Trypsin inhibition by macrocyclic and open-chain variants of the squash inhibitor MCoTI-II

MCoTl-I and MCoTl-II from the seeds of Momordica cochinchinensis are inhibitors of trypsin-like proteases and the only known members of the large family of squash inhibitors that are cyclic and contain an additional loop connecting the amino- and the carboxy-terminus. To investigate the contribution of macrocycle formation to biological activity, we synthesized a set of open-chain variants of MCoTl-II that lack the cyclization loop and contain various natural and non-natural amino acid substitutions in the reactive-site loop. Upon replacement of P1 lysine residue \#10 within the open-chain variant of MCoTl-II by the non-natural isosteric nucleo amino acid AlaG{[}beta-(guanin-9-yl)-L-alanine], a conformationally restricted arginine mimetic, residual inhibitory activity was detected, albeit reduced by four orders of magnitude. While the cyclic inhibitors MCoTl-I and MCoTl-II were found to be very potent trypsin inhibitors, with picomolar inhibition constants, the open-chain variants displayed an approximately 10-fold lower affinity. These data suggest that the formation of a circular backbone in the MCoTI squash inhibitors results in enhanced affinity and therefore is a determinant of biological activity

Improving Pareto Front Learning via Multi-Sample Hypernetworks

Pareto Front Learning (PFL) was recently introduced as an effective approach to obtain a mapping function from a given trade-off vector to a solution on the Pareto front, which solves the multi-objective optimization (MOO) problem. Due to the inherent trade-off between conflicting objectives, PFL offers a flexible approach in many scenarios in which the decision makers can not specify the preference of one Pareto solution over another, and must switch between them depending on the situation. However, existing PFL methods ignore the relationship between the solutions during the optimization process, which hinders the quality of the obtained front. To overcome this issue, we propose a novel PFL framework namely PHN-HVI, which employs a hypernetwork to generate multiple solutions from a set of diverse trade-off preferences and enhance the quality of the Pareto front by maximizing the Hypervolume indicator defined by these solutions. The experimental results on several MOO machine learning tasks show that the proposed framework significantly outperforms the baselines in producing the trade-off Pareto front.Comment: Accepted to AAAI-2

A Framework for Controllable Pareto Front Learning with Completed Scalarization Functions and its Applications

Pareto Front Learning (PFL) was recently introduced as an efficient method for approximating the entire Pareto front, the set of all optimal solutions to a Multi-Objective Optimization (MOO) problem. In the previous work, the mapping between a preference vector and a Pareto optimal solution is still ambiguous, rendering its results. This study demonstrates the convergence and completion aspects of solving MOO with pseudoconvex scalarization functions and combines them into Hypernetwork in order to offer a comprehensive framework for PFL, called Controllable Pareto Front Learning. Extensive experiments demonstrate that our approach is highly accurate and significantly less computationally expensive than prior methods in term of inference time.Comment: Under Review at Neural Networks Journa

The epidemiology and aetiology of diarrhoeal disease in infancy in southern Vietnam: a birth cohort study.

OBJECTIVES: Previous studies indicate a high burden of diarrhoeal disease in Vietnamese children, however longitudinal community-based data on burden and aetiology are limited. The findings from a large, prospective cohort study of diarrhoeal disease in infants in southern Vietnam are presented herein. METHODS: Infants were enrolled at birth in urban Ho Chi Minh City and a semi-rural district in southern Vietnam, and followed for 12 months (n=6706). Diarrhoeal illness episodes were identified through clinic-based passive surveillance, hospital admissions, and self-reports. RESULTS: The minimum incidence of diarrhoeal illness in the first year of life was 271/1000 infant-years of observation for the whole cohort. Rotavirus was the most commonly detected pathogen (50% of positive samples), followed by norovirus (24%), Campylobacter (20%), Salmonella (18%), and Shigella (16%). Repeat infections were identified in 9% of infants infected with rotavirus, norovirus, Shigella, or Campylobacter, and 13% of those with Salmonella infections. CONCLUSIONS: The minimum incidence of diarrhoeal disease in infants in both urban and semi-rural settings in southern Vietnam was quantified prospectively. A large proportion of laboratory-diagnosed disease was caused by rotavirus and norovirus. These data highlight the unmet need for a rotavirus vaccine in Vietnam and provide evidence of the previously unrecognized burden of norovirus in infants

Community, Family, and Partner-Related Stigma Experienced by Pregnant and Postpartum Women with HIV in Ho Chi Minh City, Vietnam

Pregnant and postpartum women with HIV often face stigma and discrimination at home and in the community. In Vietnam, associations between HIV and the “social evils” of drug use and sex work contribute to stigmatization of people with HIV. We conducted a qualitative study to explore discrimination experienced by HIV-positive pregnant and postpartum women in Ho Chi Minh City at home and in the community. We conducted 20 in-depth interviews and two focus group discussions. Participants described managing disclosure of their HIV infection because of fear of stigma and discrimination, particularly to the wider community. In cases where their HIV status was disclosed, women experienced both discrimination and support. The findings highlight the need for targeted interventions to support pregnant and postpartum women with HIV, particularly during this period when they are connected to the healthcare system and more readily available for counseling

The impact of albendazole treatment on the incidence of viral- and bacterial-induced diarrhea in school children in southern Vietnam: study protocol for a randomized controlled trial

Anthelmintics are one of the more commonly available classes of drugs to treat infections by parasitic helminths (especially nematodes) in the human intestinal tract. As a result of their cost-effectiveness, mass school-based deworming programs are becoming routine practice in developing countries. However, experimental and clinical evidence suggests that anthelmintic treatments may increase susceptibility to other gastrointestinal infections caused by bacteria, viruses, or protozoa. Hypothesizing that anthelmintics may increase diarrheal infections in treated children, we aim to evaluate the impact of anthelmintics on the incidence of diarrheal disease caused by viral and bacterial pathogens in school children in southern Vietnam.This is a randomized, double-blinded, placebo-controlled trial to investigate the effects of albendazole treatment versus placebo on the incidence of viral- and bacterial-induced diarrhea in 350 helminth-infected and 350 helminth-uninfected Vietnamese school children aged 6-15 years. Four hundred milligrams of albendazole, or placebo treatment will be administered once every 3 months for 12 months. At the end of 12 months, all participants will receive albendazole treatment. The primary endpoint of this study is the incidence of diarrheal disease assessed by 12 months of weekly active and passive case surveillance. Secondary endpoints include the prevalence and intensities of helminth, viral, and bacterial infections, alterations in host immunity and the gut microbiota with helminth and pathogen clearance, changes in mean z scores of body weight indices over time, and the number and severity of adverse events.In order to reduce helminth burdens, anthelmintics are being routinely administered to children in developing countries. However, the effects of anthelmintic treatment on susceptibility to other diseases, including diarrheal pathogens, remain unknown. It is important to monitor for unintended consequences of drug treatments in co-infected populations. In this trial, we will examine how anthelmintic treatment impacts host susceptibility to diarrheal infections, with the aim of informing deworming programs of any indirect effects of mass anthelmintic administrations on co-infecting enteric pathogens.ClinicalTrials.gov: NCT02597556 . Registered on 3 November 2015