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Abstract This research examined the impact of aerobic exercise intensity and dose on acute post‐exercise cerebral shear stress and blood flow. Fourteen young adults (27 ± 5 years of age, eight females) completed a maximal oxygen uptake (V̇O2max) treadmill test followed by three randomized study visits: treadmill exercise at 30% of V̇O2max for 30 min, 70% of V̇O2max for 30 min and 70% of V̇O2max for a duration that resulted in caloric expenditure equal to that in the 30% V̇O2max visit (EqEE). A venous blood draw and internal carotid artery (ICA) ultrasound were collected before and immediately following exercise. ICA diameter and blood velocity were determined using automated edge detection software, and blood flow was calculated. Using measures of blood viscosity, shear stress was calculated. Aerobic exercise increased ICA shear stress (time: P = 0.005, condition: P = 0.012) and the increase was greater following exercise at 70% V̇O2max (∆4.1 ± 3.5 dyn/cm2) compared with 30% V̇O2max (∆1.1 ± 1.9 dyn/cm2; P = 0.041). ICA blood flow remained elevated following exercise (time: P = 0.002, condition: P = 0.010) with greater increases after 70% V̇O2max (Δ268 ± 150 mL/min) compared with 30% V̇O2max (∆125 ± 149 mL/min; P = 0.041) or 70% V̇O2max EqEE (∆127 ± 177 mL/min; P = 0.004). Therefore, aerobic exercise resulted in both intensity‐ and dose‐dependent effects on acute post‐exercise ICA blood flow whereby vigorous intensity exercise provoked a larger increase in ICA blood flow compared to light intensity exercise when performed at a higher dose.

Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4, but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here, we identify the domains of LRMP essential for this regulation, show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating, and demonstrate that multiple unique regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we identified the initial 227 residues of LRMP and the N-terminus of HCN4 as necessary for LRMP to associate with HCN4. We found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. Finally, we demonstrated that LRMP-regulation can be conferred to HCN2 by addition of the HCN4 N-terminus along with mutation of five residues in the S5 region and C-linker to the cognate HCN4 residues. Taken together, these results suggest that LRMP inhibits HCN4 through an isoform-specific interaction involving the N-terminals of both proteins that prevents the transduction of cAMP binding into a change in channel gating, most likely via an HCN4-specific orientation of the N-terminus, C-linker, and S4-S5 linker.

Summary: Functional studies in post-embryonic Xenopus tadpoles are challenging because embryonic perturbations often lead to developmental consequences, such as lethality. Here, we describe a high-throughput protocol for tail vein injection to introduce fluorescent tracers into tadpoles, which we have previously used to effectively inject morpholinos and molecular antagonists. We describe steps for safely positioning tadpoles onto agarose double-coated plates, draining media, injecting into the ventral tail vein, rehydrating plates, and sorting tadpoles by fluorescence with minimal injury for high-throughput experiments.For complete details on the use and execution of this protocol, please refer to Kakebeen et al.,1 Patel et al.,2 and Patel et al.,3 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Influenza is a highly contagious respiratory disease, resulting in an estimated 3 to 5 million cases of severe illness annually. While most influenza vaccines are administered parenterally via injection, one shortcoming is that they do not generate a strong immune response at the site of infection, which can become important in a pandemic. Intranasal vaccines can generate both local and systemic protective immune responses, can reduce costs, and enhance ease of administration. Previous studies showed that parenterally administered outer membrane vesicles (OMVs) that carry sequences of the M2e protein (OMV-M2e) protect against influenza A/PR8 challenge in mice and ferrets. In the current study, we measured the effectiveness of the intranasal route of the OMV-M2e vaccine against the influenza A/PR8 strain in mice. We observed high anti-M2e IgG and IgA titers post-challenge in mice vaccinated intranasally with OMV-M2e. In addition, we observed a Th1/Tc1 bias in the vaccinated mice, and an increased Th17/Tc17 response, both of which correlated with survival to A/PR8 challenge and significantly lower lung viral titers. We conclude that the intranasal-route administration of the OMV-M2e vaccine is a promising approach toward generating protection against influenza A as it leads to an increased proinflammatory immune response correlating with survival to viral challenge.

Warming in southern California during the 21st century is unprecedented in the instrumental record. To place this warming in a multi-century historical context, we analyzed tree ring data sampled from Jeffrey pine (Pinus jeffreyi) and sugar pine (Pinus lambertiana) collected from minimally disturbed, old-growth high-elevation forests within Mt. San Jacinto State Park California, USA. Based on a calibration/verification period of 1960–2020 between earlywood radial growth and California Climate Division 6 climate data, we reconstructed annual (November–October) minimum temperature (Tmin) from 1658 to 2020. During the 61-year calibration/verification period, instrumental Tmin increased (r = 0.69, p < 0.01) and was positively associated with annual radial growth (r = 0.71, p < 0.01). Using regime shift analysis, we found that the 363-year reconstruction revealed Tmin stability until 1958 and then decreased until 1980, followed by the two warmest regimes (1981–2007, 2008–2020) on record. The last 13-year period was 0.77 °C warmer than the multi-century average with nine of the ten warmest years in the reconstruction recorded. These results suggest that 21st century warming in southern California is unique in the context of the past four centuries, indicating the rarity of exceptional warmth captured in the tree ring record.

Abstract Experimental vaccines for the deadly zoonotic Nipah (NiV), Hendra (HeV), and Ebola (EBOV) viruses have focused on targeting individual viruses, although their geographical and bat reservoir host overlaps warrant creation of multivalent vaccines. Here we explored whether replication-incompetent pseudotyped vesicular stomatitis virus (VSV) virions or NiV-based virus-like particles (VLPs) were suitable multivalent vaccine platforms by co-incorporating multiple surface glycoproteins from NiV, HeV, and EBOV onto these virions. We then enhanced the vaccines’ thermotolerance using carbohydrates to enhance applicability in global regions that lack cold-chain infrastructure. Excitingly, in a Syrian hamster model of disease, the VSV multivalent vaccine elicited safe, strong, and protective neutralizing antibody responses against challenge with NiV, HeV, or EBOV. Our study provides proof-of-principle evidence that replication-incompetent multivalent viral particle vaccines are sufficient to provide protection against multiple zoonotic deadly viruses with high pandemic potential.

Abstract Background Cambodia has made significant progress towards achieving malaria elimination by 2025. Cases continue to decrease and are primarily concentrated in forested areas. Forest-goers are most at risk of malaria due to their proximity to the forest, poor sleeping conditions, frequent mobility, and distance from health services. Consistent use of long-lasting insecticidal nets or hammock nets (LLINs/LLIHNs), early diagnosis and treatment of cases are central to reducing disease burden. The aim of this study was to understand forest-goers’ knowledge, attitudes, and practices related to malaria prevention and care-seeking, and to identify key behavioural determinants of LLIN/LLIHN use and prompt care-seeking within 24 h of developing a fever. Methods A mixed-methods study design consisting of a cross-sectional survey and qualitative in-depth interviews was implemented in two Cambodian provinces. Survey participants (N = 654) were recruited using respondent driven sampling. Interview participants (N = 28) were selected using purposive sampling. Findings from the survey were analysed using univariate and bivariate analysis and multivariate weighted logistic regression. Interviews were coded and analysed using thematic content analysis. Results All study participants had heard of malaria and 98% knew that malaria was transmitted by mosquitoes. LLIN/LLIHN ownership was high (94%). Although 99% of participants perceived LLIN/LLIHN use as an important malaria prevention measure, only 76% reported using one during their last visit to the forest. Only 39% of survey participants who reported seeking care did so within the recommended 24 h from fever onset during their last febrile illness. Among all study participants, 43% did not seek any healthcare during their last febrile episode. In controlled regression models, perceived community social norms were significantly associated with LLIN/LLIHN use (OR: 2.7, 96% CI 1.99–2.64) and care-seeking within 24 h of fever onset (OR: 1.7, 95% CI 1.00–2.88). Social support from other forest-goers was also significantly associated with LLIN/LLIHN use (OR: 4.9, 95% CI 1.32–18.12). Conclusions Study findings are consistent with other studies on LLIN/LLIHN use and care-seeking behaviours. While rates of LLIN/LLIHN ownership were high among the study population, rates of use were not as high. More concerning were the delayed care-seeking behaviours. Social behaviour change activities should incorporate social norms and social support as mechanisms for behaviour change given the identified positive correlations with LLIN/LLIHN use and prompt care-seeking.

As detailed in its flagship report, Genome UK, the UK government recognises the vital role that broad public engagement across whole populations plays in the field of genomics. However, there is limited evidence about how to do this at scale. Most public audiences do not feel actively connected to science, are often unsure of the relevance to their lives and rarely talk to their family and friends about it; we term this dis-connection a ‘disengaged public audience’. We use a narrative review to explore: (i) UK attitudes towards genetics and genomics and what may influence reluctance to engage with these topics; (ii) innovative public engagement approaches that have been used to bring diverse public audiences into conversations about the technology. Whilst we have found some novel engagement methods that have used participatory arts, film, social media and deliberative methods, there is no clear agreement on best practice. We did not find a consistently used, evidence-based strategy for delivering public engagement about genomics across diverse and broad populations, nor a specific method that is known to encourage engagement from groups that have historically felt (in terms of perception) and been (in reality) excluded from genomic research. We argue there is a need for well-defined, tailor-made engagement strategies that clearly articulate the audience, the purpose and the proposed impact of the engagement intervention. This needs to be coupled with robust evaluation frameworks to build the evidence-base for population-level engagement strategies.

Endothelial damage and vascular pathology have been recognized as major features of COVID-19 since the beginning of the pandemic. Two main theories regarding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages endothelial cells and causes vascular pathology have been proposed: direct viral infection of endothelial cells or indirect damage mediated by circulating inflammatory molecules and immune mechanisms. However, these proposed mechanisms remain largely untested in vivo. In the present study, we utilized a set of new mouse genetic tools developed in our lab to test both the necessity and sufficiency of endothelial human angiotensin-converting enzyme 2 (hACE2) in COVID-19 pathogenesis. Our results demonstrate that endothelial ACE2 and direct infection of vascular endothelial cells do not contribute significantly to the diverse vascular pathology associated with COVID-19.

IntroductionRituximab (R), an anti-CD20 monoclonal antibody (mAb) and the world’s first approved antibody for oncology patients, was combined with the CHOP chemotherapy regimen and markedly improved the prognosis of all B- cell–derived lymphomas, the most common hematological malignancy worldwide. However, there is a 35% disease recurrence with no advancement in the first-line treatment since R was combined with the archetypal CHOP chemotherapy regimen nearly 30 years ago. There is evidence that R synergizes with chemotherapy, but the pharmacological interactions between R and CHOP or between newer anti-CD20 mAbs and CHOP remain largely unexplored.MethodsWe used in vitro models to score pharmacological interactions between R and CHOP across various lymphoma cell lines. We compared these pharmacological interactions to ofatumumab, a second-generation anti-CD20 mAb, and CHOP. Lastly, we used RNA-sequencing to characterize the transcriptional profiles induced by these two antibodies and potential molecular pathways that mediate their different effects.ResultsWe discovered vast heterogeneity in the pharmacological interactions between R and CHOP in a way not predicted by the current clinical classification. We then discovered that R and ofatumumab differentially synergize with the cytotoxic and cytostatic capabilities of CHOP in separate distinct subsets of B-cell lymphoma cell lines, thereby expanding favorable immunochemotherapy interactions across a greater range of cell lines beyond those induced by R-CHOP. Lastly, we discovered these two mAbs differentially modulate genes enriched in the JNK and p38 MAPK family, which regulates apoptosis and proliferation.DiscussionOur findings were completely unexpected because these mAbs were long considered to be biological and clinical equivalents but, in practice, may perform better than the other in a patient-specific manner. This finding may have immediate clinical significance because both immunochemotherapy combinations are already FDA-approved with no difference in toxicity across phase I, II, and III clinical trials. Therefore, this finding could inform a new precision medicine strategy to provide additional therapeutic benefit to patients with B-cell lymphoma using immunochemotherapy combinations that already meet the clinical standard of care.

Summary: Background: The use of demographic variables in the medical literature has been a topic of much recent debate. Recent studies found that race and socioeconomic status (SES) are inconsistently reported. Best-practice use of sex and gender has been contentious. We aimed to characterise the state of medical demographic reporting in greater detail, especially regarding geography and specific terms used in articles. Methods: Original articles were included from issues of the New England Journal of Medicine (NEJM), JAMA, The Lancet, and the American Journal of Epidemiology (AJE) published from 1 January to 31 December 2020 (n = 640). Articles without human participants, case reports, or with only aggregate data were excluded, leaving 594 articles. Use of age, sex, gender, race, ethnicity, and SES were coded, as well as corresponding author and participant geography. Findings: 99.0% of articles reported age. While 92.9% reported sex alone, only 4.7% used the term gender and 1.0% transgender. 47.8% of articles reported race and 29.6% reported ethnicity. Studies with U.S. corresponding authors or participants were significantly more likely to report race (72.9% and 73.7% respectively) or ethnicity (47.3% and 45.3% respectively) than those without (25.9% and 25.6% for race, 14.2% and 16.3% for ethnicity), p

The kinase Itk is normally required for differentiation of IL-17-producing CD4 T-helper (Th)17 cells however, Elmore, Carter et al. now report that Itk can be bypassed during Th17 differentiation in Saccharopolyspora rectivirgula induced hypersensitivity pneumonitis. This study suggests that some inflammatory signals can override normal T cell activation and differentiation pathways.

One of the most proliferative periods for T cells occurs during their development in the thymus. Increased DNA replication can result in increased DNA mutations in the nuclear genome, but also in mitochondrial genomes. A high frequency of mitochondrial DNA mutations can lead to abnormal mitochondrial function and have negative implications on human health. Furthermore, aging is accompanied by an increase in such mutations through oxidative damage and replication errors. Increased mitochondrial DNA mutations cause loss of mitochondrial protein function, and decrease energy production, substrates, and metabolites. Here we have evaluated the effect of increased mitochondrial DNA mutations on T cell development in the thymus. Using mice carrying a mutant mitochondrial DNA polymerase γ (PolG) that causes increased mitochondrial DNA mutations, we show that high fidelity replication of mitochondrial DNA is pivotal for proper T cell development. Reducing the fidelity of mitochondrial DNA replication results in a premature age-dependent reduction in the total number of CD4/CD8 double negative and double positive thymocytes. Analysis of mitochondrial density in thymocyte subpopulations suggests that this may be due to reduced proliferation in specific double negative stages. Taken together, this work suggests that T cell development is regulated by the ability of mitochondria to faithfully replicate their DNA.

Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While its central role in Coronavirus Disease 2019 (COVID-19) pathogenesis is indisputable, there remains significant debate regarding the role of this transmembrane carboxypeptidase in the disease course. These include the role of soluble versus membrane-bound ACE2, as well as ACE2-independent mechanisms that may contribute to viral spread. Testing these roles requires in vivo models. Here, we report humanized ACE2-floxed mice in which hACE2 is expressed from the mouse Ace2 locus in a manner that confers lethal disease and permits cell-specific, Cre-mediated loss of function, and LSL-hACE2 mice in which hACE2 is expressed from the Rosa26 locus enabling cell-specific, Cre-mediated gain of function. Following exposure to SARS-CoV-2, hACE2-floxed mice experienced lethal cachexia, pulmonary infiltrates, intravascular thrombosis and hypoxemia-hallmarks of severe COVID-19. Cre-mediated loss and gain of hACE2 demonstrate that neuronal infection confers lethal cachexia, hypoxemia, and respiratory failure in the absence of lung epithelial infection. In this series of genetic experiments, we demonstrate that ACE2 is absolutely and cell-autonomously required for SARS-CoV-2 infection in the olfactory epithelium, brain, and lung across diverse cell types. Therapies inhibiting or blocking ACE2 at these different sites are likely to be an effective strategy towards preventing severe COVID-19.

The human milk microbiome (HMM) is hypothesized to be seeded by multiple factors, including the infant oral microbiome during breastfeeding. However, it is not known whether breastfeeding patterns (e.g., frequency or total time) impact the composition of the HMM. As part of the Mother-Infant Microbiomes, Behavior, and Ecology Study (MIMBES), we analyzed data from naturalistic observations of 46 mother-infant dyads living in the US Pacific Northwest and analyzed milk produced by the mothers for its bacterial diversity and composition. DNA was extracted from milk and the V1-V3 region of the 16S rRNA gene was amplified and sequenced. We hypothesized that number of breastfeeding bouts (breastfeeding sessions separated by >30 seconds) and total time breastfeeding would be associated with HMM α-diversity (richness, diversity, or evenness) and differential abundance of HMM bacterial genera. Multiple linear regression was used to examine associations between HMM α-diversity and the number of breastfeeding bouts or total time breastfeeding and selected covariates (infant age, maternal work outside the home, frequency of allomother physical contact with the infant, non-household caregiving network). HMM richness was inversely associated with number of breastfeeding bouts and frequency of allomother physical contact, but not total time breastfeeding. Infants' non-household caregiving network was positively associated with HMM evenness. In two ANCOM-BC analyses, abundances of 5 of the 35 most abundant genera were differentially associated with frequency of breastfeeding bouts (Bifidobacterium, Micrococcus, Pedobacter, Acidocella, Achromobacter); 5 genera (Bifidobacterium, Agreia, Pedobacter, Rugamonas, Stenotrophomonas) were associated with total time breastfeeding. These results indicate that breastfeeding patterns and infant caregiving ecology may play a role in influencing HMM composition. Future research is needed to identify whether these relationships are consistent in other populations and if they are associated with variation in the infant's gastrointestinal (including oral) microbiome.

Bone and muscle are coupled through developmental, mechanical, paracrine, and autocrine signals. Genetic variants at the CPED1-WNT16 locus are dually associated with bone- and muscle-related traits. While Wnt16 is necessary for bone mass and strength, this fails to explain pleiotropy at this locus. Here, we show wnt16 is required for spine and muscle morphogenesis in zebrafish. In embryos, wnt16 is expressed in dermomyotome and developing notochord, and contributes to larval myotome morphology and notochord elongation. Later, wnt16 is expressed at the ventral midline of the notochord sheath, and contributes to spine mineralization and osteoblast recruitment. Morphological changes in wnt16 mutant larvae are mirrored in adults, indicating that wnt16 impacts bone and muscle morphology throughout the lifespan. Finally, we show that wnt16 is a gene of major effect on lean mass at the CPED1-WNT16 locus. Our findings indicate that Wnt16 is secreted in structures adjacent to developing bone (notochord) and muscle (dermomyotome) where it affects the morphogenesis of each tissue, thereby rendering wnt16 expression into dual effects on bone and muscle morphology. This work expands our understanding of wnt16 in musculoskeletal development and supports the potential for variants to act through WNT16 to influence bone and muscle via parallel morphogenetic processes.

Abstract Background Patients with rheumatoid arthritis (RA) commonly experience pain despite the availability of disease-modifying treatments. Sleep disturbances are frequently reported in RA, with pain often a contributing factor. The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference and Sleep Disturbance item banks were initially developed to provide insights into the patient experience of pain and sleep, respectively, though they were not specifically intended for use in RA populations. This study evaluated the content validity of the PROMIS Pain Interference and Sleep Disturbance item banks in RA and identified relevant content for short forms for patients with RA that achieved high measurement precision across a broad range of health. Methods A qualitative approach consisting of hybrid concept elicitation and cognitive debriefing interviews was used to evaluate the content validity of the item banks in RA. Interviews were semi-structured and open-ended, allowing a range of concepts and responses to be captured. Findings from the qualitative interviews were used to select the most relevant items for the short forms, and psychometric evaluation, using existing item-response theory (IRT) item parameters, was used to evaluate the marginal reliability and measurement precision of the short forms across the range of the latent variables (i.e. pain interference and sleep disturbance). Results Thirty-two participants were interviewed. Participants reported that RA-related pain and sleep disturbances have substantial impacts on their daily lives, particularly with physical functioning. The PROMIS Pain Interference and Sleep Disturbance item banks were easy to understand and mostly relevant to their RA experiences, and the 7-day recall period was deemed appropriate. Qualitative and IRT-based approaches identified short forms for Pain Interference (11 items) and Sleep Disturbance (7 items) that had high relevance and measurement precision, with good coverage of the concepts identified by participants during concept elicitation. Conclusion Pain and sleep disturbances affect many aspects of daily life in patients with RA and should be considered when novel treatments are developed. This study supports the use of the PROMIS Pain Interference and Sleep Disturbance item banks in RA, and the short forms developed herein have the potential to be used in clinical studies of RA.

As part of developing the University of Arizona Cooperative Extension 4-H Common Measures system, we created resources for communicating results to stakeholders with research-based visual tools. We outline the creation of two tools that may be useful to CE personnel to use evaluation findings to better "tell their story" to a variety of stakeholders. Effectively telling this story often means addressing the question "so what?". These tools, 1) Outcome Linkages and 2) Infographics can translate the program's "so what?" in easily interpretable and visually engaging ways. Step by step processes are reviewed to guide creation and use of both tools.

Postsecondary students with disabilities risk facing challenges while pursuing their academic goals. Although disability service providers are encouraged to support their goal pursuit, its actualization and the role of individual differences remain poorly researched. We examine the role of autonomy striving dispositional styles, need satisfaction, and goal action crisis. A three-wave, semester-long study was conducted with 234 university students with disabilities. Through path analysis, a type of structural equation modeling, four hypotheses were tested. Assisted autonomy was associated with higher need satisfaction and less severe goal action crises in the middle of the semester. Indirect effects were also evidenced on goal progress and positive affect at the end of the semester. Striving to satisfy their autonomy need through collaborative means supports well-being and academic goal progress for university students with disabilities. Disability service providers and university settings are thus encouraged to create need-supportive environments and foster collaboration across campuses.

Experimental research on perception and cognition has shown that inherent and manipulated visual features of mathematics problems impact individuals' problem-solving behavior and performance. In a recent study, we manipulated the spacing between symbols in arithmetic expressions to examine its effect on 174 undergraduate students' arithmetic performance but found results that were contradictory to most of the literature (Closser et al., 2023). Here, we applied educational data mining (EDM) methods to that dataset at the problem level to investigate whether inherent features of the 32 experimental problems (i.e., problem composition, problem order) may have caused unintended effects on students' performance. We found that students were consistently faster to correctly simplify expressions with the higher-order operator on the left, rather than right, side of the expression. Furthermore, average response times varied based on the symbol spacing of the current and preceding problems, suggesting that problem sequencing matters. However, including or excluding problem identifiers in analyses changed the interpretation of results, suggesting that the effect of sequencing may be impacted by other, undefined problem-level factors. These results advance cognitive theories on perceptual learning and provide implications for educational researchers: online experiments designed to investigate students' performance on mathematics problems should include a variety of problems, systematically examine the effects of problem order, and consider applying different analytical approaches to detect effects of inherent problem features. Moreover, EDM methods can be a tool to identify nuanced effects on behavior and performance as observed through data from online platforms.

Type 1 regulatory T (Tr1) cells are an immunoregulatory CD4+ Foxp3- IL-10high T cell subset with therapeutic potential for various inflammatory diseases. Retroviral (RV) transduction has been a valuable tool in defining the signaling pathways and transcription factors that regulate Tr1 differentiation and suppressive function. This protocol describes a method for RV transduction of naïve CD4+ T cells differentiating under Tr1 conditions, without the use of reagents such as polybrene or RetroNectin. A major advantage of this protocol over others is that it allows for the role of genes of interest on both differentiation and function of Tr1 cells to be interrogated. This is due to the high efficiency of RV transduction combined with the use of an IL10GFP/Foxp3RFP dual reporter mouse model, which enables successfully transduced Tr1 cells to be identified and sorted for functional assays. In addition, this protocol may be utilized for dual/multiple transduction approaches and transduction of other lymphocyte populations, such as CD8+ T cells.

The fifth annual summer research summit organized by the Center of Excellence (COE) in Health Equity, Training and Research, Baylor College of Medicine (BCM), was held on May 17, 2022. The theme of this year’s summit was ‘Academic-Community Partnerships: Change Agents for Advancing Health Equity.’ Given the ongoing pandemic, the summit was conducted virtually through digital platforms. This program was intended for both BCM and external audiences interested in advancing health equity, diversity, and inclusion in healthcare among healthcare providers and trainees, biomedical scientists, social workers, nurses, and individuals involved in talent acquisition and development, such as hiring managers (HR professionals), supervisors, college and hospital affiliate leadership and administrators, as well as diversity and inclusion excellence practitioners. We had attendees from all regions of the United States as well as from Saudi Arabia. The content in this Book of Abstracts encapsulates a summary of the research efforts by the BCM COE scholars (which includes post-baccalaureate students, medical students, clinical fellows, and junior faculty from BCM) as well as the external summit participants. The range of topics in this year’s summit was quite diverse, encompassing disparities in relation to maternal and child health (MCH), immigrant health, cancers, vaccination uptakes, and COVID-19 infections. Various solutions were ardently presented to address these disparities, including community engagement and partnerships, improvement in health literacy, and the development of novel technologies and therapeutics. With this summit, BCM continues to build on its long history of educational outreach initiatives to promote diversity in medicine by focusing on programs aimed at increasing the number of diverse and highly qualified medical professionals ready to introduce effective and innovative approaches to reduce or eliminate health disparities. These programs will improve information resources, clinical education, curricula, research, and cultural competence as they relate to minority health issues and social determinants of health. The year’s summit was a great success! Copyright © 2022 Dongarwar et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY 4.0.

Snark is a form of verbal aggression that uses humor to diminish a victim. The present study explored predictors of U.S. teachers' use of snark in the classroom. Kindergarten-12th grade teachers (N = 516) self-reported on their social and emotional competencies (i.e., perspective taking, forgiveness, mindfulness, expressive suppression, and decision-making skills), experiences of occupational health and personal well-being (i.e., burnout, job satisfaction, depression, and life satisfaction) and snark use. Stepwise multilevel models indicated that teachers' social and emotional competencies, and subsequently, their occupational health and well-being, explained significant portions of the variance in snark use. Specifically, teachers with greater perspective taking skills reported less frequent snark use, and those who used expressive suppression reported more frequent snark use. Burnout, job satisfaction, depression, and life satisfaction were all positively associated with greater snark use. Results are described in relation to research on adult social and emotional competencies, teachers' occupational health and well-being, and teachers' conflict management strategies. This study sets the stage for future research to investigate the effects of teachers' snark use on student outcomes.

CD4+Foxp3+ regulatory T cells (Tregs) play a crucial role in preventing autoimmunity and inflammation. There are naturally-derived in the thymus (tTreg), generated extrathymically in the periphery (pTreg), and induced in vitro culture (iTreg) with different characteristics of suppressiveness, stability, and plasticity. There is an abundance of published data on neuropilin-1 (Nrp-1) as a tTreg marker, but little data exist on iTreg. The fidelity of Nrp-1 as a tTreg marker and its role in iTreg remains to be explored. This study found that Nrp-1 was expressed by a subset of Foxp3+CD4+T cells in the central and peripheral lymphoid organs in intact mice, as well as in iTreg. Nrp-1+iTreg and Nrp-1-iTreg were adoptively transferred into a T cell-mediated colitis model to determine their ability to suppress inflammation. Differences in gene expression between Nrp-1+ and Nrp-1-iTreg were analyzed by RNA sequencing. We demonstrated that the Nrp-1+ subset of the iTreg exhibited enhanced suppressive function and stability compared to the Nrp-1- counterpart both in vivo and in vitro, partly depending on IL-10. We found that Nrp-1 is not an exclusive marker of tTreg, however, it is a biomarker identifying a new subset of iTreg with enhanced suppressive function, implicating a potential for Nrp-1+iTreg cell therapy for autoimmune and inflammatory diseases.

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p

We examined the effects of increasing summertime precipitation variability from 1950 to 2022 on the radial-growth responses of five tree species native to central North Carolina, USA. Tree-ring data were collected from chestnut oak, post oak, longleaf pine, shortleaf pine, and Virginia pine and processed following standard dendrochronology procedures. Adjusted latewood chronologies for each species were created and correlated with either monthly or multi-monthly combinations of summertime precipitation for above average (AA, > 1 σ above mean), below average (BA, σ ) precipitation years. June–September precipitation variability and other summertime monthly combinations significantly increased during the study period, with a 10.2% increase in AA/BA years during the 21st century. Climate-growth correlations ranged from 0.40–0.51 using all years within the study period. However, using AA and BA years exclusively, climate-growth responses ranged from 0.44–0.71, with post oak and longleaf pine experiencing significantly higher correlations. No significant changes in climate-growth responses occurred for chestnut oak, shortleaf pine, and Virginia pine. These findings suggest the effects of increased precipitation variability on climate-growth responses are species-dependent and affected by the precipitation classification (i.e. AA or BA years). These responses help explain temporal variations in the strength of climate-growth responses, particularly for some species, and offer additional considerations for dendroclimatological research.

Abstract Regulatory T cells (Tregs) play an important role in controlling autoimmunity and limiting tissue damage and inflammation. IL2‐inducible T cell kinase (Itk) is part of the Tec family of tyrosine kinases and is a critical component of T cell receptor mediated signaling. Here, we showed that either genetic ablation of Itk signaling or inhibition of Itk signaling pathways resulted in increased frequency of “noncanonical” CD4+CD25−FOXP3+ Tregs (ncTregs), as well as of “canonical” CD4+CD25+FOXP3+ Tregs (canTregs). Using in vivo models, we showed that ncTregs can avert the formation of acute graft‐versus‐host disease (GVHD), in part by reducing conventional T cell proliferation, proinflammatory cytokine production, and tissue damage. This reduction in GVHD occurred without disruption of graft‐versus‐leukaemia (GVL) effects. RNA sequencing revealed that a number of effector, cell adhesion, and migration molecules were upregulated in Itk–/− ncTregs. Furthermore, disrupting the SLP76: ITK interaction using a specific peptide inhibitor led to enhanced Treg development in both mouse and primary human cells. This peptide inhibitor also significantly reduced inflammatory cytokine production in primary GVHD patient samples and mouse T cells without causing cell death or apoptosis. We provide evidence that specifically targeting Itk signaling could be a therapeutic strategy to treat autoimmune disorders.

Oxidation of indole by nitrate radical (NO3) was previously proposed to form nitroindole, largely responsible for the brown color of indole secondary organic aerosol (SOA). As there are seven known nitroindole isomers, we used chromatographic separation to show that a single nitroindole isomer is produced in the indole + NO3 reaction and definitively assigned it to 3-nitroindole by comparison with chromatograms of nitroindole standards. Mass spectra of aerosolized 3-nitroindole particles were recorded with an aerosol mass spectrometer and directly compared to mass spectra of SOA from smog chamber oxidation of indole by NO3 in order to help identify peaks unique to nitroindole (m/z 162, 132, and 116). Quantum chemical calculations were done to determine the energetics of hypothesized indole + NO3 intermediates and products. The combination of these data suggests a mechanism, wherein a hydrogen atom is first abstracted from the N-H bond in indole, followed by isomerization to a carbon-centered radical in the 3-position and followed by addition of NO2. Alternative mechanisms involving a direct abstraction of a H atom from a C-H bond or a NO3 addition to the ring are predicted to be energetically unfavorable from large barriers for the initial reaction steps.

BACKGROUND: Only a subset of patients at risk for ARDS go on to develop it, and the contribution of preexisting comorbidities (eg, diabetes) to ARDS risk is not well understood. Prior studies of the association between diabetes and ARDS have yielded conflicting results. RESEARCH QUESTION: Does assessing ARDS risk based on hemoglobin A1c (HbA1c) as a marker of long-term blood glucose levels, rather than a charted diagnosis of diabetes, clarify the relationship between diabetes and ARDS? STUDY DESIGN AND METHODS: Using data from two prospective observational cohorts of critically ill adults (Validating Acute Lung Injury Biomarkers for Diagnosis [VALID] and Early Assessment of Renal and Lung Injury [EARLI]), we analyzed the association between clinical HbA1c category and development of ARDS in patients with a risk factor for ARDS and at least one clinical HbA1c measurement within the 180 days prior through 14 days after enrollment. RESULTS: A total of 599 patients in VALID and 276 in EARLI met inclusion criteria, of whom 164 and 58 developed ARDS, respectively. Patients with a charted diagnosis of diabetes were not shown to be more likely to develop ARDS (VALID: 24.6% ARDS in those categorized as nondiabetic vs 30.0% in those categorized as diabetic, P = .14; EARLI: 19.6% vs 22.8%, respectively; P = .55). However, in VALID, patients categorized as diabetic with inadequate glycemic control based on their HbA1c had an increased risk of developing ARDS compared with those with nondiabetic HbA1c (20.9% vs 34.0%, respectively; P = .0073), a finding that persisted in multivariable analysis (OR for those categorized as diabetic with inadequate glycemic control vs those categorized as nondiabetic range HbA1c, 1.25; 95% CI, 1.01-1.57). These findings were not reproduced in the smaller EARLI cohort, but were appreciated when the cohorts were combined for analysis. INTERPRETATION: Elevated HbA1c may be associated with risk of developing ARDS, independent of clinical diagnosis of diabetes, but prospective validation is needed. If confirmed, these findings suggest that inadequate glycemic control could be an unrecognized risk factor for ARDS.

OBJECTIVE: Describe the clinical characteristics, treatment strategies, and outcome data of children with papilledema associated with Lyme disease at a large tertiary care pediatric hospital. METHODS: Retrospective cohort study of children 1-18 years old who received care at our institution between 1995 and 2019 with concurrent diagnoses of papilledema and Lyme disease. Data were abstracted from records and prospective family surveys. RESULTS: Among 44 children included (median age 9.7 years), 66% (29/44) had additional cranial neuropathies, and 78% (32/41) had cerebrospinal fluid pleocytosis. All children were treated with antibiotics (39% oral, 55% intravenous, 7% both); 61% (27/44) were also treated with oral acetazolamide. Symptoms fully resolved in 86% (30/35) of children with follow-up data. Proportion recovered did not significantly differ by antibiotic administration route or presence/absence of cerebrospinal fluid pleocytosis. CONCLUSIONS: Papilledema in Lyme disease may occur with or without cerebrospinal fluid pleocytosis. Most children recover without residual deficits following treatment, although exceptions exist.