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Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance 1 – 3 . Teixobactin 4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan 5 . Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin 4 . The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates. Using a combination of methods, the mechanism of the antibiotic teixobactin is revealed.

Schistosome parasites infect more than 200 million people annually, mostly in sub-Saharan Africa, where people may be co-infected with more than one species of the parasite. Infection risk for any single species is determined, in part, by the distribution of its obligate intermediate host snail. As the World Health Organization reprioritizes snail control to reduce the global burden of schistosomiasis, there is renewed importance in knowing when and where to target those efforts, which could vary by schistosome species. This study estimates factors associated with schistosomiasis risk in 16 villages located in the Senegal River Basin, a region hyperendemic for Schistosoma haematobium and S . mansoni . We first analyzed the spatial distributions of the two schistosomes’ intermediate host snails ( Bulinus spp. and Biomphalaria pfeifferi , respectively) at village water access sites. Then, we separately evaluated the relationships between human S . haematobium and S . mansoni infections and (i) the area of remotely-sensed snail habitat across spatial extents ranging from 1 to 120 m from shorelines, and (ii) water access site size and shape characteristics. We compared the influence of snail habitat across spatial extents because, while snail sampling is traditionally done near shorelines, we hypothesized that snails further from shore also contribute to infection risk. We found that, controlling for demographic variables, human risk for S . haematobium infection was positively correlated with snail habitat when snail habitat was measured over a much greater radius from shore (45 m to 120 m) than usual. S . haematobium risk was also associated with large, open water access sites. However, S . mansoni infection risk was associated with small, sheltered water access sites, and was not positively correlated with snail habitat at any spatial sampling radius. Our findings highlight the need to consider different ecological and environmental factors driving the transmission of each schistosome species in co-endemic landscapes.

Obesity affects over 2 billion people worldwide and is accompanied by peripheral neuropathy (PN) and an associated poorer quality of life. Despite high prevalence, the molecular mechanisms underlying the painful manifestations of PN are poorly understood, and therapies are restricted to use of painkillers or other drugs that do not address the underlying disease. Studies have demonstrated that the gut microbiome is linked to metabolic health and its alteration is associated with many diseases, including obesity. Pathologic changes to the gut microbiome have recently been linked to somatosensory pain, but any relationships between gut microbiome and PN in obesity have yet to be explored. Our data show that mice fed a Western diet developed indices of PN that were attenuated by concurrent fecal microbiome transplantation (FMT). In addition, we observed changes in expression of genes involved in lipid metabolism and calcium handling in cells of the peripheral nerve system (PNS). FMT also induced changes in the immune cell populations of the PNS. There was a correlation between an increase in the circulating shortchain fatty acid butyrate and pain improvement following FMT. Additionally, butyrate modulated gene expression and immune cells in the PNS. Circulating butyrate was also negatively correlated with distal pain in 29 participants with varied body mass index. Our data suggest that the metabolite butyrate, secreted by the gut microbiome, underlies some of the effects of FMT. Targeting the gut microbiome, butyrate, and its consequences may represent novel viable approaches to prevent or relieve obesity-associated neuropathies.

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that infects multiple immune cell types and integrates into host cell DNA termed provirus. Under antiretroviral control, provirus in cells is able to evade targeting by both host immune surveillance and antiretroviral drug regimens. Additionally, the provirus remains integrated for the life of the cell, and clonal expansion establishes a persistent reservoir. As host cells become quiescent following the acute stage of infection, the provirus also enters a latent state characterized by low levels of transcription and virion production. Proviral latency may last years or even decades, but stimuli such as immune activation, accumulation of viral proteins, and certain medications can trigger reactivation of proviral gene expression. Left untreated, this can lead to virema, development of pathogenic out comes, and even death as the immune system becomes weakened and dysregulated. Over the last few decades, the role of chromatin in both HIV-1 latency and reactivation has been characterized in-depth, and a number of host factors have been identified as key players in modifying the local (2D) chromatin environment of the provirus. Here, the impact of the 2D chromatin environment and its related factors are reviewed. Enzymes that catalyze the addition or removal of covalent groups from histone proteins, such as histone deacetylase complexes (HDACs) and methyltransferases (HMTs) are of particular interest, as they both alter the affinity of histones for proviral DNA and function to recruit other proteins that contribute to chromatin remodeling and gene expression from the provirus. More recently, advances in next-generation sequencing and imaging technology has enabled the study of how the higher-order (3D) chromatin environment relates to proviral latency, including the impacts of integration site and cell type. All together, these multi-dimensional factors regulate latency by influencing the degree of accessibility to the proviral DNA by transcription machinery. Finally, additional implications for therapeutics and functional studies are proposed and discussed.

Purpose Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL. Methods MRI at 3.0 T of upper extremity and torso anatomy, fat and muscle tissue composition, and T 2 relaxometry were applied in left and right axillae of healthy control ( n  = 24) and symptomatic BCRL ( n  = 22) participants to test the primary hypothesis that fat-to-muscle volume fraction is elevated in symptomatic BCRL relative to healthy participants, and the secondary hypothesis that fat-to-muscle volume fraction is correlated with MR relaxometry of affected tissues and BCRL stage (significance criterion: two-sided p  < 0.05). Results Fat-to-muscle volume fraction in healthy participants was symmetric in the right and left sides ( p  = 0.51); in BCRL participants matched for age, sex, and BMI, fat-to-muscle volume fraction was elevated on the affected side (fraction = 0.732 ± 0.184) versus right and left side in controls (fraction = 0.545 ± 0.221, p  < 0.001). Fat-to-muscle volume fraction directly correlated with muscle T 2 ( p  = 0.046) and increased with increasing level of BCRL stage ( p  = 0.041). Conclusion Adiposity quantified by MRI is elevated in the affected upper extremity of women with BCRL and may provide a surrogate marker of condition onset or severity. Clinical trial NCT02611557.

Recently, the World Health Organization recognized that efforts to interrupt schistosomiasis transmission through mass drug administration have been ineffective in some regions; one of their new recommended strategies for global schistosomiasis control emphasizes targeting the freshwater snails that transmit schistosome parasites. We sought to identify robust indicators that would enable precision targeting of these snails. At the site of the world’s largest recorded schistosomiasis epidemic—the Lower Senegal River Basin in Senegal—intensive sampling revealed positive relationships between intermediate host snails (abundance, density, and prevalence) and human urogenital schistosomiasis reinfection (prevalence and intensity in schoolchildren after drug administration). However, we also found that snail distributions were so patchy in space and time that obtaining useful data required effort that exceeds what is feasible in standard monitoring and control campaigns. Instead, we identified several environmental proxies that were more effective than snail variables for predicting human infection: the area covered by suitable snail habitat (i.e., floating, nonemergent vegetation), the percent cover by suitable snail habitat, and size of the water contact area. Unlike snail surveys, which require hundreds of person-hours per site to conduct, habitat coverage and site area can be quickly estimated with drone or satellite imagery. This, in turn, makes possible large-scale, high-resolution estimation of human urogenital schistosomiasis risk to support targeting of both mass drug administration and snail control efforts.

Schistosomiasis is a debilitating parasitic disease of poverty that affects more than 200 million people worldwide, mostly in sub-Saharan Africa, and is clearly associated with the construction of dams and water resource management infrastructure in tropical and subtropical areas. Changes to hydrology and salinity linked to water infrastructure development may create conditions favorable to the aquatic vegetation that is suitable habitat for the intermediate snail hosts of schistosome parasites. With thousands of small and large water reservoirs, irrigation canals, and dams developed or under construction in Africa, it is crucial to accurately assess the spatial distribution of high-risk environments that are habitat for freshwater snail intermediate hosts of schistosomiasis in rapidly changing ecosystems. Yet, standard techniques for monitoring snails are labor-intensive, time-consuming, and provide information limited to the small areas that can be manually sampled. Consequently, in low-income countries where schistosomiasis control is most needed, there are formidable challenges to identifying potential transmission hotspots for targeted medical and environmental interventions. In this study, we developed a new framework to map the spatial distribution of suitable snail habitat across large spatial scales in the Senegal River Basin by integrating satellite data, high-definition, low-cost drone imagery, and an artificial intelligence (AI)-powered computer vision technique called semantic segmentation. A deep learning model (U-Net) was built to automatically analyze high-resolution satellite imagery to produce segmentation maps of aquatic vegetation, with a fast and robust generalized prediction that proved more accurate than a more commonly used random forest approach. Accurate and up-to-date knowledge of areas at highest risk for disease transmission can increase the effectiveness of control interventions by targeting habitat of disease-carrying snails. With the deployment of this new framework, local governments or health actors might better target environmental interventions to where and when they are most needed in an integrated effort to reach the goal of schistosomiasis elimination.

Michael Taylor, Marco Marra and colleagues analyze spatial tumor heterogeneity in 9 medulloblastomas, 16 high-grade gliomas and 10 renal cell carcinomas, using a combination of transcriptomic and genomic profiling of multiregional biopsies. They find that medulloblastomas have spatially homogeneous transcriptomes, whereas somatic mutations that affect genes suitable for targeted therapeutics are spatially heterogeneous. Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Popular fears about human infectious disease often focus on pathogens spread by person-to-person contact. By contrast, we show that 70–80% of human pathogens are environmentally transmitted (ie, people are infected through contact with free-living stages or environmental reservoirs including soil, water, vectors, food, or non- human hosts in the environment). In fact, environmentally transmitted diseases represent about 40% of today's global burden of human infectious disease (or 150 million disability adjusted life-years). Here, we call for renewed attention to the connection between human health and environmental factors, with a focus on identifying ecological solutions to interrupt transmission. We developed a simple modelling framework that is able to capture the two main transmission pathways—namely, direct (host-to-host transmission, such in the case of influenza and measles) and transmission through an environmental reservoir (such, in the case of cholera, vector borne diseases, helminthiasis and sapronosis). We used the epidemiological model to analyse the role of ecological drivers for environmentally transmitted parasites and pathogens and to investigate the effectiveness of drug treatment for both directly and environmentally transmitted diseases. Through the analysis of system dynamics, we show that periodic drug treatments that lead to the elimination of directly transmitted diseases might fail to do so in the case of human pathogens with an environmental reservoir. For environmentally transmitted diseases, more effective control can be achieved when classic treatment strategies are complemented with interventions that act on the environmental reservoir of the pathogen or reduce exposure. Control of environmentally transmitted diseases can be more effective when human treatment is complemented with interventions targeting the environmental reservoir of the pathogen. Wherever environmental approaches to reduce human disease and preserve ecosystems are available, health practitioners, environmental scientists, and communities can work synergistically to solve health problems. National Science Foundation, Bill and Melinda Gates Foundation, NIMBioS, SNAP-NCEAS, Stanford FSI-SEED-GDP.

During the COVID-19 pandemic, acute respiratory infection (ARI) antibiotic prescribing in ambulatory care markedly decreased. It is unclear if antibiotic prescription rates will remain lowered. We used trend analyses of antibiotics prescribed during and after the first wave of COVID-19 to determine whether ARI antibiotic prescribing rates in ambulatory care have remained suppressed compared to pre-COVID-19 levels. Retrospective data was used from patients with ARI or UTI diagnosis code(s) for their encounter from 298 primary care and 66 urgent care practices within four academic health systems in New York, Wisconsin, and Utah between January 2017 and June 2022. The primary measures included antibiotic prescriptions per 100 non-COVID ARI encounters, encounter volume, prescribing trends, and change from expected trend. At baseline, during and after the first wave, the overall ARI antibiotic prescribing rates were 54.7, 38.5, and 54.7 prescriptions per 100 encounters, respectively. ARI antibiotic prescription rates saw a statistically significant decline after COVID-19 onset (step change -15.2, 95% CI: -19.6 to -4.8). During the first wave, encounter volume decreased 29.4% and, after the first wave, remained decreased by 188%. After the first wave, ARI antibiotic prescription rates were no longer significantly suppressed from baseline (step change 0.01, 95% CI: -6.3 to 6.2). There was no significant difference between UTI antibiotic prescription rates at baseline versus the end of the observation period. The decline in ARI antibiotic prescribing observed after the onset of COVID-19 was temporary, not mirrored in UTI antibiotic prescribing, and does not represent a long-term change in clinician prescribing behaviors. During a period of heightened awareness of a viral cause of ARI, a substantial and clinically meaningful decrease in clinician antibiotic prescribing was observed. Future efforts in antibiotic stewardship may benefit from continued study of factors leading to this reduction and rebound in prescribing rates.