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Abstract Next-generation T-cell-directed vaccines for COVID-19 focus on establishing lasting T-cell immunity against current and emerging SARS-CoV-2 variants. Precise identification of conserved T-cell epitopes is critical for designing effective vaccines. Here we introduce a comprehensive computational framework incorporating a machine learning algorithm—MHCvalidator—to enhance mass spectrometry-based immunopeptidomics sensitivity. MHCvalidator identifies unique T-cell epitopes presented by the B7 supertype, including an epitope from a + 1-frameshift in a truncated Spike antigen, supported by ribosome profiling. Analysis of 100,512 COVID-19 patient proteomes shows Spike antigen truncation in 0.85% of cases, revealing frameshifted viral antigens at the population level. Our EpiTrack pipeline tracks global mutations of MHCvalidator-identified CD8 + T-cell epitopes from the BNT162b4 vaccine. While most vaccine epitopes remain globally conserved, an immunodominant A*01-associated epitope mutates in Delta and Omicron variants. This work highlights SARS-CoV-2 antigenic features and emphasizes the importance of continuous adaptation in T-cell vaccine development.

Ambient air pollutants, including PM2.5 (aerodynamic diameter d ~2.5 μm), PM10 (d ~10 μm), and ultrafine particles (UFP: d

BACKGROUND: Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. OBJECTIVES: Herein, we sought to determine the molecular and cellular changes that occur in the colon in response to uranium bearing dust (UBD) exposure. METHODS: Human colonoids from three biologically distinct donors were acutely exposed to UBD then digested for single cell RNA sequencing to define the molecular changes that occur to specific identities of colonic epithelial cells. Validation in colonoids was assessed using morphological and imaging techniques. RESULTS: Human colonoids acutely exposed to UBD exhibited disrupted proliferation and hyperplastic differentiation of the secretory lineage cell, enteroendocrine cells (EEC). Single-cell RNA sequencing also showed more EEC subtypes present in UBD-exposed colonoids. DISCUSSION: These findings highlight the significance of crypt-based proliferative cells and secretory cell differentiation using human colonoids to model major colonic responses to uranium-bearing particulate dust exposure. https://doi.org/10.1289/EHP13855, Introduction Uranium mining in the United States arose in the 1940s, peaked in the 1970s, and subsided in the late 1980s, with extensive activity concentrated in Navajo, Puebloan, and other [...]

Abstract Background MicroRNAs (miRNAs) are presented in the uterine lumen of many mammals, and in vitro experiments have determined that several miRNAs are important for the regulation of endometrial and trophoblast functions. Our aim was to identify and contrast the miRNAs present in extracellular vesicles (EVs) in the uterine lumen fluid (ULF) at the onset of attachment in cattle pregnancies (gestation d 18) initiated by artificial insemination (AI) or by the transfer of an in vitro-produced blastocyst (IVP-ET). A third group had no conceptus after the transfer of an IVP embryo. Results The abundance of 263 annotated miRNAs was quantified in the EVs collected from ULF. There was an increase in the transcript abundance of 20 miRNAs in the ULF EVs from the AI pregnant group, while 4 miRNAs had a lower abundance relative to the group not containing a conceptus. Additionally, 4 miRNAs were more abundant in ULF EVs in the AI pregnant group relative to IVP-ET group (bta-mir-17, bta-mir-7-3, MIR7-1, MIR18A). Specific miRNAs in the ULF EVs were co-expressed with messenger RNAs expressed in extra-embryonic tissues and endometrium, including genes that are known to be their targets. Conclusions The results provide biological insights into the participation of miRNAs in the regulation of trophoblast proliferation and differentiation, as well as in endometrium receptivity. The knowledge that in vitro cultured embryos can contribute to the altered abundance of specific miRNAs in the uterine lumen can lead to the development of corrective approaches to reduce conceptus losses during the first month of pregnancy in cattle.

Abstract Background Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated. Methods Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days. Lung macrophages were isolated for bulk RNA sequencing. Precision-cut lung slices (PCLS) from WT and dKO mice were pre-treated with SP-A and then infected with IAV for 48 h. Results Viral load was significantly increased in bronchoalveolar lavage (BAL) fluid of dKO mice compared to all other strains of mice. dKO mice had significantly less recruitment of neutrophils into the lung compared to Tollip KO mice. SP-A treatment of PCLS enhanced expression of TNF and reduced viral load in dKO mouse lung tissue. Pathway analysis of bulk RNA sequencing data suggests that macrophages from IAV-infected dKO mice reduced expression of genes involved in neutrophil recruitment, IL-17 signaling, and Toll-like receptor signaling. Conclusions Our data suggests that both Tollip and SP-A are essential for the lung to exert more effective innate defense against IAV infection.

Background: Little is known about how school breakfast programs are associated with school attendance and academic performance. This study evaluated Dallas Independent School District's (DISD) breakfast after the bell (BATB) program that provides breakfast for both habitually tardy and non-tardy students on (1) academic performance and (2) student attendance over 2 school years. Methods: A pre-post study design evaluated the impact of the BATB program in elementary/middle/high schools on student attendance and academic outcomes. Paired t-tests evaluated changes in outcomes between 2017 to 2018 and 2018 to 2019 school years. Results: The analytical sample consisted of 30,493 students (70.32% BATB participants, 50.47% male, 68.78% Hispanic). BATB participants were over 2.5 times more likely to attend school versus non-BATB participants (aOR = 2.55; 95% confidence interval [CI]: 2.23-2.92; p < 0.001). Compared to pre-participation (2017-2018), unadjusted models showed 2018 to 2019 BATB participants' mean reading scores increased from 1502.72 to 1545.76 during the 2018 to 2019 academic year (p < 0.001). There were no significant changes in reading and math scores over the 2-year implementation after adjustment. Conclusions: Results here showed that a school breakfast program that is housed in a large public school system that serves predominantly low resource, ethnically diverse students is associated with increased student attendance.

Abstract We develop a large-scale single-cell ATAC-seq method by combining Tn5-based pre-indexing with 10× Genomics barcoding, enabling the indexing of up to 200,000 nuclei across multiple samples in a single reaction. We profile 449,953 nuclei across diverse tissues, including the human cortex, mouse brain, human lung, mouse lung, mouse liver, and lung tissue from a club cell secretory protein knockout (CC16−/−) model. Our study of CC16−/− nuclei uncovers previously underappreciated technical artifacts derived from remnant 129 mouse strain genetic material, which cause profound cell-type-specific changes in regulatory elements near many genes, thereby confounding the interpretation of this commonly referenced mouse model.

Abstract Background Recruitment of participants is the greatest risk to completion of most clinical trials, with 20–40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier 1), followed by phone screening and medical records review (tier 2) prior to a final in-person visit to confirm eligibility and consent. Methods Two tiers of screening were established: an initial screen of general eligibility using a patient-facing web portal (tier 1), followed by a more detailed screen that included phone survey and medical record review (tier 2). If potential participants passed the tier 2 screen, they were referred directly to visit 1 at a study site, where final in-person screening and consent were performed. Rates of screening were tracked during the period of trial recruitment and sources of referrals were noted. Results The approach to screening and recruitment resulted in 6125 tier 1 screens, leading to 1121 referrals to tier 2. The tier 2 screening resulted in 224 medical record requests and identification of 86 qualifying participants for referral to sites. The study attained a viable recruitment rate of 6 enrolled per month prior to being disrupted by COVID 19. Conclusions A tiered approach to eligibility screening using a hybrid of web-based portals to self-identify and screen for general eligibility followed by a more detailed phone and medical record review allowed the study to use fewer sites and reduce cost. Despite the difficult and narrow population of patients suffering moderate chronic disability from stroke, this strategy produced a viable recruitment rate for this invasive study of intracranially injected neural stem cells. Trial registration ClinicalTrials.gov Identifier: NCT03629275

Rhinovirus C (RV-C) infection can trigger asthma exacerbations in children and adults, and RV-C-induced wheezing illnesses in preschool children correlate with the development of childhood asthma. Surfactant protein A (SP-A) plays a critical role in regulating pulmonary innate immunity by binding to numerous respiratory pathogens. Mature SP-A consists of multiple isoforms that form the hetero-oligomers of SP-A1 and SP-A2, organized in 18-mers. In this report, we examined the efficacy of SP-A to antagonize RV-C infection using the wild-type (RV-C15) and reporter-expressing (RV-C15-GFP) viruses in differentiated nasal epithelial cells (NECs) from asthmatic and non-asthmatic children. We also determined the antiviral mechanism of action of SP-A on RV-C15 infection. The native SP-A was purified from alveolar proteinosis patients. The recombinant (r) SP-A1 and SP-A2 variants were expressed in FreeStyle™ 293-F cells. SP-A reduced the fluorescent focus-forming units (FFUs) after RV-C15-GFP infection of NECs by 99%. Both simultaneous and 4 h post-infection treatment with SP-A inhibited RV-C15 and RV-C15-GFP viral RNA load by 97%. In addition, the antiviral genes and chemokines (IFN-λ, IRF-7, MDA-5, and CXLC11) were not induced in the infected NECs due to the inhibition of RV-C propagation by SP-A. Furthermore, SP-A bound strongly to RV-C15 in a dose- and Ca2+-dependent manner, and this interaction inhibited RV-C15 binding to NECs. In contrast, rSP-A1 did not bind to solid-phase RV-C15, whereas the rSP-A2 variants, [A91, K223] and [P91, Q223], had strong binding affinities to RV-C15, similar to native SP-A. This study demonstrates that SP-A might have potential as an antiviral for RV infection and RV-induced asthma exacerbations.

Objectives: The purpose of this scoping review is to explore research studies on the association between chronic pain and polycystic ovary syndrome to create local (U.S.-based) and global recommendations to improve access to and quality of affordable symptom management and treatment options for patients with polycystic ovary syndrome. Methods: The study sections used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews as a checklist reference. The review followed the York methodology by Arksey and O’Malley for the extraction, analysis, and presentation of results in scoping reviews. Results: Final analysis included two conference abstracts published in peer-reviewed journals and two peer-reviewed articles. The relationship between pain perception and health-related quality of life warrants further investigation in patients with polycystic ovary syndrome as the interconnected pathophysiology of symptoms renders exploring associations between the two factors difficult. A comprehensive understanding of the causes of polycystic ovary syndrome-associated symptoms, particularly those relating to pain perceptions can provide more insight into polycystic ovary syndrome pathophysiology and aid in the development of innovative therapeutic approaches for long-term polycystic ovary syndrome management and care. Conclusion: Future studies are necessary to examine associations between the disease and pathophysiological symptoms for a better quality of life for patients with polycystic ovary syndrome.

IntroductionWe present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST).MethodsWe performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children’s Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0ResultsOf 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had

Abstract Tropical forest frontier areas support the well‐being of local populations in myriad ways. Not only do they provide the material basis for people's livelihoods, they also sustain socio‐cultural foundations through relational values. They host some of the most biodiverse ecosystems and largest carbon stocks on the planet, and are thus a focus of global conservation efforts. They are also a prime location for the production of many global agricultural commodities. These dynamics—often intertwined—may trap local populations between powerful interests, with the potential to affect their well‐being. We conducted 100 structured interviews in four biodiversity‐rich landscapes of north‐eastern Madagascar to investigate how multi‐dimensional human well‐being is affected by the recent establishment of protected areas and surge in cash crop prices. We asked households about their satisfaction—and changes in satisfaction—with locally relevant well‐being components, mapping their answers through Nussbaum's Central Capabilities approach. We also investigated the cultural significance of key natural resources beyond the material benefits they provide. All issues were explored along four variables: site, main source of rice, gender and household land use portfolio. Our findings are as follows: first, human capabilities are interconnected and mutually interdependent, with relational values linking many of them. Second, subjective accounts of well‐being are influenced by cognitive biases, such as treadmill effects, adaptive preferences and recency bias. Third, while households perceived a positive influence of protected areas, those most reliant on forest land and products held a more negative view of conservation interventions. And fourth, while households more engaged in commercial agriculture may be benefitting economically from the recent increase in cash crop prices, these very dynamics might be leading to trade‐offs between capabilities. This is most notably so for the Bodily Health capability (e.g. greater spending on housing) and Affiliation and Bodily Integrity (i.e. worsening social relations and security). These insights highlight the importance of addressing the multiple dimensions of well‐being when assessing the impacts of conservation and economic dynamics in forest frontier populations. Particular attention should be paid to the relational values ascribed to the natural resources the communities rely on. Read the free Plain Language Summary for this article on the Journal blog.

Although only a small fraction will ever develop the active form of tuberculosis (ATB) disease, chemoprophylaxis treatment in latent TB infected (LTBI) individuals is an effective strategy to control pathogen transmission. Characterizing immune responses in LTBI upon chemoprophylactic treatment is important to facilitate treatment monitoring, and thus improve TB control strategies. Here, we studied changes in the blood transcriptome in a cohort of 42 LTBI and 8 ATB participants who received anti-TB therapy. Based on the expression of previously published gene signatures of progression to ATB, we stratified the LTBI cohort in two groups and examined if individuals deemed to be at elevated risk of developing ATB before treatment (LTBI-Risk) differed from others (LTBI-Other). We found that LTBI-Risk and LTBI-Other groups were associated with two distinct transcriptomic treatment signatures, with the LTBI-Risk signature resembling that of treated ATB patients. Notably, overlapping genes between LTBI-Risk and ATB treatment signatures were associated with risk of progression to ATB and interferon (IFN) signaling, and were selectively downregulated upon treatment in the LTBI-Risk but not the LTBI-Other group. Our results suggest that transcriptomic reprogramming following treatment of LTBI is heterogeneous and can be used to distinguish LTBI-Risk individuals from the LTBI cohort at large.

Abstract Non-technical summary Research for development (R4D) projects are designed to enhance the research community's contribution to implementation of the 2030 Agenda of the United Nations. We studied seven R4D projects that specifically addressed Sustainable Development Goal (SDG) 15 (life on land) in 14 contexts across Asia, Africa, and South America. We then analyzed how these projects interacted with other SDGs. Our findings reveal that the positive and negative interactions between project objectives and SDG targets vary significantly across contexts, highlighting the importance of considering local conditions when designing and implementing R4D initiatives. Technical summary We analyze how the objectives of research for development (R4D) projects that focus on a particular Sustainable Development Goal (SDG) – SDG 15 (life on land) – interact with the targets of other SDGs. We studied seven R4D projects in 14 contexts across Asia, Africa, and Latin America, comparing expert judgement of interactions between project objectives and SDG targets. Our findings indicate that the success of these projects depends largely on whether they are also working toward SDG targets other than those contained in SDG 15. In particular, working toward targets contained within SDGs on poverty, hunger, water, energy, production and consumption, and global partnerships – was often considered indivisible from the project objectives. Further, while all of the projects focused on SDG 15, our findings suggest that addressing only this goal is not sufficient. A range of other targets that were a priori not the immediate focus of the projects were revealed as ‘crucial’ to the project objectives across contexts. Finally, we list several implications, such as the need for policies to integrate local realities and the need for environmental R4D projects to adopt a holistic scope, particularly in terms of (a) securing social foundations, (b) building enabling institutions, and (c) negotiating competing claims on land. Social media summary What can we learn from land-related research for development projects and their links to the SDGs in concrete contexts?

The rapid worldwide increase in resource extraction is evident in Madagascar—a global biodiversity hotspot. This study examines the localized effects of operational and planned large-scale extractive investments on social-ecological systems in Madagascar and links them to the Sustainable Development Goals. The focus is on sites owned or explored by foreign investors, specifically Ambatovy Moramanga, Ambatovy Tamatave, QIT Madagascar Minerals/Rio Tinto, Ranobe, and Tantalum Rare Earth Malagasy. Employing a counterfactual approach, we gathered survey responses from 459 small-scale farming, agro-pastoral, and artisanal-fisheries-based households. The survey provided information on general household characteristics, land use, land management, livelihoods, well-being, and any perceived changes to these variables, as well as any perceived mining impacts related to the changes. Overall, respondents reported predominantly negative effects on land (and sea) use, livelihoods, well-being, and security. Mining pollution, primarily from operational sites, had reduced access to water and fisheries resources, and natural forest areas had diminished. Reduced productivity due to pollution of soils, water, and air had a negative impact on various land uses and affected people's health, particularly in the surroundings of QIT Madagascar Minerals/Rio Tinto. Although some projects, such as Ambatovy, had eventually improved healthcare and infrastructure, most negative mining impacts had occurred during both the exploratory and the operational phases of the projects. Overall, this study offers a comprehensive view of how large-scale extractive investments affect land (and sea) use and human well-being. In addition, we highlight policy implications that must be considered if large-scale extractive investments are to support progress on the 2030 Agenda.

IntroductionRecent evidence supports the contribution of gut microbiota dysbiosis to the pathophysiology of rheumatic diseases, neuropathic pain, and neurodegenerative disorders. The bidirectional gut-brain communication network and the occurrence of chronic pain both involve contributions of the autonomic nervous system and the hypothalamic pituitary adrenal axis. Nevertheless, the current understanding of the association between gut microbiota and chronic pain is still not clear. Therefore, the aim of this study is to systematically evaluate the existing knowledge about gut microbiota alterations in chronic pain conditions.MethodsFour databases were consulted for this systematic literature review: PubMed, Web of Science, Scopus, and Embase. The Newcastle-Ottawa Scale was used to assess the risk of bias. The study protocol was prospectively registered at the International prospective register of systematic reviews (PROSPERO, CRD42023430115). Alpha-diversity, β-diversity, and relative abundance at different taxonomic levels were summarized qualitatively, and quantitatively if possible.ResultsThe initial database search identified a total of 3544 unique studies, of which 21 studies were eventually included in the systematic review and 11 in the meta-analysis. Decreases in alpha-diversity were revealed in chronic pain patients compared to controls for several metrics: observed species (SMD= -0.201, 95% CI from -0.04 to -0.36, p=0.01), Shannon index (SMD= -0.27, 95% CI from -0.11 to -0.43, p