The outbreak and high speed global spread of the new strain of influenza A/H1N1 virus in 2009 posed a serious threat to global health. It is more likely that drug-resistant influenza strains will arise after the extensive use of anti-influenza drugs. Consequently, the identification of the potential resistant sites for drugs in advance and the understanding of the corresponding molecular mechanisms that cause drug resistance are quite important in the design of new drug candidates with better potency to combat drug resistance. Here, we performed molecular simulations to evaluate the potency of oseltamivir to combat drug resistance caused by the mutations in 2009 A/H1N1 neuraminidase (NA). We examined three representative drug-resistant mutations in NA, consisting of H274Y, N294S, and Y252H. First, a theoretical structure of A/H1N1 NA in complex with oseltamivir was constructed using homology modeling. Then, molecular dynamics (MD) simulations, molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations, and MM/GBSA free energy decomposition were used to characterize the binding of oseltamivir with the wild type (WT) and three mutated NAs. Our predictions show that N294S and H274Y, two popular drug-resistant mutations in different variants of NA, still cause significant resistance to oseltamivir. However, the Y252H mutation does not impair the interactions between oseltamivir and A/H1N1 NA. An examination of individual energy components shows that the loss of polar interactions is the key source for the resistance of the studied mutations to oseltamivir. Moreover, free energy decomposition analysis and structural analysis reveal that the N294S or H274Y mutation triggers the large-scale conformational changes of the binding pocket and then impairs the affinity of oseltamivir. We expect that our results will be useful for the rational design of NA inhibitors with high potency against drug-resistant A/H1N1 mutants.

maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats. Am J Physiol Gastrointest Liver Physiol 304: G311-G321, 2013. First published November 8, 2012; doi:10.1152/ajpgi.00338.2012.-Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain in association with altered bowel movements. The underlying mechanisms of visceral hypersensitivity remain elusive. This study was designed to examine the role for sodium channels in a rat model of chronic visceral hyperalgesia induced by neonatal maternal deprivation (NMD). Abdominal withdrawal reflex (AWR) scores were performed on adult male rats. Colon-specific dorsal root ganglion (DRG) neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel current under whole-cell patch-clamp configurations. The expression of NaV1.8 was analyzed by Western blot and quantitative real-time PCR. NMD significantly increased AWR scores, which lasted for ϳ6 wk in an association with hyperexcitability of colon DRG neurons. TTXresistant but not TTX-sensitive sodium current density was greatly enhanced in colon DRG neurons in NMD rats. Compared with controls, activation curves showed a leftward shift in NMD rats whereas inactivation curves did not differ significantly. NMD markedly accelerated the activation time of peak current amplitude without any changes in inactivation time. Furthermore, NMD remarkably enhanced expression of Na V1.8 at protein levels but not at mRNA levels in colon-related DRGs. The expression of NaV1.9 was not altered after NMD. These data suggest that NMD enhances TTXresistant sodium activity of colon DRG neurons, which is most likely mediated by a leftward shift of activation curve and by enhanced expression of NaV1.8 at protein levels, thus identifying a specific molecular mechanism underlying chronic visceral pain and sensitization in patients with IBS. dorsal root ganglion; neonatal maternal deprivation; irritable bowel syndrome; visceral pain; voltage-gated sodium channel IRRITABLE BOWEL SYNDROME (IBS) remains a common and challenging disorder for clinicians. It is defined by recurrent symptoms of abdominal pain or discomfort associated with alterations in bowel habits. The pathophysiology of IBS involves psychological disorder, altered intestinal motility, and visceral hypersensitivity (18, 33). However, the exact causes of IBS have not been clearly elucidated and effective therapeutics for the primary symptoms has been unavailable. Psychological factors and stresses appear to play an important role in the development of IBS (4, 39). Recent studies in rodents found that early life stress in the form of neonatal maternal deprivation (NMD) induced rats to develop stress-produced intestinal mucosal dysfunction and visceral hypersensitivity at adulthood, mimicking main pathophysiological features of IBS in human (3,12,20). Indeed, early traumatic experiences such as childhood neglect, abuse, loss of a parent, and lif...

The rapid development of social media brings about vast user generated content. Computational cyber-psychology, an interdisciplinary subject area, employs machine learning approaches to explore underlying psychological patterns. Our research aims at identifying users' mental health status through their social media behavior. We collected both users' social media data and mental health data from the most popular Chinses microblog service provider, Sina Weibo. By extracting linguistic and behavior features, and applying machine learning algorithms, we made preliminary exploration to identify users' mental health status automaticly, which previously is mainly measured by well-designed psychological questionnaire. Our classification model achieves the accuracy of 72%, and the continous predicting model achieved correlation of 0.3 with questionnaire based score.