Targeting neuronal PAS domain protein 2 and KN motif/ankyrin repeat domains 1:Advances in type 2 diabetes therapy

This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.

EPAS1 and VEGFA gene variants are related to the symptoms of acute mountain sickness in Chinese Han population: a cross-sectional study

Background: More people ascend to high altitude(HA) for various activities, and some individuals are susceptible to HA illness after rapidly ascending from plains. Acute mountain sickness(AMS) is a general complaint that affects activities of daily living at HA. Although genomic association analyses suggest that single nucleotide polymorphisms(SNPs) are involved in the genesis of AMS, no major gene variants associated with AMS-related symptoms have been identified.Methods: In this cross-sectional study, 604 young, healthy Chinese Han men were recruited in June and July of 2012 in Chengdu, and rapidly taken to above 3700 m by plane. Basic demographic parameters were collected at sea level, and heart rate, pulse oxygen saturation(Sp O2), systolic and diastolic blood pressure and AMS-related symptoms were determined within 18–24 h after arriving in Lhasa. AMS patients were identified according to the latest Lake Louise scoring system(LLSS). Potential associations between variant genotypes and AMS/AMS-related symptoms were identified by logistic regression after adjusting for potential confounders(age, body mass index and smoking status).Results: In total, 320 subjects(53.0%) were diagnosed with AMS, with no cases of high-altitude pulmonary edema or high-altitude cerebral edema. Sp O2 was significantly lower in the AMS group than that in the non-AMS group(P=0.003). Four SNPs in hypoxia-inducible factor-related genes were found to be associated with AMS before multiple hypothesis testing correction. The rs6756667(EPAS1) was associated with mild gastrointestinal symptoms(P=0.013), while rs3025039(VEGFA) was related to mild headache(P=0.0007). The combination of rs6756667 GG and rs3025039 CT/TT further increased the risk of developing AMS(OR=2.70, P<0.001).Conclusions: Under the latest LLSS, we find that EPAS1 and VEGFA gene variants are related to AMS susceptibility through different AMS-related symptoms in the Chinese Han population;this tool might be useful for screening susceptible populations and predicting clinical symptoms leading to AMS before an individual reaches HA.Trial registration: Chinese Clinical Trial Registration, Chi CTR-RCS-12002232. Registered 31 May 2012.

Insight into the Urea Binding and K166R Mutation Stabilizing Mechanism of TIpB： Molecular Dynamics and Principal Component Analysis Study

Chemoreceptor TlpB（Tlp=transducer-like protein）, which has been demonstrated to respond to pH sensing function, is crucial for the survival ofHelicobacterpylori（H, pylori） in host stomach. Urea was proposed to be essen- tial for TlpB＇s pH sensing function via binding with the Per-ARNT-Sim（PAS） domain of TlpB. Additionally, KI66R mutation of the TlpB protein has also been proven to have a similar effect on TlpB pH sensing as urea binding. Al- though X-ray crystallographic studies have been carried out for urea-bound Tlpl3, the molecular mechanism for the stabilization of TIpB induced by urea binding and K166R mutation remains to be elucidated. In this study, molecular dynamics simulations combined with principal component analysis（PCA） for the simulation results were used to gain an insight into the molecular mechanism of the stabilization of urea on TlpB protein. The formed H-bonds and salt-bridges surrounding Aspll4, which were induced by both urea binding and K166R mutation of TIpB, were im- portant to the stabilization of TlpB by urea. The similarity between the urea binding and K166R mutation as well as their differences in effect has been explicitly demonstrated with computer simulations at atomic-level. The findings may Dave the wav for the further researches of TlpB.