Differential SNARE chaperoning by Munc13-1 and Munc18-1 dictates fusion pore fate at the release site.

The regulated release of chemical messengers is crucial for cell-to-cell communication; abnormalities in which impact coordinated human body function. During vesicular secretion, multiple SNARE complexes assemble at the release site, leading to fusion pore opening. How membrane fusion regulators act on heterogeneous SNARE populations to assemble fusion pores in a timely and synchronized manner, is unknown. Here, we demonstrate the role of SNARE chaperones Munc13-1 and Munc18-1 in rescuing individual nascent fusion pores from their diacylglycerol lipid-mediated inhibitory states. At the onset of membrane fusion, Munc13-1 clusters multiple SNARE complexes at the release site and synchronizes release events, while Munc18-1 stoichiometrically interacts with trans-SNARE complexes to enhance N- to C-terminal zippering. When both Munc proteins are present simultaneously, they differentially access dynamic trans-SNARE complexes to regulate pore properties. Overall, Munc proteins' direct action on fusion pore assembly indicates their role in controlling quantal size during vesicular secretion.

Advancing beyond reverse transcriptase inhibitors: The new era of hepatitis B polymerase inhibitors.

Hepatitis B virus (HBV) is a genetically diverse blood-borne virus responsible for chronic hepatitis B. The HBV polymerase plays a key role in viral genome replication within the human body and has been identified as a potential drug target for chronic hepatitis B therapeutics. However, available nucleotide reverse transcriptase inhibitors only target the reverse transcriptase domain of the HBV polymerase; they also pose resistance issues and require lifelong treatment that can burden patients financially. In this study, various chemical classes are reviewed that have been developed to target different domains of the HBV polymerase: Terminal protein, which plays a vital role in the formation of the viral DNA; Reverse transcriptase, which is responsible for the synthesis of the viral DNA from RNA, and; Ribonuclease H, which is responsible for degrading the RNA strand in the RNA-DNA duplex formed during the reverse transcription process. Host factors that interact with the HBV polymerase to achieve HBV replication are also reviewed; these host factors can be targeted by inhibitors to indirectly inhibit polymerase functionality. A detailed analysis of the scope and limitations of these inhibitors from a medicinal chemistry perspective is provided. The structure-activity relationship of these inhibitors and the factors that may affect their potency and selectivity are also examined. This analysis will be useful in supporting the further development of these inhibitors and in designing new inhibitors that can inhibit HBV replication more efficiently.

Attitude and perception of undergraduate medical students toward the problem-based learning in Chitwan Medical College, Nepal.

BACKGROUND: Problem-based learning (PBL) was introduced into Basic Medical Sciences early in the 1980s at Tribhuvan University (TU), Nepal, followed by other universities where didactic lecture method was still followed as the main teaching strategy. Despite gaining its popularity worldwide as integrated teaching learning method, PBL is not given importance in Nepal. This study aimed to assess the attitude and perceptions of undergraduate medical students regarding learning outcomes of PBL and to know their views about role and qualities of effective tutors for its successful implementation. METHODS: This descriptive study was based on a self-administered questionnaire. The first part of the questionnaire measured students' perception and attitude toward benefits of PBL and the second part measured students' perception about role of PBL tutor. Bachelor of Medicine and Bachelor of Surgery (MBBS) first year (2014/2015 academic year) students at Chitwan Medical College, TU, were asked to express their opinions about the importance of learning outcomes by rating each statement on a five-point Likert scale and the responses were combined into three categorical variables: "agree" (strongly agree plus agree), "neutral", and "disagree" (strongly disagree plus disagree). Data were analyzed using SPSS version 21.0. RESULTS: Approximately 85.5% participants agreed that PBL is an interesting method of teaching learning. Most of them (86.7%) accepted that PBL is an interactive and a mutual learning method and improves self-directed learning (83.2%). Although 78% had recommended it better than lecture, many (54.2%) pointed it out as a time-consuming method. The participants were also highly rated (80.5%) to the statement - the tutor's role in enhancing the constructive active learning and maintaining good intra-personal behavior. CONCLUSION: Student's attitude toward PBL was positive. They highly appreciated the roles of a tutor as facilitators and motivators for proper activities in PBL session. PBL sessions were considered effective in improving students professional knowledge and refining problem-solving and self-directed learning skills along with enriching teamwork experience.

Association between obesity and heart rate variability indices: an intuition toward cardiac autonomic alteration - a risk of CVD.

BACKGROUND: Obese people have a higher prevalence of cardiovascular disease, which is supposed to be due to autonomic dysfunction and/or metabolic disorder. The alterations in cardiac autonomic functions bring out the changes in the heart rate variability (HRV) indicators, an assessing tool for cardiac autonomic conditions. OBJECTIVE: To compare the cardiac autonomic activity between obese and normal weight adults and find out the highest association between the indices of HRV and obesity. METHODS: The study was conducted in 30 adult obese persons (body mass index [BMI] >30 kg/m2) and 29 healthy normal weight controls (BMI 18-24 kg/m2). Short-term HRV variables were assessed using standard protocol. Data were compared between groups using Mann-Whitney U test. Obesity indices such as waist circumference, hip circumference, waist-hip ratio (WHR), and BMI were measured and calculated, and they were correlated with HRV indices using Spearman's correlation analysis. RESULTS: In the obese group, there was a significant increase in the mean heart rate, whereas the HRV parasympathetic indicators were less (eg, root mean square of differences of successive RR intervals [28.75 {16.72-38.35} vs 41.55 {30.6-56.75} ms, p=0.018], number of RR intervals that differ by >50 ms, that is, NN50 [15.5 {2-39} vs 83.5 {32.75-116.25}, p=0.010], etc) and the sympathetic indicator low frequency (LF)/high frequency (HF) ratio (1.2 [0.65-2.20] vs 0.79 [0.5-1.02], p=0.045) was more than that of the normal weight group. Spearman's correlation between HRV and obesity indices showed significant positive correlation of WHR with LF in normalized unit (r=0.478, p<0.01) and LF/HF ratio (r=0.479, p<0.01), whereas it had significant negative correlation with high frequency power ms2 (r=-0.374, p<0.05) and HF in normalized unit (r=-0.478, p<0.01). There was a nonsignificant correlation of BMI with HRV variables in obese individuals. CONCLUSION: Increased WHR, by far an indicator of visceral adiposity, was strongly associated with reduced cardiac parasympathetic and increased sympathetic activity in obese individuals defined by BMI. However, BMI itself has a weak relationship with HRV cardiac autonomic markers. Thus, even with a slight increase in WHR in an individual, there could be a greater risk of cardiovascular morbidity and mortality brought about by cardiac autonomic alterations.