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The environmental justice movement has stimulated community-driven research about the living and working conditions of people of color and low-income communities. We describe an epidemiological study designed to link research with community education and organizing for social justice. In eastern North Carolina, high-density industrial swine production occurs in communities of low-income people and people of color. We investigated relationships between the resulting pollution and the health and quality of life of the hog operations’ neighbors. A repeat-measures longitudinal design, community involvement in data collection, and integration of qualitative and quantitative research methods helped promote data quality while providing opportunities for community education and organizing. Research could affect policy through its findings and its mobilization of communities.

Since their emancipation Black farmers have fought to become economically independent and for the right to self-determine the paths of their lives. Land acquisition has been central to this struggle. Impressively, by 1920 Black farmers neared the one million mark and owned roughly 15 million acres of farmland. Yet, in subsequent years their numbers declined at an alarming rate, approaching 50 percent nearly every 10 years during the second half of the Century. Arguably the most united attempt to rectify the racially motivated decline of Black farmers and the loss of Black-owned farmland across America has been the collective support of the class-action lawsuit Timothy Pigford et al., v. Dan Glickman, Secretary, United States Department of Agriculture in 1996.

Environmental triggers is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the environmental triggers section is focused on the main research gaps in elucidating causality of environmental factors in IBD. Research gaps were identified in: 1) epidemiology of exposures; 2) identification of signatures of biological response to exposures; and 3) mechanisms of how environmental exposures drive IBD. To address these gaps, the implementation of longitudinal prospective studies to determine disease evolution and identify sub-clinical changes in response to exposures is proposed. This can help define critical windows of vulnerability and risk prediction. In addition, systems biology analysis and in silico modeling were proposed as approaches to integrate the IBD exposome for the identification of biological signatures of response to exposures, and to develop prediction models of the effects of environmental factors in driving disease activity and response to therapy. This research could lead to identification of biomarkers of exposures and new modalities for therapeutic intervention. Finally, hypothesis-driven mechanistic studies to understand gene-environment interactions and to validate causality of priority factors should be performed to determine how environment influences clinical outcomes.

Summary Inhibition of mammalian target of rapamycin, mTOR, extends lifespan and reduces age-related disease. It is not known what role mTOR plays in the arterial aging phenotype or if mTOR inhibition by dietary rapamycin ameliorates age-related arterial dysfunction. To explore this, young (3.8 ± 0.6 months) and old (30.3 ± 0.2 months) male B6D2F1 mice were fed a rapamycin supplemented or control diet for 6-8 weeks. Although there were few other notable changes in animal characteristics after rapamycin treatment, we found that glucose tolerance improved in old mice, but was impaired in young mice, after rapamycin supplementation (both P < 0.05). Aging increased mTOR activation in arteries evidenced by elevated S6K phosphorylation (P < 0.01), and this was reversed after rapamycin treatment in old mice (P < 0.05). Aging was also associated with impaired endothelium-dependent dilation (EDD) in the carotid artery (P < 0.05). Rapamycin improved EDD in old mice (P < 0.05). Superoxide production and NADPH oxidase expression were higher in arteries from old compared to young mice (P < 0.05), and rapamycin normalized these (P < 0.05) to levels not different from young mice. Scavenging superoxide improved carotid artery EDD in untreated (P < 0.05), but not rapamycin-treated, old mice. While aging increased large artery stiffness evidenced by increased aortic pulse-wave velocity (PWV) (P < 0.01), rapamycin treatment reduced aortic PWV (P < 0.05) and collagen content (P < 0.05) in old mice. Aortic adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and expression of the cell cycle-related proteins PTEN and p27kip were increased with rapamycin treatment in old mice (all P < 0.05). Lastly, aging resulted in augmentation of the arterial senescence marker, p19 (P < 0.05), and this was ameliorated by rapamycin treatment (P < 0.05). These results demonstrate beneficial effects of rapamycin treatment on arterial function in old mice and suggest these improvements are associated with reduced oxidative stress, AMPK activation and increased expression of proteins involved in the control of the cell cycle.

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH ( Dnmt3a R878H/+ ), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A -knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs. Clonal hematopoiesis is driven by the selective advantage of mutant hematopoietic stem cells. Here, authors discover that elevated mitochondrial activity is a targetable mechanism by which mutant hematopoietic stem cells gain a selective advantage.

Since amphibian declines were first proposed as a global phenomenon over a quarter century ago, the conservation community has made little progress in halting or reversing these trends. The early search for a “smoking gun” was replaced with the expectation that declines are caused by multiple drivers. While field observations and experiments have identified factors leading to increased local extinction risk, evidence for effects of these drivers is lacking at large spatial scales. Here, we use observations of 389 time-series of 83 species and complexes from 61 study areas across North America to test the effects of 4 of the major hypothesized drivers of declines. While we find that local amphibian populations are being lost from metapopulations at an average rate of 3.79% per year, these declines are not related to any particular threat at the continental scale; likewise the effect of each stressor is variable at regional scales. This result - that exposure to threats varies spatially, and populations vary in their response - provides little generality in the development of conservation strategies. Greater emphasis on local solutions to this globally shared phenomenon is needed.

Advances in genomics have revealed many of the genetic underpinnings of human disease, but exposomics methods are currently inadequate to obtain a similar level of understanding of environmental contributions to human disease. Exposomics methods are limited by low abundance of xenobiotic metabolites and lack of authentic standards, which precludes identification using solely mass spectrometry-based criteria. Here, we develop and validate a method for enzymatic generation of xenobiotic metabolites for use with high-resolution mass spectrometry (HRMS) for chemical identification. Generated xenobiotic metabolites were used to confirm identities of respective metabolites in mice and human samples based upon accurate mass, retention time and co-occurrence with related xenobiotic metabolites. The results establish a generally applicable enzyme-based identification (EBI) for mass spectrometry identification of xenobiotic metabolites and could complement existing criteria for chemical identification. Humans are exposed to many xenobiotic chemicals, but identification of low abundance xenobiotic exposures is limited by a lack of authentic standards for xenobiotic metabolites. Here the authors develop methods for enzymatic generation of diverse xenobiotic metabolites for use with high-resolution mass spectrometry for biology-based chemical identification.

Tenecteplase has potential benefits over alteplase, the standard agent for intravenous thrombolysis in acute ischaemic stroke, because it is administered as a single bolus and might have superior efficacy. The ATTEST-2 trial investigated whether tenecteplase was non-inferior or superior to alteplase within 4·5 h of onset. We undertook a prospective, randomised, parallel-group, open-label trial with masked endpoint evaluation in 39 UK stroke centres. Previously independent adults with acute ischaemic stroke, eligible for intravenous thrombolysis less than 4·5 h from last known well, were randomly assigned 1:1 to receive intravenous alteplase 0·9 mg/kg or tenecteplase 0·25 mg/kg, by use of a telephone-based interactive voice response system. The primary endpoint was the distribution of the day 90 modified Rankin Scale (mRS) score and was analysed using ordinal logistic regression in the modified intention-to-treat population. We tested the primary outcome for non-inferiority (odds ratio for tenecteplase vs alteplase non-inferiority limit of 0·75), and for superiority if non-inferiority was confirmed. Safety outcomes were mortality, symptomatic intracranial haemorrhage, radiological intracranial haemorrhage, and major extracranial bleeding. The trial was prospectively registered on ClinicalTrials.gov (NCT02814409). Between Jan 25, 2017, and May 30, 2023, 1858 patients were randomly assigned to a treatment group, of whom 1777 received thrombolytic treatment and were included in the modified intention-to-treat population (n=885 allocated tenecteplase and n=892 allocated alteplase). The mean age of participants was 70·4 (SD 12·9) years and median National Institutes of Health Stroke Scale was 7 (IQR 5–13) at baseline. Tenecteplase was non-inferior to alteplase for mRS score distribution at 90 days, but was not superior (odds ratio 1·07; 95% CI 0·90–1·27; p value for non-inferiority<0·0001; p=0·43 for superiority). 68 (8%) patients in the tenecteplase group compared with 75 (8%) patients in the alteplase group died, symptomatic intracerebral haemorrhage (defined by SITS-MOST criteria) occurred in 20 (2%) versus 15 (2%) patients, parenchymal haematoma type 2 occurred in 37 (4%) versus 26 (3%) patients, post-treatment intracranial bleed occurred in 94 (11%) versus 78 (9%) patients, significant extracranial haemorrhage occurred in 13 (1%) versus six (1%) patients, respectively, and angioedema occurred in six (1%) participants in both groups. Tenecteplase 0·25 mg/kg was non-inferior to 0·9 mg/kg alteplase within 4·5 h of symptom onset in acute ischaemic stroke. Easier administration of tenecteplase, especially in the context of interhospital transfers, indicates that tenecteplase should be preferred to alteplase for thrombolysis in acute ischaemic stroke. The ATTEST-2 population was large and representative of thrombolysis-eligible patients in the UK and, together with findings from other trials, provides robust evidence supporting the introduction of tenecteplase in preference to alteplase. The Stroke Association and British Heart Foundation.

This protocol describes an immunogen evaluation pipeline containing two main components that enable vaccine candidates to be rank-ordered. Predicting immune responses before vaccination is challenging because of the complexity of the governing parameters. Nevertheless, recent work has shown that B cell receptor (BCR)-antigen engagement in vitro can prove a powerful means of informing the design of antibody-based vaccines. We have developed this principle into a two-phased immunogen evaluation pipeline to rank-order vaccine candidates. In phase 1, recombinant antigens are screened for reactivity to the germline precursors that produce the antibody responses of interest. To both mimic the architecture of initial antigen engagement and facilitate rapid immunogen screening, these antibodies are expressed as membrane-anchored IgM (mIgM) in 293F indicator cells. In phase 2, the binding hits are multimerized by nanoparticle or proteoliposome display, and they are evaluated for BCR triggering in an engineered B cell line displaying the IgM sequences of interest. Key developments that complement existing methodology in this area include the following: (i) introduction of a high-throughput screening step before evaluation of more time-intensive BCR-triggering analyses; (ii) generalizable multivalent antigen-display platforms needed for BCR activation; and (iii) engineered use of a human B cell line that does not display endogenous antibody, but only ectopically expressed BCR sequences of interest. Through this pipeline, the capacity to initiate favorable antibody responses is evaluated. The entire protocol can be completed within 2.5 months.