUBP1 was performed on 180 cancerous tissues and 60 normal paraffin-embedded tissues from patients with CRC. In total, 85 and 83% of 180 patients revealed positive expression of FAM172A and NUBP1, respectively. FAM172A expression level was associated with Tumor-Node-Metastasis (TNM) staging (P<0.001), the levels of serum carcinoembryonic antigen (CEA; P=0.023) and carbohydrate antigen 19-9 (CA19-9; P=0.016), lymph node involvement (P=0.004), tissue type (P=0.016), Dukes' staging (P<0.001) and NUBP1 (P=0.026). Furthermore, the expression level of NUBP1 was also markedly associated with the levels of serum CEA (P=0.006) and CA19-9 (P=0.001), TNM staging (P<0.001), lymph node involvement (P=0.005), histological typing (P=0.024) and Dukes' stage (P<0.001). Results of the univariate analysis demonstrated that there was a negative correlation between the expression level of FAM172A and overall survival (OS) and relapse-free survival (RFS) (P=0.013 and P=0.012, respectively), and there was also a negative correlation between NUBP1 expression level and OS and RFS (P<0.001 and P<0.001, respectively). With regards to OS and RFS, multivariate analysis revealed that expression levels of FAM172A and NUBP1 and tumor stage may be independent prognostic factors Thus, the present study suggested that FAM172A and NUBP1 may be prognostic makers for CRC. Title: Characterization and functional analysis of a carboxylesterase gene associated with chlorpyrifos resistance in Nilaparvata lugens (Stal) Lu K, Wang Y, Chen X, Zhang Z, Li Y, Li W, Zhou Q Ref: Comparative Biochemistry & Physiology C Toxicol Pharmacol, 203:12, 2017 : PubMed ESTHER: Lu_2017_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_203_12 PubMedSearch: Lu 2017 Comp.Biochem.Physiol.C.Toxicol.Pharmacol 203 12 PubMedID: 29054582 Gene_locus related to this paper: nillu-NlCarE Inhibitor(s) related to this paper: TPHP Abstract The widespread and extensive application of insecticides have promoted the development of resistance in the brown planthopper Nilaparvata lugens (Stal), one of the most important rice pests in Asia. To better understand the underlying molecular mechanisms of metabolic resistance to insecticides, a chlorpyrifos-resistant (CR) strain of N. lugens was selected and its possible resistance mechanism was investigated. Synergistic tests using carboxylesterases (CarEs) inhibitor triphenyl phosphate (TPP) decreased the resistance of N. lugens to chlorpyrifos, and CarE activities could be induced by low concentrations of chlorpyrifos. Subsequently, a gene putatively encoding CarE, namely NlCarE, predominant in the midgut and ovary was isolated and characterized. The expression levels of NlCarE were detected and compared between the CR and a susceptible (SS) strain of N. lugens. Consistent with the increased CarE activity, this gene was overexpressed in the CR strain compared to the SS strain. The transcript levels of NlCarE were up-regulated by chlorpyrifos exposure, showing dose- and time-dependent expression patterns. Furthermore, RNA interference (RNAi)-mediated knockdown of NlCarE followed by insecticide application significantly increased the susceptibility of N. lugens to chlorpyrifos. These results demonstrate that NlCarE plays an important role in chlorpyrifos detoxification and its overexpression may be involved in chlorpyrifos resistance in N. lugens. Title: Granularity and Laxative Effect of Ultrafine Powder of Dendrobium officinale Luo D, Qu C, Zhang Z, Xie J, Xu L, Yang H, Li C, Lin G, Wang H, Su Z Ref: J Med Food, 20:180, 2017 : PubMed ESTHER: Luo_2017_J.Med.Food_20_180 PubMedSearch: Luo 2017 J.Med.Food 20 180 PubMedID: 28146409 Abstract Constipation is a common disorder that is a significant source of morbidity among people around the world ranging from 2% to 28%. Dendrobium officinale Kimura et Migo is a traditional herbal medicine and health food used for tonicity of the stomach and promotion of body fluid production in China. This study aimed to prepare the ultrafine powder of Dendrobium officinale (UDO) and investigate its laxative effect and potential mechanism in mice with diphenoxylate-induced constipation. Results indicated that the mean diameter (d50) of UDO obtained by ball milling was 6.56 mum. UDO (62.5, 125, and 250 mg/kg, p.o.) could significantly enhance the gastrointestinal transit ratio and promote fecal output. Moreover, UDO treatment resulted in significant increases in the serum levels of acetylcholinesterase (AChE), gastrin (Gas), motilin (MTL), and substance P (SP), and obviously decreased serum contents of somatostatin (SS). Taken together, UDO, which can be easily obtained through milling to a satisfactory particle size, exhibited obvious laxative effect in diphenoxylate-induced constipated mice, and the mechanism might be associated with elevated levels of AChE, Gas, MTL, SP, and reduced production of SS. UDO has the potential for further development into an alternative effective diet therapy for constipation. Title: What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis Qiu C, Zeng P, Li X, Zhang Z, Pan B, Peng ZYF, Li Y, Ma Y, Leng Y, Chen R Ref: Lipids Health Dis, 16:111, 2017 : PubMed ESTHER: Qiu_2017_Lipids.Health.Dis_16_111 PubMedSearch: Qiu 2017 Lipids.Health.Dis 16 111 PubMedID: 28606094 Abstract BACKGROUND: PCSK9 rs505151 and rs11591147 polymorphisms are identified as gain- and loss-of-function mutations, respectively. The effects of these polymorphisms on serum lipid levels and cardiovascular risk remain to be elucidated. Title: Hepatotoxicity induced by radix Sophorae tonkinensis in mice and increased serum cholinesterase as a potential supplemental biomarker for liver injury Wang L, Lu J, Sun W, Gu Y, Zhang C, Jin R, Li L, Zhang Z, Tian X Ref: Exp Toxicol Pathol, 69:193, 2017 : PubMed ESTHER: Wang_2017_Exp.Toxicol.Pathol_69_193 PubMedSearch: Wang 2017 Exp.Toxicol.Pathol 69 193 PubMedID: 28126209 Abstract Radix Sophorae tonkinensis (S. tonkinensis) is used in Chinese folk medicine to treat sore throats, viral hepatitis, and jaundice. However, little is known about the hepatotoxicity induced by it. This study is to investigate hepatotoxicity induced by radix S. tonkinensis and a potential supplemental biomarker for liver injury through acute toxicity, accumulative toxicity, tolerance test, and sub-chronic toxicity. The contents of cytisine (CYT), matrine (MT), and oxymatrine (OMT) in radix S. tonkinensis extracts were determined simultaneously by the method we developed. In the acute toxicity study, mice were scheduled for single oral gavage at doses of 0, 2.4, 3.2, 4.2, 5.6, 7.5g/kg of radix S. tonkinensis extracts respectively. Another three groups of mice received radix S. tonkinensis extracts orally in single doses of 0, 4.3, 5.6g/kg, while the two groups of the hepatic injury model were induced by intraperitoneal injection with 0.1% and 0.2% carbon tetrachloride (CCl4). Mortality rate, analysis of serum biochemistry, and histopathological examination were used to assess the acute toxicity. In the accumulative toxicity study, mice were treated radix S. tonkinensis extracts orally by the method of dose escalation for 20days respectively. Accumulative toxicity was assessed by mortality rate. In the tolerance test, half of the mice of test group in the accumulative toxicity were administered the dose of 4.3g/kg radix S. tonkinensis extracts, and the rest of the mice in the test group were assigned to receive the dose of 5.6g/kg radix S. tonkinensis extracts. In the sub-chronic toxicity study, mice were treated with daily doses of 0, 0.25, 1.0, 2.5g/kg radix S. tonkinensis extracts for 90days. Assessments of body weights, serum biochemical analysis, and histopathological examination were performed. An enzyme-inhibition assay for butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) of CYT, MT, and OMT was also carried out. The contents of CYT, MT, and OMT in radix S. tonkinensis extracts were 5.63mg/g, 27.63mg/g, and 16.20mg/g respectively. In the acute toxicity study, LD50 of radix S. tonkinensis extracts was 4.3g/kg. No mice were found dead in the accumulative toxicity study. In the acute toxicity and tolerance test, increased ALT, AST, and CHE levels were observed in a dose-response manner, while the severity of histological changes in liver was shown in a dose-dependent mode. In the sub-chronic toxicity, though there was a decline trend of ALT and AST levels found in 0.25g/kg, 1.0g/kg, and 2.5g/kg radix S. tonkinensis extracts as compared to control, which might be related to weight loss, the severity of histopathological changes in the liver and the increased serum CHE level was shown in a dose-response manner. MT, OMT, and CYT showed inhibitory effects on BuChE and AChE in the enzyme-inhibition assay. The results of this study indicate that radix S. tonkinensis should have hepatotoxicity, and increased serum CHE is a potential supplemental biomarker for liver injury. Title: Scallop genome provides insights into evolution of bilaterian karyotype and development Wang S, Zhang J, Jiao W, Li J, Xun X, Sun Y, Guo X, Huan P, Dong B and Bao Z <42 more author(s)> Wang S, Zhang J, Jiao W, Li J, Xun X, Sun Y, Guo X, Huan P, Dong B, Zhang L, Hu X, Sun X, Wang J, Zhao C, Wang Y, Wang D, Huang X, Wang R, Lv J, Li Y, Zhang Z, Liu B, Lu W, Hui Y, Liang J, Zhou Z, Hou R, Li X, Liu Y, Li H, Ning X, Lin Y, Zhao L, Xing Q, Dou J, Mao J, Guo H, Dou H, Li T, Mu C, Jiang W, Fu Q, Fu X, Miao Y, Liu J, Yu Q, Li R, Liao H, Kong Y, Jiang Z, Chourrout D, Bao Z (- 42) Ref: Nat Ecol Evol, 1:120, 2017 : PubMed ESTHER: Wang_2017_Nat.Ecol.Evol_1_120 PubMedSearch: Wang 2017 Nat.Ecol.Evol 1 120 PubMedID: 28812685 Gene_locus related to this paper: mizye-a0a210qls6, mizye-a0a210qis3, mizye-a0a210qg00, mizye-a0a210ped6, mizye-a0a210q4h5, mizye-a0a210q4h9, mizye-a0a210q4j1, mizye-a0a210qf86, mizye-a0a210q332, mizye-a0a210pqn0, mizye-a0a210q7t5, mizye-a0a210pij5, mizye-a0a210qyk8, mizye-a0a210pwl7, mizye-a0a210q8u5, mizye-a0a210r5n9, mizye-a0a210qbv2, mizye-a0a210pu25, mizye-a0a210pek1, mizye-a0a210pul3, mizye-a0a210pum3, mizye-a0a210ptr6, mizye-a0a210ptq5, mizye-a0a210ptc4.1, mizye-a0a210ptc4.2, mizye-a0a210ptv1, mizye-a0a210ptv7, mizye-a0a210qgl6, mizye-a0a210qg90, mizye-a0a210ptq0, mizye-a0a210qg72, mizye-a0a210ptb1, mizye-a0a210pjd3, mizye-a0a210qg92, mizye-a0a210q8v2, mizye-a0a210qg93, mizye-a0a210q160.1, mizye-a0a210q160.2, mizye-a0a210qes4, mizye-a0a210pk25, mizye-a0a210q1b8, mizye-a0a210q110, mizye-a0a210r503, mizye-P021348901.1, mizye-P021348901.2 Abstract Reconstructing the genomes of bilaterian ancestors is central to our understanding of animal evolution, where knowledge from ancient and/or slow-evolving bilaterian lineages is critical. Here we report a high-quality, chromosome-anchored reference genome for the scallop Patinopecten yessoensis, a bivalve mollusc that has a slow-evolving genome with many ancestral features. Chromosome-based macrosynteny analysis reveals a striking correspondence between the 19 scallop chromosomes and the 17 presumed ancestral bilaterian linkage groups at a level of conservation previously unseen, suggesting that the scallop may have a karyotype close to that of the bilaterian ancestor. Scallop Hox gene expression follows a new mode of subcluster temporal co-linearity that is possibly ancestral and may provide great potential in supporting diverse bilaterian body plans. Transcriptome analysis of scallop mantle eyes finds unexpected diversity in phototransduction cascades and a potentially ancient Pax2/5/8-dependent pathway for noncephalic eyes. The outstanding preservation of ancestral karyotype and developmental control makes the scallop genome a valuable resource for understanding early bilaterian evolution and biology. Title: A comparative study on kinetics and substrate specificities of Phospholipase A1 with Thermomyces lanuginosus lipase Xin R, Khan FI, Zhao Z, Zhang Z, Yang B, Wang Y Ref: J Colloid Interface Sci, 488:149, 2017 : PubMed ESTHER: Xin_2017_J.Colloid.Interface.Sci_488_149 PubMedSearch: Xin 2017 J.Colloid.Interface.Sci 488 149 PubMedID: 27821336 Abstract The mechanism of lipase binding to the lipid-water interface is crucial for substrate specificity and kinetic properties. In this study, the chain-length specificity, regiospecificity and substrate specificity of Phospholipase A1 (PLA1) and its parent enzyme Thermomyces lanuginosus lipase (TLL) have been investigated using a classical emulsion system. The results show that both PLA1 and TLL are 1,3-regioselective lipases. Additionally, the hydrolytic activity of PLA1 is comparatively lower on short-chain triacylglyceride (TAG) and higher on phosphatidylcholine (PC) than the hydrolytic activity of TLL. Further, the results obtained with monolayer film techniques demonstrate that the C-terminal region regulates the binding of PLA1 to PC. A hypothesis is presented according to which the alpha9 helix of C-terminal region in PLA1 not only controls the opening of lid but also serves as a membrane anchor that assists in binding to PC. These findings bring new insight into rational design of novel lipases with intriguing functionalities. Title: Depletion of juvenile hormone esterase extends larval growth in Bombyx mori Zhang Z, Liu X, Shiotsuki T, Wang Z, Xu X, Huang Y, Li M, Li K, Tan A Ref: Insect Biochemistry & Molecular Biology, 81:72, 2017 : PubMed ESTHER: Zhang_2017_Insect.Biochem.Mol.Biol_81_72 PubMedSearch: Zhang 2017 Insect.Biochem.Mol.Biol 81 72 PubMedID: 28057597 Abstract Two major hormones, juvenile hormone (JH) and 20-hydroxyecdysone (20E), regulate insect growth and development according to their precisely coordinated titres, which are controlled by both biosynthesis and degradation pathways. Juvenile hormone esterase (JHE) is the primary JH-specific degradation enzyme that plays a key role in regulating JH titers, along with JH epoxide hydrolase (JHEH) and JH diol kinase (JHDK). In the current study, a loss-of-function analysis of JHE in the silkworm, Bombyx mori, was performed by targeted gene disruption using the transgenic CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/RNA-guided Cas9 nucleases) system. Depletion of B. mori JHE (BmJHE) resulted in the extension of larval stages, especially the penultimate and ultimate larval stages, without deleterious effects to silkworm physiology. The expression of JHEH and JHDK was upregulated in mutant animals, indicating the existence of complementary routes in the JH metabolism pathway in which inactivation of one enzyme will activate other enzymes. RNA-Seq analysis of mutant animals revealed that genes involved in protein processing in the endoplasmic reticulum and in amino acid metabolism were affected by BmJHE depletion. Depletion of JHE and subsequent delayed JH metabolism activated genes in the TOR pathway, which are ultimately responsible for extending larval growth. The transgenic Cas9 system used in the current study provides a promising approach for analysing the actions of JH, especially in nondrosophilid insects. Furthermore, prolonging larval stages produced larger larvae and cocoons, which is greatly beneficial to silk production. Title: Sunitinib, a Clinically Used Anticancer Drug, Is a Potent AChE Inhibitor and Attenuates Cognitive Impairments in Mice Huang L, Lin J, Xiang S, Zhao K, Yu J, Zheng J, Xu D, Mak SH, Hu S and Wang Q <12 more author(s)> Huang L, Lin J, Xiang S, Zhao K, Yu J, Zheng J, Xu D, Mak SH, Hu S, Nirasha S, Wang C, Chen X, Zhang J, Xu S, Wei X, Zhang Z, Zhou D, Zhou W, Cui W, Han YF, Hu Z, Wang Q (- 12) Ref: ACS Chem Neurosci, 7:1047, 2016 : PubMed ESTHER: Huang_2016_ACS.Chem.Neurosci_7_1047 PubMedSearch: Huang 2016 ACS.Chem.Neurosci 7 1047 PubMedID: 27046396 Abstract Sunitinib, a tyrosine kinase inhibitor, is clinically used for the treatment of cancer. In this study, we found for the first time that sunitinib inhibits acetylcholinesterase (AChE) at submicromolar concentrations in vitro. In addition, sunitinib dramatically decreased the hippocampal and cortical activity of AChE in a time-dependent manner in mice. Molecular docking analysis further demonstrates that sunitinib might interact with both the catalytic anion and peripheral anionic sites within AChE, which is in accordance with enzymatic activity results showing that sunitinib inhibits AChE in a mixed pattern. Most importantly, we evaluated the effects of sunitinib on scopolamine-induced cognitive impairments in mice by using novel object recognition and Morris water maze tests. Surprisingly, sunitinib could attenuate cognitive impairments to a similar extent as donepezil, a marketed AChE inhibitor used for the treatment of Alzheimer's disease. In summary, our results have shown that sunitinib could potently inhibit AChE and attenuate cognitive impairments in mice. Title: Biochemical basis of synergism between pathogenic fungus Metarhizium anisopliae and insecticide chlorantraniliprole in Locusta migratoria (Meyen) Jia M, Cao G, Li Y, Tu X, Wang G, Nong X, Whitman DW, Zhang Z Ref: Sci Rep, 6:28424, 2016 : PubMed ESTHER: Jia_2016_Sci.Rep_6_28424 PubMedSearch: Jia 2016 Sci.Rep 6 28424 PubMedID: 27328936 Abstract We challenged Locusta migratoria (Meyen) grasshoppers with simultaneous doses of both the insecticide chlorantraniliprole and the fungal pathogen, Metarhizium anisopliae. Our results showed synergistic and antagonistic effects on host mortality and enzyme activities. To elucidate the biochemical mechanisms that underlie detoxification and pathogen-immune responses in insects, we monitored the activities of 10 enzymes. After administration of insecticide and fungus, activities of glutathione-S-transferase (GST), general esterases (ESTs) and phenol oxidase (PO) decreased in the insect during the initial time period, whereas those of aryl acylamidase (AA) and chitinase (CHI) increased during the initial period and that of acetylcholinesterase (AChE) increased during a later time period. Activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) decreased at a later time period post treatment. Interestingly, treatment with chlorantraniliprole and M. anisopliae relieved the convulsions that normally accompany M. anisopliae infection. We speculate that locust mortality increased as a result of synergism via a mechanism related to Ca(2+) disruption in the host. Our study illuminates the biochemical mechanisms involved in insect immunity to xenobiotics and pathogens as well as the mechanisms by which these factors disrupt host homeostasis and induce death. We expect this knowledge to lead to more effective pest control. Title: Silibinin rescues learning and memory deficits by attenuating microglia activation and preventing neuroinflammatory reactions in SAMP8 mice Jin G, Bai D, Yin S, Yang Z, Zou D, Zhang Z, Li X, Sun Y, Zhu Q Ref: Neuroscience Letters, 629:256, 2016 : PubMed ESTHER: Jin_2016_Neurosci.Lett_629_256 PubMedSearch: Jin 2016 Neurosci.Lett 629 256 PubMedID: 27276653 Abstract Silibinin was reported to be effective in reversing the learning and memory deficits of several AD animal models. These improvements are thought to be regulated by various factors, including antioxidative stress, inhibition of acetylcholinesterase activity and Abeta aggregation. However, there are still no reports that demonstrate the effect of silibinin on microglia activation in vivo. Thus, in this study, we used the senescence-accelerated mouse (SAMP8) strain to test the effects of silibinin on behavioral impairments and microglia activation-induced neuroinflammation. Silibinin treatment significantly rescued memory deficits in novel object recognition test and Morris water maze test. Silibinin treatment significantly attenuated microglial activation; down-regulated the level of the proinflammatory cytokine IL-6, anti-inflammatory cytokine IL-4, and inflammation-associated proteins, iNOS and COX-2; and further modulated MAPK to protect neural cells. These results suggest that silibinin could be a potential candidate for the therapy of neurodegenerative disorders. Title: Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer's disease Liu W, Lang M, Youdim MB, Amit T, Sun Y, Zhang Z, Wang Y, Weinreb O Ref: Neuropharmacology, 109:376, 2016 : PubMed ESTHER: Liu_2016_Neuropharmacol_109_376 PubMedSearch: Liu 2016 Neuropharmacol 109 376 PubMedID: 27318273 Inhibitor(s) related to this paper: MT-031 Abstract Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the "N-methyl" position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo. Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H2O2-induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD. Title: Comparative Genomics Analysis of Streptomyces Species Reveals Their Adaptation to the Marine Environment and Their Diversity at the Genomic Level Tian X, Zhang Z, Yang T, Chen M, Li J, Chen F, Yang J, Li W, Zhang B and Xiao J <3 more author(s)> Tian X, Zhang Z, Yang T, Chen M, Li J, Chen F, Yang J, Li W, Zhang B, Wu J, Zhang C, Long L, Xiao J (- 3) Ref: Front Microbiol, 7:998, 2016 : PubMed ESTHER: Tian_2016_Front.Microbiol_7_998 PubMedSearch: Tian 2016 Front.Microbiol 7 998 PubMedID: 27446038 Gene_locus related to this paper: 9actn-a0a1e7k9d4, 9actn-a0a1e7l883, 9actn-a0a1e7kw84, 9actn-a0a1e7kkk9, 9actn-a0a1e7jip1, 9actn-a0a1e7jjj1, 9actn-a0a1e7k159, 9actn-a0a1e7kfw2, 9actn-a0a1e7l1n0, 9actn-a0a1e7jf99 Abstract Over 200 genomes of streptomycete strains that were isolated from various environments are available from the NCBI. However, little is known about the characteristics that are linked to marine adaptation in marine-derived streptomycetes. The particularity and complexity of the marine environment suggest that marine streptomycetes are genetically diverse. Here, we sequenced nine strains from the Streptomyces genus that were isolated from different longitudes, latitudes, and depths of the South China Sea. Then we compared these strains to 22 NCBI downloaded streptomycete strains. Thirty-one streptomycete strains are clearly grouped into a marine-derived subgroup and multiple source subgroup-based phylogenetic tree. The phylogenetic analyses have revealed the dynamic process underlying streptomycete genome evolution, and lateral gene transfer is an important driving force during the process. Pan-genomics analyses have revealed that streptomycetes have an open pan-genome, which reflects the diversity of these streptomycetes and guarantees the species a quick and economical response to diverse environments. Functional and comparative genomics analyses indicate that the marine-derived streptomycetes subgroup possesses some common characteristics of marine adaptation. Our findings have expanded our knowledge of how ocean isolates of streptomycete strains adapt to marine environments. The availability of streptomycete genomes from the South China Sea will be beneficial for further analysis on marine streptomycetes and will enrich the South China Sea's genetic data sources. Title: Exploration of the chlorpyrifos escape pathway from acylpeptide hydrolases using steered molecular dynamics simulations Wang D, Jin H, Wang J, Guan S, Zhang Z, Han W Ref: J Biomol Struct Dyn, 34:749, 2016 : PubMed ESTHER: Wang_2016_J.Biomol.Struct.Dyn_34_749 PubMedSearch: Wang 2016 J.Biomol.Struct.Dyn 34 749 PubMedID: 26155973 Gene_locus related to this paper: aerpe-APE1547 Inhibitor(s) related to this paper: Chlorpyrifos Abstract Acylpeptide hydrolases (APH) catalyze the removal of an N-acylated amino acid from blocked peptides. APH is significantly more sensitive than acetylcholinesterase, a target of Alzheimer's disease, to inhibition by organophosphorus (OP) compounds. Thus, OP compounds can be used as a tool to probe the physiological functions of APH. Here, we report the results of a computational study of molecular dynamics simulations of APH bound to the OP compounds and an exploration of the chlorpyrifos escape pathway using steered molecular dynamics (SMD) simulations. In addition, we apply SMD simulations to identify potential escape routes of chlorpyrifos from hydrolase hydrophobic cavities in the APH-inhibitor complex. Two previously proposed APH pathways were reliably identified by CAVER 3.0, with the estimated relative importance of P1 > P2 for its size. We identify the major pathway, P2, using SMD simulations, and Arg526, Glu88, Gly86, and Asn65 are identified as important residues for the ligand leaving via P2. These results may help in the design of APH-targeting drugs with improved efficacy, as well as in understanding APH selectivity of the inhibitor binding in the prolyl oligopeptidase family. Title: Rapid eye movement sleep behavior disorder in patients with probable Alzheimer's disease Wang P, Wing YK, Xing J, Liu Y, Zhou B, Zhang Z, Yao H, Guo Y, Shang Y, Zhang X Ref: Aging Clin Exp Res, 28:951, 2016 : PubMed ESTHER: Wang_2016_Aging.Clin.Exp.Res_28_951 PubMedSearch: Wang 2016 Aging.Clin.Exp.Res 28 951 PubMedID: 26022447 Abstract BACKGROUND AND AIMS: Rapid eye movement (REM) sleep behavior disorder (RBD) is commonly associated with neurodegenerative disorders characterized by alpha-synuclein deposition, including Parkinson's disease, multiple system atrophy, and Lewy body dementia. However, this tendency in tauopathy-mediated diseases is rare and only sporadically reported. We systematically illustrate the occurrence of RBD and sleep features among a cohort of patients with Alzheimer's disease (AD), a non-synucleinopathy. Title: A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Abeta25-35-impaired mouse cognitive function Zhang Z, Chen R, An W, Wang C, Liao G, Dong X, Bi A, Yin Z, Luo L Ref: Psychopharmacology (Berl), 233:599, 2016 : PubMed ESTHER: Zhang_2016_Psychopharmacology.(Berl)_233_599 PubMedSearch: Zhang 2016 Psychopharmacology.(Berl) 233 599 PubMedID: 26554390 Abstract RATIONALE: The mechanism involved in AD is complex, which has prompted to develop compounds that could simultaneously interact with several potential targets. Here, we report a new synthesized compound SCR-1693 which is designed to target both AChE and calcium channels that are potential for AD therapy. OBJECTIVES: We investigated the effects of SCR-1693 on AChE and calcium channels, the effects of neuroprotection and anti-amnesia in icv-Abeta25-35-injected mice, and the potential mechanisms. Title: Characterization of a Desiccation Stress Induced Lipase Gene from Brassica napus L. Zhang H, Zhou J, Zheng X, Zhang Z, Wang Z, Tan X Ref: J Agr Sci Tech, 18:1129, 2016 : PubMed ESTHER: Zhang_2016_J.Agr.Sci.Tech_18_1129 PubMedSearch: Zhang 2016 J.Agr.Sci.Tech 18 1129 Abstract Lipases are known to have important functions in many physiological processes in plants. Here, we cloned a lipase gene via Rapid Amplification of cDNA Ends (RACE) technique from Brassica napus L., designated as BnDIL1 (B. napus Desiccation-Induced Lipase 1). The lipase enzyme activity was confirmed by estimating the lipase activity and reduced lipids content in Saccharomyces cerevisiae (pep4) transformant. Two B. napus lines with different oil contents were employed to examine the transcription profiles of BnDIL1 during the processes of seed morphogenesis, maturation, dormancy, pregermination and germination. The transcription level of lipid degradation pathway was enhanced during the processes of seed maturation, dormancy, pregermination and germination, and was higher in seeds of low oil-contents line than that of high oil-contents line. However, BnDIL1 was significantly activated when seed desiccation started. Both slow desiccation and -fast desiccation- treatments on seedlings dramatically activated the transcription of BnDIL1, while only -slow desiccation- stress, which would induce the cell apoptosis, significantly activated the transcription of lipid degradation gene. This result demonstrated that BnDIL1 in B. napus was desiccation stress dependent gene rather than fatty acids degradation gene. Title: Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders Chandra G, Bagh MB, Peng S, Saha A, Sarkar C, Moralle M, Zhang Z, Mukherjee AB Ref: Hum Mol Genet, 24:5416, 2015 : PubMed ESTHER: Chandra_2015_Hum.Mol.Genet_24_5416 PubMedSearch: Chandra 2015 Hum.Mol.Genet 24 5416 PubMedID: 26160911 Gene_locus related to this paper: mouse-ppt Abstract Neurodegeneration is a devastating manifestation in the majority of >50 lysosomal storage disorders (LSDs). Neuronal ceroid lipofuscinoses (NCLs) are the most common childhood neurodegenerative LSDs. Mutations in 13 different genes (called CLNs) underlie various types of NCLs, of which the infantile NCL (INCL) and congenital NCL (CNCL) are the most lethal. Although inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1) cause INCL, those in the CLN10 gene encoding cathepsin D (CD) underlie CNCL. PPT1 is a lysosomal thioesterase that cleaves the thioester linkage in S-acylated proteins required for their degradation by lysosomal hydrolases like CD. Thus, PPT1 deficiency causes lysosomal accumulation of these lipidated proteins (major constituents of ceroid) leading to INCL. We sought to determine whether there is a common pathogenic link between INCL and CNCL. Using biochemical, histological and confocal microscopic analyses of brain tissues and cells from Cln1(-/-) mice that mimic INCL, we uncovered that Cln10/CD is overexpressed. Although synthesized in the endoplasmic reticulum, the CD-precursor protein (pro-CD) is transported through endosome to the lysosome where it is proteolytically processed to enzymatically active-CD. We found that despite Cln10 overexpression, the maturation of pro-CD to enzymatically active-CD in lysosome was disrupted. This defect impaired lysosomal degradative function causing accumulation of undegraded cargo in lysosome leading to INCL. Notably, treatment of intact Cln1(-/-) mice as well as cultured brain cells derived from these animals with a thioesterase-mimetic small molecule, N-tert-butyl-hydroxylamine, ameliorated the CD-processing defect. Our findings are significant in that they define a pathway in which Cln1 mutations disrupt the maturation of a major degradative enzyme in lysosome contributing to neuropathology in INCL and suggest that lysosomal CD deficiency is a common pathogenic link between INCL and CNCL. Title: A general method to improve fluorophores for live-cell and single-molecule microscopy Grimm JB, English BP, Chen J, Slaughter JP, Zhang Z, Revyakin A, Patel R, Macklin JJ, Normanno D and Lavis LD <2 more author(s)> Grimm JB, English BP, Chen J, Slaughter JP, Zhang Z, Revyakin A, Patel R, Macklin JJ, Normanno D, Singer RH, Lionnet T, Lavis LD (- 2) Ref: Nat Methods, 12:244, 2015 : PubMed ESTHER: Grimm_2015_Nat.Methods_12_244 PubMedSearch: Grimm 2015 Nat.Methods 12 244 PubMedID: 25599551 Abstract Specific labeling of biomolecules with bright fluorophores is the keystone of fluorescence microscopy. Genetically encoded self-labeling tag proteins can be coupled to synthetic dyes inside living cells, resulting in brighter reporters than fluorescent proteins. Intracellular labeling using these techniques requires cell-permeable fluorescent ligands, however, limiting utility to a small number of classic fluorophores. Here we describe a simple structural modification that improves the brightness and photostability of dyes while preserving spectral properties and cell permeability. Inspired by molecular modeling, we replaced the N,N-dimethylamino substituents in tetramethylrhodamine with four-membered azetidine rings. This addition of two carbon atoms doubles the quantum efficiency and improves the photon yield of the dye in applications ranging from in vitro single-molecule measurements to super-resolution imaging. The novel substitution is generalizable, yielding a palette of chemical dyes with improved quantum efficiencies that spans the UV and visible range. Title: Inhibiting beta-Amyloid-Associated Alzheimer's Pathogenesis In Vitro and In Vivo by a Multifunctional Dimeric Bis(12)-hupyridone Derived from Its Natural Analogue Hu S, Wang R, Cui W, Zhang Z, Mak SH, Xu D, Choi C, Tsim KWK, Carlier PR and Han Y <1 more author(s)> Hu S, Wang R, Cui W, Zhang Z, Mak SH, Xu D, Choi C, Tsim KWK, Carlier PR, Lee M, Han Y (- 1) Ref: Journal of Molecular Neuroscience, 55:1014, 2015 : PubMed ESTHER: Hu_2015_J.Mol.Neurosci_55_1014 PubMedSearch: Hu 2015 J.Mol.Neurosci 55 1014 PubMedID: 25407821 Abstract Fibrillar aggregates of beta-amyloid protein (Abeta) is the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit the formation of Abeta fibrils and block Abeta fibrils-associated toxicity may have therapeutic potential to combat AD. Bis(12)-hupyridone (B12H) is a multifunctional homodimer derived from huperzine A, which is an anti-AD drug in China. In the current study, the inhibitory effect of B12H on the formation of Abeta fibrils and their associated toxicity was investigated both in vitro and in vivo. By using Thioflavin T fluorescence assay, we found that B12H (0.3-3 muM) directly inhibited Abeta fibrils formation following co-incubation of B12H and Abeta1-40 at 37 degrees C for 6 days in vitro. However, huperzine A, at the same concentrations, did not show significant inhibitory effect on Abeta1-40 fibrils formation. Moreover, B12H markedly reduced Abeta1-40-induced cytotoxicity in cultured SH-SY5Y cells, as evidenced by the increase in cell viability, the decrease in lactate dehydrogenase release, and the reduction of apoptotic nuclei. Most importantly, B12H (0.2 and 0.4 mg/kg) reduced intracerebroventricular Abeta1-40 infusion-induced cognitive and memory impairments in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with increasing choline acetyltransferase activity and decreasing acetylcholinesterase activity. Collectively, our study provided novel sights into the potential application of B12H in AD treatment. Title: Pharmacokinetic and Metabolic Studies of ADTM: A Novel Danshensu Derivative Confers Cardioprotection by HPLC-UV and LC-MS/MS Li S, Shan L, Zhang Z, Li W, Liao K, Sheng X, Yu P, Wang Y Ref: Journal of Chromatography Sci, 53:872, 2015 : PubMed ESTHER: Li_2015_J.Chromatogr.Sci_53_872 PubMedSearch: Li 2015 J.Chromatogr.Sci 53 872 PubMedID: 25609599 Abstract (R)-(3,5,6-Trimethylpyrazinyl) methyl-2-acetoxy-3-(3,4-diacetoxyphenyl) propanoate (ADTM) is a novel Danshensu (DSS) derivative regarded as a potential new agent for the treatment of myocardial ischemia. A validated high performance liquid chromatography (HPLC) approach with a detection limit of 5 ng/mL was used for pharmacokinetic evaluation of ADTM in rat plasma. The intra- and interday precision in terms of relative standard deviation were <4.98 and 4.84%, respectively, at concentration levels of 0.02, 0.20 and 0.80 microg/mL. ADTM's absolute oral bioavailability value was 30.4% and t1/2 was 34.33 +/- 11.51 and 29.94 +/- 8.19 min after oral and intravenous administration of 20 mg/kg. In addition, the major metabolites both in vitro and in vivo were 2-hydroxymethy-3,5,6-trimethylpyrazin and DSS. The results indicated that the hydrolysis was the main metabolic pathway of ADTM, and carboxylesterase may play an important role in ADTM's metabolism. The present work provides basic information for ADTM's further preclinical research and DSS's chemical structure modification. Title: Cloning of Two Acetylcholinesterase Genes and Analysis of Point Mutations Putatively Associated with Triazophos Resistance in Chilo auricilius (Lepidoptera: Pyralidae) Luo G, Li X, Zhang Z, Liu B, Huang S, Fang J Ref: J Econ Entomol, 108:1289, 2015 : PubMed ESTHER: Luo_2015_J.Econ.Entomol_108_1289 PubMedSearch: Luo 2015 J.Econ.Entomol 108 1289 PubMedID: 26470257 Gene_locus related to this paper: 9neop-a0a076vew9, 9neop-a0a076vj71 Abstract Acetylcholinesterase (AChE) is the target of organophosphate (OP) and carbamate insecticides. Mutations in the AChE gene (ace) leading to decreased insecticide susceptibility is the main resistance mechanism in insects. In this study, two Chilo auricilius acetylcholinesterase genes, designated as Caace1 and Caace2, were cloned using RT-PCR and RACE. Caace1 cDNA is 2534 bp, with ORF of 2082 bp, and it encodes an acetylcholinesterase 1 (CaAChE1) protein comprising a calculated 693 amino acid (aa) residues. Caace2 cDNA contains 2280 bp, with a full-length ORF of 1917 bp, encoding acetylcholinesterase 2 (CaAChE2) comprising a calculated 638 aa residues. At the aa level, CaAChE1 displays the highest similarity (97%) with the Chilo suppressalis AChE1, and CaAChE2 shows the highest similarity with the C. suppressalis AChE2 (99%). From the restriction fragment length polymorphism (RFLP) PCR (RFLP-PCR) analysis, one mutation in Caace1, similar to the ace1 mutation associated with triazophos resistance in C. suppressalis, was detected. Detailed examination of field populations of C. auricilius indicated this resistance mutation in C. auricilius is still quite infrequent. Based on the assay of AChE activity and RFLP-PCR testing, an individual that contains resistance mutation has lower AChE activities, while the individual that does not contain the resistance mutation has higher AChE activities. This study provides a basis for future investigations into the mechanism of OP resistance in C. auricilius, as well as a guidance for C. auricilius control with reasonable choice of pesticides. Title: Whole-Genome Sequence of the Microcystin-Degrading Bacterium Sphingopyxis sp. Strain C-1 Okano K, Shimizu K, Maseda H, Kawauchi Y, Utsumi M, Itayama T, Zhang Z, Sugiura N Ref: Genome Announc, 3:, 2015 : PubMed ESTHER: Okano_2015_Genome.Announc_3_e00838 PubMedSearch: Okano 2015 Genome.Announc 3 e00838 PubMedID: 26227601 Gene_locus related to this paper: 9sphn-a0a0m9tza8, 9sphn-a0a0m9ty34 Abstract This report describes the whole-genome sequence of an alkalitolerant microcystin-degrading bacterium, Sphingopyxis sp. strain C-1, isolated from a lake in China. Title: Expression and Characterization of a Novel Thermo-Alkalistable Lipase from Hyperthermophilic Bacterium Thermotoga maritima Tian R, Chen H, Ni Z, Zhang Q, Zhang Z, Zhang T, Zhang C, Yang S Ref: Appl Biochem Biotechnol, 176:1482, 2015 : PubMed ESTHER: Tian_2015_Appl.Biochem.Biotechnol_176_1482 PubMedSearch: Tian 2015 Appl.Biochem.Biotechnol 176 1482 PubMedID: 25957275 Abstract A gene coding for lipase (Tm1350) from the hyperthermophilic bacterium Thermotoga maritima MSB8 was cloned and overexpressed by Escherichia coli. The enzyme can degrade substrates with both short and long acyl chain lengths. The apparent Km and Vmax values for p-nitrophenyl butyrate were 8 mM and 333 U/mg, respectively. The enzyme displayed optimal activity at pH 7.5 and 70 degrees C, maintained 66 % of the original activity after 8 h of incubation, and its half-lives at pHs 9 and 10 were 8 and 1 h. The activity of Tm1350 was stimulated up to 131 or 151 % of the original activity by incubating with 4 M urea or 20 % (v/v) methanol, and 90.1 or 70.2 % of the activity was maintained after 8 h incubation of the enzyme in 20 or 75 % (v/v) of the methanol, showing potential for biodiesel production. The activity of the enzyme without cysteine residue was stimulated up to 618 and 550 % of the original activity by incubating with dithiothreitol (DTT) and reduced glutathione (GSH) at a concentration of 1 mM. However, the circular dichroism spectra of the enzyme have no obvious change after DTT treatment. It is speculated that DTT interacts with potential residues in some key active sites without influence of structure. Title: Transcriptomic and proteomic analysis of pre-diapause and non-diapause eggs of migratory locust, Locusta migratoria L. (Orthoptera: Acridoidea) Tu X, Wang J, Hao K, Whitman DW, Fan Y, Cao G, Zhang Z Ref: Sci Rep, 5:11402, 2015 : PubMed ESTHER: Tu_2015_Sci.Rep_5_11402 PubMedSearch: Tu 2015 Sci.Rep 5 11402 PubMedID: 26091374 Abstract Low temperature induces diapause in locusts. However, the physiological processes and initiation mechanism of diapause are not well understood. To understand the molecular basis of diapause, 'omics' analyses were performed to examine the differences between diapause and non-diapause eggs at both transcriptional and translational levels. Results indicated that a total of 62,241 mRNAs and 212 proteins were differentially expressed. Among them, 116 transcripts had concurrent transcription and translation profiles. Up-regulated genes related to diapause included glutathiones-S-transferase et al., and down-regulated genes including juvenile hormone esterase-like protein et al. KEGG analysis mapped 7,243 and 99 differentially expressed genes and proteins, to 83 and 25 pathways, respectively. Correlation enriched pathways indicated that there were nine identical pathways related to diapause. Gene Ontology analysis placed these genes and proteins into three categories, and a higher proportion of genes related to metabolism was up-regulated than down-regulated. Furthermore, three up-regulated pathways were linked to cryoprotection. This study demonstrates the applicability of high-throughput omics tools to identify molecules linked to diapause in the locust. In addition, it reveals cellular metabolism in diapause eggs is more active than in non-diapause eggs, and up-regulated enzymes may play roles in cryoprotection and storing energy for diapause and post-diapause stages. Title: FgRIC8 is involved in regulating vegetative growth, conidiation, deoxynivalenol production and virulence in Fusarium graminearum Wu J, Liu Y, Lv W, Yue X, Que Y, Yang N, Zhang Z, Ma Z, Talbot NJ, Wang Z Ref: Fungal Genet Biol, 83:92, 2015 : PubMed ESTHER: Wu_2015_Fungal.Genet.Biol_83_92 PubMedSearch: Wu 2015 Fungal.Genet.Biol 83 92 PubMedID: 26341536 Abstract Proteins of the resistance to inhibitors of cholinesterase 8 (Ric8) group act as guanine nucleotide exchange factors (GEFs) and play important roles in regulating G-protein signaling in animals. In filamentous fungi, putative Ric8 orthologs have so far been identified in Magnaporthe oryzae, Neurospora crassa, Aspergillus nidulans and Aspergillus fumigatus. Here, we report the functional investigation of a potential RIC8 ortholog (FgRIC8) in the wheat head blight pathogen Fusarium graminearum. Targeted gene deletion mutants of FgRIC8 exhibited a significant reduction in vegetative growth, conidiation, pigment production as well as deoxynivalenol (DON) biosynthesis. Pathogenicity assays using a point-inoculated spikelet approach showed that the mutants were severely impaired in virulence on flowering wheat heads. Quantitative RT-PCR analysis revealed that genes encoding F. graminearum Galpha (FgGpa1 and FgGpa3), Gbeta (FgGpb1) and Ggamma (FgGpg1) subunits were significantly down-regulated in Fgric8 mutants. Moreover, we showed that FgRic8 physically interacts with both FgGpa1 and FgGpa3, but not FgGpa2, in yeast two-hybrid assays. The intracellular cAMP levels in Fgric8 mutants were significantly decreased compared to the isogenic wild-type strain. Taken together, our results indicate that FgRic8 plays critical roles in fungal development, secondary metabolism and virulence in F. graminearum and may act as a regulator of G protein alpha subunits. Title: Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity Zhang Z, Wang W, Zhong P, Liu SJ, Long JZ, Zhao L, Gao HQ, Cravatt BF, Liu QS Ref: Hippocampus, 25:16, 2015 : PubMed ESTHER: Zhang_2015_Hippocampus_25_16 PubMedSearch: Zhang 2015 Hippocampus 25 16 PubMedID: 25131612 Gene_locus related to this paper: human-MGLL Abstract The endocannabinoid ligand 2-arachidonoylglycerol (2-AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant- and anxiolytic-like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive-like behaviors and decreased the number of bromodeoxyuridine-labeled neural progenitor cells and doublecortin-positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long-term potentiation (LTP) in the DG known to be neurogenesis-dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS-exposed mice. These results suggest that enhanced adult neurogenesis and long-term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant- and anxiolytic-like behavioral effects of JZL184. Title: Crystallization and preliminary X-ray diffraction analysis of a putative carbon-carbon bond hydrolase from Mycobacterium abscessus 103 Zhang Z, Jiang YL, Wu Y, He YX Ref: Acta Crystallographica F Struct Biol Commun, 71:239, 2015 : PubMed ESTHER: Zhang_2015_Acta.Crystallogr.F.Struct.Biol.Commun_71_239 PubMedSearch: Zhang 2015 Acta.Crystallogr.F.Struct.Biol.Commun 71 239 PubMedID: 25664803 Abstract The PhlG protein from Mycobacterium abscessus 103 (mPhlG), which shares 30% sequence identity with phloretin hydrolase from Eubacterium ramulus and 38% sequence identity with 2,4-diacetylphloroglucinol hydrolase from Pseudomonas fluorescens Pf-5, is a putative carbon-carbon bond hydrolase. Here, the expression, purification and crystallization of mPhlG are reported. Crystals were obtained using a precipitant consisting of 100 mM citric acid pH 5.0, 1.0 M lithium chloride, 8%(w/v) polyethylene glycol 6000. The crystals diffracted to 1.87 A resolution and belonged to space group P21, with unit-cell parameters a = 71.0, b = 63.4, c = 74.7 A, alpha = 90.0, beta = 103.2, gamma = 90.0 degrees . Assuming the presence of two mPhlG molecules in the asymmetric unit, VM was calculated to be 2.5 A(3) Da(-1), which corresponds to a solvent content of 50%. Title: Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population Zhang Z, Yu H, Jiang S, Liao J, Lu T, Wang L, Zhang D, Yue W Ref: PLoS ONE, 10:e0144719, 2015 : PubMed ESTHER: Zhang_2015_PLoS.One_10_e0144719 PubMedSearch: Zhang 2015 PLoS.One 10 e0144719 PubMedID: 26674772 Abstract Multiple risk variants of schizophrenia have been identified by Genome-wide association studies (GWAS). As a complement for GWAS, previous pathway-based analysis has indicated that cell adhesion molecules (CAMs) pathway might be involved in the pathogenesis of schizophrenia. However, less replication studies have been reported. Our objective was to investigate the association between CAMs pathway and schizophrenia in the Chinese Han population. We first performed a pathway analysis utilizing our previous GWAS data. The CAMs pathway (hsa04514) was significantly associated with schizophrenia using hybrid gene set-based test (P = 1.03x10-10) and hypergeometric test (P = 5.04x10-6). Moreover, 12 genes (HLA-A, HLA-C, HLA-DOB, HLA-DPB1, HLA-DQA2, HLA-DRB1, MPZ, CD276, NLGN1, NRCAM, CLDN1 and ICAM3) were modestly significantly associated with schizophrenia (P<0.01). Then, we selected one promising gene neuroligin 1 (NLGN1) to further investigate the association between eight significant SNPs and schizophrenia in an independent sample (1814 schizophrenia cases and 1487 healthy controls). Our study showed that seven SNPs of NLGN1 and two haplotype blocks were significantly associated with schizophrenia. This association was confirmed by the results of combined analysis. Among them, SNP rs9835385 had the most significant association with schizophrenia (P = 2.83x10-7). Furthermore, in silico analysis we demonstrated that NLGN1 is preferentially expressed in human brain and SNP rs1488547 was related to the expression level. We validated the association of CAMs pathway with schizophrenia in pathway-level and identified one susceptibility gene NLGN1. Further investigation of the roles of CAMs pathway in the pathogenesis of schizophrenia is warranted. Title: Analysis of essential amino acid residues for catalytic activity of cis-epoxysuccinate hydrolase from Bordetella sp. BK-52 Bao W, Pan H, Zhang Z, Cheng Y, Xie Z, Zhang J, Li Y Ref: Applied Microbiology & Biotechnology, 98:1641, 2014 : PubMed ESTHER: Bao_2014_Appl.Microbiol.Biotechnol_98_1641 PubMedSearch: Bao 2014 Appl.Microbiol.Biotechnol 98 1641 PubMedID: 23764769 Abstract cis-Epoxysuccinate hydrolase (CESH) from Bordetella sp. BK-52, an epoxide hydrolase (EH), catalyzes the stereospecific hydrolysis of cis-epoxysuccinate to D(-)-tartrate. The enzyme, which shows no homology to other reported EHs, belongs to the DUF849 superfamily of prokaryotic proteins, which have unknown function. Metal composition analysis revealed that the CESH is a Zn(2+)-dependent enzyme with an approximately 1:1 molar ratio of zinc to enzyme. The results of an (18)O-labeling study suggest that the enzyme catalyzes epoxide hydrolysis by means of a one-step mechanism. We evaluated the relationship between the structure and function of the enzyme by means of sequence alignment, modeling, substrate binding, and reaction kinetics studies. The CESH has a canonical (beta/alpha)8 TIM barrel fold, and we used site-directed mutagenesis to identify eight residues (H47, H49, R51, T82, Y138, N140, W164, and D251) as being localized to the active site or highly conserved. On the basis of these results and theoretical considerations, we identified H47 and H49 as zinc-binding ligands, and we propose that a zinc atom and R51, T82, Y138, N140, W164, and D251 are the catalytic residues and participate in substrate binding. In summary, the structure and catalytic mechanism of the CESH from Bordetella sp. BK-52 differ from those of classic EHs, which have an alpha/beta hydrolase fold, act via a two-step catalytic mechanism, and do not require cofactors, prosthetic groups, or metal ions. Title: Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype Bouchelion A, Zhang Z, Li Y, Qian H, Mukherjee AB Ref: Ann Clin Transl Neurol, 1:1006, 2014 : PubMed ESTHER: Bouchelion_2014_Ann.Clin.Transl.Neurol_1_1006 PubMedSearch: Bouchelion 2014 Ann.Clin.Transl.Neurol 1 1006 PubMedID: 25574475 Gene_locus related to this paper: mouse-ppt Abstract OBJECTIVE: Nonsense mutations account for 5-70% of all genetic disorders. In the United States, nonsense mutations in the CLN1/PPT1 gene underlie >40% of the patients with infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of INCL carrying the most common Ppt1 nonsense mutation (c.451C>T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo. Title: Conformational transition pathway in the inhibitor binding process of human monoacylglycerol lipase Chen H, Tian R, Ni Z, Zhang Z, Guo Q, Saier MH, Jr. Ref: Protein J, 33:503, 2014 : PubMed ESTHER: Chen_2014_Protein.J_33_503 PubMedSearch: Chen 2014 Protein.J 33 503 PubMedID: 25078047 Abstract Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix alpha4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix alpha4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix alpha4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix alpha4, and elicited the large-scale conformational rearrangement of the helix alpha4, leading to the complete folding of the helix alpha4. Moreover, NEB simulations revealed that the conformational transition pathway of helix alpha4 underwent an almost 180 degrees counter-clockwise rotation of the helix alpha4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism. Title: A Ric8/Synembryn Homolog Promotes Gpa1 and Gpa2 Activation To Respectively Regulate Cyclic AMP and Pheromone Signaling in Cryptococcus neoformans Gong J, Grodsky JD, Zhang Z, Wang P Ref: Eukaryot Cell, 13:1290, 2014 : PubMed ESTHER: Gong_2014_Eukaryot.Cell_13_1290 PubMedSearch: Gong 2014 Eukaryot.Cell 13 1290 PubMedID: 25084863 Abstract The G protein alpha subunits Gpa1, Gpa2, and Gpa3 mediate signal transduction and are important in the growth and virulence of Cryptococcus neoformans. To understand how Gpa1 functions without a conventional Gbeta subunit, we characterized a resistance to inhibitors of cholinesterase 8 (Ric8) homolog from C. neoformans, which shares amino acid sequence homology with other Ric8 proteins that exhibit guanine nucleotide exchange factor (GEF) activity toward Galpha. We found that the ric8 mutant was reduced in capsule size and melanin formation, which could be suppressed by cyclic AMP (cAMP) supplementation or by introducing the activated GPA1(Q284L) allele. Consistent with the fact that Ric8 participates in cAMP signaling to regulate virulence, the ric8 mutant was attenuated in virulence toward mice. Interestingly, disruption of RIC8 also resulted in opposing effects on pheromone signaling, as the ric8 mutant showed reduced mating but an enhanced ability to induce the pheromone response in the mating partner. To identify Ric8 functional mechanisms, we examined the interactions between Ric8 and the three Galpha proteins. Ric8 interacted with Gpa1 and Gpa2, but not Gpa3. The presence of Gpa1(Q284L) negatively affected its interaction with Ric8, whereas the activated Gpa2(Q203L) allele abolished the interaction. Collectively, these findings suggest that Ric8 functions as a GEF to facilitate the activation of Gpa1-cAMP signaling and to promote Gpa2, affecting mating efficiency. Our study highlights the distinct and conserved characteristics associated with G protein signaling and contributes to our overall understanding of how G protein alpha subunits function with or without a canonical Gbeta partner in C. neoformans. Title: Tissue distribution, bioconcentration, metabolism, and effects of erythromycin in crucian carp (Carassius auratus) Liu J, Lu G, Ding J, Zhang Z, Wang Y Ref: Sci Total Environ, 490C:914, 2014 : PubMed ESTHER: Liu_2014_Sci.Total.Environ_490C_914 PubMedSearch: Liu 2014 Sci.Total.Environ 490C 914 PubMedID: 24911771 Abstract In this study, the tissue distribution, bioconcentration, metabolism and biological effects of the macrolide antibiotic erythromycin (ERY) were investigated in fish using crucian carp (Carassius auratus) as a model. Crucian carp were exposed to various concentrations of ERY (4, 20, and 100mug/L) for 28days. The UPLC/MS/MS analysis of both water and tissue provided the bioconcentration of ERY and its metabolites in the fish body. The results from tissue samples showed that a maximum tissue concentration occurred in the muscle and that the bioconcentration factor (BCF) of 72.2 was lower than the theoretical BCF of 90.4 calculated from the octanol-water coefficient of ERY. A significant portion of the absorbed ERY was metabolized via demethylation and dehydration and observed in the form of descladinose in fish. In addition, the relevant biomarkers, including acetylcholinesterase in the brain, as well as 7-ethoxyresorufin O-deethylase and superoxide dismutase in the liver, changed significantly during 28days of exposure (P<0.05). These results clearly indicated that ERY accumulated in fish and that similar metabolites as those observed in mammals were produced, resulting in the biochemical disturbance of biological systems. Title: SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell Liu H, Gu Y, Yin J, Zheng G, Wang C, Zhang Z, Deng M, Liu J, Jia X, He Z Ref: Cell Signal, 26:2710, 2014 : PubMed ESTHER: Liu_2014_Cell.Signal_26_2710 PubMedSearch: Liu 2014 Cell.Signal 26 2710 PubMedID: 25152373 Abstract Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) have been shown to play roles in resistance to chemotherapy. Here, we utilized a proteomics-based method and identified a significant downregulation of the metastasis suppressor NDRG1 in drug resistant lung cancer cells. We showed that downregulation of DNRG1 constitutes a mechanism for acquisition of EMT phenotype and endows lung cancer cells with an increased resistance to cisplatin. We also identified a signal cascade, namely, SET--- PP2A---| c-myc---| NDRG1, in which upregulation of SET is critical for inhibition of NDRG1. We also found that blockade of SET (or reactivation of PP2A) by FTY720 reverted EMT, restored drug sensitivity, and inhibited invasiveness and growth of lung tumor xenografts. Together, our results indicated a functional link between SET-mediated NDRG1 regulation and acquisition of EMT phenotype and drug resistance, and provided an evidence that blockade of SET-driven EMT can overcome drug resistance and inhibit tumor progression. Title: Whole-genome sequencing of cultivated and wild peppers provides insights into Capsicum domestication and specialization Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M and Zhang Z <58 more author(s)> Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M, Luo Y, Yang Y, Wu Z, Mao L, Wu H, Ling-Hu C, Zhou H, Lin H, Gonzalez-Morales S, Trejo-Saavedra DL, Tian H, Tang X, Zhao M, Huang Z, Zhou A, Yao X, Cui J, Li W, Chen Z, Feng Y, Niu Y, Bi S, Yang X, Cai H, Luo X, Montes-Hernandez S, Leyva-Gonzalez MA, Xiong Z, He X, Bai L, Tan S, Liu D, Liu J, Zhang S, Chen M, Zhang L, Zhang Y, Liao W, Wang M, Lv X, Wen B, Liu H, Luan H, Yang S, Wang X, Xu J, Li X, Li S, Wang J, Palloix A, Bosland PW, Li Y, Krogh A, Rivera-Bustamante RF, Herrera-Estrella L, Yin Y, Yu J, Hu K, Zhang Z (- 58) Ref: Proc Natl Acad Sci U S A, 111:5135, 2014 : PubMed ESTHER: Qin_2014_Proc.Natl.Acad.Sci.U.S.A_111_5135 PubMedSearch: Qin 2014 Proc.Natl.Acad.Sci.U.S.A 111 5135 PubMedID: 24591624 Gene_locus related to this paper: capch-q75qh4, capan-a0a1u8fuf5, capan-a0a1u8gmz3, capan-a0a1u8f879, capan-a0a1u8ftr2, capan-a0a1u8g8s6 Abstract As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded approximately 0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of approximately 81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs. Title: Complete Genome Sequence of Acinetobacter baumannii ZW85-1 Wang X, Zhang Z, Hao Q, Wu J, Xiao J, Jing H Ref: Genome Announc, 2:e01083, 2014 : PubMed ESTHER: Wang_2014_Genome.Announc_2_e01083 PubMedSearch: Wang 2014 Genome.Announc 2 e01083 PubMedID: 24459253 Gene_locus related to this paper: aciba-a0a009wzt4 Abstract Acinetobacter baumannii is an aerobic, nonmotile Gram-negative bacterium that causes nosocomial infections worldwide. Here, we report the complete genome sequence of Acinetobacter baumannii strain ZW85-1 and its two plasmids. One of the plasmids carries genes for NDM-1, which can hydrolyze a wide range of antibiotics. Title: Structural insights into the specific recognition of N-heterocycle biodenitrogenation-derived substrates by microbial amide hydrolases Wu G, Chen D, Tang H, Ren Y, Chen Q, Lv Y, Zhang Z, Zhao YL, Yao Y, Xu P Ref: Molecular Microbiology, 91:1009, 2014 : PubMed ESTHER: Wu_2014_Mol.Microbiol_91_1009 PubMedSearch: Wu 2014 Mol.Microbiol 91 1009 PubMedID: 24397579 Gene_locus related to this paper: psep6-f8g0m2 Abstract N-heterocyclic compounds from industrial wastes, including nicotine, are environmental pollutants or toxicants responsible for a variety of health problems. Microbial biodegradation is an attractive strategy for the removal of N-heterocyclic pollutants, during which carbon-nitrogen bonds in N-heterocycles are converted to amide bonds and subsequently severed by amide hydrolases. Previous studies have failed to clarify the molecular mechanism through which amide hydrolases selectively recognize diverse amide substrates and complete the biodenitrogenation process. In this study, structural, computational and enzymatic analyses showed how the N-formylmaleamate deformylase Nfo and the maleamate amidase Ami, two pivotal amide hydrolases in the nicotine catabolic pathway of Pseudomonas putida S16, specifically recognize their respective substrates. In addition, comparison of the alpha-beta-alpha groups of amidases, which include Ami, pinpointed several subgroup-characteristic residues differentiating the two classes of amide substrates as containing either carboxylate groups or aromatic rings. Furthermore, this study reveals the molecular mechanism through which the specially tailored active sites of deformylases and amidases selectively recognize their unique substrates. Our work thus provides a thorough elucidation of the molecular mechanism through which amide hydrolases accomplish substrate-specific recognition in the microbial N-heterocycles biodenitrogenation pathway. Title: Discovery of dipeptidyl peptidase IV (DPP4) inhibitors based on a novel indole scaffold Xiao P, Guo R, Huang S, Cui H, Ye S, Zhang Z Ref: Chin Chem Lett, 25:673, 2014 : PubMed ESTHER: Xiao_2014_Chin.Chem.Lett_25_673 PubMedSearch: Xiao 2014 Chin.Chem.Lett 25 673 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: Indolesufonamide1 Abstract Dipeptidyl peptidase IV (DPP4) inhibitors are proven in the treatment of type 2 diabetes. We designed and synthesized a series of novel indole compounds that selectively inhibit the activity of DPP4 over dipeptidyl peptidase 9 (DPP9) (>200 fold). We further co-crystallized DPP4 with indole sulfonamide (compound 1) to confirm a proposed binding mode. Good metabolic stability of the indole compounds represents another positive attribute for further development. Title: Efficient strategy for maintaining and enhancing the huperzine A production of Shiraia sp. Slf14 through inducer elicitation Yan R, Zhang Z, Wang Y, Yang H, Zeng Q, Zhu D Ref: J Ind Microbiol Biotechnol, 41:1175, 2014 : PubMed ESTHER: Yan_2014_J.Ind.Microbiol.Biotechnol_41_1175 PubMedSearch: Yan 2014 J.Ind.Microbiol.Biotechnol 41 1175 PubMedID: 24865990 Abstract Huperzine A (HupA), a naturally occurring lycopodium alkaloid, is a potent, highly specific and reversible inhibitor of acetylcholinesterase and is a potential treatment for Alzheimer's disease. However, isolating HupA from Huperziaceae plants is inefficient; thus, extracting this compound from endophytic fungi may be more controllable and sustainable. However, the large-scale production of this chemical from endophytes is limited by the innate instability of endophytic fungi. In this study, we maintained the stability and viability of the HupA-producing endophytic fungus Shiraia sp. Slf14 and enhanced the HupA titers during fermentation by adding Huperzia serrata extracts (HSE), L-lysine, and acetic acid into the culture as inducers. Adding trace amounts of HupA clearly improved the HupA production of Shiraia sp. Slf14, reaching a maximum content of approximately 40 mug g(-1). Moreover, the addition of HSE and L-lysine promoted HupA production in the flask fermentation. The aforementioned bioprocessing strategy may be potentially applied to other endophytic fungal culture systems for the efficient production of plant secondary metabolites. Title: Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, Zhang HT, Cravatt BF, Liu QS Ref: Neuropsychopharmacology, 39:1763, 2014 : PubMed ESTHER: Zhong_2014_Neuropsychopharmacology_39_1763 PubMedSearch: Zhong 2014 Neuropsychopharmacology 39 1763 PubMedID: 24476943 Abstract The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization-induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB1 receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling. Title: Genome Sequence of Mycoplasma columbinum Strain SF7 Guo Z, Xu X, Zheng Q, Li T, Kuang S, Zhang Z, Chen Y, Lu X, Zhou R and Jin H <1 more author(s)> Guo Z, Xu X, Zheng Q, Li T, Kuang S, Zhang Z, Chen Y, Lu X, Zhou R, Bi D, Jin H (- 1) Ref: Genome Announc, 1:e0015713, 2013 : PubMed ESTHER: Guo_2013_Genome.Announc_1_e0015713 PubMedSearch: Guo 2013 Genome.Announc 1 e0015713 PubMedID: 23599295 Abstract Mycoplasma columbinum is a member of nonglycolytic Mycoplasma species which can hydrolyze arginine. Increasingly research has revealed that M. columbinum is associated with respiratory disease of pigeons and that the respiratory disease symptoms could be eliminated via the use of mycoplasma treatment medicine. Here we report the genome sequence of M. columbinum strain SF7, which is the first genome report for M. columbinum. Title: Dynamic palmitoylation links cytosol-membrane shuttling of acyl-protein thioesterase-1 and acyl-protein thioesterase-2 with that of proto-oncogene H-ras product and growth-associated protein-43 Kong E, Peng S, Chandra G, Sarkar C, Zhang Z, Bagh MB, Mukherjee AB Ref: Journal of Biological Chemistry, 288:9112, 2013 : PubMed ESTHER: Kong_2013_J.Biol.Chem_288_9112 PubMedSearch: Kong 2013 J.Biol.Chem 288 9112 PubMedID: 23396970 Abstract Acyl-protein thioesterase-1 (APT1) and APT2 are cytosolic enzymes that catalyze depalmitoylation of membrane-anchored, palmitoylated H-Ras and growth-associated protein-43 (GAP-43), respectively. However, the mechanism(s) of cytosol-membrane shuttling of APT1 and APT2, required for depalmitoylating their substrates H-Ras and GAP-43, respectively, remained largely unknown. Here, we report that both APT1 and APT2 undergo palmitoylation on Cys-2. Moreover, blocking palmitoylation adversely affects membrane localization of both APT1 and APT2 and that of their substrates. We also demonstrate that APT1 not only catalyzes its own depalmitoylation but also that of APT2 promoting dynamic palmitoylation (palmitoylation-depalmitoylation) of both thioesterases. Furthermore, shRNA suppression of APT1 expression or inhibition of its thioesterase activity by palmostatin B markedly increased membrane localization of APT2, and shRNA suppression of APT2 had virtually no effect on membrane localization of APT1. In addition, mutagenesis of the active site Ser residue to Ala (S119A), which renders catalytic inactivation of APT1, also increased its membrane localization. Taken together, our findings provide insight into a novel mechanism by which dynamic palmitoylation links cytosol-membrane trafficking of APT1 and APT2 with that of their substrates, facilitating steady-state membrane localization and function of both. Title: Jujube promotes learning and memory in a rat model by increasing estrogen levels in the blood and nitric oxide and acetylcholine levels in the brain Li B, Wang L, Liu Y, Chen Y, Zhang Z, Zhang J Ref: Exp Ther Med, 5:1755, 2013 : PubMed ESTHER: Li_2013_Exp.Ther.Med_5_1755 PubMedSearch: Li 2013 Exp.Ther.Med 5 1755 PubMedID: 23837068 Abstract The aim of this study was to observe the effects of jujube on learning and memory in ovariectomized rats. The effects of jujube on learning and memory in ovariectomized rats were observed using the Morris water maze method. The serum follicle-stimulating hormone (FSH), estrogen and luteinizing hormone (LH) levels, and the brain nitric oxide synthase (NOS) and acetylcholinesterase (AChE) levels of the rats were determined. The results indicated that jujube reduced the latency period and increased the number of crossings made by the ovariectomized rats in the Morris water maze test. Jujube also increased the serum estrogen level, reduced the serum FSH and corpus luteum LH levels, increased brain NOS activity and reduced AChE activity. The results indicate that jujube promoted the learning and memory of the ovariectomized rats. This effect may be correlated with the increase in the estrogen level in the blood, and the changes in the nitric oxide and acetylcholine levels in the brain. Title: Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter Li J, Zhang X, Zhang Z, Padakanti PK, Jin H, Cui J, Li A, Zeng D, Rath NP and Tu Z <3 more author(s)> Li J, Zhang X, Zhang Z, Padakanti PK, Jin H, Cui J, Li A, Zeng D, Rath NP, Flores H, Perlmutter JS, Parsons SM, Tu Z (- 3) Ref: Journal of Medicinal Chemistry, 56:6216, 2013 : PubMed ESTHER: Li_2013_J.Med.Chem_56_6216 PubMedSearch: Li 2013 J.Med.Chem 56 6216 PubMedID: 23802889 Abstract To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over sigma1 and sigma2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[(11)C]24b (Ki = 0.78 nM for VAChT, 1200-fold over sigma receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[(11)C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain. Title: [Design, synthesis and cholinesterase inhibitory activity of quinoline-polyamine conjugates] Luo W, Huang K, Zhang Z, Hong C, Wang CJ Ref: Yao Xue Xue Bao, 48:269, 2013 : PubMed ESTHER: Luo_2013_Yao.Xue.Xue.Bao_48_269 PubMedSearch: Luo 2013 Yao.Xue.Xue.Bao 48 269 PubMedID: 23672025 Abstract A series of quinoline-polyamine conjugates (8a-8n) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs). Some of these compounds had potent ChEs inhibitory activity with IC50 values at micromolar range. Compound 8n exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC50 value of 8.78 micromol x L(-1), and compound 8i showed the most potent inhibition on butyrylcholinesterase (BChE) with IC50 value of 1.60 micromol x L(-1) which was slightly better than rivastigmine. The structure-activity relationship revealed that the chain length of polyamine and linker played important roles for inhibitory activity. Molecular modeling studies showed that 8i targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of cholinesterases. Title: Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL Sarkar C, Chandra G, Peng S, Zhang Z, Liu A, Mukherjee AB Ref: Nat Neurosci, 16:1608, 2013 : PubMed ESTHER: Sarkar_2013_Nat.Neurosci_16_1608 PubMedSearch: Sarkar 2013 Nat.Neurosci 16 1608 PubMedID: 24056696 Gene_locus related to this paper: mouse-ppt Abstract Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disease (LSD) that has no effective treatment. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 deficiency impairs the cleavage of thioester linkage in palmitoylated proteins (constituents of ceroid), preventing degradation by lysosomal hydrolases. Consequently, accumulation of lysosomal ceroid leads to INCL. Thioester linkage is cleaved by nucleophilic attack. Hydroxylamine, a potent nucleophilic cellular metabolite, may have therapeutic potential for INCL, but its toxicity precludes clinical application. We found that a hydroxylamine derivative, N-(tert-Butyl) hydroxylamine (NtBuHA), was non-toxic, cleaved thioester linkage in palmitoylated proteins and mediated lysosomal ceroid depletion in cultured cells from INCL patients. In Ppt1(-/-) mice, which mimic INCL, NtBuHA crossed the blood-brain barrier, depleted lysosomal ceroid, suppressed neuronal apoptosis, slowed neurological deterioration and extended lifespan. Our findings provide a proof of concept that thioesterase-mimetic and antioxidant small molecules such as NtBuHA are potential drug targets for thioesterase deficiency diseases such as INCL. Title: Discovery of XEN445: A potent and selective endothelial lipase inhibitor raises plasma HDL-cholesterol concentration in mice Sun S, Dean R, Jia Q, Zenova A, Zhong J, Grayson C, Xie C, Lindgren A, Samra P and Zhang Z <6 more author(s)> Sun S, Dean R, Jia Q, Zenova A, Zhong J, Grayson C, Xie C, Lindgren A, Samra P, Sojo L, van Heek M, Lin L, Percival D, Fu JM, Winther MD, Zhang Z (- 6) Ref: Bioorganic & Medicinal Chemistry, 21:7724, 2013 : PubMed ESTHER: Sun_2013_Bioorg.Med.Chem_21_7724 PubMedSearch: Sun 2013 Bioorg.Med.Chem 21 7724 PubMedID: 24211162 Gene_locus related to this paper: human-LIPG Inhibitor(s) related to this paper: XEN445 Abstract Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice. Title: Improved thermal stability of lipase in W/O microemulsion by temperature-sensitive polymers Tao Q, Li A, Liu X, Gao H, Zhang Z, Ma R, An Y, Shi L Ref: Colloids Surf B Biointerfaces, 111C:587, 2013 : PubMed ESTHER: Tao_2013_Colloids.Surf.B.Biointerfaces_111C_587 PubMedSearch: Tao 2013 Colloids.Surf.B.Biointerfaces 111C 587 PubMedID: 23907047 Abstract Lipase is active at the water-oil interface and thus very useful for many applications in non-aqueous media. However, the use of lipase is often limited due to the heat inactivation which is mainly caused by the irreversible aggregation among lipase molecules. The temperature-sensitive polymers can spontaneously form complexes with lipases at higher temperature in the confined spaces of the water in oil microemulsion. With cooling, lipases are released from the complexes and refold into the native state. In this way, the thermal stability of lipase in a microemulsion is effectively improved, and so is the stability of lipase at ambient temperature. Apart from proving the effectiveness and generality of this method, the temperature-sensitive polymers/lipase microemulsion represents a simple and efficient system which could be used in practical applications, since lipase retains the interfacial activity in this system. Moreover, the influences of some factors on the improvement are discussed and the mechanism of this method is suggested after exploring the process by dynamic light scattering and fluorescence measurements. Title: Synthesis of poly(sigma-caprolactone) by an immobilized lipase coated with ionic liquids in a solvent-free condition Wu C, Zhang Z, Chen C, He F, Zhuo R Ref: Biotechnol Lett, 35:1623, 2013 : PubMed ESTHER: Wu_2013_Biotechnol.Lett_35_1623 PubMedSearch: Wu 2013 Biotechnol.Lett 35 1623 PubMedID: 23708876 Abstract Polycaprolactone (PCL) was synthesized by ring-opening polymerization of sigma-caprolactone through two different enzymatic processes. The lipase from Candida antarctica B, immobilized on macroporous acrylic acid beads, was employed either untreated or coated with small amounts of ionic liquids (ILs). Monocationic ionic liquids, [C(n)MIm][NTf2] (n = 2, 6, 12), as well as a dicationic ionic liquid, ([C4(C6Im)2][NTf2]2), were used to coat the immobilized lipase and also as the reaction medium. In both methods, the polarity, anion of the ILs concentration and viscosity strongly influenced the reaction. Coating the immobilized enzyme with ILs improved catalytic activity and less ILs was required to produce PCL with a higher molecular weight and reaction yield. At 60 degreesC and ILs/Novozyme-435 coating ratio of 3:1 (w/w) for 48 h, the highest M(w) and reaction yield of PCL were 35,600 g/mol and 62% in the case of [C12MIm][NTf2], while the M(w) and reaction yield of PCL was 20,300 g/mol and 54 % with [C12MIm][NTf2] and catalyzed by untreated lipase. Title: Enzymatic synthesis of poly(sigma-caprolactone) in monocationic and dicationic ionic liquids Wu C, Zhang Z, He F, Zhuo R Ref: Biotechnol Lett, 35:879, 2013 : PubMed ESTHER: Wu_2013_Biotechnol.Lett_35_879 PubMedSearch: Wu 2013 Biotechnol.Lett 35 879 PubMedID: 23479410 Abstract Enzymatic polymerization can offer metal-free routes to polymer materials that could be used in biomedical applications. To take advantage of the unique properties of ionic liquids (ILs) for enzyme stability, monocationic ionic liquid (MIL) and dicationic ionic liquid (DIL) were used to promote the ring-opening polymerization of sigma-caprolactone (sigma-CL) using Candida antarctica lipase B as catalyst. Considering the molecular weight (M n ) and reaction yield of the resulting polymer (PCL), high density and viscosity of ILs would be good, especially in the case of DIL. With the same total alkyl chain length, the density and viscosity of [C4(C6Im)2][PF6]2 were higher than that of [C12MIm][PF6]. Using a lipase/CL/ILs ratio of 1:20:20 (by wt) for 48 h at 90 degreesC, the highest M n and reaction yield of PCL were 26,200 g/mol and 62 % with [C4(C6Im)2][PF6]2, while the M n and reaction yield of PCL obtained in [C12MIm][PF6] were 11,700 g/mol and 37 %. Title: Alterations in activity and mRNA expression of acetylcholinesterase in the liver, kidney and gill of common carp exposed to atrazine and chlorpyrifos Xing H, Wu H, Sun G, Zhang Z, Xu S, Li S Ref: Environ Toxicol Pharmacol, 35:47, 2013 : PubMed ESTHER: Xing_2013_Environ.Toxicol.Pharmacol_35_47 PubMedSearch: Xing 2013 Environ.Toxicol.Pharmacol 35 47 PubMedID: 23237783 Abstract Insecticides and herbicides are widely used in modern agricultural production. The intensive use of insecticide chlorpyrifos (CPF) and herbicide atrazine (ATR) has resulted in serious environmental problems. Herein, we investigated alteration in activity and mRNA levels of AChE in the liver, kidney and gill from common carp after 40d exposure to CPF and ATR alone or in combination and 20d recovery treatment. Results indicated that activity and mRNA levels of AChE at all high-dose groups have been significantly decreased after CPF and ATR alone or ATR/CPF mixture exposure, and the changes were improved in the end of recovery tests in varying degrees, the activity and gene expression of AChE in the joint toxicity of ATR and CPF groups were significantly lower than that in the single toxicant group. Our study suggests that the decrease of AChE activity observed at all high-dose groups (CPF and ATR alone or in combination) may be directly related to a lower AChE expression, and the joint toxicity of ATR and CPF is higher than ATR and CPF alone. Title: Effects of Di-n-butyl Phthalate and Diethyl Phthalate on Acetylcholinesterase Activity and Neurotoxicity Related Gene Expression in Embryonic Zebrafish Xu H, Shao X, Zhang Z, Zou Y, Chen Y, Han S, Wang S, Wu X, Yang L, Chen Z Ref: Bulletin of Environmental Contamination & Toxicology, 91:635, 2013 : PubMed ESTHER: Xu_2013_Bull.Environ.Contam.Toxicol_91_635 PubMedSearch: Xu 2013 Bull.Environ.Contam.Toxicol 91 635 PubMedID: 24042840 Gene_locus related to this paper: danre-ACHE Abstract In the present study, zebrafish embryos were used to assess the neurotoxicity of di-n-butyl phthalate (DBP), diethyl phthalate (DEP) and their mixture. Four-hour post-fertilization (hpf) zebrafish embryos were exposed to various concentrations of DBP, DEP and their mixture (DBP-DEP) until 96 hpf. The transcriptions levels of selected neuron-related genes reported as neurotoxicity biomarkers were analyzed. The results showed that transcripts of growth associated protein 43 (gap43), embryonic lethal abnormal vision-like 3 (elavl3), glial fibrillary acidic protein (gfap), myelin basic protein (mbp), alpha1-tubulin and neurogenin1 (ngn1) were significantly up-regulated after DBP, DEP and DBP-DEP mixture exposure. In addition, acetylcholinesterase activity was significantly inhibited in the embryos. These results indicate that DBP and DEP have the potential neurotoxicity in zebrafish embryos. Title: Characterization of streptonigrin biosynthesis reveals a cryptic carboxyl methylation and an unusual oxidative cleavage of a N-C bond Xu F, Kong D, He X, Zhang Z, Han M, Xie X, Wang P, Cheng H, Tao M and Lin S <2 more author(s)> Xu F, Kong D, He X, Zhang Z, Han M, Xie X, Wang P, Cheng H, Tao M, Zhang L, Deng Z, Lin S (- 2) Ref: Journal of the American Chemical Society, 135:1739, 2013 : PubMed ESTHER: Xu_2013_J.Am.Chem.Soc_135_1739 PubMedSearch: Xu 2013 J.Am.Chem.Soc 135 1739 PubMedID: 23301954 Gene_locus related to this paper: 9actn-l7pij2 Abstract Streptonigrin (STN, 1) is a highly functionalized aminoquinone alkaloid with broad and potent antitumor activity. Here, we reported the biosynthetic gene cluster of STN identified by genome scanning of a STN producer Streptomyces flocculus CGMCC4.1223. This cluster consists of 48 genes determined by a series of gene inactivations. On the basis of the structures of intermediates and shunt products accumulated from five specific gene inactivation mutants and feeding experiments, the biosynthetic pathway was proposed, and the sequence of tailoring steps was preliminarily determined. In this pathway, a cryptic methylation of lavendamycin was genetically and biochemically characterized to be catalyzed by a leucine carboxyl methyltransferase StnF2. A [2Fe-2S](2+) cluster-containing aromatic ring dioxygenase StnB1/B2 system was biochemically characterized to catalyze a regiospecific cleavage of the N-C8' bond of the indole ring of the methyl ester of lavendamycin. This work provides opportunities to illuminate the enzymology of novel reactions involved in this pathway and to create, using genetic and chemo-enzymatic methods, new streptonigrinoid analogues as potential therapeutic agents. Title: The genome of the hydatid tapeworm Echinococcus granulosus Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y and Wang S <21 more author(s)> Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y, Liu J, Kang H, Chen J, Wang L, Chen A, Yu S, Gao Z, Jin L, Gu W, Wang Z, Zhao L, Shi B, Wen H, Lin R, Jones MK, Brejova B, Vinar T, Zhao G, McManus DP, Chen Z, Zhou Y, Wang S (- 21) Ref: Nat Genet, 45:1168, 2013 : PubMed ESTHER: Zheng_2013_Nat.Genet_45_1168 PubMedSearch: Zheng 2013 Nat.Genet 45 1168 PubMedID: 24013640 Gene_locus related to this paper: echgr-k4epc5, echmu-u6hbw4, echgr-w6ugl0, echgr-w6u7y4, echgr-w6vaq5, echgr-a0a068wxj3, echgr-a0a068wgw1, echgr-a0a068wl60 Abstract Cystic echinococcosis (hydatid disease), caused by the tapeworm E. granulosus, is responsible for considerable human morbidity and mortality. This cosmopolitan disease is difficult to diagnose, treat and control. We present a draft genomic sequence for the worm comprising 151.6 Mb encoding 11,325 genes. Comparisons with the genome sequences from other taxa show that E. granulosus has acquired a spectrum of genes, including the EgAgB family, whose products are secreted by the parasite to interact and redirect host immune responses. We also find that genes in bile salt pathways may control the bidirectional development of E. granulosus, and sequence differences in the calcium channel subunit EgCavbeta1 may be associated with praziquantel sensitivity. Our study offers insights into host interaction, nutrient acquisition, strobilization, reproduction, immune evasion and maturation in the parasite and provides a platform to facilitate the development of new, effective treatments and interventions for echinococcosis control. Title: Complete genome analysis of three Acinetobacter baumannii clinical isolates in China for insight into the diversification of drug resistance elements Zhu L, Yan Z, Zhang Z, Zhou Q, Zhou J, Wakeland EK, Fang X, Xuan Z, Shen D, Li QZ Ref: PLoS ONE, 8:e66584, 2013 : PubMed ESTHER: Zhu_2013_PLoS.ONE_8_E66584 PubMedSearch: Zhu 2013 PLoS.ONE 8 E66584 PubMedID: 23826102 Gene_locus related to this paper: aciba-f5iht4, aciba-a0a009wzt4 Abstract BACKGROUND: The emergence and rapid spreading of multidrug-resistant Acinetobacter baumannii strains has become a major health threat worldwide. To better understand the genetic recombination related with the acquisition of drug-resistant elements during bacterial infection, we performed complete genome analysis on three newly isolated multidrug-resistant A. baumannii strains from Beijing using next-generation sequencing technology. METHODOLOGIES/PRINCIPAL FINDINGS: Whole genome comparison revealed that all 3 strains share some common drug resistant elements including carbapenem-resistant bla OXA-23 and tetracycline (tet) resistance islands, but the genome structures are diversified among strains. Various genomic islands intersperse on the genome with transposons and insertions, reflecting the recombination flexibility during the acquisition of the resistant elements. The blood-isolated BJAB07104 and ascites-isolated BJAB0868 exhibit high similarity on their genome structure with most of the global clone II strains, suggesting these two strains belong to the dominant outbreak strains prevalent worldwide. A large resistance island (RI) of about 121-kb, carrying a cluster of resistance-related genes, was inserted into the ATPase gene on BJAB07104 and BJAB0868 genomes. A 78-kb insertion element carrying tra-locus and bla OXA-23 island, can be either inserted into one of the tniB gene in the 121-kb RI on the chromosome, or transformed to conjugative plasmid in the two BJAB strains. The third strains of this study, BJAB0715, which was isolated from spinal fluid, exhibit much more divergence compared with above two strains. It harbors multiple drug-resistance elements including a truncated AbaR-22-like RI on its genome. One of the unique features of this strain is that it carries both bla OXA-23 and bla OXA-58 genes on its genome. Besides, an Acinetobacter lwoffii adeABC efflux element was found inserted into the ATPase position in BJAB0715. Title: In a model of Batten disease, palmitoyl protein thioesterase-1 deficiency is associated with brown adipose tissue and thermoregulation abnormalities Khaibullina A, Kenyon N, Guptill V, Quezado MM, Wang L, Koziol D, Wesley R, Moya PR, Zhang Z and Quezado ZM <2 more author(s)> Khaibullina A, Kenyon N, Guptill V, Quezado MM, Wang L, Koziol D, Wesley R, Moya PR, Zhang Z, Saha A, Mukherjee AB, Quezado ZM (- 2) Ref: PLoS ONE, 7:e48733, 2012 : PubMed ESTHER: Khaibullina_2012_PLoS.One_7_e48733 PubMedSearch: Khaibullina 2012 PLoS.One 7 e48733 PubMedID: 23139814 Gene_locus related to this paper: mouse-ppt Abstract Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1). We have previously shown that children with INCL have increased risk of hypothermia during anesthesia and that PPT1-deficiency in mice is associated with disruption of adaptive energy metabolism, downregulation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), and mitochondrial dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model of INCL that shows many of the neurologic manifestations of the disease, would recapitulate the thermoregulation impairment observed in children with INCL. We also hypothesized that when exposed to cold, Ppt1-knockout mice would be unable to maintain body temperature as in mice thermogenesis requires upregulation of Pgc-1alpha and uncoupling protein 1 (Ucp-1) in brown adipose tissue. We found that the Ppt1-KO mice had lower basal body temperature as they aged and developed hypothermia during cold exposure. Surprisingly, this inability to maintain body temperature during cold exposure in Ppt1-KO mice was associated with an adequate upregulation of Pgc-1alpha and Ucp-1 but with lower levels of sympathetic neurotransmitters in brown adipose tissue. In addition, during baseline conditions, brown adipose tissue of Ppt1-KO mice had less vacuolization (lipid droplets) compared to wild-type animals. After cold stress, wild-type animals had significant decreases whereas Ppt1-KO had insignificant changes in lipid droplets compared with baseline measurements, thus suggesting that Ppt1-KO had less lipolysis in response to cold stress. These results uncover a previously unknown phenotype associated with PPT1 deficiency, that of altered thermoregulation, which is associated with impaired lipolysis and neurotransmitter release to brown adipose tissue during cold exposure. These findings suggest that INCL should be added to the list of neurodegenerative diseases that are linked to alterations in peripheral metabolic processes. In addition, extrapolating these findings clinically, impaired thermoregulation and hypothermia are potential risks in patients with INCL. Title: Structure-based design of pyridopyrimidinediones as dipeptidyl peptidase IV inhibitors Lam B, Zhang Z, Stafford JA, Skene RJ, Shi L, Gwaltney SL, 2nd Ref: Bioorganic & Medicinal Chemistry Lett, 22:6628, 2012 : PubMed ESTHER: Lam_2012_Bioorg.Med.Chem.Lett_22_6628 PubMedSearch: Lam 2012 Bioorg.Med.Chem.Lett 22 6628 PubMedID: 23025999 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: CHEMBL2159182 Abstract Dipeptidyl peptidase IV (DPP-4) inhibitors have been shown to enhance GLP-1 levels and thereby improve hyperglycemia in type II diabetes. From a small fragment hit, using structure-based design, we have discovered a new class of non-covalent, potent and selective DPP-4 inhibitors. Title: Characterization of a thermostable beta-glucosidase from Aspergillus fumigatus Z5, and its functional expression in Pichia pastoris X33 Liu D, Zhang R, Yang X, Zhang Z, Song S, Miao Y, Shen Q Ref: Microb Cell Fact, 11:25, 2012 : PubMed ESTHER: Liu_2012_Microb.Cell.Fact_11_25 PubMedSearch: Liu 2012 Microb.Cell.Fact 11 25 PubMedID: 22340848 Abstract BACKGROUND: Recently, the increased demand of energy has strongly stimulated the research on the conversion of lignocellulosic biomass into reducing sugars for the subsequent production, and beta-glucosidases have been the focus because of their important roles in a variety fundamental biological processes and the synthesis of useful beta-glucosides. Although the beta-glucosidases of different sources have been investigated, the amount of beta-glucosidases are insufficient for effective conversion of cellulose. The goal of this work was to search for new resources of beta-glucosidases, which was thermostable and with high catalytic efficiency. Title: [Design, synthesis and evaluation of tacrine-methoxybenzene hybrids as cholinesterases inhibitors] Luo W, Zhao YM, Zhang Z, Su YB, Wang CJ Ref: Yao Xue Xue Bao, 47:916, 2012 : PubMed ESTHER: Luo_2012_Yao.Xue.Xue.Bao_47_916 PubMedSearch: Luo 2012 Yao.Xue.Xue.Bao 47 916 PubMedID: 22993857 Abstract A series of tacrine-methoxybenzene hybrids (5a-5i) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs). All the compounds had better ChEs inhibitory activities than tacrine with IC50 values at the nanomolar range. Compound 5h exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC50 value of 6.74 nmol x L(-1) and compound 5f showed the most potent inhibition on butyrylcholinesterase with IC50 value of 3.83 nmol x L(-1). Kinetic and molecular modeling studies showed that these hybrids targeted both the catalytic active site and the peripheral anionic site of AChE. Title: Evaluation of neurodegeneration in a mouse model of infantile batten disease by magnetic resonance imaging and magnetic resonance spectroscopy Munasinghe J, Zhang Z, Kong E, Heffer A, Mukherjee AB Ref: Neurodegener Dis, 9:159, 2012 : PubMed ESTHER: Munasinghe_2012_Neurodegener.Dis_9_159 PubMedSearch: Munasinghe 2012 Neurodegener.Dis 9 159 PubMedID: 22327870 Gene_locus related to this paper: mouse-ppt Abstract Neuronal ceroid lipofuscinoses (NCLs) represent a group of common hereditary childhood neurodegenerative storage disorders that have no effective treatment. Mutations in eight different genes cause various forms of NCLs. Infantile NCL (INCL), the most lethal disease, is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. The availability of Ppt1-knockout (Ppt1-KO) mice, which recapitulate virtually all clinical and pathological features of INCL, provides an opportunity to test the effectiveness of novel therapeutic strategies in vivo. However, such studies will require noninvasive methods that can be used to perform serial evaluations of the same animal receiving an experimental therapy. Thus, the development of noninvasive method(s) of evaluation is urgently needed. Here, we report our evaluation of the progression of neurodegeneration in Ppt1-KO mice starting at 3 months of age by MRI and MR spectroscopy (MRS) and repeating these tests using the same mice at 4, 5 and 6 months of age. Our results showed progressive cerebral atrophy, which was associated with histological loss of neuronal content and increase in astroglia. Remarkably, while the brain volumes in Ppt1-KO mice progressively declined with advancing age, the MRS signals, which were significantly lower than those of their wild-type littermates, remained virtually unchanged from 3 to 6 months of age. In addition, our results also showed an abnormality in cerebral blood flow in these mice, which showed progression with age. Our findings provide methods to serially examine the brains of mouse models of neurodegenerative diseases (e.g. Ppt1-KO mice) using noninvasive and nonlethal procedures such as MRI and MRS. These methods may be useful in studies to understand the progression of neuropathology in animal models of neurodegenerative diseases as they allow repeated evaluations of the same animal in which experimental therapies are tested. Title: The blood-brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol Saha A, Sarkar C, Singh SP, Zhang Z, Munasinghe J, Peng S, Chandra G, Kong E, Mukherjee AB Ref: Hum Mol Genet, 21:2233, 2012 : PubMed ESTHER: Saha_2012_Hum.Mol.Genet_21_2233 PubMedSearch: Saha 2012 Hum.Mol.Genet 21 2233 PubMedID: 22331300 Gene_locus related to this paper: mouse-ppt Abstract Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains unclear whether BBB is disrupted in INCL and if so, what might be the molecular mechanism(s) of this complication. We previously reported that the Ppt1-knockout (Ppt1-KO) mice that mimic INCL manifest high levels of oxidative stress and neuroinflammation. Recently, it has been reported that CD4(+) T-helper 17 (T(H)17) lymphocytes may mediate BBB disruption and neuroinflammation, although the precise molecular mechanism(s) remain unclear. We sought to determine: (i) whether the BBB is disrupted in Ppt1-KO mice, (ii) if so, do T(H)17-lymphocytes underlie this complication, and (iii) how might T(H)17 lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1-KO mice and that T(H)17 lymphocytes producing IL-17A mediate disruption of the BBB by stimulating production of matrix metalloproteinases (MMPs), which degrade the tight junction proteins essential for maintaining BBB integrity. Importantly, dietary supplementation of resveratrol (RSV), a naturally occurring antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T(H)17 cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which improved the BBB integrity in Ppt1-KO mice. Intriguingly, we found that RSV suppressed the differentiation of CD4(+) T lymphocytes to IL-17A-positive T(H)17 cells. Our findings uncover a mechanism by which T(H)17 lymphocytes mediate BBB disruption and suggest that small molecules such as RSV that suppress T(H)17 differentiation are therapeutic targets for neurodegenerative disorders such as INCL. Title: Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L and Wang FS <5 more author(s)> Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv S, He W, Geng H, Jin L, Liu Z, Wang FS (- 5) Ref: Stem Cells Transl Med, 1:725, 2012 : PubMed ESTHER: Shi_2012_Stem.Cells.Transl.Med_1_725 PubMedSearch: Shi 2012 Stem.Cells.Transl.Med 1 725 PubMedID: 23197664 Abstract Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. Title: Comparative analysis of the genomes of two field isolates of the rice blast fungus Magnaporthe oryzae Xue M, Yang J, Li Z, Hu S, Yao N, Dean RA, Zhao W, Shen M, Zhang H and Peng YL <8 more author(s)> Xue M, Yang J, Li Z, Hu S, Yao N, Dean RA, Zhao W, Shen M, Zhang H, Li C, Liu L, Cao L, Xu X, Xing Y, Hsiang T, Zhang Z, Xu JR, Peng YL (- 8) Ref: PLoS Genet, 8:e1002869, 2012 : PubMed ESTHER: Xue_2012_PLoS.Genet_8_E1002869 PubMedSearch: Xue 2012 PLoS.Genet 8 E1002869 PubMedID: 22876203 Gene_locus related to this paper: maggr-q0pnd2, mago7-g4mk92, mago7-g4mkc6, mago7-g4mkk9, mago7-g4mns9, mago7-g4ms19, mago7-g4mvm8, mago7-g4mvw5, mago7-g4mvw6, mago7-g4n6j4, mago7-g4nal1, mago7-g4nba0, mago7-g4nbs0, mago7-g4nc41, mago7-g4ncz9, mago7-g4nhn9, mago7-g4nil3, mago7-g4nky6, mago7-g5ehg6, mago7-g5ehv6, mago7-g4msm5, magoy-l7il05, magoy-l7i6m7, magoy-l7ic25 Abstract Rice blast caused by Magnaporthe oryzae is one of the most destructive diseases of rice worldwide. The fungal pathogen is notorious for its ability to overcome host resistance. To better understand its genetic variation in nature, we sequenced the genomes of two field isolates, Y34 and P131. In comparison with the previously sequenced laboratory strain 70-15, both field isolates had a similar genome size but slightly more genes. Sequences from the field isolates were used to improve genome assembly and gene prediction of 70-15. Although the overall genome structure is similar, a number of gene families that are likely involved in plant-fungal interactions are expanded in the field isolates. Genome-wide analysis on asynonymous to synonymous nucleotide substitution rates revealed that many infection-related genes underwent diversifying selection. The field isolates also have hundreds of isolate-specific genes and a number of isolate-specific gene duplication events. Functional characterization of randomly selected isolate-specific genes revealed that they play diverse roles, some of which affect virulence. Furthermore, each genome contains thousands of loci of transposon-like elements, but less than 30% of them are conserved among different isolates, suggesting active transposition events in M. oryzae. A total of approximately 200 genes were disrupted in these three strains by transposable elements. Interestingly, transposon-like elements tend to be associated with isolate-specific or duplicated sequences. Overall, our results indicate that gain or loss of unique genes, DNA duplication, gene family expansion, and frequent translocation of transposon-like elements are important factors in genome variation of the rice blast fungus. Title: Galantamine versus donepezil in Chinese patients with Alzheimer's disease: results from a randomized, double-blind study Zhang Z, Yu L, Gaudig M, Schauble B, Richarz U Ref: Neuropsychiatr Dis Treat, 8:571, 2012 : PubMed ESTHER: Zhang_2012_Neuropsychiatr.Dis.Treat_8_571 PubMedSearch: Zhang 2012 Neuropsychiatr.Dis.Treat 8 571 PubMedID: 23233806 Abstract BACKGROUND: Acetylcholinesterase inhibitors are considered standard of care for Alzheimer's disease in many countries. Galantamine is an acetylcholinesterase inhibitor that may also act via allosteric modulation of nicotinic acetylcholine receptors. Therefore, it may provide benefits compared with other acetylcholinesterase inhibitors. The present study compared galantamine (n = 116) with donepezil (n = 117) in a double-blind trial at nine hospitals in China. Title: Fervidobacterium changbaicum Lip1: identification, cloning, and characterization of the thermophilic lipase as a new member of bacterial lipase family V Cai J, Xie Y, Song B, Wang Y, Zhang Z, Feng Y Ref: Applied Microbiology & Biotechnology, 89:1463, 2011 : PubMed ESTHER: Cai_2011_Appl.Microbiol.Biotechnol_89_1463 PubMedSearch: Cai 2011 Appl.Microbiol.Biotechnol 89 1463 PubMedID: 21046373 Gene_locus related to this paper: 9them-a1yv97 Abstract A novel lipase gene encoded 315 amino acid residues was obtained using lipase-prospecting primers and genome walking from hyperthermophilic bacterium Fervidobacterium changbaicum CBS-1. Sequence alignment and phylogenetic analysis revealed this novel lipase is a new member of bacterial lipase family V. The recombinant enzyme F. changbaicum lipase 1 (FCLip1) showed maximum activity at 78 degreesC and pH 7.8. It displayed extreme thermostability at 70 degreesC and was also stable across a wide pH range from 6.0 to 12.0. Kinetic study demonstrated FCLip1 preferentially hydrolyzed middle-length acyl chains, especially p-nitrophenyl caprate and tricaprylin. With p-nitrophenyl caprate as a substrate, the enzyme exhibited a K(m) and k(cat) of 4.67 microM and 22.7/s, respectively. In addition, FCLip1 was resistant to various detergents and organic solvents. This enzyme is the first reported thermophilic lipase from bacterial family Thermotogaceae. Its extreme stability with respect to temperature and pH, along with its triglyceride hydrolysis activity, indicate that FCLip1 has high potential for future application. Title: Bis(12)-hupyridone, a novel multifunctional dimer, promotes neuronal differentiation more potently than its monomeric natural analog huperzine A possibly through alpha7 nAChR Cui W, Cui GZ, Li W, Zhang Z, Hu S, Mak SH, Zhang H, Carlier PR, Choi CL and Han YF <2 more author(s)> Cui W, Cui GZ, Li W, Zhang Z, Hu S, Mak SH, Zhang H, Carlier PR, Choi CL, Wong YT, Lee SM, Han YF (- 2) Ref: Brain Research, 1401:10, 2011 : PubMed ESTHER: Cui_2011_Brain.Res_1401_10 PubMedSearch: Cui 2011 Brain.Res 1401 10 PubMedID: 21665194 Abstract The cause of many neurodegenerative disorders can be ascribed to the loss of functional neurons, and thus agents capable of promoting neuronal differentiation may have therapeutic benefits to patients of these disorders. In this study, the effects and underlying mechanisms of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase inhibitor modified from huperzine A (HA), on neuronal differentiation were investigated using both the rat PC12 pheochromocytoma cell line and adult rat hippocampus neural stem cells. B12H (3-30 muM), characterized by morphological changes and expression of GAP-43, induced neurite outgrowth in a concentration- and time-dependent manner, with almost 3-fold higher efficacy than that of HA in PC12 cells. Furthermore, B12H (2.5-10 muM), but not HA, promoted neuronal differentiation as shown by the percentage increase of betaIII-tubulin positive neurons in neural stem cells. The activities of extracellular signal-regulated kinase (ERK), as well as its downstream transcription factors Elk-1 and cAMP response element-binding protein (CREB) were elevated in the B12H-treated PC12 cells. Mitogen-activated protein kinase kinase inhibitors and alpha7-nicotinic acetylcholine receptor (alpha7nAChR) antagonist blocked the neurite outgrowth and the activation of ERK induced by B12H. All these findings suggest that B12H potently induces pro-neuronal cells into differentiated neurons by activating the ERK pathway possibly via regulating alpha7nAChR. These findings support the recent proposition that alpha7nAChR is required for the neuronal dendritic arborization and differentiation in the adult mice hippocampus, and provide insights into the possible therapeutic potential of B12H in treating neurodegenerative disorders. Title: The novel small molecule alpha9alpha10 nicotinic acetylcholine receptor antagonist ZZ-204G is analgesic Holtman JR, Dwoskin LP, Dowell C, Wala EP, Zhang Z, Crooks PA, McIntosh JM Ref: European Journal of Pharmacology, 670:500, 2011 : PubMed ESTHER: Holtman_2011_Eur.J.Pharmacol_670_500 PubMedSearch: Holtman 2011 Eur.J.Pharmacol 670 500 PubMedID: 21944926 Abstract Chronic pain is inadequately managed with currently available classes of analgesic drugs. Recently, peptide antagonists of the alpha9alpha10 nicotinic acetylcholine receptor were shown to be analgesic. The present study was conducted to characterize a novel small molecule, non-peptide antagonist at nicotinic receptors. The tetrakis-quaternary ammonium compound ZZ-204G was evaluated for functional activity on cloned nicotinic receptors expressed in Xenopus oocytes. In-vivo efficacy was assessed in rat models of tonic inflammatory pain (formalin test), neuropathic pain (chronic constriction nerve injury), and thermal nociception (tail flick test). ZZ-204G was an antagonist at nicotinic receptors inhibiting the alpha9alpha10 subtype with an IC(5)(0) of 0.51 (0.35-0.72) nM. Antagonist activity at other nicotinic subtypes (alpha1beta1deltaepsilon, alpha2beta2, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, alpha6/alpha3beta2beta3, alpha6/alpha3beta4 and alpha7) was 10-1000-fold lower than at the alpha9alpha10 subtype. In competition binding assays, the k(i) of ZZ-204G at gamma-aminobutyric acid(A), serotonin(3), gamma-aminobutyric acid(B), kappa- and mu-opioid receptors was 1000- to >10,000-fold lower than at alpha9alpha10 nicotinic receptors. Parenteral administration of ZZ-204G dose-dependently decreased nociceptive behaviors (paw flinches) in the formalin test and mechanical hyperalgesia in the chronic constriction nerve injury model of neuropathic pain. ZZ-204G was not antinociceptive in the tail flick assay. Results from the rotarod assay indicated that lower doses of ZZ-204G that were analgesic did not alter motor function. In summary, ZZ-204G represents a prototype small molecule antagonist for alpha9alpha10 nicotinic receptors and provides a novel molecular scaffold for analgesic agents with the potential to treat chronic inflammatory or neuropathic pain. Title: RNA-Seq improves annotation of protein-coding genes in the cucumber genome Li Z, Zhang Z, Yan P, Huang S, Fei Z, Lin K Ref: BMC Genomics, 12:540, 2011 : PubMed ESTHER: Li_2011_BMC.Genomics_12_540 PubMedSearch: Li 2011 BMC.Genomics 12 540 PubMedID: 22047402 Gene_locus related to this paper: cucsa-a0a0a0ktw5, cucsa-a0a0a0lnt6, cucsa-a0a0a0kpn7, cucsa-a0a0a0lvt9, cucsa-a0a0a0kdx8, cucsa-a0a0a0m228, cucsa-a0a0a0kz31, cucsa-a0a0a0k5t5, cucsa-a0a0a0kfs7, cucsa-a0a0a0kjj7, cucsa-a0a0a0kzs7, cucsa-a0a0a0l0a6, cucsa-a0a0a0l4w4, cucsa-a0a0a0lpz0 Abstract BACKGROUND: As more and more genomes are sequenced, genome annotation becomes increasingly important in bridging the gap between sequence and biology. Gene prediction, which is at the center of genome annotation, usually integrates various resources to compute consensus gene structures. However, many newly sequenced genomes have limited resources for gene predictions. In an effort to create high-quality gene models of the cucumber genome (Cucumis sativus var. sativus), based on the EVidenceModeler gene prediction pipeline, we incorporated the massively parallel complementary DNA sequencing (RNA-Seq) reads of 10 cucumber tissues into EVidenceModeler. We applied the new pipeline to the reassembled cucumber genome and included a comparison between our predicted protein-coding gene sets and a published set. Title: Switch of substrate specificity of hyperthermophilic acylaminoacyl peptidase by combination of protein and solvent engineering Liu C, Yang G, Wu L, Tian G, Zhang Z, Feng Y Ref: Protein Cell, 2:497, 2011 : PubMed ESTHER: Liu_2011_Protein.Cell_2_497 PubMedSearch: Liu 2011 Protein.Cell 2 497 PubMedID: 21748600 Abstract The inherent evolvability of promiscuous enzymes endows them with great potential to be artificially evolved for novel functions. Previously, we succeeded in transforming a promiscuous acylaminoacyl peptidase (apAAP) from the hyperthermophilic archaeon Aeropyrum pernix K1 into a specific carboxylesterase by making a single mutation. In order to fulfill the urgent requirement of thermostable lipolytic enzymes, in this paper we describe how the substrate preference of apAAP can be further changed from p-nitrophenyl caprylate (pNP-C8) to p-nitrophenyl laurate (pNP-C12) by protein and solvent engineering. After one round of directed evolution and subsequent saturation mutagenesis at selected residues in the active site, three variants with enhanced activity towards pNP-C12 were identified. Additionally, a combined mutant W474V/F488G/R526V/T560W was generated, which had the highest catalytic efficiency (k (cat)/K (m)) for pNP-C12, about 71-fold higher than the wild type. Its activity was further increased by solvent engineering, resulting in an activity enhancement of 280-fold compared with the wild type in the presence of 30% DMSO. The structural basis for the improved activity was studied by substrate docking and molecular dynamics simulation. It was revealed that W474V and F488G mutations caused a significant change in the geometry of the active center, which may facilitate binding and subsequent hydrolysis of bulky substrates. In conclusion, the combination of protein and solvent engineering may be an effective approach to improve the activities of promiscuous enzymes and could be used to create naturally rare hyperthermophilic enzymes. Title: Indolizidine (-)-235B' and related structural analogs: discovery of nicotinic receptor antagonists that inhibit nicotine-evoked [3H]dopamine release Pivavarchyk M, Smith AM, Zhang Z, Zhou D, Wang X, Toyooka N, Tsuneki H, Sasaoka T, McIntosh JM and Dwoskin LP <1 more author(s)> Pivavarchyk M, Smith AM, Zhang Z, Zhou D, Wang X, Toyooka N, Tsuneki H, Sasaoka T, McIntosh JM, Crooks PA, Dwoskin LP (- 1) Ref: European Journal of Pharmacology, 658:132, 2011 : PubMed ESTHER: Pivavarchyk_2011_Eur.J.Pharmacol_658_132 PubMedSearch: Pivavarchyk 2011 Eur.J.Pharmacol 658 132 PubMedID: 21371454 Abstract Although several therapeutic agents are available to aid in tobacco smoking cessation, relapse rates continue to be high, warranting the development of alternative pharmacotherapies. Nicotine-evoked dopamine release from its presynaptic terminals in the central nervous system leads to reward which maintains continued tobacco use. The ability of indolizidine (-)-235B' and a sub-library of structurally related analogs to inhibit nicotine-evoked [(3)H]dopamine release from rat striatal slices was determined in the current study. Indolizidine (-)-235B' inhibited nicotine-evoked [(3)H]dopamine release in a concentration-dependent manner (IC(50)=42 nM, I(max)=55%). Compound (-)-237D, the double bond-reduced analog, afforded the greatest inhibitory potency (IC(50)=0.18 nM, I(max)=76%), and was 233-fold more potent than indolizidine (-)-235B'. The des-8-methyl aza-analog of indolizidine (-)-235B', ZZ-272, also inhibited nicotine-evoked [(3)H]dopamine release (IC(50)=413 nM, I(max)=59%). Concomitant exposure to maximally effective concentrations of indolizidine (-)-235B', ZZ-272 or (-)-237D with a maximally effective concentration of alpha-conotoxin MII, a selective antagonist for alpha6beta2-containing nicotinic receptors, resulted in inhibition of nicotine-evoked [(3)H]dopamine release no greater than that produced by each compound alone. The latter results suggest that indolizidine (-)-235B', (-)-237D, ZZ-272 and alpha-conotoxin MII inhibit the same alpha-conotoxin MII-sensitive nicotinic receptor subtypes. Thus, indolizidine (-)-235B' and its analogs act as antagonists of alpha6beta2-nicotinic receptors and constitute a novel structural scaffold for the discovery of pharmacotherapies for smoking cessation. Title: N-butyryl-homoserine lactone, a bacterial quorum-sensing signaling molecule, induces intracellular calcium elevation in Arabidopsis root cells Song S, Jia Z, Xu J, Zhang Z, Bian Z Ref: Biochemical & Biophysical Research Communications, 414:355, 2011 : PubMed ESTHER: Song_2011_Biochem.Biophys.Res.Commun_414_355 PubMedSearch: Song 2011 Biochem.Biophys.Res.Commun 414 355 PubMedID: 21964296 Abstract N-acyl-L-homoserine lactones (AHLs) are quorum sensing (QS) signal molecules that are commonly used in gram-negative bacteria. Recently, it has become evident that AHLs can influence the behavior of plant cells. However, little is known about the mechanism of the plants' response to these bacterial signals. Calcium ions (Ca(2+)), ubiquitous intracellular second messengers, play an essential role in numerous signal transduction pathways in plants. In this study, the cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) was measured by a luminometric method in the excised root cells of Arabidopsis plants that were treated with N-butyryl-homoserine lactone (C4-HSL). There was a transient and immediate increase in [Ca(2+)](cyt) levels, and the highest level (0.4 muM), approximately 2-fold higher than the basal level, was observed at the 6th second after the addition of 10 muM C4-HSL. Pretreatments with La(3+), verapamil or ethylene glycol tetraacetic acid (EGTA) inhibited the increase in [Ca(2+)](cyt) caused by C4-HSL, whereas it remained unaffected by pretreatment with Li(+), indicating that the Ca(2+) contributing to the increase in [Ca(2+)](cyt) was mobilized from the extracellular medium via the plasma membrane Ca(2+) channels but not from the intracellular Ca(2+) stores. Furthermore, electrophysiological approaches showed that the transmembrane Ca(2+) current was significantly increased with the addition of C4-HSL. Taken together, our observations suggest that C4-HSL may act as an elicitor from bacteria to plants and that Ca(2+) signaling participates in the ability of plant cells to sense the bacterial QS signals. Title: The genome of the mesopolyploid crop species Brassica rapa Wang X, Wang H, Wang J, Sun R, Wu J, Liu S, Bai Y, Mun JH, Bancroft I and Zhang Z <88 more author(s)> Wang X, Wang H, Wang J, Sun R, Wu J, Liu S, Bai Y, Mun JH, Bancroft I, Cheng F, Huang S, Li X, Hua W, Freeling M, Pires JC, Paterson AH, Chalhoub B, Wang B, Hayward A, Sharpe AG, Park BS, Weisshaar B, Liu B, Li B, Tong C, Song C, Duran C, Peng C, Geng C, Koh C, Lin C, Edwards D, Mu D, Shen D, Soumpourou E, Li F, Fraser F, Conant G, Lassalle G, King GJ, Bonnema G, Tang H, Belcram H, Zhou H, Hirakawa H, Abe H, Guo H, Jin H, Parkin IA, Batley J, Kim JS, Just J, Li J, Xu J, Deng J, Kim JA, Yu J, Meng J, Min J, Poulain J, Hatakeyama K, Wu K, Wang L, Fang L, Trick M, Links MG, Zhao M, Jin M, Ramchiary N, Drou N, Berkman PJ, Cai Q, Huang Q, Li R, Tabata S, Cheng S, Zhang S, Sato S, Sun S, Kwon SJ, Choi SR, Lee TH, Fan W, Zhao X, Tan X, Xu X, Wang Y, Qiu Y, Yin Y, Li Y, Du Y, Liao Y, Lim Y, Narusaka Y, Wang Z, Li Z, Xiong Z, Zhang Z (- 88) Ref: Nat Genet, 43:1035, 2011 : PubMed ESTHER: Wang_2011_Nat.Genet_43_1035 PubMedSearch: Wang 2011 Nat.Genet 43 1035 PubMedID: 21873998 Gene_locus related to this paper: braol-Q8GTM3, braol-Q8GTM4, brarp-m4ei94, brarp-m4c988, brana-a0a078j4a9, brana-a0a078e1m0, brana-a0a078cd75, brarp-m4dwa6, brana-a0a078j4f0, brana-a0a078cus4, brana-a0a078f8c2, brana-a0a078jql1, brana-a0a078dgj3, brana-a0a078hw50, brana-a0a078cuu0, brana-a0a078dfa9, brana-a0a078ic91, brarp-m4ctw3, brana-a0a078ca65, brana-a0a078ctc8, brana-a0a078h021, brana-a0a078jx23, brarp-m4da84, brarp-m4dwr7, brana-a0a078dh94, brana-a0a078h612, brana-a0a078j2t3, braol-a0a0d3dpb2, braol-a0a0d3dx76, brana-a0a078jxa8, brana-a0a078i2k3, brarp-m4cwq4, brarp-m4dcj8, brarp-m4eh17, brarp-m4eey4, brarp-m4dnj8, brarp-m4ey83, brarp-m4ey84 Abstract We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops. Title: Lipoprotein lipase gene polymorphisms and risks of childhood obesity in Chinese preschool children Wang LN, Yu Q, Xiong Y, Liu LF, Zhang Z, Zhang XN, Cheng H, Wang B Ref: Eur J Pediatr, 170:1309, 2011 : PubMed ESTHER: Wang_2011_Eur.J.Pediatr_170_1309 PubMedSearch: Wang 2011 Eur.J.Pediatr 170 1309 PubMedID: 21431783 Abstract Childhood obesity is increasingly prevalent in the community and is related to many adult diseases. Lipoprotein lipase (LPL) plays a central role in dyslipidemia, and polymorphisms of the LPL gene may result in the disturbance in the lipid's metabolism. The aim of this study is to test the hypothesis that genetic variants of LPL and serum lipid levels are associated with the risk of childhood obesity. We genotyped +495T > G and PvuII T > C in an LPL gene and measured the serum lipid levels in a case-control study of 124 obese children and 346 frequency-matched normal controls in preschool Chinese children. The variant genotypes of LPL + 495GG and PvuII CC were associated with a significantly increased risk of childhood obesity [adjusted odds ratio (OR) = 2.39, 95% CI = 1.09-5.23 for +495 GG; adjusted OR = 2.00, 95% CI = 1.04-3.83 for PvuII CC], compared with their wild-type genotypes, respectively. In addition, compared with the lower serum level cut off by the control median, the higher level of serum triglyceride (TG) (>0.59 mmol/L) was associated with a 1.32-fold increased risk of childhood obesity, and the higher level of high density lipoprotein cholesterol (HDLC) (>1.14 mmol/L) was associated with a 36% decrease in risk of childhood obesity. Furthermore, the median levels of TG were higher in obese children carrying LPL +495TT/TG and PvuII TT/CT genotypes than those in controls, the HDLC levels were lower in obese children carrying LPL +495TG and PvuII CT/CC genotypes than those in controls. In conclusion, the LPL gene +495T > G and PvuII T > C polymorphisms may modulate the magnitude of dyslipidemia in Chinese early-onset obesity. Title: [Isolation of endophytic fungi from Huperzia serrata and their acetylcholinesterase inhibitory activity] Wang Y, Zeng Q, Zhang Z, Yan R, Wang L, Du Z Ref: Zhongguo Zhong Yao Za Zhi, 36:734, 2011 : PubMed ESTHER: Wang_2011_Zhongguo.Zhong.Yao.Za.Zhi_36_734 PubMedSearch: Wang 2011 Zhongguo.Zhong.Yao.Za.Zhi 36 734 PubMedID: 21710741 Abstract A total of 127 strains of endophytic fungi were isolated from roots, branches and leaves of Huperzia serrata. These strains were identified into 19 genera based on morphological characters and ribosomal DNA (rDNA) sequence analysis, there into Penicillium, Aspergillus and Podospora were dominant populations in H. serrata. From analysis results we found some endophytic fungi showed a certain degree of tissue preference. The isolation rate and colonization rate of stems were both larger than those of leaf and roots. After testing the acetylcholinesterase (AChE) inhibitory activity of these endophytic fungi, a total of 39 endophytic fungi belonging to 15 genera showed AChE inhibition. Eleven endophytic fungi showed potent AChE inhibition, 7 of which were isolated from leaf. The research not only provided theoretical basis for developing and utilizing the resources of endophytic fungi in H. serrata but also showed a new path for searching medicines resource which has AChE inhibitory activity. Title: bPiDI: a novel selective alpha6beta2* nicotinic receptor antagonist and preclinical candidate treatment for nicotine abuse Wooters TE, Smith AM, Pivavarchyk M, Siripurapu KB, McIntosh JM, Zhang Z, Crooks PA, Bardo MT, Dwoskin LP Ref: British Journal of Pharmacology, 163:346, 2011 : PubMed ESTHER: Wooters_2011_Br.J.Pharmacol_163_346 PubMedSearch: Wooters 2011 Br.J.Pharmacol 163 346 PubMedID: 21232049 Abstract BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nAChRs) containing alpha6beta2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the alpha6beta2* nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) inhibits nicotine-evoked dopamine release from dorsal striatum and decreases nicotine self-administration in rats. However, overt toxicity emerged with repeated bPiDDB treatment. The current study evaluated the preclinical pharmacology of a bPiDDB analogue. EXPERIMENTAL APPROACH: The C(1)(0) analogue of bPiDDB, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), was evaluated preclinically for nAChR antagonist activity. KEY Title: Genome sequence and analysis of the tuber crop potato Xu X, Pan S, Cheng S, Zhang B, Mu D, Ni P, Zhang G, Yang S, Li R and Visser RG <87 more author(s)> Xu X, Pan S, Cheng S, Zhang B, Mu D, Ni P, Zhang G, Yang S, Li R, Wang J, Orjeda G, Guzman F, Torres M, Lozano R, Ponce O, Martinez D, De la Cruz G, Chakrabarti SK, Patil VU, Skryabin KG, Kuznetsov BB, Ravin NV, Kolganova TV, Beletsky AV, Mardanov AV, Di Genova A, Bolser DM, Martin DM, Li G, Yang Y, Kuang H, Hu Q, Xiong X, Bishop GJ, Sagredo B, Mejia N, Zagorski W, Gromadka R, Gawor J, Szczesny P, Huang S, Zhang Z, Liang C, He J, Li Y, He Y, Xu J, Zhang Y, Xie B, Du Y, Qu D, Bonierbale M, Ghislain M, Herrera Mdel R, Giuliano G, Pietrella M, Perrotta G, Facella P, O'Brien K, Feingold SE, Barreiro LE, Massa GA, Diambra L, Whitty BR, Vaillancourt B, Lin H, Massa AN, Geoffroy M, Lundback S, DellaPenna D, Buell CR, Sharma SK, Marshall DF, Waugh R, Bryan GJ, Destefanis M, Nagy I, Milbourne D, Thomson SJ, Fiers M, Jacobs JM, Nielsen KL, Sonderkaer M, Iovene M, Torres GA, Jiang J, Veilleux RE, Bachem CW, De Boer J, Borm T, Kloosterman B, van Eck H, Datema E, Hekkert B, Goverse A, van Ham RC, Visser RG (- 87) Ref: Nature, 475:189, 2011 : PubMed ESTHER: Xu_2011_Nature_475_189 PubMedSearch: Xu 2011 Nature 475 189 PubMedID: 21743474 Gene_locus related to this paper: soltu-q2tqv0, soltu-q4h433, soltu-m0zl00, soltu-m1aw23, soltu-m0zxh5, soltu-m1d3q4, soltu-m1bz14, soltu-m1d3q6, sollc-k4b1g3, soltu-m0zzn8, soltu-m1ba60, sollc-k4bf33, soltu-m1c8d8, soltu-m1ced9, soltu-m1a385, soltu-m1bz15, soltu-m1a7s9, soltu-m1bc84, soltu-m1bpd1, sollc-k4bm34, soltu-m1a487, soltu-m1a5u0, soltu-m1cjx7, soltu-m1bvq8, soltu-m1baq1, soltu-m1cfh4, soltu-m1azl4, soltu-m0ztj0, soltu-m1d6d0, soltu-m1cap1, soltu-m1a7m1, soltu-m1d3s6 Abstract Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop. Title: Novel bis-, tris-, and tetrakis-tertiary amino analogs as antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release Zhang Z, Zheng G, Pivavarchyk M, Deaciuc AG, Dwoskin LP, Crooks PA Ref: Bioorganic & Medicinal Chemistry Lett, 21:88, 2011 : PubMed ESTHER: Zhang_2011_Bioorg.Med.Chem.Lett_21_88 PubMedSearch: Zhang 2011 Bioorg.Med.Chem.Lett 21 88 PubMedID: 21147530 Abstract A series of tertiary amine analogs derived from lead azaaromatic quaternary ammonium salts has been designed and synthesized. The preliminary structure-activity relationships of these new analogs suggest that such tertiary amine analogs, which potently inhibit nicotine-evoked dopamine release from rat striatum, represent drug-like inhibitors of alpha6-containing nicotinic acetylcholine receptors. The bis-tertiary amine analog 7 exhibited an IC(50) of 0.95 nM, while the tris-tertiary amine analog 19 had an IC(50) of 0.35 nM at nAChRs mediating nicotine-evoked dopamine release. Title: Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV Zhang Z, Wallace MB, Feng J, Stafford JA, Skene RJ, Shi L, Lee B, Aertgeerts K, Jennings A and Gwaltney SL <5 more author(s)> Zhang Z, Wallace MB, Feng J, Stafford JA, Skene RJ, Shi L, Lee B, Aertgeerts K, Jennings A, Xu R, Kassel DB, Kaldor SW, Navre M, Webb DR, Gwaltney SL (- 5) Ref: Journal of Medicinal Chemistry, 54:510, 2011 : PubMed ESTHER: Zhang_2011_J.Med.Chem_54_510 PubMedSearch: Zhang 2011 J.Med.Chem 54 510 PubMedID: 21186796 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: Pyrimidinone-inhibitor1, Pyrimidinone-inhibitor3, Xanthine-inhibitor-4, CHEMBL2159182, Alogliptin Abstract The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development. Title: Discovery of non-peptide, small molecule antagonists of alpha9alpha10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain Zheng G, Zhang Z, Dowell C, Wala E, Dwoskin LP, Holtman JR, McIntosh JM, Crooks PA Ref: Bioorganic & Medicinal Chemistry Lett, 21:2476, 2011 : PubMed ESTHER: Zheng_2011_Bioorg.Med.Chem.Lett_21_2476 PubMedSearch: Zheng 2011 Bioorg.Med.Chem.Lett 21 2476 PubMedID: 21397497 Abstract A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective alpha9alpha10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of alpha9alpha10 nAChRs and greater selectivity over alpha7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain. Title: Transcriptome sequencing and comparative analysis of cucumber flowers with different sex types Guo S, Zheng Y, Joung JG, Liu S, Zhang Z, Crasta OR, Sobral BW, Xu Y, Huang S, Fei Z Ref: BMC Genomics, 11:384, 2010 : PubMed ESTHER: Guo_2010_BMC.Genomics_11_384 PubMedSearch: Guo 2010 BMC.Genomics 11 384 PubMedID: 20565788 Gene_locus related to this paper: cucsa-a0a0a0ktw5, cucsa-a0a0a0lnt6, cucsa-a0a0a0kpn7, cucsa-a0a0a0lvt9, cucsa-a0a0a0kdx8, cucsa-a0a0a0m228, cucsa-a0a0a0kz31, cucsa-a0a0a0k5t5, cucsa-a0a0a0kfs7, cucsa-a0a0a0kjj7, cucsa-a0a0a0kzs7, cucsa-a0a0a0l0a6, cucsa-a0a0a0l4w4, cucsa-a0a0a0lpz0 Abstract BACKGROUND: Cucumber, Cucumis sativus L., is an economically and nutritionally important crop of the Cucurbitaceae family and has long served as a primary model system for sex determination studies. Recently, the sequencing of its whole genome has been completed. However, transcriptome information of this species is still scarce, with a total of around 8,000 Expressed Sequence Tag (EST) and mRNA sequences currently available in GenBank. In order to gain more insights into molecular mechanisms of plant sex determination and provide the community a functional genomics resource that will facilitate cucurbit research and breeding, we performed transcriptome sequencing of cucumber flower buds of two near-isogenic lines, WI1983G, a gynoecious plant which bears only pistillate flowers, and WI1983H, a hermaphroditic plant which bears only bisexual flowers. RESULT: Using Roche-454 massive parallel pyrosequencing technology, we generated a total of 353,941 high quality EST sequences with an average length of 175bp, among which 188,255 were from gynoecious flowers and 165,686 from hermaphroditic flowers. These EST sequences, together with approximately 5,600 high quality cucumber EST and mRNA sequences available in GenBank, were clustered and assembled into 81,401 unigenes, of which 28,452 were contigs and 52,949 were singletons. The unigenes and ESTs were further mapped to the cucumber genome and more than 500 alternative splicing events were identified in 443 cucumber genes. The unigenes were further functionally annotated by comparing their sequences to different protein and functional domain databases and assigned with Gene Ontology (GO) terms. A biochemical pathway database containing 343 predicted pathways was also created based on the annotations of the unigenes. Digital expression analysis identified approximately 200 differentially expressed genes between flowers of WI1983G and WI1983H and provided novel insights into molecular mechanisms of plant sex determination process. Furthermore, a set of SSR motifs and high confidence SNPs between WI1983G and WI1983H were identified from the ESTs, which provided the material basis for future genetic linkage and QTL analysis. CONCLUSION: A large set of EST sequences were generated from cucumber flower buds of two different sex types. Differentially expressed genes between these two different sex-type flowers, as well as putative SSR and SNP markers, were identified. These EST sequences provide valuable information to further understand molecular mechanisms of plant sex determination process and forms a rich resource for future functional genomics analysis, marker development and cucumber breeding. Title: Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1 Kim SJ, Zhang Z, Saha A, Sarkar C, Zhao Z, Xu Y, Mukherjee AB Ref: Neuroscience Letters, 479:292, 2010 : PubMed ESTHER: Kim_2010_Neurosci.Lett_479_292 PubMedSearch: Kim 2010 Neurosci.Lett 479 292 PubMedID: 20561933 Gene_locus related to this paper: mouse-ppt Abstract Reactive oxygen species (ROS) damage brain lipids, carbohydrates, proteins, as well as DNA and may contribute to neurodegeneration. We previously reported that ER- and oxidative stress cause neuronal apoptosis in infantile neuronal ceroid lipofuscinosis (INCL), a lethal neurodegenerative storage disease, caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. Polyunsaturated fatty acids (PUFA) are essential components of cell membrane phospholipids in the brain and excessive ROS may cause oxidative damage of PUFA leading to neuronal death. Using cultured neurons and neuroprogenitor cells from mice lacking Ppt1, which mimic INCL, we demonstrate that Ppt1-deficient neurons and neuroprogenitor cells contain high levels of ROS, which may cause peroxidation of PUFA and render them incapable of providing protection against oxidative stress. We tested whether treatment of these cells with omega-3 or omega-6 PUFA protects the neurons and neuroprogenitor cells from oxidative stress and suppress apoptosis. We report here that both omega-3 and omega-6 fatty acids protect the Ppt1-deficient cells from ER- as well as oxidative stress and suppress apoptosis. Our results suggest that PUFA supplementation may have neuroprotective effects in INCL. Title: The sequence and de novo assembly of the giant panda genome Li R, Fan W, Tian G, Zhu H, He L, Cai J, Huang Q, Cai Q, Li B and Yang H <103 more author(s)> Li R, Fan W, Tian G, Zhu H, He L, Cai J, Huang Q, Cai Q, Li B, Bai Y, Zhang Z, Zhang Y, Wang W, Li J, Wei F, Li H, Jian M, Nielsen R, Li D, Gu W, Yang Z, Xuan Z, Ryder OA, Leung FC, Zhou Y, Cao J, Sun X, Fu Y, Fang X, Guo X, Wang B, Hou R, Shen F, Mu B, Ni P, Lin R, Qian W, Wang G, Yu C, Nie W, Wang J, Wu Z, Liang H, Min J, Wu Q, Cheng S, Ruan J, Wang M, Shi Z, Wen M, Liu B, Ren X, Zheng H, Dong D, Cook K, Shan G, Zhang H, Kosiol C, Xie X, Lu Z, Li Y, Steiner CC, Lam TT, Lin S, Zhang Q, Li G, Tian J, Gong T, Liu H, Zhang D, Fang L, Ye C, Zhang J, Hu W, Xu A, Ren Y, Zhang G, Bruford MW, Li Q, Ma L, Guo Y, An N, Hu Y, Zheng Y, Shi Y, Li Z, Liu Q, Chen Y, Zhao J, Qu N, Zhao S, Tian F, Wang X, Wang H, Xu L, Liu X, Vinar T, Wang Y, Lam TW, Yiu SM, Liu S, Huang Y, Yang G, Jiang Z, Qin N, Li L, Bolund L, Kristiansen K, Wong GK, Olson M, Zhang X, Li S, Yang H (- 103) Ref: Nature, 463:311, 2010 : PubMed ESTHER: Li_2010_Nature_463_311 PubMedSearch: Li 2010 Nature 463 311 PubMedID: 20010809 Gene_locus related to this paper: ailme-ABH15, ailme-ACHE, ailme-BCHE, ailme-d2gtv3, ailme-d2gty9, ailme-d2gu87, ailme-d2gu97, ailme-d2gve7, ailme-d2gwu1, ailme-d2gx08, ailme-d2gyt0, ailme-d2gz36, ailme-d2gz37, ailme-d2gz38, ailme-d2gz39, ailme-d2gz40, ailme-d2h5r9, ailme-d2h7b7, ailme-d2h9c9, ailme-d2h794, ailme-d2hau7, ailme-d2hau8, ailme-d2hcd9, ailme-d2hdi6, ailme-d2heu6, ailme-d2hga4, ailme-d2hqw5, ailme-d2hs98, ailme-d2hsx4, ailme-d2hti6, ailme-d2htv3, ailme-d2htz6, ailme-d2huc7, ailme-d2hwj8, ailme-d2hwy7, ailme-d2hxm1, ailme-d2hyc8, ailme-d2hyv2, ailme-d2hz11, ailme-d2hza3, ailme-d2hzr4, ailme-d2i1l4, ailme-d2i2g8, ailme-g1l7m3, ailme-g1lu36, ailme-g1m769, ailme-g1mc29, ailme-g1mdj8, ailme-g1mdr5, ailme-g1mfp4, ailme-g1mfx5, ailme-g1lj41, ailme-g1lm28, ailme-g1l3u1, ailme-g1l7l1, ailme-g1m5i3, ailme-g1l2f6, ailme-g1lji5, ailme-g1lqk3, ailme-g1l8s9, ailme-d2h717, ailme-d2h718, ailme-d2h719, ailme-d2h720, ailme-g1m5v0, ailme-g1m5y7, ailme-g1lkt7, ailme-g1l2a1, ailme-g1lsc8, ailme-g1lrp4, ailme-d2gv02, ailme-g1mik5, ailme-g1ljr1, ailme-g1lxw7, ailme-d2h8b5, ailme-d2h2r2, ailme-d2h9w7, ailme-g1meh3, ailme-g1m719 Abstract Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes. Title: Complete genome sequences of Yersinia pestis from natural foci in China Shen X, Wang Q, Xia L, Zhu X, Zhang Z, Liang Y, Cai H, Zhang E, Wei J and Hai R <4 more author(s)> Shen X, Wang Q, Xia L, Zhu X, Zhang Z, Liang Y, Cai H, Zhang E, Wei J, Chen C, Song Z, Zhang H, Yu D, Hai R (- 4) Ref: Journal of Bacteriology, 192:3551, 2010 : PubMed ESTHER: Shen_2010_J.Bacteriol_192_3551 PubMedSearch: Shen 2010 J.Bacteriol 192 3551 PubMedID: 20453098 Gene_locus related to this paper: yerpe-dlhh, yerpe-PIP, yerpe-PLDB, yerpe-PTRB, yerpe-y1616, yerpe-y3224, yerpe-YPLA, yerpe-YPO0180, yerpe-YPO0667, yerpe-YPO0773, yerpe-YPO0986, yerpe-YPO2526, yerpe-YPO2814 Abstract Yersinia pestis, the causative agent of plague, is a deadly bacterium that affects humans. Strain D106004 was isolated from a new plague focus in Yulong County, China, in 2006. To gain insights into the epidemic origin, we have sequenced the genomes of D106004 and strains Z176003 and D182038, isolated from neighboring regions. Title: Repeated nicotine administration robustly increases bPiDDB inhibitory potency at alpha6beta2-containing nicotinic receptors mediating nicotine-evoked dopamine release Smith AM, Pivavarchyk M, Wooters TE, Zhang Z, Zheng G, McIntosh JM, Crooks PA, Bardo MT, Dwoskin LP Ref: Biochemical Pharmacology, 80:402, 2010 : PubMed ESTHER: Smith_2010_Biochem.Pharmacol_80_402 PubMedSearch: Smith 2010 Biochem.Pharmacol 80 402 PubMedID: 20346923 Abstract The novel nicotinic receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), and its chemically reduced analog, r-bPiDDB, potently inhibit nicotine-evoked dopamine (DA) release from rat striatal slices. Since tobacco smokers self-administer nicotine repeatedly, animal models incorporating repeated nicotine treatment allow for mechanistic evaluation of therapeutic candidates following neuroadaptive changes. The current study determined the ability of bPiDDB, r-bPiDDB and alpha-conotoxin MII (alpha-CtxMII), a peptide antagonist selective for alpha6beta2-containing nAChRs, to inhibit nicotine-evoked [(3)H]DA release from striatal slices from rats repeatedly administered nicotine (0.4mg/kg for 10 days) or saline (control). Concomitant exposure to maximally effective concentrations of r-bPiDDB (1nM) and alpha-CtxMII (1nM) resulted in inhibition of nicotine-evoked [(3)H]DA release no greater than that produced by either antagonist alone, suggesting that r-bPiDDB inhibits alpha6beta2-containing nAChRs. Repeated nicotine treatment increased locomotor activity, demonstrating behavioral sensitization. Concentration-response curves for nicotine-evoked [(3)H]DA release were not different between nicotine-treated and control groups. Maximal inhibition for alpha-CtxMII was greater following repeated nicotine compared to control (I(max)=90% vs. 62%), with no change in potency. bPiDDB was 3-orders of magnitude more potent in inhibiting nicotine-evoked [(3)H]DA release in nicotine-treated rats compared to control rats (IC(50)=5pM vs. 6nM), with no change in maximal inhibition. Neither a shift to the left in the concentration response nor a change in maximal inhibition was observed for r-bPiDDB following repeated nicotine. Thus, repeated nicotine treatment may differentially regulate the stoichiometry, conformation and/or composition of alpha6beta2-containing nAChRs mediating nicotine-evoked striatal DA release. Therefore, bPiDDB and r-bPiDDB appear to target different alpha6beta2-containing nAChR subtypes. Title: Study of paraoxonase-1 function on tissue damage of dichlorvos Wang NN, Dai H, Yuan L, Han ZK, Sun J, Zhang Z, Zhao M Ref: Toxicol Lett, 196:125, 2010 : PubMed ESTHER: Wang_2010_Toxicol.Lett_196_125 PubMedSearch: Wang 2010 Toxicol.Lett 196 125 PubMedID: 20412842 Abstract To examine the protective efficacy of paraoxonase-1 (PON1) against tissue damage caused by dichlorvos, purified rabbit PON1 was injected intravenously into rats 30min before they were given dichlorvos, while dichlorvos administration group and corn coil administration group were conducted to compare. Blood was collected at different time points after dichlorvos administration to examine the acetyl cholinesterase (AChE) inhibition level and clinical signs were observed after poisoning. 72h later, animals were anesthetized and the hippocampus, liver, lung and kidney were removed for observation of ultrastructure. AChE activities in PON1 pretreament group were statistically significant from dichlorvos administration group (P<0.01). The clinical signs were alleviated by PON1 significantly (P<0.05). The most common change of organophosphorus poisoning damage to liver was small lipid-like structures could be seen throughout the liver structure. In kidney, dense bodies were seen. The most significant changes in lung were lost of lamellar structure of lamellar bodies in type II alveolar epithelial cell. As for changes of hippocampus, demyaliation takes place after acute organophosphorus, but neural edema was not improved significantly in our study. In conclusion, PON1 can decrease the AChE inhibition, and alleviated clinical signs and tissue damage caused by dichlorvos. Title: Lipase immobilized by modification-coupled and adsorption-cross-linking methods: A comparative study Yang J, Ma X, Zhang Z, Chen B, Li S, Wang G Ref: Biotechnol Adv, 28:644, 2010 : PubMed ESTHER: Yang_2010_Biotechnol.Adv_28_644 PubMedSearch: Yang 2010 Biotechnol.Adv 28 644 PubMedID: 20478376 Abstract Candida antarctica lipase was immobilized by an adsorption and cross-linking method with NW-ZT2 and by modification-coupled method with a silica-PEG gel. The final product silica-PEG-lipase was confirmed by IR spectra. The optimum pH value, the optimum temperature, the thermo-stabilities and operational stabilities for two kinds of immobilized lipase were also determined. Results show that the silica-PEG-lipase gel was superior to the lipase immobilized by adsorption and cross-linking, however both are viable for use in transesterification reactions. Title: Novel bis-2,2,6,6-tetramethylpiperidine (bis-TMP) and bis-mecamylamine antagonists at neuronal nicotinic receptors mediating nicotine-evoked dopamine release Zhang Z, Pivavarchyk M, Subramanian KL, Deaciuc AG, Dwoskin LP, Crooks PA Ref: Bioorganic & Medicinal Chemistry Lett, 20:1420, 2010 : PubMed ESTHER: Zhang_2010_Bioorg.Med.Chem.Lett_20_1420 PubMedSearch: Zhang 2010 Bioorg.Med.Chem.Lett 20 1420 PubMedID: 20079634 Abstract By linking two or three mecamylamine or 2,2,6,6-tetramethylpiperidine (TMP) molecules together via a linear lipophilic bis-methylene linker or a specially designed conformationally restricted tris-linker, a series of bis- and tris-tertiary amine analogs has been synthesized and evaluated as potent antagonists at nAChRs mediating nicotine-evoked [3H]dopamine release from rat striatal slices. Compounds 7e, 14b and 16 demonstrated high potency in decreasing nicotine-evoked [3H]dopamine release (IC50=2.2, 46, and 107 nM, respectively). The preliminary structure-activity data obtained with these new analogs suggest the importance of the length of the methylene linker in the bis-analog series. Such bis-tertiary amino analogs may provide a new strategy for the design of drugable ligands that have high inhibitory potency against nAChRs mediating nicotine-evoked dopamine release in striatum, which have been suggested to be target receptors of interest in the development of potential smoking cessation therapies. Title: Bio-resolution of glycidyl (o, m, p)-methylphenyl ethers by Bacillus megaterium Zhang Z, Sheng Y, Jiang K, Wang Z, Zheng Y, Zhu Q Ref: Biotechnol Lett, 32:513, 2010 : PubMed ESTHER: Zhang_2010_Biotechnol.Lett_32_513 PubMedSearch: Zhang 2010 Biotechnol.Lett 32 513 PubMedID: 20013303 Abstract A newly isolated Bacillus megaterium with epoxide hydrolase activity resolved racemic glycidyl (o, m, p)-methylphenyl ethers to give enantiopure epoxides in 84-99% enantiomeric excess and with 21-73 enantiomeric ratios. The (S)-enantiomer was obtained from rac-glycidyl (o or m)-methylphenyl ether while the (R)-epoxides was obtained from glycidyl p-methylphenyl ether. The observations are explained at the level by enzyme-substrate docking studies. Title: Complete genome sequence of the rifamycin SV-producing Amycolatopsis mediterranei U32 revealed its genetic characteristics in phylogeny and metabolism Zhao W, Zhong Y, Yuan H, Wang J, Zheng H, Wang Y, Cen X, Xu F, Bai J and Zhao GP <16 more author(s)> Zhao W, Zhong Y, Yuan H, Wang J, Zheng H, Wang Y, Cen X, Xu F, Bai J, Han X, Lu G, Zhu Y, Shao Z, Yan H, Li C, Peng N, Zhang Z, Zhang Y, Lin W, Fan Y, Qin Z, Hu Y, Zhu B, Wang S, Ding X, Zhao GP (- 16) Ref: Cell Res, 20:1096, 2010 : PubMed ESTHER: Zhao_2010_Cell.Res_20_1096 PubMedSearch: Zhao 2010 Cell.Res 20 1096 PubMedID: 20567260 Gene_locus related to this paper: amyme-ester, amymu-d8hj63, amymu-d8hka5, amymu-d8hl19, amymu-d8hp99, amymu-d8hpp2, amymu-d8htc9, amymu-d8hu68, amymu-d8hu87, amymu-d8hy40, amymu-d8hy73, amymu-d8i2j5, amymu-d8i4g6, amymu-d8i8i8, amymu-d8hri1, amymu-d8hsx7, amymu-d8hzu8, amymu-d8i5g7, amyms-g0g7f0, amymu-a0a0h3cwx4, amymu-a0a0h3d2a5, amymu-a0a0h3d6r8 Abstract Amycolatopsis mediterranei is used for industry-scale production of rifamycin, which plays a vital role in antimycobacterial therapy. As the first sequenced genome of the genus Amycolatopsis, the chromosome of strain U32 comprising 10,236,715 base pairs, is one of the largest prokaryotic genomes ever sequenced so far. Unlike the linear topology found in streptomycetes, this chromosome is circular, particularly similar to that of Saccharopolyspora erythraea and Nocardia farcinica, representing their close relationship in phylogeny and taxonomy. Although the predicted 9,228 protein-coding genes in the A. mediterranei genome shared the greatest number of orthologs with those of S. erythraea, it was unexpectedly followed by Streptomyces coelicolor rather than N. farcinica, indicating the distinct metabolic characteristics evolved via adaptation to diverse ecological niches. Besides a core region analogous to that common in streptomycetes, a novel 'quasi-core' with typical core characteristics is defined within the non-core region, where 21 out of the total 26 gene clusters for secondary metabolite production are located. The rifamycin biosynthesis gene cluster located in the core encodes a cytochrome P450 enzyme essential for the conversion of rifamycin SV to B, revealed by comparing to the highly homologous cluster of the rifamycin B-producing strain S699 and further confirmed by genetic complementation. The genomic information of A. mediterranei demonstrates a metabolic network orchestrated not only for extensive utilization of various carbon sources and inorganic nitrogen compounds but also for effective funneling of metabolic intermediates into the secondary antibiotic synthesis process under the control of a seemingly complex regulatory mechanism. Title: A novel endophytic Huperzine A-producing fungus, Shiraia sp. Slf14, isolated from Huperzia serrata Zhu D, Wang J, Zeng Q, Zhang Z, Yan R Ref: J Appl Microbiol, 109:1469, 2010 : PubMed ESTHER: Zhu_2010_J.Appl.Microbiol_109_1469 PubMedSearch: Zhu 2010 J.Appl.Microbiol 109 1469 PubMedID: 20602655 Abstract AIMS: To characterize and identify a novel Huperzine A (HupA)-producing fungal strain Slf14 isolated from Huperzia serrata (Thunb. ex Murray) Trev. in China. METHODS AND RESULTS: The isolation, identification and characterization of a novel endophytic fungus producing HupA specifically and consistently from the leaves of H. serrata were investigated. The fungus was identified as Shiraia sp. Slf14 by molecular and morphological methods. The HupA produced by this endophytic fungus was shown to be identical to authentic HupA analysed by thin layer chromatographic, High-performance liquid chromatography (HPLC), LC-MS, (1) H NMR and acetylcholinesterase (AChE) inhibition activity in vitro. The amount of HupA produced by Shiraia sp. Slf14 was quantified to be 327.8 mug l(-1) by HPLC, which was far higher than that of the reported endophytic fungi, Acremonium sp., Blastomyces sp. and Botrytis sp. CONCLUSIONS: The production of HupA by endophyte Shiraia sp. Slf14 is an enigmatic observation. It would be interesting to further study the HupA production and regulation by the cultured endophyte in H. serrata and in axenic cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: Although the current accumulation of HupA by the endophyte is not very high, it could provide a promising alterative approach for large-scale production of HupA. However, further strain improvement and the fermentation process optimization are required to result in the consistent and dependable production. Title: Nicotinic receptor-based therapeutics and candidates for smoking cessation Dwoskin LP, Smith AM, Wooters TE, Zhang Z, Crooks PA, Bardo MT Ref: Biochemical Pharmacology, 78:732, 2009 : PubMed ESTHER: Dwoskin_2009_Biochem.Pharmacol_78(7)_732 PubMedSearch: Dwoskin 2009 Biochem.Pharmacol 78(7) 732 PubMedID: 19523455 Abstract Tobacco dependence is the most preventable cause of death and is a chronic, relapsing disorder in which compulsive tobacco use persists despite known negative health consequences. All currently available cessation agents (nicotine, varenicline and bupropion) have limited efficacy and are associated with high relapse rates, revealing a need for more efficacious, alternative pharmacotherapies. The major alkaloid in tobacco, nicotine, activates nicotinic receptors (nAChRs) which increase brain extracellular dopamine producing nicotine reward leading to addiction. nAChRs are located primarily presynaptically and modulate synaptic activity by regulating neurotransmitter release. Subtype-selective nAChR antagonists that block reward-relevant mesocorticolimbic and nigrostriatal dopamine release induced by nicotine may offer advantages over current therapies. An innovative approach is to provide pharmacotherapies which are antagonists at nAChR subtypes mediating nicotine evoked dopamine release. In addition, providing multiple medications with a wider array of targets and mechanisms should provide more treatment options for individuals who are not responsive to the currently available pharmacotherapies. This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors. Title: Targeting reward-relevant nicotinic receptors in the discovery of novel pharmacotherapeutic agents to treat tobacco dependence Dwoskin LP, Pivavarchyk M, Joyce BM, Neugebauer NM, Zheng G, Zhang Z, Bardo MT, Crooks PA Ref: Nebr Symp Motiv, 55:31, 2009 : PubMed ESTHER: Dwoskin_2009_Nebr.Symp.Motiv_55_31 PubMedSearch: Dwoskin 2009 Nebr.Symp.Motiv 55 31 PubMedID: 19013938 Title: The genome of the cucumber, Cucumis sativus L Huang S, Li R, Zhang Z, Li L, Gu X, Fan W, Lucas WJ, Wang X, Xie B and Du Y <77 more author(s)> Huang S, Li R, Zhang Z, Li L, Gu X, Fan W, Lucas WJ, Wang X, Xie B, Ni P, Ren Y, Zhu H, Li J, Lin K, Jin W, Fei Z, Li G, Staub J, Kilian A, van der Vossen EA, Wu Y, Guo J, He J, Jia Z, Tian G, Lu Y, Ruan J, Qian W, Wang M, Huang Q, Li B, Xuan Z, Cao J, Asan, Wu Z, Zhang J, Cai Q, Bai Y, Zhao B, Han Y, Li Y, Li X, Wang S, Shi Q, Liu S, Cho WK, Kim JY, Xu Y, Heller-Uszynska K, Miao H, Cheng Z, Zhang S, Wu J, Yang Y, Kang H, Li M, Liang H, Ren X, Shi Z, Wen M, Jian M, Yang H, Zhang G, Yang Z, Chen R, Ma L, Liu H, Zhou Y, Zhao J, Fang X, Fang L, Liu D, Zheng H, Zhang Y, Qin N, Li Z, Yang G, Yang S, Bolund L, Kristiansen K, Li S, Zhang X, Wang J, Sun R, Zhang B, Jiang S, Du Y (- 77) Ref: Nat Genet, 41:1275, 2009 : PubMed ESTHER: Huang_2009_Nat.Genet_41_1275 PubMedSearch: Huang 2009 Nat.Genet 41 1275 PubMedID: 19881527 Gene_locus related to this paper: cucsa-a0a0a0ktw5, cucsa-a0a0a0lnt6, cucsa-a0a0a0kpn7, cucsa-a0a0a0lvt9, cucsa-a0a0a0kdx8, cucsa-a0a0a0m228, cucsa-a0a0a0kz31, cucsa-a0a0a0k5t5, cucsa-a0a0a0kfs7, cucsa-a0a0a0kjj7, cucsa-a0a0a0kzs7, cucsa-a0a0a0l0a6, cucsa-a0a0a0l4w4, cucsa-a0a0a0lpz0, cucsa-a0a0a0ls66 Abstract Cucumber is an economically important crop as well as a model system for sex determination studies and plant vascular biology. Here we report the draft genome sequence of Cucumis sativus var. sativus L., assembled using a novel combination of traditional Sanger and next-generation Illumina GA sequencing technologies to obtain 72.2-fold genome coverage. The absence of recent whole-genome duplication, along with the presence of few tandem duplications, explains the small number of genes in the cucumber. Our study establishes that five of the cucumber's seven chromosomes arose from fusions of ten ancestral chromosomes after divergence from Cucumis melo. The sequenced cucumber genome affords insight into traits such as its sex expression, disease resistance, biosynthesis of cucurbitacin and 'fresh green' odor. We also identify 686 gene clusters related to phloem function. The cucumber genome provides a valuable resource for developing elite cultivars and for studying the evolution and function of the plant vascular system. Title: Selective inhibition of acetylcholine-evoked responses of alpha7 neuronal nicotinic acetylcholine receptors by novel tris- and tetrakis-azaaromatic quaternary ammonium antagonists Lopez-Hernandez GY, Thinschmidt JS, Zheng G, Zhang Z, Crooks PA, Dwoskin LP, Papke RL Ref: Molecular Pharmacology, 76:652, 2009 : PubMed ESTHER: Lopez-Hernandez_2009_Mol.Pharmacol_76_652 PubMedSearch: Lopez-Hernandez 2009 Mol.Pharmacol 76 652 PubMedID: 19556356 Abstract A family of 20 tris-azaaromatic quaternary ammonium (AQA) compounds were tested for their inhibition of alpha7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes. The potency of inhibitory activity was related to the hydrophobic character of the tris head groups. Two tris-AQA compounds were studied in detail: the highly effective inhibitor 1,3,5-tri-[5-(1-quinolinum)-pent-1-yn-1-yl]-benzene tribromide (tPyQB) and the less potent antagonist 1,3,5,-tri-{5-[1-(2-picolinium)]-pent-1-yn-1-yl}benzene tribromide (tPy2PiB). In addition, we evaluated 1,2,4,5-tetra-{5-[1-(3-benzyl)pyridinium]pent-1-yl}benzene tetrabromide (tkP3BzPB), a tetrakis-AQA with very hydrophobic headgroups. We compared the activity of the AQA compounds to the frequently used alpha7-antagonist methyllycaconitine (MLA). Both tPyQB and tkP3BzPB were selective antagonists of alpha7. However, although inhibition by tPyQB was reversible within 5 min, the recovery time constant for tkP3BzPB inhibition was 26.6 +/- 0.8 min, so that the equilibrium inhibition in the prolonged presence of nanomolar concentrations of tkP3BzPB was nearly 100%. The potency, selectivity, and slow reversibility of tkP3BzPB were comparable with or greater than that of MLA. The inhibitory actions of tPyQB, tPy2PiB, and tkP3BzPB were evaluated on the acetylcholine (ACh)-evoked responses of native nAChRs in rat brain slices. The alpha7-mediated responses of hippocampal interneurons were effectively reduced by 1 microM tPyQB and tkP3BzPB but not tPy2PiB. In rat medial septum, tkP3BzPB produced a greater inhibition of ACh-evoked responses of cells with fast inward currents (type I) than of cells with predominantly slow kinetics (type II), suggesting that tkP3BzPB can block alpha7 yet preserve the responsiveness of non-alpha7 receptors. These agents might be helpful in elucidating complex receptor responses in brain regions with mixed populations of nAChRs. Title: An integrated genetic and cytogenetic map of the cucumber genome Ren Y, Zhang Z, Liu J, Staub JE, Han Y, Cheng Z, Li X, Lu J, Miao H and Huang S <6 more author(s)> Ren Y, Zhang Z, Liu J, Staub JE, Han Y, Cheng Z, Li X, Lu J, Miao H, Kang H, Xie B, Gu X, Wang X, Du Y, Jin W, Huang S (- 6) Ref: PLoS ONE, 4:e5795, 2009 : PubMed ESTHER: Ren_2009_PLoS.ONE_4_E5795 PubMedSearch: Ren 2009 PLoS.ONE 4 E5795 PubMedID: 19495411 Gene_locus related to this paper: cucsa-a0a0a0ktw5, cucsa-a0a0a0lnt6, cucsa-a0a0a0kpn7, cucsa-a0a0a0lvt9, cucsa-a0a0a0kdx8, cucsa-a0a0a0m228, cucsa-a0a0a0kz31, cucsa-a0a0a0k5t5, cucsa-a0a0a0kfs7, cucsa-a0a0a0kjj7, cucsa-a0a0a0kzs7, cucsa-a0a0a0l0a6, cucsa-a0a0a0l4w4, cucsa-a0a0a0lpz0 Abstract The Cucurbitaceae includes important crops such as cucumber, melon, watermelon, squash and pumpkin. However, few genetic and genomic resources are available for plant improvement. Some cucurbit species such as cucumber have a narrow genetic base, which impedes construction of saturated molecular linkage maps. We report herein the development of highly polymorphic simple sequence repeat (SSR) markers originated from whole genome shotgun sequencing and the subsequent construction of a high-density genetic linkage map. This map includes 995 SSRs in seven linkage groups which spans in total 573 cM, and defines approximately 680 recombination breakpoints with an average of 0.58 cM between two markers. These linkage groups were then assigned to seven corresponding chromosomes using fluorescent in situ hybridization (FISH). FISH assays also revealed a chromosomal inversion between Cucumis subspecies [C. sativus var. sativus L. and var. hardwickii (R.) Alef], which resulted in marker clustering on the genetic map. A quarter of the mapped markers showed relatively high polymorphism levels among 11 inbred lines of cucumber. Among the 995 markers, 49%, 26% and 22% were conserved in melon, watermelon and pumpkin, respectively. This map will facilitate whole genome sequencing, positional cloning, and molecular breeding in cucumber, and enable the integration of knowledge of gene and trait in cucurbits. Title: The novel nicotinic receptor antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked [(3)H]norepinephrine overflow from rat hippocampal slices Smith AM, Dhawan GK, Zhang Z, Siripurapu KB, Crooks PA, Dwoskin LP Ref: Biochemical Pharmacology, 78:889, 2009 : PubMed ESTHER: Smith_2009_Biochem.Pharmacol_78(7)_889 PubMedSearch: Smith 2009 Biochem.Pharmacol 78(7) 889 PubMedID: 19631612 Abstract Smoking is a significant health concern and strongly correlated with clinical depression. Depression is associated with decreased extracellular NE concentrations in brain. Smokers may be self-medicating and alleviating their depression through nicotine stimulated norepinephrine (NE) release. Several antidepressants inhibit NE transporter (NET) function, thereby augmenting extracellular NE concentrations. Antidepressants, such as bupropion, also inhibit nicotinic receptor (nAChR) function. The current study determined if a recently discovered novel nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked NE release from superfused rat hippocampal slices. Previous studies determined that bPiDDB potently (IC(50)=2 nM) inhibits nicotine-evoked striatal [(3)H]dopamine (DA) release in vitro, nicotine-evoked DA release in nucleus accumbens in vivo, and nicotine self-administration in rats. In the current study, nicotine stimulated [(3)H]NE release from rat hippocampal slices (EC(50)=50 microM). bPiDDB inhibited (IC(50)=430 nM; I(max)=90%) [(3)H]NE release evoked by 30 microM nicotine. For comparison, the nonselective nAChR antagonist, mecamylamine, and the alpha7 antagonist, methyllycaconitine, also inhibited nicotine-evoked [(3)H]NE release (IC(50)=31 and 275 nM, respectively; I(max)=91% and 72%, respectively). Inhibition by bPiDDB and mecamylamine was not overcome by increasing nicotine concentrations; Schild regression slope was different from unity, consistent with allosteric inhibition. Thus, bPiDDB was 200-fold more potent inhibiting nAChRs mediating nicotine-evoked [(3)H]DA release from striatum than those mediating nicotine-evoked [(3)H]NE release from hippocampus. Title: The Bifidobacterium dentium Bd1 genome sequence reflects its genetic adaptation to the human oral cavity Ventura M, Turroni F, Zomer A, Foroni E, Giubellini V, Bottacini F, Canchaya C, Claesson MJ, He F and van Sinderen D <13 more author(s)> Ventura M, Turroni F, Zomer A, Foroni E, Giubellini V, Bottacini F, Canchaya C, Claesson MJ, He F, Mantzourani M, Mulas L, Ferrarini A, Gao B, Delledonne M, Henrissat B, Coutinho P, Oggioni M, Gupta RS, Zhang Z, Beighton D, Fitzgerald GF, O'Toole PW, van Sinderen D (- 13) Ref: PLoS Genet, 5:e1000785, 2009 : PubMed ESTHER: Ventura_2009_PLoS.Genet_5_E1000785 PubMedSearch: Ventura 2009 PLoS.Genet 5 E1000785 PubMedID: 20041198 Gene_locus related to this paper: 9bifi-b1s8c5, bifdb-d2q6z7, bifdb-d2q9l6, bifdb-d2q844, bifdb-d2q9j3 Abstract Bifidobacteria, one of the relatively dominant components of the human intestinal microbiota, are considered one of the key groups of beneficial intestinal bacteria (probiotic bacteria). However, in addition to health-promoting taxa, the genus Bifidobacterium also includes Bifidobacterium dentium, an opportunistic cariogenic pathogen. The genetic basis for the ability of B. dentium to survive in the oral cavity and contribute to caries development is not understood. The genome of B. dentium Bd1, a strain isolated from dental caries, was sequenced to completion to uncover a single circular 2,636,368 base pair chromosome with 2,143 predicted open reading frames. Annotation of the genome sequence revealed multiple ways in which B. dentium has adapted to the oral environment through specialized nutrient acquisition, defences against antimicrobials, and gene products that increase fitness and competitiveness within the oral niche. B. dentium Bd1 was shown to metabolize a wide variety of carbohydrates, consistent with genome-based predictions, while colonization and persistence factors implicated in tissue adhesion, acid tolerance, and the metabolism of human saliva-derived compounds were also identified. Global transcriptome analysis demonstrated that many of the genes encoding these predicted traits are highly expressed under relevant physiological conditions. This is the first report to identify, through various genomic approaches, specific genetic adaptations of a Bifidobacterium taxon, Bifidobacterium dentium Bd1, to a lifestyle as a cariogenic microorganism in the oral cavity. In silico analysis and comparative genomic hybridization experiments clearly reveal a high level of genome conservation among various B. dentium strains. The data indicate that the genome of this opportunistic cariogen has evolved through a very limited number of horizontal gene acquisition events, highlighting the narrow boundaries that separate commensals from opportunistic pathogens. Title: Glu88 in the non-catalytic domain of acylpeptide hydrolase plays dual roles: charge neutralization for enzymatic activity and formation of salt bridge for thermodynamic stability Yang G, Bai A, Gao L, Zhang Z, Zheng B, Feng Y Ref: Biochimica & Biophysica Acta, 1794:94, 2009 : PubMed ESTHER: Yang_2009_Biochim.Biophys.Acta_1794_94 PubMedSearch: Yang 2009 Biochim.Biophys.Acta 1794 94 PubMedID: 18930847 Abstract Acylpeptide hydrolase of Aeropyrum pernix K1 is composed of a catalytic alpha/beta hydrolase domain and a non-catalytic beta-propeller domain. The Glu88 residue of the propeller domain is highly conserved in the prolyl oligopeptidase family and forms an inter-domain salt bridge with Arg526, a key residue for substrate binding. We have dissected the functions of Glu88 using site-directed mutagenesis, steady-state kinetics analyses, and molecular dynamics simulations. In E88A and E88A/R526K mutants, with a broken inter-domain salt bridge and a positive charge at position 526, catalytic activities for both a peptidase substrate and an esterase substrate were almost abolished. Analysis of the pH dependence of the mutants' reaction kinetics indicates that these mutations lead to changes in the electrostatic environment of the active site, which can be modulated by chloride ions. These findings indicate that the neutralization at position 526 is favorable for the activity of the enzyme, which is also verified by the catalytic behavior of E88A/R526V mutant. All mutants have lower thermodynamic stability than the wild-type. Therefore, Glu88 plays two major roles in the function of the enzyme: neutralizing the positive charge of Arg526, thereby increasing the enzymatic activity, and forming the Glu88-Arg526 salt bridge, thereby stabilizing the protein. Title: [Cloning, expression and characterization of a novel lipase gene lipB from Aspergillus niger F044] Yang J, Zhang Z, Liu L, Yan Y Ref: Wei Sheng Wu Xue Bao, 49:1095, 2009 : PubMed ESTHER: Yang_2009_Wei.Sheng.Wu.Xue.Bao_49_1095 PubMedSearch: Yang 2009 Wei.Sheng.Wu.Xue.Bao 49 1095 PubMedID: 19835173 Abstract OBJECTIVE: We cloned, expressed and characterized a novel lipase gene lipB from Aspergillus niger F044, to facilitate the large scale production and application of that enzyme. METHOD: We cloned lipB gene and the cDNA sequence by PCR and RT-PCR, and then cloned the open reading frame of lipB into pET28a vector and expressed by isopropyl beta-D-1-thiogalactopyranoside (IPTG) induction. After Ni-agarose purification, the characteristics were determined and the conformation change was checked by circular dichroism methods. RESULTS: The novel lipase genes cDNA of lipB were cloned from Aspergillus niger F044 (GenBank: FJ536287, FJ536288) and expressed in Escherichia coli. The molecular weight of LipB was about 43 kDa. The optimal substrate of this enzyme is 4-nitrophenyl octanoate (pNPC-C8) with Km = 5.98 mmol/L. The optimal temperature and pH was 50 degrees C and pH 6.0. The enzyme was stable below 40 degrees C. After incubated at 60 degrees C for 1 h, only 18.8% activity remained. After treated by 2 mmol/L Ca2+ for 1 h, the activity improved 2.6-fold. CONCLUSION: Enzymatic characteristics of LipB determined showed this enzyme might have potential in industrial applications. Title: Annotation and expression of carboxylesterases in the silkworm, Bombyx mori Yu QY, Lu C, Li WL, Xiang ZH, Zhang Z Ref: BMC Genomics, 10:553, 2009 : PubMed ESTHER: Yu_2009_BMC.Genomics_10_553 PubMedSearch: Yu 2009 BMC.Genomics 10 553 PubMedID: 19930670 Abstract BACKGROUND: Carboxylesterase is a multifunctional superfamily and ubiquitous in all living organisms, including animals, plants, insects, and microbes. It plays important roles in xenobiotic detoxification, and pheromone degradation, neurogenesis and regulating development. Previous studies mainly used Dipteran Drosophila and mosquitoes as model organisms to investigate the roles of the insect COEs in insecticide resistance. However, genome-wide characterization of COEs in phytophagous insects and comparative analysis remain to be performed. RESULTS: Based on the newly assembled genome sequence, 76 putative COEs were identified in Bombyx mori. Relative to other Dipteran and Hymenopteran insects, alpha-esterases were significantly expanded in the silkworm. Genomics analysis suggested that BmCOEs showed chromosome preferable distribution and 55% of which were tandem arranged. Sixty-one BmCOEs were transcribed based on cDNA/ESTs and microarray data. Generally, most of the COEs showed tissue specific expressions and expression level between male and female did not display obvious differences. Three main patterns could be classified, i.e. midgut-, head and integument-, and silk gland-specific expressions. Midgut is the first barrier of xenobiotics peroral toxicity, in which COEs may be involved in eliminating secondary metabolites of mulberry leaves and contaminants of insecticides in diet. For head and integument-class, most of the members were homologous to odorant-degrading enzyme (ODE) and antennal esterase. RT-PCR verified that the ODE-like esterases were also highly expressed in larvae antenna and maxilla, and thus they may play important roles in degradation of plant volatiles or other xenobiotics. CONCLUSION: B. mori has the largest number of insect COE genes characterized to date. Comparative genomic analysis suggested that the gene expansion mainly occurred in silkworm alpha-esterases. Expression evidence indicated that the expanded genes were specifically expressed in midgut, integument and head, implying that these genes may have important roles in detoxifying secondary metabolites of mulberry leaves, contaminants in diet, and odorants. Our results provide some new insights into functions and evolutionary characteristics of COEs in phytophagous insects. Title: Synaptotagmin IV: a multifunctional regulator of peptidergic nerve terminals Zhang Z, Bhalla A, Dean C, Chapman ER, Jackson MB Ref: Nat Neurosci, 12:163, 2009 : PubMed ESTHER: Zhang_2009_Nat.Neurosci_12_163 PubMedSearch: Zhang 2009 Nat.Neurosci 12 163 PubMedID: 19136969 Abstract Many members of the synaptotagmin (Syt) protein family bind Ca(2+) and trigger exocytosis, but some Syt proteins appear to have no Ca(2+)-dependent actions and their biological functions remain obscure. Syt IV is an activity-induced brain protein with no known Ca(2+)-dependent interactions and its subcellular localization and biological functions have sparked considerable controversy. We found Syt IV on both micro- and dense-core vesicles in posterior pituitary nerve terminals in mice. In terminals from Syt IV knockout mice compared with those from wild types, low Ca(2+) entry triggered more exocytosis, high Ca(2+) entry triggered less exocytosis and endocytosis was accelerated. In Syt IV knockouts, dense-core and microvesicle fusion was enhanced in cell-attached patches and dense-core vesicle fusion pores had conductances that were half as large as those in wild types. Given the neuroendocrine functions of the posterior pituitary, changes in Syt IV levels could be involved in endocrine transitions involving alterations in the release of the neuropeptides oxytocin and vasopressin. Title: Spatial variation of Yersinia pestis from Yunnan Province of China Zhang Z, Hai R, Song Z, Xia L, Liang Y, Cai H, Shen X, Zhang E, Xu J and Yu XJ <1 more author(s)> Zhang Z, Hai R, Song Z, Xia L, Liang Y, Cai H, Shen X, Zhang E, Xu J, Yu D, Yu XJ (- 1) Ref: American Journal of Tropical Medicine & Hygiene, 81:714, 2009 : PubMed ESTHER: Zhang_2009_Am.J.Trop.Med.Hyg_81_714 PubMedSearch: Zhang 2009 Am.J.Trop.Med.Hyg 81 714 PubMedID: 19815893 Gene_locus related to this paper: yerpe-BIOH, yerpe-dlhh, yerpe-PIP, yerpe-PLDB, yerpe-PTRB, yerpe-Y0507, yerpe-y1616, yerpe-y3224, yerpe-YPLA, yerpe-YPO0180, yerpe-YPO0667, yerpe-YPO0773, yerpe-YPO0986, yerpe-YPO1501, yerpe-YPO2526, yerpe-YPO2814 Abstract Yunnan Province of China is considered the site of origin for modern plague. We analyzed the genotypes of eight Yersinia pestis strains isolated from three counties in Yunnan Province by pulse field gel electrophoresis (PFGE). PFGE showed that strains isolated from the same site were identical regardless of hosts or year of isolation. However, Y. pestis strains isolated from geographically distinct loci were genetically divergent. Whole genome sequences of two strains from two foci in Yunnan showed that the genetic variation of Y. pestis strains was caused by genome rearrangement. We concluded that Y. pestis strains in each epidemic focus in Yunnan were a clonal population and selected by host environments. The genomic variability of the Y. pestis strains from different foci were caused by genome rearrangement, which may provide a positive selective advantage for Y. pestis to adapt to its host environments. Title: Trimethylene carbonate and epsilon-caprolactone based (co)polymer networks: mechanical properties and enzymatic degradation Bat E, Plantinga JA, Harmsen MC, van Luyn MJ, Zhang Z, Grijpma DW, Feijen J Ref: Biomacromolecules, 9:3208, 2008 : PubMed ESTHER: Bat_2008_Biomacromolecules_9_3208 PubMedSearch: Bat 2008 Biomacromolecules 9 3208 PubMedID: 18855440 Abstract High molecular weight trimethylene carbonate (TMC) and epsilon-caprolactone (CL) (co)polymers were synthesized. Melt pressed (co)polymer films were cross-linked by gamma irradiation (25 kGy or 50 kGy) in vacuum, yielding gel fractions of up to 70%. The effects of copolymer composition and irradiation dose on the cytotoxicity, surface properties, degradation behavior, and mechanical and thermal properties of these (co)polymers and networks were investigated. Upon incubation with cell culture medium containing extracts of (co)polymers and networks, human foreskin fibroblasts remained viable. For all (co)polymers and networks, cell viabilities were determined to be higher than 94%. The formed networks were flexible, with elastic moduli ranging from 2.7 to 5.8 MPa. Moreover, these form-stable networks were creep resistant under dynamic conditions. The permanent deformation after 2 h relaxation was as low as 1% after elongating to 50% strain for 20 times. The in vitro enzymatic erosion behavior of these hydrophobic (co)polymers and networks was investigated using aqueous lipase solutions. The erosion rates in lipase solution could be tuned linearly from 0.8 to 45 mg/(cm (2) x day) by varying the TMC to CL ratio and the irradiation dose. The copolymers and networks degraded essentially by a surface erosion mechanism. Title: N,N'-Alkane-diyl-bis-3-picoliniums as nicotinic receptor antagonists: inhibition of nicotine-evoked dopamine release and hyperactivity Dwoskin LP, Wooters TE, Sumithran SP, Siripurapu KB, Joyce BM, Lockman PR, Manda VK, Ayers JT, Zhang Z and Bardo MT <3 more author(s)> Dwoskin LP, Wooters TE, Sumithran SP, Siripurapu KB, Joyce BM, Lockman PR, Manda VK, Ayers JT, Zhang Z, Deaciuc AG, McIntosh JM, Crooks PA, Bardo MT (- 3) Ref: Journal of Pharmacology & Experimental Therapeutics, 326:563, 2008 : PubMed ESTHER: Dwoskin_2008_J.Pharmacol.Exp.Ther_326_563 PubMedSearch: Dwoskin 2008 J.Pharmacol.Exp.Ther 326 563 PubMedID: 18460644 Abstract The current study evaluated a new series of N,N'-alkane-diyl-bis-3-picolinium (bAPi) analogs with C6-C12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [3H]dopamine (DA) overflow, for blood-brain barrier choline transporter affinity, and for attenuation of discriminative stimulus and locomotor stimulant effects of nicotine. bAPi analogs exhibited little affinity for alpha4beta2* (* indicates putative nAChR subtype assignment) and alpha7* high-affinity ligand binding sites and exhibited no inhibition of DA transporter function. With the exception of C6, all analogs inhibited nicotine-evoked [3H]DA overflow (IC50 = 2 nM-6 microM; Imax = 54-64%), with N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; C12) being most potent. bPiDDB did not inhibit electrically evoked [3H]DA overflow, suggesting specific nAChR inhibitory effects and a lack of toxicity to DA neurons. Schild analysis suggested that bPiDDB interacts in an orthosteric manner at nAChRs mediating nicotine-evoked [3H]DA overflow. To determine whether bPiDDB interacts with alpha-conotoxin MII-sensitive alpha6beta2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and alpha-conotoxin MII (1 nM). Inhibition of nicotine-evoked [3H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with alpha6beta2-containing nAChRs. C7, C8, C10, and C12 analogs exhibited high affinity for the blood-brain barrier choline transporter in vivo, suggesting brain bioavailability. Although none of the analogs altered the discriminative stimulus effect of nicotine, C8, C9, C10, and C12 analogs decreased nicotine-induced hyperactivity in nicotine-sensitized rats, without reducing spontaneous activity. Further development of nAChR antagonists that inhibit nicotine-evoked DA release and penetrate brain to antagonize DA-mediated locomotor stimulant effects of nicotine as novel treatments for nicotine addiction is warranted. Title: Palmitoyl protein thioesterase-1 deficiency impairs synaptic vesicle recycling at nerve terminals, contributing to neuropathology in humans and mice Kim SJ, Zhang Z, Sarkar C, Tsai PC, Lee YC, Dye L, Mukherjee AB Ref: J Clinical Investigation, 118:3075, 2008 : PubMed ESTHER: Kim_2008_J.Clin.Invest_118_3075 PubMedSearch: Kim 2008 J.Clin.Invest 118 3075 PubMedID: 18704195 Gene_locus related to this paper: mouse-ppt, human-PPT1 Abstract Neuronal ceroid lipofuscinoses represent the most common childhood neurodegenerative storage disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is caused by palmitoyl protein thioesterase-1 (PPT1) deficiency. Although INCL patients show signs of abnormal neurotransmission, manifested by myoclonus and seizures, the molecular mechanisms by which PPT1 deficiency causes this abnormality remain obscure. Neurotransmission relies on repeated cycles of exo- and endocytosis of the synaptic vesicles (SVs), in which several palmitoylated proteins play critical roles. These proteins facilitate membrane fusion, which is required for neurotransmitter exocytosis, recycling of the fused SV membrane components, and regeneration of fresh vesicles. However, palmitoylated proteins require depalmitoylation for recycling. Using postmortem brain tissues from an INCL patient and tissue from the PPT1-knockout (PPT1-KO) mice that mimic INCL, we report here that PPT1 deficiency caused persistent membrane anchorage of the palmitoylated SV proteins, which hindered the recycling of the vesicle components that normally fuse with the presynaptic plasma membrane during SV exocytosis. Thus, the regeneration of fresh SVs, essential for maintaining the SV pool size at the synapses, was impaired, leading to a progressive loss of readily releasable SVs and abnormal neurotransmission. This abnormality may contribute to INCL neuropathology. Title: [Experimental study on peripheral nerve plasticity in rats] Ma N, Lu L, Ma L, Zhang J, Zhang Z Ref: Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 22:1073, 2008 : PubMed ESTHER: Ma_2008_Zhongguo.Xiu.Fu.Chong.Jian.Wai.Ke.Za.Zhi_22_1073 PubMedSearch: Ma 2008 Zhongguo.Xiu.Fu.Chong.Jian.Wai.Ke.Za.Zhi 22 1073 PubMedID: 18822731 Abstract OBJECTIVE: To observe the plastic changes of sensory nerve in terms of structure and function when target organ changed through making the rat model of nerve regeneration by anastomosing the proximal end of sensory nerve and the distal end of motor nerve. Title: Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras Papke RL, Dwoskin LP, Crooks PA, Zheng G, Zhang Z, McIntosh JM, Stokes C Ref: Neuropharmacology, 54:1189, 2008 : PubMed ESTHER: Papke_2008_Neuropharmacol_54_1189 PubMedSearch: Papke 2008 Neuropharmacol 54 1189 PubMedID: 18448138 Abstract Heterologous expression systems have increased the feasibility of developing selective ligands to target nicotinic acetylcholine receptor (nAChR) subtypes. However, the alpha6 subunit, a component in nAChRs that mediates some of the reinforcing effects of nicotine, is not easily expressed in systems such as the Xenopus oocyte. Certain aspects of alpha6-containing receptor pharmacology have been studied by using chimeric subunits containing the alpha6 ligand-binding domain. However, these chimeras would not be sensitive to an alpha6-selective channel blocker; therefore we developed an alpha6 chimera (alpha4/6) that has the transmembrane and intracellular domains of alpha6 and the extracellular domain of alpha4. We examined the pharmacological properties of alpha4/6-containing receptors and other important nAChR subtypes, including alpha7, alpha4beta2, alpha4beta4, alpha3beta4, alpha3beta2, and alpha3beta2beta3, as well as receptors containing alpha6/3 and alpha6/4 chimeras. Our data show that the absence or presence of the beta4 subunit is an important factor for sensitivity to the ganglionic blocker mecamylamine, and that dihydro-beta-erythroidine is most effective on subtypes containing the alpha4 subunit extracellular domain. Receptors containing the alpha6/4 subunit are sensitive to alpha-conotoxin PIA, while receptors containing the reciprocal alpha4/6 chimera are insensitive. In experiments with novel antagonists of nicotine-evoked dopamine release, the alpha4/6 chimera indicated that structural rigidity was a key element of compounds that could result in selectivity for noncompetitive inhibition of alpha6-containing receptors. Our data extend the information available on prototypical nAChR antagonists, and establish the alpha4/6 chimera as a useful new tool for screening drugs as selective nAChR antagonists. Title: The novel nicotinic receptor antagonist N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide decreases nicotine-induced dopamine metabolism in rat nucleus accumbens Rahman S, Neugebauer NM, Zhang Z, Crooks PA, Dwoskin LP, Bardo MT Ref: European Journal of Pharmacology, 601:103, 2008 : PubMed ESTHER: Rahman_2008_Eur.J.Pharmacol_601_103 PubMedSearch: Rahman 2008 Eur.J.Pharmacol 601 103 PubMedID: 19000671 Abstract The current study examined the effect of the novel nicotinic acetylcholine receptor antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), on nicotine-induced dopamine metabolism in rat nucleus accumbens, striatum and medial prefrontal cortex. Acute nicotine (0.5 mg/kg, s.c.) produced an increase in the content of dihydroxyphenylacetic acid (DOPAC) in nucleus accumbens, but not in striatum or medial prefrontal cortex. Pretreatment with bPiDDB (1 or 3 mg/kg, s.c.) dose-dependently inhibited the nicotine-induced increase in DOPAC content in nucleus accumbens. These results indicate that bPiDDB inhibits the nicotine-induced increase in DOPAC in reward-relevant brain region targeting nicotinic acetylcholine receptors. Title: Region-specific effects of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide on nicotine-induced increase in extracellular dopamine in vivo Rahman S, Zhang Z, Papke RL, Crooks PA, Dwoskin LP, Bardo MT Ref: British Journal of Pharmacology, 153:792, 2008 : PubMed ESTHER: Rahman_2008_Br.J.Pharmacol_153_792 PubMedSearch: Rahman 2008 Br.J.Pharmacol 153 792 PubMedID: 18059317 Abstract BACKGROUND AND PURPOSE: Systemic administration of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), an antagonist of nicotinic acetylcholine receptors (nAChRs) attenuated the nicotine-induced increase in dopamine levels in nucleus accumbens (NAcc). EXPERIMENTAL APPROACH: Using in vivo microdialysis, we investigated the effects of local perfusion of the novel nAChR antagonist bPiDDB into the NAcc or ventral tegmental area (VTA) on increased extracellular dopamine in NAcc, induced by systemic nicotine. We also examined the concentration-dependent effects of bPiDDB on the acetylcholine (ACh)-evoked response of specific recombinant neuronal nAChR subtypes expressed in Xenopus oocytes, using electrophysiological methods. KEY Title: RAGE signaling contributes to neuroinflammation in infantile neuronal ceroid lipofuscinosis Saha A, Kim SJ, Zhang Z, Lee YC, Sarkar C, Tsai PC, Mukherjee AB Ref: FEBS Letters, 582:3823, 2008 : PubMed ESTHER: Saha_2008_FEBS.Lett_582_3823 PubMedSearch: Saha 2008 FEBS.Lett 582 3823 PubMedID: 18948101 Gene_locus related to this paper: mouse-ppt, human-PPT1 Abstract Palmitoyl-protein thioesterase-1 (PPT1) deficiency causes infantile neuronal ceroid lipofuscinosis (INCL), a devastating childhood neurodegenerative storage disorder. We previously reported that neuronal apoptosis in INCL is mediated by endoplasmic reticulum-stress. ER-stress disrupts Ca(2+)-homeostasis and stimulates the expression of Ca(2+)-binding proteins. We report here that in the PPT1-deficient human and mouse brain the levels of S100B, a Ca(2+)-binding protein, and its receptor, RAGE (receptor for advanced glycation end-products) are elevated. We further demonstrate that activation of RAGE signaling in astroglial cells mediates pro-inflammatory cytokine production, which is inhibited by SiRNA-mediated suppression of RAGE expression. We propose that RAGE signaling contributes to neuroinflammation in INCL. Title: Structure-based design and synthesis of benzimidazole derivatives as dipeptidyl peptidase IV inhibitors Wallace MB, Feng J, Zhang Z, Skene RJ, Shi L, Caster CL, Kassel DB, Xu R, Gwaltney SL, 2nd Ref: Bioorganic & Medicinal Chemistry Lett, 18:2362, 2008 : PubMed ESTHER: Wallace_2008_Bioorg.Med.Chem.Lett_18_2362 PubMedSearch: Wallace 2008 Bioorg.Med.Chem.Lett 18 2362 PubMedID: 18346892 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: 2-phenylbenzylamine, Benzimidazole-derivative-2 Abstract A novel series of non-covalent, benzimidazole-based inhibitors of DPP-4 has been developed from a small fragment hit using structure-based drug design. A highly versatile synthetic route was created for the development of SAR, which led to the discovery of potent and selective inhibitors with excellent pharmaceutical properties. Title: ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones Wei H, Kim SJ, Zhang Z, Tsai PC, Wisniewski KE, Mukherjee AB Ref: Hum Mol Genet, 17:469, 2008 : PubMed ESTHER: Wei_2008_Hum.Mol.Genet_17_469 PubMedSearch: Wei 2008 Hum.Mol.Genet 17 469 PubMedID: 17989065 Abstract It is estimated that more than 40 different lysosomal storage disorders (LSDs) cumulatively affect one in 5000 live births, and in the majority of the LSDs, neurodegeneration is a prominent feature. Neuronal ceroid lipofuscinoses (NCLs), as a group, represent one of the most common (one in 12,500 births) neurodegenerative LSDs. The infantile NCL (INCL) is the most devastating neurodegenerative LSD, which is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. We previously reported that neuronal death by apoptosis in INCL, and in the PPT1-knockout (PPT1-KO) mice that mimic INCL, is at least in part caused by endoplasmic reticulum (ER) and oxidative stresses. In the present study, we sought to determine whether ER and oxidative stresses are unique manifestations of INCL or they are common to both neurodegenerative and non-neurodegenerative LSDs. Unexpectedly, we found that ER and oxidative stresses are common manifestations in cells from both neurodegenerative and non-neurodegenerative LSDs. Moreover, all LSD cells studied show extraordinary sensitivity to brefeldin-A-induced apoptosis, which suggests pre-existing ER stress conditions. Further, we uncovered that chemical disruption of lysosomal homeostasis in normal cells causes ER stress, suggesting a cross-talk between the lysosomes and the ER. Most importantly, we found that chemical chaperones that alleviate ER and oxidative stresses are also cytoprotective in all forms of LSDs studied. We propose that ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative LSDs and suggest that the beneficial effects of chemical/pharmacological chaperones are exerted, at least in part, by alleviating these stress conditions. Title: The genome of a lepidopteran model insect, the silkworm Bombyx mori Xia Q, Wang J, Zhou Z, Li R, Fan W, Cheng D, Cheng T, Qin J, Duana J and Morishita S <88 more author(s)> Xia Q, Wang J, Zhou Z, Li R, Fan W, Cheng D, Cheng T, Qin J, Duana J, Xu H, Li Q, Li N, Wang M, Dai F, Liu C, Lin Y, Zhao P, Zhang H, Liu S, Zha X, Li C, Zhao A, Pan M, Pan G, Shen Y, Gao Z, Wang Z, Wang G, Wu Z, Hou Y, Chai C, Yu Q, He N, Zhang Z, Li S, Yang H, Lu C, Xiang Z, Mita K, Kasahara M, Nakatani Y, Yamamoto K, Abe H, Ahsan B, Daimoni T, Doi K, Fujii T, Fujiwara H, Fujiyama A, Futahashi R, Hashimotol S, Ishibashi J, Iwami M, Kadono-Okuda K, Kanamori H, Kataoka H, Katsuma S, Kawaoka S, Kawasaki H, Kohara Y, Kozaki T, Kuroshu RM, Kuwazaki S, Matsushima K, Minami H, Nagayasu Y, Nakagawa T, Narukawa J, Nohata J, Ohishi K, Ono Y, Osanai-Futahashi M, Ozaki K, Qu W, Roller L, Sasaki S, Sasaki T, Seino A, Shimomura M, Shin-I T, Shinoda T, Shiotsuki T, Suetsugu Y, Sugano S, Suwa M, Suzuki Y, Takiya S, Tamura T, Tanaka H, Tanaka Y, Touhara K, Yamada T, Yamakawa M, Yamanaka N, Yoshikawa H, Zhong YS, Shimada T, Morishita S (- 88) Ref: Insect Biochemistry & Molecular Biology, 38:1036, 2008 : PubMed ESTHER: Xia_2008_Insect.Biochem.Mol.Biol_38_1036 PubMedSearch: Xia 2008 Insect.Biochem.Mol.Biol 38 1036 PubMedID: 19121390 Gene_locus related to this paper: bommo-a0mnw6, bommo-a1yw85, bommo-a9ls22, bommo-ACHE1, bommo-ACHE2, bommo-b0fgv8, bommo-b1q137, bommo-b1q139, bommo-b1q140, bommo-b1q141, bommo-b2zdz0, bommo-b3gef6, bommo-b3gef7, bommo-b3gs55, bommo-b3gs56, bommo-d2ktu3, bommo-d2ktu5, bommo-d9ile0, bommo-e1cga5, bommo-e1cga6, bommo-g8fpz6, bommo-h9iu43, bommo-h9iu46, bommo-h9iu47.1, bommo-h9iu47.2, bommo-h9iue5, bommo-h9ivg2, bommo-h9iwj7, bommo-h9iwj8, bommo-h9ix58, bommo-h9ixi1.1, bommo-h9ixi1.2, bommo-h9iy47, bommo-h9izw1, bommo-h9j0s4, bommo-h9j1y0, bommo-h9j3r0, bommo-h9j3w6, bommo-h9j3w7, bommo-h9j5t0, bommo-h9j8g3, bommo-h9j9k9, bommo-h9j066, bommo-h9j067, bommo-h9j593, bommo-h9j594, bommo-h9j990, bommo-h9jde8, bommo-h9jde9, bommo-h9jdf0, bommo-h9jds4, bommo-h9jle7, bommo-h9jn83, bommo-h9jn85, bommo-h9jrg2, bommo-h9jyh9, bommo-JHE, bommo-m1rmh6, bommo-q1hq05, bommo-q4tte1, bommo-h9j592, bommo-h9j604, bommo-h9jpm8, bommo-h9iss4, bommo-h9j2c7 Abstract Bombyx mori, the domesticated silkworm, is a major insect model for research, and the first lepidopteran for which draft genome sequences became available in 2004. Two independent data sets from whole-genome shotgun sequencing were merged and assembled together with newly obtained fosmid- and BAC-end sequences. The remarkably improved new assembly is presented here. The 8.5-fold sequence coverage of an estimated 432 Mb genome was assembled into scaffolds with an N50 size of approximately 3.7 Mb; the largest scaffold was 14.5 million base pairs. With help of a high-density SNP linkage map, we anchored 87% of the scaffold sequences to all 28 chromosomes. A particular feature was the high repetitive sequence content estimated to be 43.6% and that consisted mainly of transposable elements. We predicted 14,623 gene models based on a GLEAN-based algorithm, a more accurate prediction than the previous gene models for this species. Over three thousand silkworm genes have no homologs in other insect or vertebrate genomes. Some insights into gene evolution and into characteristic biological processes are presented here and in other papers in this issue. The massive silk production correlates with the existence of specific tRNA clusters, and of several sericin genes assembled in a cluster. The silkworm's adaptation to feeding on mulberry leaves, which contain toxic alkaloids, is likely linked to the presence of new-type sucrase genes, apparently acquired from bacteria. The silkworm genome also revealed the cascade of genes involved in the juvenile hormone biosynthesis pathway, and a large number of cuticular protein genes. Title: Tetrakis-azaaromatic quaternary ammonium salts: novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release Zhang Z, Zheng G, Pivavarchyk M, Deaciuc AG, Dwoskin LP, Crooks PA Ref: Bioorganic & Medicinal Chemistry Lett, 18:5753, 2008 : PubMed ESTHER: Zhang_2008_Bioorg.Med.Chem.Lett_18_5753 PubMedSearch: Zhang 2008 Bioorg.Med.Chem.Lett 18 5753 PubMedID: 18851914 Abstract A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC(50)=3, 28 and 56nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists. Title: Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, Navre M, Shi L, Skene RJ and Gwaltney SL, 2nd <4 more author(s)> Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, Navre M, Shi L, Skene RJ, Asakawa T, Takeuchi K, Xu R, Webb DR, Gwaltney SL, 2nd (- 4) Ref: Journal of Medicinal Chemistry, 50:2297, 2007 : PubMed ESTHER: Feng_2007_J.Med.Chem_50_2297 PubMedSearch: Feng 2007 J.Med.Chem 50 2297 PubMedID: 17441705 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: Alogliptin Abstract Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes. Title: The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens Rahman S, Neugebauer NM, Zhang Z, Crooks PA, Dwoskin LP, Bardo MT Ref: Neuropharmacology, 52:755, 2007 : PubMed ESTHER: Rahman_2007_Neuropharmacol_52_755 PubMedSearch: Rahman 2007 Neuropharmacol 52 755 PubMedID: 17097117 Abstract The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence. Title: Association of the genetic polymorphism of EPHX1 and EPHX2 with the susceptibility to chronic benzene poisoning Sun P, Zhang Z, Wu F, Wan J, Jin X, Xia Z Ref: Front Med China, 1:320, 2007 : PubMed ESTHER: Sun_2007_Front.Med.China_1_320 PubMedSearch: Sun 2007 Front.Med.China 1 320 PubMedID: 24573875 Abstract The aim of this study was to explore the association of the genetic polymorphism of EPHX1 and EPHX2 with the susceptibility to chronic benzene poisoning (CBP). A case-control study of 268 patients with CBP and 268 healthy workers matched by age and sex, all of whom were occupationally exposed to benzene, was conducted. The single nucleotide polymorphisms (SNPs, rs2854451, rs3738047, rs2234922 and rs1051741) of EPHX1 gene and the SNP (rs751141) of EPHX2 gene were tested by the TaqMan PCR method. In the subjects carrying the genotype of EPHX1 rs3738047 GG, the risk of CBP was decreased in the individuals simultaneously carrying EPHX1 rs2234922 G (P = 0.02). Alternatively, in the subjects carrying the genotype of EPHX1 rs2234922 AA, the risk of CBP was increased in the individuals simultaneously carrying the allele of EPHX2 rs751141A (P = 0.03). It was also found that there were potential interactions between alcohol consumption and the polymorphism of EPHX1 rs1051741 (chiH (2) = 5.28, P = 0.02) or rs2234922 (chiH (2) = 6.71, P = 0.01). Compared to individuals with EPHX1 rs1051741 CC or rs2234922 AA genotype in the drinkers, the risk of CBP in those carrying genotypes of EPHX1 rs1051741 CT+TT or rs2234922 AG+GG was decreased, respectively (P = 0.04, P < 0.01). Haplotype analysis of polymorphisms in EPHX1 showed that the risk of CBP was increased in the subjects with haplotype 2 (rs2854451-A, rs3738047-G, rs2234922-A, rs1051741-C) or haplotype 4 (rs2854451-G, rs3738047-A, rs2234922-G, rs1051741-T), but decreased in those with haplotype 6 (rs2854451-G, rs3738047-G, rs2234922-G, rs1051741-T) or haplotype 10 (rs2854451-A, rs3738047-A, rs2234922-G, rs1051741-T), respectively. Logistic regression analysis revealed that smoking might play a role in modifying the risk of CBP (OR = 0.313, 95% CI: 0.123-0.794, P = 0.015). The genetic polymorphism in EPHX1 may be associated with the risk of CBP in the Chinese occupational population and further research is needed for the association between the genetic polymorphism in EPHX2 and the susceptibility to CBP. Title: Molecular characterization of hsp20, encoding a small heat shock protein of bifidobacterium breve UCC2003 Ventura M, Canchaya C, Zhang Z, Fitzgerald GF, van Sinderen D Ref: Applied Environmental Microbiology, 73:4695, 2007 : PubMed ESTHER: Ventura_2007_Appl.Environ.Microbiol_73_4695 PubMedSearch: Ventura 2007 Appl.Environ.Microbiol 73 4695 PubMedID: 17513584 Gene_locus related to this paper: biflo-BL0581 Abstract Small heat shock proteins (sHSPs) are members of a diverse family of stress proteins that are important in cells to protect proteins under stressful conditions. Genome analysis of Bifidobacterium breve UCC2003 revealed a single sHSP-encoding gene, which was classified as a hsp20 gene by comparative analyses. Genomic surveillance of available genome sequences indicated that hsp20 homologs are not widely distributed in bacteria. In members of the genus Bifidobacterium, this gene appears to be present in only 7 of the 30 currently described species. Moreover, phylogenetic analysis using all available bacterial and eukaryotic sHSP sequences revealed a close relationship between bifidobacterial HSP20 and the class B sHSPs found in members of the division Firmicutes. The results of this comparative analysis and variation in codon usage content suggest that hsp20 was acquired by certain bifidobacteria through horizontal gene transfer. Analysis by slot blot, Northern blot, and primer extension experiments showed that transcription of hsp20 is strongly induced in response to severe heat shock regimens and by osmotic shock. Title: Blockade of phosphodiesterase Type 5 enhances rat neurohypophysial excitability and electrically evoked oxytocin release Zhang Z, Klyachko V, Jackson MB Ref: The Journal of Physiology, 584:137, 2007 : PubMed ESTHER: Zhang_2007_J.Physiol_584_137 PubMedSearch: Zhang 2007 J.Physiol 584 137 PubMedID: 17690141 Abstract Phosphodiesterase type 5 (PDE5) acts specifically on cyclic guanosine monophosphate (cGMP) and terminates cGMP-mediated signalling. PDE5 has a well established role in vascular smooth muscle, where specific inhibitors of PDE5 such as sildenafil correct erectile dysfunction by augmenting cGMP-mediated vascular relaxation. However, the role of PDE5 outside of the vasculature has received little attention. The present study tested PDE5 inhibitors on the cGMP-mediated modulation of K(+) channels in the neurohypophysis (posterior pituitary). Photolysis of caged-cGMP enhanced current through Ca(2+)-activated K(+) channels, and this enhancement recovered in about 2 min. Sildenafil essentially eliminated this recovery, suggesting that the reversal of K(+) current enhancement depends on cGMP breakdown. Activation of nitric oxide synthase during trains of activity in pituitary nerve terminals enhances excitability. When trains of stimulation were applied at regular intervals, sildenafil enhanced the excitability of neurohypophysial nerve terminals and increased the action potential firing probability. T-1032, a compound with high specificity for PDE5 over PDE6, had a similar action. Voltage imaging in intact neurohypophysis with a voltage sensitive absorbance dye showed that T-1032 reduced the failure of propagating action potentials during trains of activity. This indicates that PDE5 activity limits action potential propagation in neurohypophysial axons. Immunoassay of oxytocin, a neuropeptide hormone secreted by the posterior pituitary, demonstrated that sildenafil increased electrically evoked release. Thus, PDE5 plays an important role in the regulation of neurohypophysial function, and blockade of this enzyme can enhance the use-dependent facilitation of neurohypophysial secretion. Title: Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Saha A, Wei H, Xu Y, Xiao YJ and Mukherjee AB <2 more author(s)> Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Saha A, Wei H, Xu Y, Xiao YJ, Zhang P, Heffer A, Mukherjee AB (- 2) Ref: Hum Mol Genet, 16:837, 2007 : PubMed ESTHER: Zhang_2007_Hum.Mol.Genet_16_837 PubMedSearch: Zhang 2007 Hum.Mol.Genet 16 837 PubMedID: 17341491 Gene_locus related to this paper: mouse-ppt Abstract In the majority of neurodegenerative storage disorders, neuronal death in the brain is followed by infiltration of phagocytic cells (e.g. activated microglia, astroglia and macrophages) for the efficient removal of cell corpses. However, it is increasingly evident that these phagocytes may also cause death of adjoining viable neurons contributing to rapid progression of neurodegeneration. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating, neurodegenerative, lysosomal storage disorder caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 catalyzes the cleavage of thioester linkages in S-acylated (palmitoylated) proteins and its deficiency leads to abnormal accumulation of thioesterified polypeptides (ceroid) in lysosomes causing INCL pathogenesis. PPT1-knockout (PPT1-KO) mice mimic the clinical and pathological features of human INCL including rapid neuronal death by apoptosis and phagocyte infiltration. We previously reported that in PPT1-KO mice, the neurons undergo endoplasmic reticulum stress activating unfolded protein response, which mediates caspase-12 activation and apoptosis. However, the molecular mechanism(s) by which the phagocytic cells are recruited in the PPT1-KO mouse brain remains poorly understood. We report here that increased production of lysophosphatidylcholine (LPC), catalyzed by the activation of cytosolic phospholipase A(2) (cPLA(2)) in the PPT1-KO mouse brain, is a 'lipid signal' for phagocyte recruitment. We also report that an age-dependent increase in LPC levels in the PPT1-KO mouse brain positively correlates with elevated expression of the genes characteristically associated with phagocytes. We propose that increased cPLA(2)-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology. Title: Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation Zheng G, Zhang Z, Pivavarchyk M, Deaciuc AG, Dwoskin LP, Crooks PA Ref: Bioorganic & Medicinal Chemistry Lett, 17:6734, 2007 : PubMed ESTHER: Zheng_2007_Bioorg.Med.Chem.Lett_17_6734 PubMedSearch: Zheng 2007 Bioorg.Med.Chem.Lett 17 6734 PubMedID: 18029180 Abstract A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure-activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release. Title: Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL Kim SJ, Zhang Z, Lee YC, Mukherjee AB Ref: Hum Mol Genet, 15:1580, 2006 : PubMed ESTHER: Kim_2006_Hum.Mol.Genet_15_1580 PubMedSearch: Kim 2006 Hum.Mol.Genet 15 1580 PubMedID: 16571600 Gene_locus related to this paper: mouse-ppt Abstract The infantile neuronal ceroid lipofuscinosis (INCL), a rare (one in 100 000 births) but one of the most lethal inherited neurodegenerative storage disorders of childhood, is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in s-acylated (palmitoylated) proteins and facilitates their degradation and/or recycling. Thus, PPT1-deficiency leads to an abnormal intracellular accumulation of s-acylated proteins causing INCL pathogenesis. Although neuronal apoptosis is the suggested cause of neurodegeneration in this disease, the molecular mechanism(s) remains poorly understood. We recently reported that one of the major pathways of neuronal apoptosis in PPT1-knockout (PPT1-KO) mice that mimic INCL, is mediated by endoplasmic reticulum (ER) stress-induced caspase-12 activation. ER stress also increases the production of reactive oxygen species (ROS), disrupts Ca(2+) homeostasis and increases the potential for destabilizing mitochondrial membrane. Mitochondrial membrane destabilization activates caspase-9 present in this organelle, and can mediate apoptosis. We report here that the levels of superoxide dismutase (SOD), most likely induced by ROS, in human INCL as well as PPT1-KO mouse brain tissues are markedly elevated. Moreover, we demonstrate that activated caspase-3 and cleaved-PARP, indicative of apoptosis, are also increased in these tissues. Using cultured neurospheres from PPT1-KO and wild-type mouse fetuses, we further demonstrate that the levels of ROS, SOD-2, cleaved-caspase-9, activated caspase-3 and cleaved-PARP are elevated. We propose that: (i) ER stress due to PPT1-deficiency increases ROS and disrupts calcium homeostasis activating caspase-9 and (ii) caspase-9 activation mediates caspase-3 activation and apoptosis contributing to rapid neurodegeneration in INCL. Title: Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL Kim SJ, Zhang Z, Hitomi E, Lee YC, Mukherjee AB Ref: Hum Mol Genet, 15:1826, 2006 : PubMed ESTHER: Kim_2006_Hum.Mol.Genet_15_1826 PubMedSearch: Kim 2006 Hum.Mol.Genet 15 1826 PubMedID: 16644870 Gene_locus related to this paper: human-PPT1 Abstract Infantile neuronal ceroid lipofuscinosis (INCL), a neurodegenerative storage disorder of childhood, is caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in S-acylated (palmitoylated) proteins and its mutation causes abnormal intracellular accumulation of fatty-acylated proteins and peptides leading to INCL pathogenesis. Although apoptosis is the suggested cause of neurodegeneration in INCL, the molecular mechanism(s) of apoptosis remains unclear. Using the PPT1-knockout (PPT1-KO) mice that mimic INCL, we previously reported that one mechanism of apoptosis involves endoplasmic reticulum (ER) stress-induced caspase-12 activation. However, the human caspase-12 gene contains several mutations, which make it functionally inactive. Thus, it has been suggested that human caspase-4 is the counterpart of murine caspase-12. Here we report that in the human INCL brain ER stress-induced activation of unfolded protein response (UPR) mediates caspase-4 and caspase-3 activation and apoptosis. Moreover, we show that the INCL brain contains high level of growth-associated protein-43 (GAP-43), which is known to undergo palmitoylation. We also demonstrate that transfection of cultured INCL cells with a green fluorescent protein-GAP-43 cDNA construct shows abnormal localization of this protein in the ER. Further, INCL cells manifest evidence of ER stress and UPR (elevated levels of Grp-78/Bip and GADD153), caspase-4 as well as caspase-3 activation and cleavage of poly(ADP)-ribose polymerase, a compelling sign of apoptosis. Most importantly, we show that inhibition of caspase-4 activity protects INCL cells from undergoing apoptosis. Our results provide insight into at least one of the molecular mechanisms of apoptosis in INCL and may allow the identification of potential targets for therapeutic intervention. Title: Overexpression and characterization of a lipase from Bacillus subtilis Ma J, Zhang Z, Wang B, Kong X, Wang Y, Cao S, Feng Y Ref: Protein Expr Purif, 45:22, 2006 : PubMed ESTHER: Ma_2006_Protein.Expr.Purif_45_22 PubMedSearch: Ma 2006 Protein.Expr.Purif 45 22 PubMedID: 16039141 Abstract A novel plasmid, pBSR2, was constructed by incorporating a strong lipase promoter and a terminator into the original pBD64. A mature lipase gene from Bacillus subtilis strain IFFI10210, an existing strain for lipase expression, was cloned into the plasmid pBSR2 and transformed into B. subtilis A.S.1.1655. Thus, an overexpression strain, BSL2, was obtained. The yield of lipase is about 8.6 mg protein/g of wet weight of cell mass and 100-fold higher than that in B. subtilis strain IFFI10210. The recombinant lipase was purified in a three-step procedure involving ammonium sulfate fractionation, ion exchange, and gel filtration chromatography. Characterizations of the purified enzyme revealed a molecular mass of 24 kDa in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, maximum activity at 43 degrees C and pH 8.5 for hydrolysis of p-nitrophenyl caprylate. The values of Km and Vm were found to be 0.37 mM and 303 micromol mg-1 min-1, respectively. The substrate specificity study showed that p-nitrophenyl caprylate is a preference of the enzyme. The metal ions Ca2+, K+, and Mg2+ can activate the lipase, whereas Fe2+, Cu2+, and Co2+ inhibited it. The activity of the lipase can be increased about 48% by sodium taurocholate at the concentration of 7 mM and inhibited at concentrations over 10 mM. Title: The DNA sequence, annotation and analysis of human chromosome 3 Muzny DM, Scherer SE, Kaul R, Wang J, Yu J, Sudbrak R, Buhay CJ, Chen R, Cree A and Gibbs RA <100 more author(s)> Muzny DM, Scherer SE, Kaul R, Wang J, Yu J, Sudbrak R, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Morgan MB, Nazareth LV, Scott G, Sodergren E, Song XZ, Steffen D, Wei S, Wheeler DA, Wright MW, Worley KC, Yuan Y, Zhang Z, Adams CQ, Ansari-Lari MA, Ayele M, Brown MJ, Chen G, Chen Z, Clendenning J, Clerc-Blankenburg KP, Davis C, Delgado O, Dinh HH, Dong W, Draper H, Ernst S, Fu G, Gonzalez-Garay ML, Garcia DK, Gillett W, Gu J, Hao B, Haugen E, Havlak P, He X, Hennig S, Hu S, Huang W, Jackson LR, Jacob LS, Kelly SH, Kube M, Levy R, Li Z, Liu B, Liu J, Liu W, Lu J, Maheshwari M, Nguyen BV, Okwuonu GO, Palmeiri A, Pasternak S, Perez LM, Phelps KA, Plopper FJ, Qiang B, Raymond C, Rodriguez R, Saenphimmachak C, Santibanez J, Shen H, Shen Y, Subramanian S, Tabor PE, Verduzco D, Waldron L, Wang Q, Williams GA, Wong GK, Yao Z, Zhang J, Zhang X, Zhao G, Zhou J, Zhou Y, Nelson D, Lehrach H, Reinhardt R, Naylor SL, Yang H, Olson M, Weinstock G, Gibbs RA (- 100) Ref: Nature, 440:1194, 2006 : PubMed ESTHER: Muzny_2006_Nature_440_1194 PubMedSearch: Muzny 2006 Nature 440 1194 PubMedID: 16641997 Gene_locus related to this paper: human-AADAC, human-AADACL2, human-ABHD5, human-ABHD6, human-ABHD10, human-ABHD14A, human-APEH, human-BCHE, human-CIB, human-LIPH, human-MGLL, human-NLGN1, human-PLA1A Abstract After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion. Title: Effect of a novel nicotinic receptor antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide, on nicotine self-administration and hyperactivity in rats Neugebauer NM, Zhang Z, Crooks PA, Dwoskin LP, Bardo MT Ref: Psychopharmacology (Berl), 184:426, 2006 : PubMed ESTHER: Neugebauer_2006_Psychopharmacology.(Berl)_184_426 PubMedSearch: Neugebauer 2006 Psychopharmacology.(Berl) 184 426 PubMedID: 16220336 Abstract RATIONALE AND OBJECTIVE: Recent work has shown that the novel compound N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) may selectively block nicotinic acetylcholine receptors involved in regulating dopamine release. The current experiments examined the acute effect of bPiDDB on nicotine self-administration, sucrose-maintained responding, and nicotine-induced changes in acute and sensitized locomotor activity. Title: Widespread adaptive evolution of Drosophila genes with sex-biased expression Proschel M, Zhang Z, Parsch J Ref: Genetics, 174:893, 2006 : PubMed ESTHER: Proschel_2006_Genetics_174_893 PubMedSearch: Proschel 2006 Genetics 174 893 PubMedID: 16951084 Abstract Many genes in higher eukaryotes show sexually dimorphic expression, and these genes tend to be among the most divergent between species. In most cases, however, it is not known whether this rapid divergence is caused by positive selection or if it is due to a relaxation of selective constraint. To distinguish between these two possibilities, we surveyed DNA sequence polymorphism in 91 Drosophila melanogaster genes with male-, female-, or nonsex-biased expression and determined their divergence from the sister species D. simulans. Using several single- and multilocus statistical tests, we estimated the type and strength of selection influencing the evolution of the proteins encoded by genes of each expression class. Adaptive evolution, as indicated by a relative excess of nonsynonymous divergence between species, was common among the sex-biased genes (both male and female). Male-biased genes, in particular, showed a strong and consistent signal of positive selection, while female-biased genes showed more variation in the type of selection they experience. Genes expressed equally in the two sexes, in contrast, showed no evidence for adaptive evolution between D. melanogaster and D. simulans. This suggests that sexual selection and intersexual coevolution are the major forces driving genetic differentiation between species. Title: Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A, Mukherjee AB Ref: Hum Mol Genet, 15:337, 2006 : PubMed ESTHER: Zhang_2006_Hum.Mol.Genet_15_337 PubMedSearch: Zhang 2006 Hum.Mol.Genet 15 337 PubMedID: 16368712 Gene_locus related to this paper: mouse-ppt Abstract Numerous proteins undergo modification by palmitic acid (S-acylation) for their biological functions including signal transduction, vesicular transport and maintenance of cellular architecture. Although palmitoylation is an essential modification, these proteins must also undergo depalmitoylation for their degradation by lysosomal proteases. Palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme, cleaves thioester linkages in S-acylated proteins and removes palmitate residues facilitating the degradation of these proteins. Thus, inactivating mutations in the PPT1 gene cause infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disorder of childhood. Although rapidly progressing brain atrophy is the most dramatic pathological manifestation of INCL, the molecular mechanism(s) remains unclear. Using PPT1-knockout (PPT1-KO) mice that mimic human INCL, we report here that the endoplasmic reticulum (ER) in the brain cells of these mice is structurally abnormal. Further, we demonstrate that the level of growth-associated protein-43 (GAP-43), a palmitoylated neuronal protein, is elevated in the brains of PPT1-KO mice. Moreover, forced expression of GAP-43 in PPT1-deficient cells results in the abnormal accumulation of this protein in the ER. Consistent with these results, we found evidence for the activation of unfolded protein response (UPR) marked by elevated levels of phosphorylated translation initiation factor, eIF2alpha, increased expression of chaperone proteins such as glucose-regulated protein-78 and activation of caspase-12, a cysteine proteinase in the ER, mediating caspase-3 activation and apoptosis. Our results, for the first time, link PPT1 deficiency with the activation of UPR, apoptosis and neurodegeneration in INCL and identify potential targets for therapeutic intervention in this uniformly fatal disease. Title: The in vivo and in vitro degradation behavior of poly(trimethylene carbonate) Zhang Z, Kuijer R, Bulstra SK, Grijpma DW, Feijen J Ref: Biomaterials, 27:1741, 2006 : PubMed ESTHER: Zhang_2006_Biomaterials_27_1741 PubMedSearch: Zhang 2006 Biomaterials 27 1741 PubMedID: 16221493 Abstract The in vivo and in vitro degradation behavior of poly(trimethylene carbonate) (PTMC) polymers with number average molecular weights of 69 x 10(3), 89 x 10(3), 291 x 10(3) and 457 x 10(3)g/mol (respectively abbreviated as PTMC(69), PTMC(89), PTMC(291) and PTMC(457)) was investigated in detail. PTMC rods (3mm in diameter and 4mm in length) implanted in the femur and tibia of rabbits degraded by surface erosion. The mass loss of high molecular weight PTMC(457) specimens was 60wt% in 8 wks, whereas the mass loss of the lower molecular weight PTMC(89) specimens in the same period was 3 times lower. PTMC discs of different molecular weights immersed in lipase solutions (lipase from Thermomyces lanuginosus) degraded by surface erosion as well. The mass and thickness of high molecular weight PTMC(291) discs decreased linearly in time with an erosion rate of 6.7 microm/d. The erosion rate of the lower molecular weight PTMC(69) specimens was only 1.4mum/d. It is suggested that the more hydrophilic surface of the PTMC(69) specimens prevents the enzyme from acquiring a (hyper)active conformation. When PTMC discs were immersed in media varying in pH from 1 to 13, the non-enzymatic hydrolysis was extremely slow for both the high and low molecular weight samples. It can be concluded that enzymatic degradation plays an important role in the surface erosion of PTMC in vivo. Title: The Genomes of Oryza sativa: a history of duplications Yu J, Wang J, Lin W, Li S, Li H, Zhou J, Ni P, Dong W, Hu S and Yang H <88 more author(s)> Yu J, Wang J, Lin W, Li S, Li H, Zhou J, Ni P, Dong W, Hu S, Zeng C, Zhang J, Zhang Y, Li R, Xu Z, Li X, Zheng H, Cong L, Lin L, Yin J, Geng J, Li G, Shi J, Liu J, Lv H, Li J, Deng Y, Ran L, Shi X, Wang X, Wu Q, Li C, Ren X, Li D, Liu D, Zhang X, Ji Z, Zhao W, Sun Y, Zhang Z, Bao J, Han Y, Dong L, Ji J, Chen P, Wu S, Xiao Y, Bu D, Tan J, Yang L, Ye C, Xu J, Zhou Y, Yu Y, Zhang B, Zhuang S, Wei H, Liu B, Lei M, Yu H, Li Y, Xu H, Wei S, He X, Fang L, Huang X, Su Z, Tong W, Tong Z, Ye J, Wang L, Lei T, Chen C, Chen H, Huang H, Zhang F, Li N, Zhao C, Huang Y, Li L, Xi Y, Qi Q, Li W, Hu W, Tian X, Jiao Y, Liang X, Jin J, Gao L, Zheng W, Hao B, Liu S, Wang W, Yuan L, Cao M, McDermott J, Samudrala R, Wong GK, Yang H (- 88) Ref: PLoS Biol, 3:e38, 2005 : PubMed ESTHER: Yu_2005_PLoS.Biol_3_e38 PubMedSearch: Yu 2005 PLoS.Biol 3 e38 PubMedID: 15685292 Gene_locus related to this paper: orysa-Q7XTC5, orysa-Q852M6, orysa-Q8GSE8, orysa-Q9S7P1, orysa-Q9FYP7, orysa-Q5ZBH3, orysa-Q5ZA26, orysa-Q5JLP6, orysa-Q8H5P9, orysa-Q8H5P5, orysa-Q7F1Y5, orysa-Q949C9, orysa-cbp1, orysa-cbp3, orysa-cbpx, orysa-Q33B71, orysa-Q8GSJ3, orysa-LPL1, orysa-Q6YSZ8, orysa-Q8S5X5, orysa-Q8LIG3, orysa-Q6K7F5, orysa-Q7F1B1, orysa-Q8H4S9, orysa-Q69UB1, orysa-Q9FW17, orysa-Q337C3, orysa-Q7F959, orysa-Q84QZ6, orysa-Q84QY7, orysa-Q851E3, orysa-Q6YTH5, orysa-Q0JK71, orysa-Q8S1D9, orysa-Q5N8V4, orysa-Q0JCY4, orysa-Q8GTK2, orysa-B9EWJ8, orysa-Q8H3K6, orysa-Q6ZDG8, orysa-Q6ZDG6, orysa-Q6ZDG5, orysa-Q6ZDG4, orysa-Q5NAI4, orysa-Q658B2, orysa-Q5JMQ8, orysa-Q5QMD9, orysa-Q5N7L1, orysa-Q8RYV9, orysa-Q8H3R3, orysa-Q5SNH3, orysa-Q8W0F0, orysa-pir7a, orysa-pir7b, orysa-q2qlm4, orysa-q2qm78, orysa-q2qm82, orysa-q2qn31, orysa-q2qnj4, orysa-q2qnt9, orysa-q2qur1, orysa-q2qx94, orysa-q2qyi1, orysa-q2qyj1, orysa-q2r051, orysa-q2r077, orysa-q2ram0, orysa-q2rat1, orysa-q2rbb3, orysa-Q4VWY7, orysa-q5na00, orysa-q5nbu1, orysa-Q5QLC0, orysa-q5smv5, orysa-Q5VP27, orysa-q5vrt2, orysa-q5w6c5, orysa-q5z5a3, orysa-q5z9i2, orysa-q5z417, orysa-q5z901, orysa-Q5ZAM8, orysa-Q5ZBI5, orysa-Q5ZCR3, orysa-q6atz0, orysa-q6ave2, orysa-q6f358, orysa-q6h6s1, orysa-q6h7i6, orysa-q6i5q3, orysa-q6i5u7, orysa-q6j657, orysa-q6k3d9, orysa-q6k4q2, orysa-q6k880, orysa-q6l5b6, orysa-Q6L5F5, orysa-q6l556, orysj-q6yse8, orysa-q6yy42, orysa-q6yzk1, orysa-q6z8b1, orysa-q6z995, orysa-q6zc62, orysa-q6zia4, orysa-q6zjq6, orysa-q7x7y5, orysa-Q7XC50, orysa-q7xej4, orysa-q7xem8, orysa-q7xkj9, orysa-q7xr62, orysa-q7xr63, orysa-q7xr64, orysa-q7xsg1, orysa-q7xsq2, orysa-q7xts6, orysa-q7xv53, orysa-Q7XVB5, orysa-Q8L562, orysa-Q8LQS5, orysa-Q8RZ40, orysa-Q8RZ79, orysa-Q8S0U8, orysa-Q8S0V0, orysa-Q8S125, orysa-Q8SAY7, orysa-Q8SAY9, orysa-Q8W3C6, orysa-Q8W3F2, orysa-Q8W3F4, orysa-Q8W3F6, orysa-Q9LHX5, orysa-q33aq0, orysa-q53lh1, orysa-q53m20, orysa-q53nd8, orysa-q60e79, orysa-q60ew8, orysa-q67iz2, orysa-q67iz3, orysa-q67iz7, orysa-q67iz8, orysa-q67j02, orysa-q67j05, orysa-q67j07, orysa-q67j09, orysa-q67j10, orysa-q67tr6, orysa-q67tv0, orysa-q67uz1, orysa-q67v34, orysa-q67wz5, orysa-q69j38, orysa-q69k08, orysa-q69md7, orysa-q69me0, orysa-q69pf3, orysa-q69ti3, orysa-q69xr2, orysa-q69y12, orysa-q69y21, orysa-q75hy2, orysa-q75i01, orysa-Q94JD7, orysa-Q0J0A4, orysa-q651a8, orysa-q651z3, orysa-q652g4, orysa-q688m0, orysa-q688m8, orysa-q688m9, orysa-Q6H8G1, orysi-a2wn01, orysi-a2xc83, orysi-a2yh83, orysi-a2z179, orysi-a2zef2, orysi-b8a7e6, orysi-b8a7e7, orysi-b8bfe5, orysi-b8bhp9, orysj-a3b9l8, orysj-b9eub8, orysj-b9eya5, orysj-b9fi05, orysj-b9fkb0, orysj-b9fn42, orysj-b9gbb7, orysj-cgep, orysj-PLA7, orysj-q0d4u5, orysj-q0djj0, orysj-q0jaf0, orysj-q5jl22, orysj-q5jlw7, orysj-q5z419, orysj-q6h7q9, orysj-q6yvk6, orysj-q6z6i1, orysj-q7f8x1, orysj-q7xcx3, orysj-q9fwm6, orysj-q10j20, orysj-q10ss2, orysj-q69uw6, orysj-q94d71, orysj-q338c0, orysi-b8bly4, orysj-b9gbs4, orysi-a2zb88, orysj-b9gbs1, orysi-b8b698, orysj-pla4, orysj-pla1 Abstract We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000-40,000. Only 2%-3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family. Title: Genome sequence of the Brown Norway rat yields insights into mammalian evolution Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC and Collins F <218 more author(s)> Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC, Burch PE, Okwuonu G, Hines S, Lewis L, DeRamo C, Delgado O, Dugan-Rocha S, Miner G, Morgan M, Hawes A, Gill R, Celera, Holt RA, Adams MD, Amanatides PG, Baden-Tillson H, Barnstead M, Chin S, Evans CA, Ferriera S, Fosler C, Glodek A, Gu Z, Jennings D, Kraft CL, Nguyen T, Pfannkoch CM, Sitter C, Sutton GG, Venter JC, Woodage T, Smith D, Lee HM, Gustafson E, Cahill P, Kana A, Doucette-Stamm L, Weinstock K, Fechtel K, Weiss RB, Dunn DM, Green ED, Blakesley RW, Bouffard GG, de Jong PJ, Osoegawa K, Zhu B, Marra M, Schein J, Bosdet I, Fjell C, Jones S, Krzywinski M, Mathewson C, Siddiqui A, Wye N, McPherson J, Zhao S, Fraser CM, Shetty J, Shatsman S, Geer K, Chen Y, Abramzon S, Nierman WC, Havlak PH, Chen R, Durbin KJ, Egan A, Ren Y, Song XZ, Li B, Liu Y, Qin X, Cawley S, Cooney AJ, D'Souza LM, Martin K, Wu JQ, Gonzalez-Garay ML, Jackson AR, Kalafus KJ, McLeod MP, Milosavljevic A, Virk D, Volkov A, Wheeler DA, Zhang Z, Bailey JA, Eichler EE, Tuzun E, Birney E, Mongin E, Ureta-Vidal A, Woodwark C, Zdobnov E, Bork P, Suyama M, Torrents D, Alexandersson M, Trask BJ, Young JM, Huang H, Wang H, Xing H, Daniels S, Gietzen D, Schmidt J, Stevens K, Vitt U, Wingrove J, Camara F, Mar Alba M, Abril JF, Guigo R, Smit A, Dubchak I, Rubin EM, Couronne O, Poliakov A, Hubner N, Ganten D, Goesele C, Hummel O, Kreitler T, Lee YA, Monti J, Schulz H, Zimdahl H, Himmelbauer H, Lehrach H, Jacob HJ, Bromberg S, Gullings-Handley J, Jensen-Seaman MI, Kwitek AE, Lazar J, Pasko D, Tonellato PJ, Twigger S, Ponting CP, Duarte JM, Rice S, Goodstadt L, Beatson SA, Emes RD, Winter EE, Webber C, Brandt P, Nyakatura G, Adetobi M, Chiaromonte F, Elnitski L, Eswara P, Hardison RC, Hou M, Kolbe D, Makova K, Miller W, Nekrutenko A, Riemer C, Schwartz S, Taylor J, Yang S, Zhang Y, Lindpaintner K, Andrews TD, Caccamo M, Clamp M, Clarke L, Curwen V, Durbin R, Eyras E, Searle SM, Cooper GM, Batzoglou S, Brudno M, Sidow A, Stone EA, Payseur BA, Bourque G, Lopez-Otin C, Puente XS, Chakrabarti K, Chatterji S, Dewey C, Pachter L, Bray N, Yap VB, Caspi A, Tesler G, Pevzner PA, Haussler D, Roskin KM, Baertsch R, Clawson H, Furey TS, Hinrichs AS, Karolchik D, Kent WJ, Rosenbloom KR, Trumbower H, Weirauch M, Cooper DN, Stenson PD, Ma B, Brent M, Arumugam M, Shteynberg D, Copley RR, Taylor MS, Riethman H, Mudunuri U, Peterson J, Guyer M, Felsenfeld A, Old S, Mockrin S, Collins F (- 218) Ref: Nature, 428:493, 2004 : PubMed ESTHER: Gibbs_2004_Nature_428_493 PubMedSearch: Gibbs 2004 Nature 428 493 PubMedID: 15057822 Gene_locus related to this paper: rat-abhea, rat-abheb, rat-cd029, rat-d3zaw4, rat-dpp9, rat-d3zhq1, rat-d3zkp8, rat-d3zuq1, rat-d3zxw8, rat-d4a4w4, rat-d4a7w1, rat-d4a9l7, rat-d4a071, rat-d4aa31, rat-d4aa33, rat-d4aa61, rat-dglb, rat-f1lz91, rat-Kansl3, rat-nceh1, rat-Tex30, ratno-1hlip, ratno-1neur, ratno-1plip, ratno-2neur, ratno-3neur, ratno-3plip, ratno-ABH15, ratno-ACHE, ratno-balip, ratno-BCHE, ratno-cauxin, ratno-Ces1d, ratno-Ces1e, ratno-Ces2f, ratno-d3ze31, ratno-d3zp14, ratno-d3zxi3, ratno-d3zxq0, ratno-d3zxq1, ratno-d4a3d4, ratno-d4aa05, ratno-dpp4, ratno-dpp6, ratno-est8, ratno-FAP, ratno-hyep, ratno-hyes, ratno-kmcxe, ratno-lmcxe, ratno-LOC246252, ratno-MGLL, ratno-pbcxe, ratno-phebest, ratno-Ppgb, ratno-q4qr68, ratno-q6ayr2, ratno-q6q629, ratno-SPG21, ratno-thyro, rat-m0rc77, rat-a0a0g2k9y7, rat-a0a0g2kb83, rat-d3zba8, rat-d3zbj1, rat-d3zcr8, rat-d3zxw5, rat-d4a340, rat-f1lvg7, rat-m0r509, rat-m0r5d4, rat-b5den3, rat-d3zxk4, rat-d4a1b6, rat-d3zmg4, rat-ab17c Abstract The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution. Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites Zhang Z, Henzel WJ Ref: Protein Science, 13:2819, 2004 : PubMed ESTHER: Zhang_2004_Protein.Sci_13_2819 PubMedSearch: Zhang 2004 Protein.Sci 13 2819 PubMedID: 15340161 Gene_locus related to this paper: human-PLA2G15, human-SCPEP1 Abstract A number of computational tools are available for detecting signal peptides, but their abilities to locate the signal peptide cleavage sites vary significantly and are often less than satisfactory. We characterized a set of 270 secreted recombinant human proteins by automated Edman analysis and used the verified cleavage sites to evaluate the success rate of a number of computational prediction programs. An examination of the frequency of amino acid in the N-terminal region of the data set showed a preference of proline and glutamine but a bias against tyrosine. The data set was compared to the SWISS-PROT database and revealed a high percentage of discrepancies with cleavage site annotations that were computationally generated. The best program for predicting signal sequences was found to be SignalP 2.0-NN with an accuracy of 78.1% for cleavage site recognition. The new data set can be utilized for refining prediction algorithms, and we have built an improved version of profile hidden Markov model for signal peptides based on the new data. Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C and Gray A <42 more author(s)> Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (- 42) Ref: Genome Res, 13:2265, 2003 : PubMed ESTHER: Clark_2003_Genome.Res_13_2265 PubMedSearch: Clark 2003 Genome.Res 13 2265 PubMedID: 12975309 Gene_locus related to this paper: human-CES3, human-CES4A Abstract A large-scale effort, termed the Secreted Protein Discovery Initiative (SPDI), was undertaken to identify novel secreted and transmembrane proteins. In the first of several approaches, a biological signal sequence trap in yeast cells was utilized to identify cDNA clones encoding putative secreted proteins. A second strategy utilized various algorithms that recognize features such as the hydrophobic properties of signal sequences to identify putative proteins encoded by expressed sequence tags (ESTs) from human cDNA libraries. A third approach surveyed ESTs for protein sequence similarity to a set of known receptors and their ligands with the BLAST algorithm. Finally, both signal-sequence prediction algorithms and BLAST were used to identify single exons of potential genes from within human genomic sequence. The isolation of full-length cDNA clones for each of these candidate genes resulted in the identification of >1000 novel proteins. A total of 256 of these cDNAs are still novel, including variants and novel genes, per the most recent GenBank release version. The success of this large-scale effort was assessed by a bioinformatics analysis of the proteins through predictions of protein domains, subcellular localizations, and possible functional roles. The SPDI collection should facilitate efforts to better understand intercellular communication, may lead to new understandings of human diseases, and provides potential opportunities for the development of therapeutics. Title: Gramicidin derivatives as membrane-based pH sensors Borisenko V, Zhang Z, Woolley GA Ref: Biochimica & Biophysica Acta, 2:26, 2002 : PubMed ESTHER: Borisenko_2002_Biochim.Biophys.Acta_2_26 PubMedSearch: Borisenko 2002 Biochim.Biophys.Acta 2 26 PubMedID: 11750261 Abstract Ion channels provide a means for sensitive pH measurement at membrane interfaces. Detailed knowledge of the structure and function of gramicidin channels permits the engineering of pH-sensitive derivatives. Two derivatives, gramicidin-ethylenediamine and gramicidin-histamine, are shown to exhibit pH-dependent single-channel behaviour over the pH ranges 9-11 and 6.5-8.5, respectively. Thermal isomerization of a carbamate group at the entrance of the channels leads to a pattern of steps in single-channel recordings. The size of the steps depends on the time-averaged degree of protonation of the appended group (ethylenediamine or histamine). Measurement of the size of the steps thus permits single-molecule pH sensing under symmetrical pH conditions or in the presence of a pH gradient. Title: 2-deoxyglucose induces LTP in layer I of rat somatosensory cortex in vitro Zhang Z, Nguyen K, Krnjevic K Ref: Brain Research, 876:103, 2000 : PubMed ESTHER: Zhang_2000_Brain.Res_876_103 PubMedSearch: Zhang 2000 Brain.Res 876 103 PubMedID: 10973598 Abstract Temporary replacement of glucose by 2-deoxyglucose (2-DG) induces a long-term potentiation (2-DG-LTP) of excitatory synaptic transmission in hippocampal slices. We therefore examined the effects of 2-DG on monosynaptic field excitatory postsynaptic potentials (fEPSPs) in slices of somatosensory cortex from rats. Monosynaptic fEPSPs were elicited in layer I by stimulating horizontal projections in the same layer. Replacement of glucose (10 mM) in the artificial cerebrospinal fluid with 10 mM 2-DG for 15-17 min produced a minor reduction (by 10-30%), followed by a sustained increase (by approximately 150%) in synaptic responses that could last for over 2 hours. Equimolar replacement of glucose with sucrose did not induce potentiation. The addition of 5 or even 2.5 mM glucose to 10 mM 2-DG largely suppressed the effects of 2-DG; but topically-applied GABA antagonists bicuculline and CGP 35348 did not prevent 2-DG-LTP. Unlike hippocampal 2-DG-LTP, neocortical 2-DG-LTP was: (1) not sensitive to 2-amino-5-phosphonopentanoic acid (AP5); and (2) usually not depotentiated by stimulation at 1 Hz. We conclude that 2-DG produces a robust and sustained increase in synaptic transmission in the neocortex through mechanisms that are independent of NMDA receptor activation. Title: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ Ref: Nucleic Acids Research, 25:3389, 1997 : PubMed ESTHER: Altschul_1997_Nucleic.Acids.Res_25_3389 PubMedSearch: Altschul 1997 Nucleic.Acids.Res 25 3389 PubMedID: 9254694 Abstract The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSI-BLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily. Title: [Environmental pollution, human exposure and its health effect of sodium pentachlorophenate in schistosomiasis prevalent area] Zheng X, Feng Y, Jiang X, Lu H, Wan Y, Fang YQ, Li YP, Huang XY, Li ZL and Zhang Z <3 more author(s)> Zheng X, Feng Y, Jiang X, Lu H, Wan Y, Fang YQ, Li YP, Huang XY, Li ZL, Fu WZ, Wang XH, Lin YZ, Zhang Z (- 3) Ref: Wei Sheng Yan Jiu, 26:24, 1997 : PubMed ESTHER: Zheng_1997_Wei.Sheng.Yan.Jiu_26_24 PubMedSearch: Zheng 1997 Wei.Sheng.Yan.Jiu 26 24 PubMedID: 15747456 Abstract Sodium pentachlorophenate (Na-PCP) has been used in China for years as an molluscacide to kill oncomelania, which is an intermediate host of Schistosome. To evaluate the effects of its long-term successive usage on environment, human exposure and health, studies were carried out in Sichuan, Jiangxi, Jiangsu and Fujian provinces, with a time gap of more than one month between sample collection and last spray of Na-PCP. Results indicated that PCP contents in surface water, soil, sediment, animals and plants were significantly higher in studied areas than in control areas. The daily intake and the content in urine of PCP were also sigificantify higher in studied areas. But, there was no difference on physical and biochemical examinations except that a 22%-28% decrease of blood cholinesterase activity was found in studied areas. The health effect of impurities in Na-PCP, dioxins and furans, was assessed and discussed. Title: Fractionated irradiation alters enteric neuroendocrine products Otterson MF, Koch TR, Zhang Z, Leming SC, Moulder JE Ref: Digestive Diseases & Sciences, 40:1691, 1995 : PubMed ESTHER: Otterson_1995_Digest.Dis.Sci_40_1691 PubMedSearch: Otterson 1995 Digest.Dis.Sci 40 1691 PubMedID: 7544259 Abstract Radiation profoundly alters the contractile activity of the small intestine and colon. We hypothesized that some motor changes of the gut might be secondary to impaired neural input to smooth muscle or abnormal release of gut endocrine peptides. The density of products within peptidergic and cholinergic nerves and gut endocrine cells was estimated in six normal controls and six dogs who had received 1500 cGy in six equal fractions of 250 cGy. Choline acetyltransferase, acetylcholinesterase, vasoactive intestinal peptide (VIP), substance P, peptide YY (PYY), and motilin were measured in tissue specimens divided into mucosal-submucosal (MS) and muscularis externa (ME) layers. Tissue samples were obtained from the duodenum, jejunum, ileum, and proximal and distal colon. In addition, serum levels of motilin and PYY were determined before and during the administration of 1500 cGy in four separate dogs instrumented to record upper gut contractile activity. Intrinsic cholinergic activity as estimated by choline acetyltransferase activity was unchanged, while acetylcholinesterase activity increased in the MS layers of distal small bowel and colon. VIP was increased in the MS layers of jejunum and proximal colon as well as in the ME layers the jejunum and ileum. By contrast, substance P increased in the jejunal and proximal colonic MS layers and in the ME layers of the jejunum and ileum. Duodenal and jejunal motilin levels markedly decreased after radiation exposure, while serum motilin levels continued to cycle at a decreased peak level with migrating motor complexes. Colonic PYY remained unchanged but serum PYY levels decreased after irradiation. Increased neuronal synthesis and inhibition of neurotransmitter release are potential explanations for elevated tissue concentrations of VIP, substance P, and acetylcholinesterase. There appeared to be differences in the sensitivity of gut endocrine cells to irradiation. Changes in gut regulatory peptides and cholinergic enzyme activity occur with fractionated doses of abdominal irradiation, while the same schedule of irradiation produces striking changes in the canine small intestinal and colonic motor activity. It is therefore likely that alterations of contractile events may be produced by changes in gut neuroendocrine products. Title: Anomalous acetylcholinesterase in CSF without clinical diagnosis of Alzheimer's disease [letter; comment] Shen ZX, Zhang Z Ref: Lancet, 342:62, 1993 : PubMed Title: Muscarinic cholinergic receptor density following small intestinal transplantation in rats Zhang Z, Koch TR, Mustin E, Walgenbach-Telford S, Telford GL Ref: American Journal of Physiology, 265:G1057, 1993 : PubMed ESTHER: Zhang_1993_Am.J.Physiol_265_G1057 PubMedSearch: Zhang 1993 Am.J.Physiol 265 G1057 PubMedID: 8279556 Abstract After small intestinal transplantation, intestinal isografts can organize migrating myoelectric complexes, and we have shown that migrating myoelectric complex frequency in the fasted state was reduced compared with controls after transplantation of the distal 50% of small intestine. We hypothesized that changes in motor activity after transplantation were related to alteration of cholinergic nerve activity or receptor density. With use of standard microsurgical techniques, the distal 50% of small intestine was orthotopically transplanted in a Lewis-to-Lewis donor-recipient combination. Resection controls were prepared by resecting the proximal 50% of small intestine, and sham controls were prepared by performing a sham laparotomy. Two months after surgery, small intestine was harvested. Choline acetyltransferase activity among the three groups was similar, suggesting that intrinsic cholinergic nerves remained intact. There was a strong trend toward decreased acetylcholinesterase activity [analysis of variance (ANOVA), P = 0.16] after transplantation, consistent with loss of extrinsic vagal nerve fibers. There were no differences in histochemical distribution of acetylcholinesterase among these groups. Muscarinic receptor density, as determined by binding to [N-methyl-3H]scopolamine, was decreased after transplantation (ANOVA, P = 0.02). There was a trend toward decreased receptor density in animals with resected small intestine. Surgical interruption of intrinsic nerve pathways rather than ischemia or extrinsic denervation might be the mechanism for diminished receptor density after transplantation, and reduced small bowel motor activity may be related to decreased density of muscarinic cholinergic receptors. < |
