Transferable neural networks for enhanced sampling of protein dynamics

Variational auto-encoder frameworks have demonstrated success in reducing complex nonlinear dynamics in molecular simulation to a single non-linear embedding. In this work, we illustrate how this non-linear latent embedding can be used as a collective variable for enhanced sampling, and present a simple modification that allows us to rapidly perform sampling in multiple related systems. We first demonstrate our method is able to describe the effects of force field changes in capped alanine dipeptide after learning a model using AMBER99. We further provide a simple extension to variational dynamics encoders that allows the model to be trained in a more efficient manner on larger systems by encoding the outputs of a linear transformation using time-structure based independent component analysis (tICA). Using this technique, we show how such a model trained for one protein, the WW domain, can efficiently be transferred to perform enhanced sampling on a related mutant protein, the GTT mutation. This method shows promise for its ability to rapidly sample related systems using a single transferable collective variable and is generally applicable to sets of related simulations, enabling us to probe the effects of variation in increasingly large systems of biophysical interest.Comment: 20 pages, 10 figure

Prevalence of malnutrition and intestinal parasites in preschool slum children in Lucknow

Objective: To assess the point prevalence of intestinal parasites and their association with nutritional parameters. Setting: Anganwadi centers under the Integrated Child Development Scheme (ICDS) in Lucknow, North India. Design: Cross-sectional survey. Methods: By random draw, 32 out of 153 Anganwadi centers were selected. All eligible subjects registered with the Anganwadi worker were enrolled. These were 1061 children (48.3% girls and 51.7% boys) between the ages of 1.5 to 3.5 years. Results: Of these, 67.6% were underweight (weight for age <- 2 SD), 62.8% were stunted (height for age <-2 SD) and 26.5% were wasted (weight for height <-2 SD). Parasites were detected in 17.5% (95% CI 15.3%-19.9%) children by a single direct fecal smear examination. Of these, Ascaris lumbricoides was found in 124 (68.1%) and Giardia lamblia in 60 (32.9%). There was no association between weight or height and parasite positivity. The mean hemoglobin levels for children who were smear positive versus smear negative for ascaris or giardia were 9.1 g/dl and 9.6 g/dl, respectively (p<0.0001). Conclusion: In the urban slums the point prevalence of intestinal parasites is 17.5% in the preschool children. Malnutrition and low hemoglobin levels are also widely prevalent. Urgent remedial steps are needed on community basis to improve their nutritional status and control parasitic infestation

Freezing Transition of Random Heteropolymers Consisting of an Arbitrary Set of Monomers

Mean field replica theory is employed to analyze the freezing transition of random heteropolymers comprised of an arbitrary number ($q$) of types of monomers. Our formalism assumes that interactions are short range and heterogeneity comes only from pairwise interactions, which are defined by an arbitrary $q \times q$ matrix. We show that, in general, there exists a freezing transition from a random globule, in which the thermodynamic equilibrium is comprised of an essentially infinite number polymer conformations, to a frozen globule, in which equilibrium ensemble is dominated by one or very few conformations. We also examine some special cases of interaction matrices to analyze the relationship between the freezing transition and the nature of interactions involved.Comment: 30 pages, 1 postscript figur

Is Heteropolymer Freezing Well Described by the Random Energy Model?

It is widely held that the Random Energy Model (REM) describes the freezing transition of a variety of types of heteropolymers. We demonstrate that the hallmark property of REM, statistical independence of the energies of states over disorder, is violated in different ways for models commonly employed in heteropolymer freezing studies. The implications for proteins are also discussed.Comment: 4 pages, 3 eps figures To appear in Physical Review Letters, May 199

Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease

Background: Small-intestinal bacterial overgrowth (SIBO) is known to be present in patients with cirrhosis, predisposing to various complications. Aim To determine the frequency of SIBO in cirrhotics and correlate with severity of cirrhosis. Methods: Small-intestinal bacterial overgrowth was determined by glucose-hydrogen breath test (GHBT). A basal breath-hydrogen >20 ppm or a rise by ≥12 ppm above baseline following glucose administration was taken as positive test. Prevalence of SIBO in cirrhotics was compared with healthy controls and correlated with severity of cirrhosis. Results: Of the 53 cirrhotics, 26 (49%) had SIBO, compared to one (8%) control (P = 0.010). The prevalence of SIBO increased with severity of cirrhosis (Child-Pugh A 20%, B 52% and C 73%; P = 0.013). On multivariate analysis, SIBO was independently associated with serum bilirubin and ascites. The best cut-off of serum bilirubin was ≥2 mg/dL [AUROC 0.77 (95% CI 0.64-0.90)] predicting SIBO with sensitivity 65%, specificity 81%, positive predictive value 77%, negative predictive value 71% and accuracy 74%. Patients having combination of ascites and serum bilirubin ≥2 mg/dL had 82% chance, while patients having neither had only 10% chance of having SIBO. Conclusions: Small-intestinal bacterial overgrowth was prevalent in about half of cirrhotics. Its frequency increased with increase in severity of cirrhosis. Ascites and raised serum bilirubin reliably predicted presence of SIBO

Improving post-partum family planning services provided by female community health volunteers in Nepal: a mixed methods study.

BACKGROUND: Family planning services in the post-partum period, termed post-partum family planning (PPFP) is critical to cover the unmet need for contraception, especially when institutional delivery rates have increased. However, the intention to choose PPFP methods such as post-partum intrauterine devices (PPIUD) remains low in countries such as Nepal. Community health workers such as Female Community Health Volunteers (FCHVs) could play an important role in improving the service coverage of PPFP in Nepal. However, their knowledge of PPFP and community-based services related to PPFP remain unclear. This study aims to assess the effect on community-based PPFP services by improving FCHV's knowledge through orientation on PPFP. METHODS: We conducted this mixed-methods study in Morang District in Nepal. The intervention involved orientation of FCHVs on PPFP methods. We collected quantitative data from three sources; via a survey of FCHVs that assessed their knowledge before and after the intervention, from their monthly reporting forms on counseling coverage of women at different stages of pregnancy from the communities, and by interviewing mothers in their immediate post-partum period in two selected hospitals. We also conducted six focus group discussions with the FCHVs to understand their perception of PPFP and the intervention. We performed descriptive and multivariable analyses for quantitative results and thematic analysis for qualitative data. RESULTS: In total, 230 FCHVs participated in the intervention and their knowledge of PPFP improved significantly after it. The intervention was the only factor significantly associated with their improved knowledge (adjusted odds ratio = 24, P < 0.001) in the multivariable analysis. FCHVs were able to counsel 83.3% of 1872 mothers at different stages of pregnancy in the communities. In the two hospitals, the proportion of mothers in their immediate post-partum period whom reported they were counseled by FCHVs during their pregnancy increased. It improved from 7% before the intervention to 18.1% (P < 0.001) after the intervention. The qualitative findings suggested that the intervention improved their knowledge in providing PPFP counseling. CONCLUSION: The orientation improved the FCHV's knowledge of PPFP and their community-based counseling. Follow-up studies are needed to assess the longer term effect of the FCHV's role in improving community-based PPFP services

Two State Behavior in a Solvable Model of β\beta-hairpin folding

Understanding the mechanism of protein secondary structure formation is an essential part of protein-folding puzzle. Here we describe a simple model for the formation of the $\beta$-hairpin, motivated by the fact that folding of a $\beta$-hairpin captures much of the basic physics of protein folding. We argue that the coupling of ``primary'' backbone stiffness and ``secondary'' contact formation (similar to the coupling between the ``secondary'' and ``tertiary'' structure in globular proteins), caused for example by side-chain packing regularities, is responsible for producing an all-or-none 2-state $\beta$-hairpin formation. We also develop a recursive relation to compute the phase diagram and single exponential folding/unfolding rate arising via a dominant transition state.Comment: Revised versio

Free Energy Self-Averaging in Protein-Sized Random Heteropolymers

Current theories of heteropolymers are inherently macrpscopic, but are applied to folding proteins which are only mesoscopic. In these theories, one computes the averaged free energy over sequences, always assuming that it is self-averaging -- a property well-established only if a system with quenched disorder is macroscopic. By enumerating the states and energies of compact 18, 27, and 36mers on a simplified lattice model with an ensemble of random sequences, we test the validity of the self-averaging approximation. We find that fluctuations in the free energy between sequences are weak, and that self-averaging is a valid approximation at the length scale of real proteins. These results validate certain sequence design methods which can exponentially speed up computational design and greatly simplify experimental realizations.Comment: 4 pages, 3 figure