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Vibrio cholerae is a noninvasive pathogen that colonizes the small intestine and produces cholera toxin, causing severe secretory diarrhea. Cholera results in long lasting immunity, and recent studies have improved our understanding of the antigenic repertoire of V. cholerae . Interactions between the host, V. cholerae , and the intestinal microbiome are now recognized as factors which impact susceptibility to cholera and the ability to mount a successful immune response to vaccination. Vibrio cholerae is a noninvasive pathogen that colonizes the small intestine and produces cholera toxin, causing severe secretory diarrhea. Cholera results in long lasting immunity, and recent studies have improved our understanding of the antigenic repertoire of V. cholerae . Interactions between the host, V. cholerae , and the intestinal microbiome are now recognized as factors which impact susceptibility to cholera and the ability to mount a successful immune response to vaccination. Here, we review recent data and corresponding models to describe immune responses to V. cholerae infection and explain how the host microbiome may impact the pathogenesis of V. cholerae . In the ongoing battle against cholera, the intestinal microbiome represents a frontier for new approaches to intervention and prevention.

Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae . V. cholerae is a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), and V. cholerae motility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, since V. cholerae is a noninvasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibit V. cholerae motility and are associated with protection against challenge in a motility-dependent manner. The mechanism of protection against cholera afforded by previous illness or vaccination is currently unknown. We have recently shown that antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae correlate highly with protection against cholera. V. cholerae is highly motile and possesses a flagellum sheathed in OSP, and motility of V. cholerae correlates with virulence. Using high-speed video microscopy and building upon previous animal-related work, we demonstrate that sera, polyclonal antibody fractions, and OSP-specific monoclonal antibodies recovered from humans surviving cholera block V. cholerae motility at both subagglutinating and agglutinating concentrations. This antimotility effect is reversed by preadsorbing sera and polyclonal antibody fractions with purified OSP and is associated with OSP-specific but not flagellin-specific monoclonal antibodies. Fab fragments of OSP-specific polyclonal antibodies do not inhibit motility, suggesting a requirement for antibody-mediated cross-linking in motility inhibition. We show that OSP-specific antibodies do not directly affect V. cholerae viability, but that OSP-specific monoclonal antibody highly protects against death in the murine cholera model. We used in vivo competitive index studies to demonstrate that OSP-specific antibodies impede colonization and survival of V. cholerae in intestinal tissues and that this impact is motility dependent. Our findings suggest that the impedance of motility by antibodies targeting V. cholerae OSP contributes to protection against cholera. IMPORTANCE Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae . V. cholerae is a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), and V. cholerae motility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, since V. cholerae is a noninvasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibit V. cholerae motility and are associated with protection against challenge in a motility-dependent manner.

Vibrio cholerae, the causative agent of cholera, is a major cause of diarrhea worldwide. Children under the age of 5 have the highest disease burden of cholera. Vibriocidal antibody responses following natural infection and oral cholera vaccination (OCV) are associated with protective immunity, but whether this holds uniformly true in young children is not known. Household contacts of cholera patients are at high risk of cholerae infection. We measured the association between baseline vibriocidal titer and the subsequent risk of infection in 50 household contacts <5 years old, 228 contacts 5-15 years old, and 548 contacts 16-70 years old in Bangladesh to determine whether vibriocidal antibody responses predict protection from cholerae infection equally in all age groups. We found that the vibriocidal titer predicted protection similarly in young children and other age strata. There was no interaction between age and vibriocidal titer. Mean baseline serum vibriocidal titers were higher in individuals in all age groups who remained uninfected compared with those who developed cholerae infection during the follow-up period. After OCV, children have comparable vibriocidal responses to adults but a shorter duration and magnitude of protection compared with adults. In persons exposed to natural infection, we found that the vibriocidal titer predicts protection uniformly in all age groups. The vibriocidal titer may not be the optimal marker to demonstrate protection after OCV, and improved markers for estimating OCV efficacy in children are needed.

ABSTRACT The mechanism of protection against cholera afforded by previous illness or vaccination is currently unknown. We have recently shown that antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae correlate highly with protection against cholera. V. cholerae is highly motile and possesses a flagellum sheathed in O-specific polysaccharide (OSP), and motility of V. cholerae correlates with virulence. Using high speed video microscopy, and building upon previous animal-related work, we demonstrate that sera, polyclonal antibody fractions, and OSP-specific monoclonal antibodies recovered from humans surviving cholera block V. cholerae motility at both subagglutinating and agglutinating concentrations. This anti-motility effect is reversed by pre-adsorbing sera and polyclonal antibody fractions with purified OSP; and is associated with OSP-specific but not flagellin-specific monoclonal antibodies. F[ab] fragments of OSP-specific polyclonal antibodies do not inhibit motility, suggesting a requirement for antibody-mediated crosslinking in motility inhibition. We show that OSP-specific antibodies do not directly affect V. cholerae viability, but that OSP-specific monoclonal antibody highly protects against death in the murine cholera model. We used in vivo competitive index studies to demonstrate that OSP-specific antibodies impede colonization and survival of V. cholerae in intestinal tissues, and that this impact is motility-dependent. Our findings suggest that the impedance of motility by antibodies targeting V. cholerae OSP contributes to protection against cholera. IMPORTANCE Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae. V. cholerae is a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), and V. cholerae motility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, since V. cholerae is a non-invasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibit V. cholerae motility and are associated with protection against challenge in a motility-dependent manner.

Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample ( N  = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits’ PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder. The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.

[...]without a strategic transition plan in place, communities that used to benefit from lymphatic filariasis control activities run the risk of undermining the gains already made for soil-transmitted helminthiasis control once GPELF is discontinued. [...]the Committee welcomes the recent approval of a new, rapidly disintegrating chewable formulation of mebendazole. [...]as for other chronic infections (e.g., tuberculosis, human immune deficiency virus [HIV], and malaria), combination therapy against soil-transmitted helminthiasis might decrease this risk and could enhance efficacy [25]. [...]the need for combination therapy is further supported by coendemicity of multiple helminth infections. [...]there is a need to develop a new survey design that (1) is sufficiently powered to assess if the prevalence of moderate- or heavy-intensity infections falls below 1% and (2) is feasible and affordable, considering the limited resources and capacity of national soil-transmitted helminthiasis control programs.

Here we report a large genome-wide association study (GWAS) for longitudinal smoking phenotypes in 286,118 individuals from the Million Veteran Program (MVP) where we identified 18 loci for smoking trajectory of current versus never in European Americans, one locus in African Americans, and one in Hispanic Americans. Functional annotations prioritized several dozen genes where significant loci co-localized with either expression quantitative trait loci or chromatin interactions. The smoking trajectories were genetically correlated with 209 complex traits, for 33 of which smoking was either a causal or a consequential factor. We also performed European-ancestry meta-analyses for smoking status in the MVP and GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) (N total  = 842,717) and identified 99 loci for smoking initiation and 13 loci for smoking cessation. Overall, this large GWAS of longitudinal smoking phenotype in multiple populations, combined with a meta-GWAS for smoking status, adds new insights into the genetic vulnerability for smoking behavior. Genome-wide association studies (GWASs) for cigarette smoking have identified several hundred loci that account for a small proportion of the overall genetic risk. Here, the authors report a large GWAS for smoking trajectories and meta-analysis for smoking status, finding multiple plausible loci.

Most RNA viruses lack the mechanisms to recognize and correct mutations that arise during genome replication, resulting in quasispecies diversity that is required for pathogenesis and adaptation. However, it is not known how viruses encoding large viral RNA genomes such as the Coronaviridae (26 to 32 kb) balance the requirements for genome stability and quasispecies diversity. Further, the limits of replication infidelity during replication of large RNA genomes and how decreased fidelity impacts virus fitness over time are not known. Our previous work demonstrated that genetic inactivation of the coronavirus exoribonuclease (ExoN) in nonstructural protein 14 (nsp14) of murine hepatitis virus results in a 15-fold decrease in replication fidelity. However, it is not known whether nsp14-ExoN is required for replication fidelity of all coronaviruses, nor the impact of decreased fidelity on genome diversity and fitness during replication and passage. We report here the engineering and recovery of nsp14-ExoN mutant viruses of severe acute respiratory syndrome coronavirus (SARS-CoV) that have stable growth defects and demonstrate a 21-fold increase in mutation frequency during replication in culture. Analysis of complete genome sequences from SARS-ExoN mutant viral clones revealed unique mutation sets in every genome examined from the same round of replication and a total of 100 unique mutations across the genome. Using novel bioinformatic tools and deep sequencing across the full-length genome following 10 population passages in vitro, we demonstrate retention of ExoN mutations and continued increased diversity and mutational load compared to wild-type SARS-CoV. The results define a novel genetic and bioinformatics model for introduction and identification of multi-allelic mutations in replication competent viruses that will be powerful tools for testing the effects of decreased fidelity and increased quasispecies diversity on viral replication, pathogenesis, and evolution.

Biocompatible polymers are widely used in tissue engineering and biomedical device applications. However, few biomaterials are suitable for use as long-term implants and these examples usually possess limited property scope, can be difficult to process, and are non-responsive to external stimuli. Here, we report a class of easily processable polyamides with stereocontrolled mechanical properties and high-fidelity shape memory behaviour. We synthesise these materials using the efficient nucleophilic thiol-yne reaction between a dipropiolamide and dithiol to yield an α,β − unsaturated carbonyl moiety along the polymer backbone. By rationally exploiting reaction conditions, the alkene stereochemistry is modulated between 35–82% cis content and the stereochemistry dictates the bulk material properties such as tensile strength, modulus, and glass transition. Further access to materials possessing a broader range of thermal and mechanical properties is accomplished by polymerising a variety of commercially available dithiols with the dipropiolamide monomer. Few biomaterials are suitable for long-term tissue engineering applications and these examples usually possess limited property scope, can be difficult to process, and are non-responsive to external stimuli. Here, the authors overcome these issues by developing a class of easily processable polyamides with stereo-controlled mechanical properties and high-fidelity shape memory behaviour.

Importance Health care workers (HCWs) face significant mental health challenges when delivering care and over the span of their careers. Despite growing recognition of these issues, barriers such as stigma, structural limitations, and individual obstacles continue to impede progress in supporting HCWs mental health needs. Digital mental health platforms continue to expand in health systems as they offer novel approaches to address these gaps, but more evidence is needed to understand their reception among HCWs. Objective To examine the perceptions of HCWs regarding their mental health, explore barriers and facilitators to accessing mental health care, and assess their experiences with digital mental health interventions within the context of the pandemic. Design A qualitative study using semi-structured interviews with HCWs who participated in a prior randomized controlled trial (RCT) assessing the impact of a digital mental health platform on anxiety and depression. Setting A large, urban, academic health system. Participants A purposive sample of 64 HCWs, including physicians, nurses, technicians, administrative staff, and social workers, was recruited. Participants were selected from the upper and lower quartiles of anxiety and depression scores from the parent RCT to capture a range of mental health symptomatology. Outcomes and measures The study aimed to identify HCWs’ attitudes toward mental health care, barriers to utilizing professional resources, and their experiences with the digital mental health platform at the local institution. A thematic content analysis was used to analyze the interview data. Results Five major themes were identified: (1) the evolving mental health challenges during and after the pandemic, (2) individual barriers to accessing care, such as personal coping strategies and familial responsibilities, (3) structural barriers like workload and limited access to mental health clinicians, (4) experiences with digital mental health interventions, including text message-based assessments, and (5) recommendations for future digital health strategies to improve access and reduce stigma. Conclusion Digital mental health interventions provide a promising avenue to support HCWs by reducing stigma and improving access to mental health resources and clinicians. However, personalized and system-level changes are necessary to address the ongoing mental health challenges faced by the workforce.