Title: Effect of Apolipoprotein E varepsilon4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer's Disease: A Systematic Review and Meta-Analysis Cheng YC, Huang YC, Liu HC Ref: Dementia & Geriatric Cognitive Disorders, 45:335, 2018 : PubMed
BACKGROUND: The apolipoprotein E varepsilon4 (APOE varepsilon4) genotype is the major genetic risk factor for Alzheimer's disease (AD). However, its effect on an individual's response to treatment is less well understood. Many studies have reported that the presence or absence of APOE varepsilon4 may have influence on the therapeutic response for acetylcholinesterase inhibitors (AChEIs), but the results were inconsistent. This study performed a systematic review and meta-analysis to evaluate the association between response of treatment with AChEIs and the APOE varepsilon4 carrier status. METHODS: Clinical studies with AD patients reporting APOE varepsilon4 genotype were included in the analysis. Cognitive outcome was measured by the change in Mini-Mental State Examination (MMSE), cognition subscales of the Alzheimer's Disease Assessment Scale (ADAS-cog), or Cognitive Abilities Screening Instrument (CASI). A random effects model was employed to calculate the standardized mean difference (SMD) and odds ratio (OR). RESULTS: Of the 284 screened abstracts, 38 studies were identified, 30 of which were included for meta-analysis. Continuous data for assessing the association between APOE epsilon4 and cognitive outcomes of AChEIs were available from 18 studies. The cognitive outcomes showed no significant difference between APOE epsilon4 carriers and APOE epsilon4 non-carriers (SMD = 0.022, 95% CI: -0.089 approximately 0.133, p = 0.702, I2 = 55.3%). Twelve studies with binary data were included, also revealing insignificant difference between the two groups (OR = 1.164, 95% CI: 0.928 approximately 1.459, p = 0.189, I2 = 16.4%). Subgroup analysis indicated that AChEIs were significantly more effective than placebo in both groups. CONCLUSIONS: APOE varepsilon4 carrier status had no significant influence on the treatment response to AChEIs in patients with AD. AChEIs had a positive therapeutic effect compared with placebo regardless of APOE epsilon4 carrier status.
Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron's oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron's intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network.
Title: Characterization and comparison of 2 distinct epidemic community-associated methicillin-resistant Staphylococcus aureus clones of ST59 lineage Chen CJ, Unger C, Hoffmann W, Lindsay JA, Huang YC, Gotz F Ref: PLoS ONE, 8:e63210, 2013 : PubMed
Sequence type (ST) 59 is an epidemic lineage of community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) isolates. Taiwanese CA-MRSA isolates belong to ST59 and can be grouped into 2 distinct clones, a virulent Taiwan clone and a commensal Asian-Pacific clone. The Taiwan clone carries the Panton-Valentine leukocidin (PVL) genes and the staphylococcal chromosomal cassette mec (SCCmec) VT, and is frequently isolated from patients with severe disease. The Asian-Pacific clone is PVL-negative, carries SCCmec IV, and a frequent colonizer of healthy children. Isolates of both clones were characterized by their ability to adhere to respiratory A549 cells, cytotoxicity to human neutrophils, and nasal colonization of a murine and murine sepsis models. Genome variation was determined by polymerase chain reaction of selected virulence factors and by multi-strain whole genome microarray. Additionally, the expression of selected factors was compared between the 2 clones. The Taiwan clone showed a much higher cytotoxicity to the human neutrophils and caused more severe septic infections with a high mortality rate in the murine model. The clones were indistinguishable in their adhesion to A549 cells and persistence of murine nasal colonization. The microarray data revealed that the Taiwan clone had lost the o3-prophage that integrates into the beta-hemolysin gene and includes staphylokinase- and enterotoxin P-encoding genes, but had retained the genes for human immune evasion, scn and chps. Production of the virulence factors did not differ significantly in the 2 clonal groups, although more alpha-toxin was expressed in Taiwan clone isolates from pneumonia patients. In conclusion, the Taiwan CA-MRSA clone was distinguished by enhanced virulence in both humans and an animal infection model. The evolutionary acquisition of PVL, the higher expression of alpha-toxin, and possibly the loss of a large portion of the beta-hemolysin-converting prophage likely contribute to its higher pathogenic potential than the Asian-Pacific clone.
Title: Heterologous expression of thermostable acetylxylan esterase gene from Thermobifida fusca and its synergistic action with xylanase for the production of xylooligosaccharides Huang YC, Chen GH, Chen YF, Chen WL, Yang CH Ref: Biochemical & Biophysical Research Communications, 400:718, 2010 : PubMed
The axe gene which encodes an acetylxylan esterase from Thermobifida fusca NTU22, was cloned, sequenced and expressed in Escherichia coli. The gene consists of 786 base pairs and encodes a protein of 262 amino acids. The deduced amino acid sequence of the acetylxylan esterase axe exhibited a high degree of similarity with BTA-hydrolase from T. fusca DSM43793, esterase from Thermobifida alba and lipase from Streptomyces albus. The optimal pH and temperature of the purified esterase were 7.5 and 60 degrees C, respectively. Cooperative enzymatic treatment of oat-spelt xylan by transformant xylanase and acetylxylan esterase significantly increased the xylooligosaccharides production compared with the xylanase or acetylxylan esterase action alone. The synergy of transformant acetylxylan esterase and xylanase cannot increase the production of reducing sugars from lignocellulolytic substrate, bagasse.
Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC(50) of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC(50) > 100 muM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.
DPP-IV (EC 3.4.14.5) is a validated drug target for human type II diabetes. DPP-IV inhibitors without DPP8/9 inhibitory activity have been sought because a possible association has been reported between a "DPP8/9 inhibitor" and severe toxicity in animals. However, at present, it is not known whether the observed toxicity is associated with DPP8/9 inhibition, or an off-target effect induced by the compound. We investigated whether the inhibition of DPP8/9 is the cause of the severe toxicity in animals using a very potent and selective DPP8/9 inhibitor with different pharmacophore, 1G244. By Ki measurement, 1G244 is 15- and 8-fold more potent against DPP8 and DPP9, respectively, than the "DPP8/9 inhibitor". Strikingly, the "DPP8/9 inhibitor" does not penetrate the plasma membrane but remains outside the cells, whereas 1G244 readily enters the cells, even at low doses. By repeatedly exposing Sprague-Dawley rats to 1G244 by intravenous injection for a period of 14 days, we observed no significant toxicological symptoms associated with 1G244. Blood and serum chemistry parameters were all within the normal ranges for the treated animals. Because of the high potency, good membrane penetration and adequate tissue distribution of 1G244, the mild symptoms observed are probably associated with DPP8/9 inhibition.
Title: [Detection carbamate pesticides residue in cucumber by immobilized acetyicholinesterase enzyme] Huang YC, Liu HM, Pei RR, Fu XQ Ref: Huan Jing Ke Xue, 27:1469, 2006 : PubMed
A novel method was described for detection carbamate pesticides residue in cucumber by immobilizing acetylcholinesterase enzyme in a micro-screen plate with 96 wells based on GA-BSA-gelatin gels. The concentrations of BSA, GA and gelatin in enzyme immobilization solution were optimized and the best concentrations were 5%, 0.5% and 0.1%, respectively. To analyze the pesticides residue 5g cucumber sample was homogenized with 10 mL acetone then an aliquot of 5mL extract was collected in a 10 mL test tube with a cap, into which 2g sodium chloride and 2mL dichloromethane were added in sequence. After shaking, 1 mL of the supernatant aliquot was evaporated by a blower in a small beaker and dissolved by 20% methanol-water solution then 50 microL was piped to a sample well. After incubation 10 minutes the absorbance was detected. The proposed method offered a rapid, simple and inexpensive means to in screen of batch samples. The minimum detection limit of this method was in a range of 0.1-0.2 mg/kg for cucumber samples.
