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Background: Pre-eclampsia is a syndrome that chiefly includes the development of new-onset hypertension and proteinuria after 20 weeks of pregnancy. Pre-eclampsia is one of the major causes of mortality and morbidity in Nepal. Hyperhomocysteinemia may be a cause of the endothelial dysfunction provoked by oxidative stress in pre-eclampsia. This study was designed to evaluate the association of homocysteine with Vitamin B12 and folate in patients with pre-eclampsia., Method: An observational cross sectional study was performed in the Gynecology and Obstetrics Department of TUTH involving seventy two subjects with pre-eclampsia. Blood pressure, urinary protein levels, serum homocysteine, Vitamin B12 and folate levels were compared in both mild and severe forms of pre-eclampsia. Concentration of Vitamin B12 and folate were measured using Vitros ECI and homocysteine was measured using CLIA. SPSS 23.0 was used to analyze the data. Tests were performed with Mann Whitney Test and Spearman's rank correlation test. A p-value < 0.05 was considered statistically significant., Results: This study showed no significant difference in age and weeks of gestation in both mild and severe forms of pre-eclampsia. Mean concentration of homocysteine was higher (13.1 ± 6.4 micromol/L) in severe Pre-eclampsia as compared to mild cases (7.6 ± 2.8 micromol/L). Mean concentration of folate was lower in severe cases (35.4 ± 24.1 micromol/L) when compared with mild cases of pre-eclampsia (57 ± 23.4 micromol/L)., Conclusion: Homocysteine levels were increased in severe Pre-eclampsia when compared with mild pre-eclampsia and this finding can be used to predict and prevent complications in patients with pre-eclampsia., (© 2024. The Author(s).)

Introduction: Proper physician-patient communication has shown to impact patients' satisfaction, and better health outcomes. On the contrary, negative impacts of poor communication have been attributed as one of the causes of increasing workplace violence. It is imperative to identify the attitude of the students towards communication skill learning. The aim of the study was to find out the attitude of undergraduate students towards communication skill learning using the communication skill attitude scale., Methods: This cross-sectional study was carried out from October, 2022 to July 2023 among undergraduate medical and dental students. Data was collected after obtaining the ethical approval from Institutional Review Committee (IRC number 2079/80/82) using a preformed proforma and the previously validated communication skills attitude scale questionnaire. Convenience sampling was done. The demographic details, educational characteristics, opinions regarding communication learning and median of positive and negative attitude scale scores were calculated using Statistical Package for the Social Sciences (SPSS)., Results: The total median (interquartile range) positive attitudes scale (PAS) and negative attitudes scale (NAS) scores were 52.00 (48.00-87.00) and 31.00 (28.00-34.00) respectively. The first year of undergraduates had higher PAS scores 56.00 (50.00-60.00) than final year 48.50 (44.25-55.00). The students who were in favour of CS learning during the clinical years of training had a higher PAS median score, 54.00 (49.00-58.00)., Conclusions: The undergraduates had overall positive attitude towards CS learning but negative attitudes were also noted, with deterioration in the scores from first to final year of undergraduation, reiterating the importance of strengthening CS learning in the curriculum early-on in the study period.

Agriculture plays a critical role in ensuring food and nutrition security, livelihood, and rural employment in Nepal. Despite substantial investments and institutional reforms, irrigation projects have faced consistently low performance. While existing studies have shed light on technical aspects of irrigation performance, they often focus on specific themes rather than holistic evaluations of sustainability. This research systematically assesses barriers and challenges to effective irrigation water management in Nepal by assessing and ranking the challenges faced by three irrigation systems in western Nepal: Mahakali, Rani Jamara Kulariya, and Babai. To investigate these challenges, we collected data from 449 households, which provided insights into 33 indicators representing key barriers to effective irrigation and agricultural management. The identified challenges were categorized into four broad thematic areas: physical and structural, agricultural and water, socioeconomic and market, and gender and governance. A comprehensive evaluation was conducted to compare these challenges among the three irrigation schemes, different thematic areas, and various locations within each scheme (namely, the head, mid, and tail sections of the system). The findings revealed that timely access and availability of fertilizers, spring water availability and fair market prices of agricultural products are the most significant challenges. The Babai irrigation system faced the most substantial challenges among the three systems, particularly in the mid section. These findings emphasize the interconnectedness of these challenges, highlighting the need for a holistic approach to planning, implementation, and management. Integrated strategies are essential to address socioeconomic, market, and endogenous farming issues, ensuring reliable irrigation water availability for sustainable agricultural production., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We produced transcriptome and promoter-interaction maps (using HiCap) of three blood stem-like cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations., (© 2024 Zhigulev et al.)

Degenerative ascending aortic aneurysm (AscAA) is a silent and potentially fatal disease characterized by excessive vascular inflammation and fibrosis. We aimed to characterize the cellular and molecular signature for the fibrotic type of endothelial mesenchymal transition (EndMT) that has previously been described in degenerative AscAA. Patients undergoing elective open-heart surgery for AscAA and/or aortic valve repair were recruited. Gene expression in the intima-media of the ascending aorta was measured in 22 patients with non-dilated and 24 with dilated aortas, and candidate genes were identified. Protein expression was assessed using immunohistochemistry. Interacting distal gene enhancer regions were identified using targeted chromosome conformation capture (HiCap) in untreated and LPS-treated THP1 cells, and the associated transcription factors were analyzed. Differential expression analysis identified SPP1 (osteopontin) as a key gene in the signature of fibrotic EndMT in patients with degenerative AscAA. The aortic intima-media expression of SPP1 correlated with the expression of inflammatory markers, the level of macrophage infiltration, and the aortic diameter. HiCap analysis, followed by transcription factor binding analysis, identified ETS1 as a potential regulator of SPP1 expression under inflammatory conditions. In conclusion, the present findings suggest that SPP1 may be involved in the development of the degenerative type of AscAA. KEY MESSAGES: In the original manuscript titled "SPP1/osteopontin, a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?" by David Freiholtz, Otto Bergman, Saliendra Pradhananga, Karin Lång, Flore-Anne Poujade, Carl Granath, Christian Olsson, Anders Franco-Cereceda, Pelin Sahlén, Per Eriksson, and Hanna M Björck, we present novel findings on regulatory factors on osteopontin (SPP1) expression in immune cells involved in degenerative ascending aortic aneurysms (AscAA). The central findings convey: SPP1 is a potential driver of the fibrotic endothelial-to-mesenchymal transition in AscAA. SPP1/osteopontin expression in AscAA is predominately by immune cells. ETS1 is a regulatory transcription factor of SPP1 expression in AscAA immune cells., (© 2023. The Author(s).)

Introduction: In renal transplantation, warm ischemia time is the interval from the removal of a procured kidney from ice storage to initiating graft reperfusion. Successful kidney transplantation depends on warm ischemia time. The study aims to find the mean warm ischemia time among kidney transplant patients in a tertiary care centre., Methods: This descriptive cross-sectional study was conducted among kidney transplant patients in a tertiary care centre. Data from 15 December 2012 to 15 October 2022 were collected between 1 December 2022 to 4 January 2023 from the hospital records. Ethical approval was taken from the Nepal Health Research Council (Reference number: 1341). All first-time living-related kidney transplant recipients were included in the study. All the patients undergoing kidney transplants from brain-dead donors were excluded from the study. Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated., Results: Among 230 patients, the mean warm ischemia time was 35.45±7.35 min. The mean first warm ischemia time was 4.28±2.05 min and the mean second warm ischemia time was 31.27±7.04 min. The mean age of the recipients was 35.14±10.49 years (range 14-64), of which 173 (75.20%) were male and 57 (24.80%) were female., Conclusions: The mean warm ischemia time among kidney transplant patients in a tertiary care centre was similar to the studies done in similar settings., Keywords: kidney transplantation; prevalence; warm ischemia.

Aims: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2., Methods and Results: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM., Conclusion: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) is proposed as a novel therapeutic for LQTS., Objective: The study sought to test the efficacy of novel, selective SGK1 inhibitors in induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQTS., Methods: The mexiletine (MEX)-sensitive SCN5A-P1332L iPSC-CMs were tested initially compared with a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 SCN5A-P1332L variant-corrected isogenic control (IC). The SGK1-I1 therapeutic efficacy, compared with MEX, was tested for APD at 90% repolarization (APD90) shortening in SCN5A-P1332L, SCN5A-R1623Q, KCNH2-G604S, and KCNQ1-V254M iPSC-CMs using FluoVolt., Results: The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared with its IC (646 ± 7 ms vs 482 ± 23 ms; P < .0001). MEX shortened the APD90 to 560 ± 7 ms (52% attenuation, P < .0001). SGK1-I1 shortened the APD90 to 518 ± 5 ms (78% attenuation, P < .0001) but did not shorten the APD90 in the IC. SGK1-I1 shortened the APD90 of the SCN5A-R1623Q iPSC-CMs (753 ± 8 ms to 475 ± 19 ms compared with 558 ± 19 ms with MEX), the KCNH2-G604S iPSC-CMs (666 ± 10 ms to 574 ± 18 ms vs 538 ± 15 ms after MEX), and the KCNQ1-V254M iPSC-CMs (544 ± 10 ms to 475 ± 11ms; P = .0004)., Conclusions: Therapeutically inhibiting SGK1 effectively shortens the APD in human iPSC-CM models of the 3 major LQTS genotypes. These preclinical data support development of SGK1 inhibitors as novel, first-in-class therapy for patients with congenital LQTS., (© 2023 Heart Rhythm Society. Published by Elsevier Inc.)

Nonalcoholic fatty liver disease (NAFLD), in a few decades, is expected to be the commonest cause of end-stage liver disease and liver cancer surpassing all other etiologies. Urbanization and modern lifestyle have led to global epidemic of NAFLD with alarming prevalence rates across the globe. Its multisystemic involvement manifests as metabolic syndrome, diabetes, cardiovascular disease, end-stage liver disease, and hepatic and extrahepatic malignancies. The absence of promising therapy for halting disease progression in NAFLD is a challenge that is not only limited to liver disease but also other organs involved. It is unrealistic to expect any significant impact of pharmacotherapies in overall survival of NAFLD patients, given that the morbidity and mortality in these patients are contributed by conditions other than that of liver. Liver-centric approach in managing NAFLD will be futile unless the problem is dealt in a holistic manner. Lifestyle modifications have been repeatedly appraised in prevention and treatment of various diseases linked to metabolic syndrome including NAFLD. Despite being inexpensive and highly efficacious in prevention and treatment of different manifestations of NAFLD, lifestyle intervention often fails to gather sufficient interest among patients and physicians alike. This review intends to highlight pleiotropic nature of this disease, limitations of currently available pharmacotherapies and evidence that emphasizing lifestyle intervention is the only way to holistically deal in patients with NAFLD., How to Cite This Article: Shrestha A, Pradhananga S. Holistic Approach in the Management of Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S51-S58., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2022; Jaypee Brothers Medical Publishers (P) Ltd.)

Key Points: The vagus nerve has been implicated in mediating behavioural effects of the gut microbiota on the central nervous system. This study examined whether the secretory products of commensal gut bacteria can modulate the excitability of vagal afferent neurons with cell bodies in nodose ganglia. Cysteine proteases from commensal bacteria increased the excitability of vagal afferent neurons via activation of protease-activated receptor 2 and modulation of the voltage dependence of Na + conductance activation. Lipopolysaccharide, a component of the cell wall of gram-negative bacteria, increased the excitability of nodose ganglia neurons via TLR4-dependent activation of nuclear factor kappa B. Our study identified potential mechanisms by which gut microbiota influences the activity of vagal afferent pathways, which may in turn impact on autonomic reflexes and behaviour., Abstract: Behavioural studies have implicated vagal afferent neurons as an important component of the microbiota-gut-brain axis. However, the mechanisms underlying the ability of the gut microbiota to affect vagal afferent pathways are unclear. We examined the effect of supernatant from a community of 33 commensal gastrointestinal bacterial derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) on the excitability of mouse vagal afferent neurons. Perforated patch clamp electrophysiology was used to measure the excitability of dissociated nodose ganglion (NG) neurons. NG neuronal excitability was assayed by measuring the amount of current required to elicit an action potential, the rheobase. MET-1 supernatant increased the excitability of NG neurons by hyperpolarizing the voltage dependence of activation of Na + conductance. The increase in excitability elicited by MET-1 supernatant was blocked by the cysteine protease inhibitor E-64 (30 nm). The protease activated receptor-2 (PAR 2 ) antagonist (GB 83, 10 μm) also blocked the effect of MET-1 supernatant on NG neurons. Supernatant from Lactobacillus paracasei 6MRS, a component of MET-1, recapitulated the effect of MET-1 supernatant on NG neurons. Lastly, we compared the effects of MET-1 supernatant and lipopolysaccharide (LPS) from Escherichia coli 05:B5 on NG neuron excitability. LPS increased the excitability of NG neurons in a toll-like receptor 4 (TLR 4 )-dependent and PAR 2 -independent manner, whereas the excitatory effects of MET-1 supernatant were independent of TLR 4 activation. Together, our findings suggest that cysteine proteases from commensal bacteria increase the excitability of vagal afferent neurons by the activation of PAR 2 ., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Objective: There have been few studies in which the prevalence of frailty of different ethnic groups has been assessed in multiethnic countries. The aim of this study was to evaluate the prevalence of frailty in different ethnic groups in the United Kingdom., Methods: Anonymized electronic health records (EHR) of 13 510 people aged 65 years and over were extracted from the database of a network of general practitioners, covering 16 clinical commissioning groups in London. Frailty was determined using the electronic Frailty Index (eFI), which was automatically calculated using EHR data. The eFI was used as a categorical variable with fit and mild frailty grouped together, and moderate and severe frailty grouped as frail., Results: The overall prevalence of frailty was 18.1% (95% confidence interval [CI], 17.4%-18.9%). The prevalence of frailty increased with age (odds ratio [OR], 1.11; 95% CI, 1.10-1.12) and body mass index (BMI; OR, 1.05; 95% CI, 1.04-1.06). The highest prevalence of frailty was observed for Bangladeshis, with 32.9% classified as frail (95% CI, 29.2-36.7); and the lowest prevalence of 14.0% (95% CI, 12.6-15.5) was observed for the Black ethnic group. Stepwise logistic regression retained ethnicity, age, and BMI as predictors of frailty., Conclusion: This pilot study identified differences in the prevalence of frailty between ethnic groups in a sample of older people living in London. Additional studies are warranted to determine the causes of such differences, including migration and socioeconomic status. It would be worthwhile carrying out a validation study of the eFI in different ethnic populations., Competing Interests: The authors declare no conflicts of interest., (© 2019 The Authors. Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.)

The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterized impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells, and the neurons themselves. Proteases produced by bacteria, or by host cells in response to bacteria, can increase or decrease the excitability of nociceptive dorsal root ganglion (DRG) neurons depending on the receptor activated. Short-chain fatty acids generated by colonic bacteria are involved in gut-brain communication, and intracolonic short-chain fatty acids have pronociceptive effects in rodents but may be antinociceptive in humans. Gut bacteria modulate the synthesis and release of enteroendocrine cell mediators, including serotonin and glucagon-like peptide-1, which activate extrinsic afferent neurons. Deciphering the complex interactions between visceral afferent neurons and the gut microbiota may lead to the development of improved probiotic therapies for visceral pain.

Increased bile acids in the colon can evoke increased epithelial secretion resulting in diarrhea, but little is known about whether colonic bile acids contribute to abdominal pain. This study aimed to investigate the mechanisms underlying activation of colonic extrinsic afferent nerves and their neuronal cell bodies by a major secondary bile acid, deoxycholic acid (DCA). All experiments were performed on male C57BL/6 mice. Afferent sensitivity was evaluated using in vitro extracellular recordings from mesenteric nerves in the proximal colon (innervated by vagal and spinal afferents) and distal colon (spinal afferents only). Neuronal excitability of cultured dorsal root ganglion (DRG) and nodose ganglion (NG) neurons was examined with perforated patch clamp. Colonic 5-HT release was assessed using ELISA, and 5-HT immunoreactive enterochromaffin (EC) cells were quantified. Intraluminal DCA increased afferent nerve firing rate concentration dependently in both proximal and distal colon. This DCA-elicited increase was significantly inhibited by a 5-HT 3 antagonist in the proximal colon but not in the distal colon, which may be in part due to lower 5-HT immunoreactive EC cell density and lower 5-HT levels in the distal colon following DCA stimulation. DCA increased the excitability of DRG neurons, whereas it decreased the excitability of NG neurons. DCA potentiated mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. Together, this study suggests that DCA can excite colonic afferents via direct and indirect mechanisms but the predominant mechanism may differ between vagal and spinal afferents. Furthermore, DCA increased mechanosensitivity of high-threshold spinal afferents and may be a mechanism of visceral hypersensitivity. NEW & NOTEWORTHY Deoxycholic acid (DCA) directly excites spinal afferents and, to a lesser extent, indirectly via mucosal 5-HT release. DCA potentiates mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. DCA increases vagal afferent firing in proximal colon via 5-HT release but directly inhibits the excitability of their cell bodies.

Background: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease., Methods: In this study, we generated high-resolution genomic interaction maps (≈750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac., Results: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated., Conclusions: In summary, we present a catalog of candidate genes regulated by coronary artery disease-related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

Future hydrological extremes, such as floods and droughts, may pose serious threats for the livelihoods in the upstream domains of the Indus, Ganges, Brahmaputra. For this reason, the impacts of climate change on future hydrological extremes is investigated in these river basins. We use a fully-distributed cryospheric-hydrological model to simulate current and future hydrological fluxes and force the model with an ensemble of 8 downscaled General Circulation Models (GCMs) that are selected from the RCP4.5 and RCP8.5 scenarios. The model is calibrated on observed daily discharge and geodetic mass balances. The climate forcing and the outputs of the hydrological model are used to evaluate future changes in climatic extremes, and hydrological extremes by focusing on high and low flows. The outcomes show an increase in the magnitude of climatic means and extremes towards the end of the 21st century where climatic extremes tend to increase stronger than climatic means. Future mean discharge and high flow conditions will very likely increase. These increases might mainly be the result of increasing precipitation extremes. To some extent temperature extremes might also contribute to increasing discharge extremes, although this is highly dependent on magnitude of change in temperature extremes. Low flow conditions may occur less frequently, although the uncertainties in low flow projections can be high. The results of this study may contribute to improved understanding on the implications of climate change for the occurrence of future hydrological extremes in the Hindu Kush-Himalayan region.

Peripheral pain signaling reflects a balance of pronociceptive and antinociceptive influences; the contribution by the gastrointestinal microbiota to this balance has received little attention. Disorders, such as inflammatory bowel disease and irritable bowel syndrome, are associated with exaggerated visceral nociceptive actions that may involve altered microbial signaling, particularly given the evidence for bacterial dysbiosis. Thus, we tested whether a community of commensal gastrointestinal bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) can affect the excitability of male mouse DRG neurons. MET-1 reduced the excitability of DRG neurons by significantly increasing rheobase, decreasing responses to capsaicin (2 μm) and reducing action potential discharge from colonic afferent nerves. The increase in rheobase was accompanied by an increase in the amplitude of voltage-gated K + currents. A mixture of bacterial protease inhibitors abrogated the effect of MET-1 effects on DRG neuron rheobase. A serine protease inhibitor but not inhibitors of cysteine proteases, acid proteases, metalloproteases, or aminopeptidases abolished the effects of MET-1. The serine protease cathepsin G recapitulated the effects of MET-1 on DRG neurons. Inhibition of protease-activated receptor-4 (PAR-4), but not PAR-2, blocked the effects of MET-1. Furthermore, Faecalibacterium prausnitzii recapitulated the effects of MET-1 on excitability of DRG neurons. We conclude that serine proteases derived from commensal bacteria can directly impact the excitability of DRG neurons, through PAR-4 activation. The ability of microbiota-neuronal interactions to modulate afferent signaling suggests that therapies that induce or correct microbial dysbiosis may impact visceral pain. SIGNIFICANCE STATEMENT Commercially available probiotics have the potential to modify visceral pain. Here we show that secretory products from gastrointestinal microbiota derived from a human donor signal to DRG neurons. Their secretory products contain serine proteases that suppress excitability via activation of protease-activated receptor-4. Moreover, from this community of commensal microbes, Faecalibacterium prausnitzii strain 16-6-I 40 fastidious anaerobe agar had the greatest effect. Our study suggests that therapies that induce or correct microbial dysbiosis may affect the excitability of primary afferent neurons, many of which are nociceptive. Furthermore, identification of the bacterial strains capable of suppressing sensory neuron excitability, and their mechanisms of action, may allow therapeutic relief for patients with gastrointestinal diseases associated with pain., (Copyright © 2017 the authors 0270-6474/17/3711758-11$15.00/0.)

Altered gastrointestinal (GI) function contributes to the debilitating symptoms of inflammatory bowel diseases (IBD). Nerve circuits contained within the gut wall and outside of the gut play important roles in modulating motility, mucosal fluid transport, and blood flow. The structure and function of these neuronal populations change during IBD. Superimposed on this plasticity is a diminished responsiveness of effector cells - smooth muscle cells, enterocytes, and vascular endothelial cells - to neurotransmitters. The net result is a breakdown in the precisely orchestrated coordination of motility, fluid secretion, and GI blood flow required for health. In this review, we consider how inflammation-induced changes to the effector innervation of these tissues, and changes to the tissues themselves, contribute to defective GI function in models of IBD. We also explore the evidence that reversing neuronal plasticity is sufficient to normalize function during IBD., (Copyright © 2017 the American Physiological Society.)

The curation of genetic variants from biomedical articles is required for various clinical and research purposes. Nowadays, establishment of variant databases that include overall information about variants is becoming quite popular. These databases have immense utility, serving as a user-friendly information storehouse of variants for information seekers. While manual curation is the gold standard method for curation of variants, it can turn out to be time-consuming on a large scale thus necessitating the need for automation. Curation of variants described in biomedical literature may not be straightforward mainly due to various nomenclature and expression issues. Though current trends in paper writing on variants is inclined to the standard nomenclature such that variants can easily be retrieved, we have a massive store of variants in the literature that are present as non-standard names and the online search engines that are predominantly used may not be capable of finding them. For effective curation of variants, knowledge about the overall process of curation, nature and types of difficulties in curation, and ways to tackle the difficulties during the task are crucial. Only by effective curation, can variants be correctly interpreted. This paper presents the process and difficulties of curation of genetic variants with possible solutions and suggestions from our work experience in the field including literature support. The paper also highlights aspects of interpretation of genetic variants and the importance of writing papers on variants following standard and retrievable methods., (Copyright © 2012. Published by Elsevier Ltd.)