BACKGROUND: no studies have compared the predictive validity of different dementia risk prediction models in Australia. OBJECTIVES: (i) to investigate the predictive validity of the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI), LIfestyle for BRAin Health (LIBRA) Index and cardiovascular risk factors, ageing and dementia study (CAIDE) models for predicting probable dementia/cognitive impairment in an Australian cohort. (ii) To develop and assess the predictive validity of a new hybrid model combining variables from the three models. METHODS: the Hunter Community Study (HCS) included 3,306 adults aged 55-85syears with a median follow-up of 7.1syears. Probable dementia/cognitive impairment was defined using Admitted Patient Data Collection, dispensing of cholinesterase inhibitors or memantine, or a cognitive test. Model validity was assessed by calibration and discrimination. A hybrid model was developed using deep neural network analysis, a machine learning method. RESULTS: 120 (3.6%) participants developed probable dementia/cognitive impairment. Mean calibration by ANU-ADRI, LIBRA, CAIDE and the hybrid model was 19, 0.5, 4.7 and 3.4%, respectively. The discrimination of the models was 0.65 (95% CI 0.60-0.70), 0.65 (95% CI 0.60-0.71), 0.54 (95% CI 0.49-0.58) and 0.80 (95% CI 0.78-0.83), respectively. CONCLUSION: ANU-ADRI and LIBRA were better dementia prediction tools than CAIDE for identification of high-risk individuals in this cohort. ANU-ADRI overestimated and LIBRA underestimated the risk. The new hybrid model had a higher predictive performance than the other models but it needs to be validated independently in longitudinal studies.
BACKGROUND & AIMS: Non-invasive stratification of the liver decompensation risk remains unmet in people with compensated cirrhosis. This study aimed to develop a non-invasive tool (NIT) to predict hepatic decompensation. METHODS: This retrospective study recruited 689 people with compensated cirrhosis (median age, 54 years; 441 men) from 5 centres from January 2016 to June 2020. Baseline abdominal computed tomography (CT), clinical features, and liver stiffness were collected, and then the first decompensation was registered during the follow-up. The spleen-based model was designed for predicting decompensation based on a deep learning segmentation network to generate the spleen volume and least absolute shrinkage and selection operator (LASSO)-Cox. The spleen-based model was trained on the training cohort of 282 individuals (Institutions I-III) and was validated in 2 external validation cohorts (97 and 310 individuals from Institutions IV and V, respectively) and compared with the conventional serum-based models and the Baveno VII criteria. RESULTS: The decompensation rate at 3 years was 23%, with a 37.6-month median (IQR 21.1-52.1 months) follow-up. The proposed model showed good performance in predicting decompensation (C-index <=0.84) and outperformed the serum-based models (C-index comparison test p <0.05) in both the training and validation cohorts. The hazard ratio (HR) for decompensation in individuals with high risk was 7.3 (95% CI 4.2-12.8) in the training and 5.8 (95% CI 3.9-8.6) in the validation (log-rank test, p <0.05) cohorts. The low-risk group had a negligible 3-year decompensation risk (>=1%), and the model had a competitive performance compared with the Baveno VII criteria. CONCLUSIONS: This spleen-based model provides a non-invasive and user-friendly method to help predict decompensation in people with compensated cirrhosis in diverse healthcare settings where liver stiffness is not available. LAY SUMMARY: People with compensated cirrhosis with larger spleen volume would have a higher risk of decompensation. We developed a spleen-based model and validated it in external validation cohorts. The proposed model might help predict hepatic decompensation in people with compensated cirrhosis when invasive tools are unavailable.
Title: The Role of N-myc Downstream-Regulated Gene Family in Glioma Based on Bioinformatics Analysis Tang T, Wang H, Han Y, Huang H, Niu W, Fei M, Zhu Y Ref: DNA & Cell Biology, 40:949, 2021 : PubMed
Glioma is the most common type of primary tumor in the central nervous system, and the molecular mechanisms remain elusive. N-myc downstream-regulated gene (NDRG) family is reported to take part in the pathogenesis of various diseases, including some preliminary exploration in glioma. However, there has been no bioinformatics analysis of NDRG family in glioma yet. Herein, we focused on the expression changes of NDRGs with their value in predicting patients' prognoses, upstream regulatory mechanisms (DNA mutation, DNA methylation, transcription factors, and microRNA regulation) and gene enrichment analysis based on co-expressed genes with data from public databases. Furthermore, the expression pattern of NDRGs was verified by the paired glioma and peritumoral samples in our institute. It was suggested that NDRGs were differentially expressed genes in glioma. In particular, the lower expression of NDRG2 or NDRG4 could serve as a predictor of higher grade tumor and poorer prognosis. Also, NDRGs might play a crucial role in signal transduction, energy metabolism, and cross-talk among cells in glioma, under the control of a complex regulatory network. This study enables us to better understand the role of NDRGs in glioma and with further research, it may contribute to the development of glioma treatment.
BACKGROUND: Neuroligin protein (NLG) is a nerve cell adhesion molecule and plays a key role in the precision apposition of presynaptic domains on inhibitory and excitatory synapses. Existing studies mainly focused on the function of NLG3 against the excitatory channel. However, the interaction between insect NLG3 and ionotropic GABA receptor, which is the main inhibitory channel, remains unclear. In this study, the Nlg3 of common cutworm (CCW), Spodoptera litura Fabricius, one important agricultural lepidopteron, is selected to explore its function in inhibitory channel. RESULTS: The SlNlg3 was obtained and the SlNLG3 contains the characteristic features including transmembrane domain, PDZ-binding motif and type-B carboxylesterases signature 2 motif. The SlNlg3 mRNA was most abundant in midgut, and exhibited multiple expression patterns in different developmental stages and tissues or body parts. Compared with the single injection of SlRDL1, the EC(50) value of GABA in activating currents was smaller in Xenopus laevis oocytes co-injected with SlRDL1 and SlNlg3. In addition, SlNlg3 could enhance the GABA-induced current of homomeric SlRDL1 channel from -391.86 +/- 15.41 nA to -2152.51 +/- 30.09 nA. DsSlNlg3 depressed the expression level of SlNlg3 mRNA more than 64.29% at 6 h. After exposure to LD(50) of fluralaner, the mortality of CCW injected with dsSlNlg3 was significantly decreased by 13.34% and 30.00% at 24 and 48 h, respectively, compared to injection of dsEGFP. CONCLUSION: NLG3 should have physiological function on ionotropic GABA receptor in vitro, which provided a favorable foundation for further research on the physiological function of Nlg gene in lepidopteron. This article is protected by copyright. All rights reserved.
Title: Influence of three insecticides targeting GABA receptor on fall armyworm Spodoptera frugiperda: Analyses from individual, biochemical and molecular levels Zhan EL, Wang Y, Jiang J, Jia ZQ, Tang T, Song ZJ, Han ZJ, Zhao CQ Ref: Pestic Biochem Physiol, 179:104973, 2021 : PubMed
The fall armyworm (FAW) Spodoptera frugiperda (Lepidoptera: Noctuidae) is a severe agricultural pest, which has invaded into China in 2019 and caused heavy damage to maize. The gamma-aminobutyric acid receptor (GABAR)-targeted insecticides including broflanilide, fluralaner and fipronil exhibit high toxicity towards lepidopteran pests. However, whether they could be used for control of FAW and their possible mode of action in FAW remain unclear. In this study, broflanilide, fluralaner and fipronil exhibited high oral toxicity in FAW larvae with median lethal dose (LD(50)) values of 0.677, 0.711, and 23.577 mg kg(-1) (active ingredient/ artificial food), respectively. In the electrophysiological assay, fluralaner and fipronil could strongly inhibit GABA-induced currents of homomeric FAW resistance to dieldrin 1 (RDL1) receptor with median inhibitory concentration (IC(50)) values of 5.018 nM (95% confidence interval (CI) 2.864-8.789) and 8.595 nM (95% CI 5.105-14.47), respectively, whereas broflanilide could not. In addition, the cytochrome P450 (P450), glutathione-S-transferase (GST) and carboxylesterase (CarE) activities were positively response to broflanilide, P450 and GST to fluralaner, and GST and CarE to fipronil, respectively, compared with those of control. In conclusion, we firstly reported a notable insecticidal activity of three representative GABAR-targeted insecticides to FAW in vivo, and in vitro using electrophysiological assay. The GST is the primary detoxification enzyme for three tested insecticides. Our results would guide the rotational use of GABAR-targeted insecticides in field.
Bacillus thermocatenulatus lipase 2 (BTL2) is a promising industrial enzyme used in biodiesel production. Although BTL2 has high thermostability and good resistance to organic solvents, the activity of BTL2 is suboptimal for industrial processes. To improve BTL2 activity, we engineered BTL2 lipase by modulating hydrophobicity of its lid domain. Through site-directed mutagenesis, we constructed three mutants, namely Y225F+S232A, S232A+T236V and Q185L, to cover all uncharged hydrophilic amino acids within the lid domain. Activities of these mutants were characterized. Our findings suggest that one mutant (Y225F+S232A) showed approximately 35% activity increase in catalyzing heterogeneous hydrolytic reactions relevant for industrial applications. A mathematical framework was established to account for different molecular events that contribute to the observed apparent catalytic activities. Increases in hydrophobicity of lid domains were associated with increased interfacial adsorption of lipases and lower molecular enzymatic activities. The measured apparent activities of lipases include contributions from both events. Lid hydrophobicity can thus result in different changes in lipase activities depending on the mutation site. Our work demonstrates the feasibility of increasing BTL2 activity by modulating the hydrophobicity of lid domains and provides some guidelines for further improving BTL2 activity.
BACKGROUND: Approximately 10% to 20% of patients with autoimmune MG do not have antibodies to the acetylcholine receptor (AChR), so-called seronegative MG (SNMG). IgG antibodies from up to 70% of SNMG patients bind to the muscle-specific receptor tyrosine kinase, MuSK. The plasmas and non-IgG fractions from SNMG patients (and some with AChR antibodies) also contain a factor, perhaps an IgM antibody, that inhibits AChR function, but it is not clear how this factor acts and whether it is related to the MuSK IgG antibodies. METHODS: The authors studied 12 unselected SNMG plasmas and their non-IgG fractions; seven were positive for MuSK IgG antibodies. Ion flux assays, electrophysiology, phosphorylation, and kinase assays were used to look at mechanisms of action. RESULTS: Eight of the 12 plasmas and their non-IgG fractions inhibited AChR function, but the inhibitory activity was transient and did not correlate with the presence of MuSK IgG antibodies. Two of three plasmas added outside of a cell-attached patch pipette inhibited AChR function within the patch, and these two plasmas also increased AChR phosphorylation. CONCLUSIONS: The authors propose that a plasma factor(s) in SNMG patients, distinct from MuSK IgG antibodies, binds to a muscle membrane receptor and activates a second messenger pathway leading to AChR phosphorylation and reduced AChR function. Identifying the target for this factor should lead to improved diagnosis of MG in MuSK antibody-negative patients and may provide new insights into the function of the neuromuscular junction and pathophysiological mechanisms in MG.
