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Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Ride-hailing businesses, including Uber and Lyft, have reshaped road traffic since they first began operating in the United States approximately a decade ago. It follows that ride-hailing may also alter the incidence and distribution of road traffic crash injuries and deaths. The available evidence relating ride-hailing to crashes is critically reviewed in this article. We present a theoretical model that synthesizes the hypothesized mechanisms, and we identify common methodological challenges and suggest priorities for future research. Mixed results have been reported for the overall incidence of road traffic crash injuries and deaths, likely due to heterogeneous impacts on vehicular traffic flow (e.g., increasing the volume of vehicles); on vehicle-, person-, and event-level characteristics (e.g., reducing alcohol-impaired driver crashes); on road-user types (e.g., increasing pedestrian crashes); and on environmental conditions (e.g., reducing crashes most substantially where public transit access is poorest). The lack of a well-developed theory of human mobility and methodological challenges that are common to many ecological studies impede exploration of these sources of moderation. Innovative solutions are required to explicate ride-hailing's heterogeneous impacts, to guide policy that can take advantage of the public health benefits of ride-hailing, and to ensure that research keeps pace with technological advances that continue to reshape road traffic use.

Continuously secreted by all cell types, extracellular vesicles (EVs) are small membrane‐bound structures which shuttle bioactive cargo between cells across their external environment. Their central role as natural molecular messengers and ability to cross biological barriers has garnered significant attention in the use of EVs as therapeutic delivery vehicles. Still, harnessing the potential of EVs is faced with many obstacles. A cell line engineering approach can be used to exploit EVs to encapsulate a bespoke cargo of interest. However, full details regarding native EV‐loading mechanisms remain under debate, making this a challenge. While Chinese hamster ovary (CHO) cells are well known to be the preferred host for recombinant therapeutic protein production, their application as an EV producer cell host has been largely overlooked. In this study, we engineered CHO DG44 cells to produce custom EVs with bespoke cargo. To this end, genetic constructs employing split green fluorescent protein technology were designed for tagging both CD81 and protein cargoes to enable EV loading via self‐assembling activity. To demonstrate this, NanoLuc and mCherry were used as model reporter cargoes to validate engineered loading into EVs. Experimental findings indicated that our custom EV approach produced vesicles with up to 15‐fold greater cargo compared with commonly used passive loading strategies. When applied to recipient cells, we observed a dose‐dependent increase in cargo activity, suggesting successful delivery of engineered cargo via our custom CHO EVs. [ABSTRACT FROM AUTHOR]

Sexual assault among higher education students has detrimental impacts on the health and educational outcomes of survivors. This systematic review aims to describe and synthesize the available quantitative evidence on sexual assault prevalence among this population. We searched Medline, EMBASE, Global Health, PsycINFO, Web of Science, ERIC, and CINAHL for studies published in English, French, Italian, and Spanish from database inception to August 2020 (updated May 2022). We screened studies using prespecified inclusion criteria for the population and context (registered higher education students), condition (self-reported sexual assault), and study design (quantitative survey). The Joanna Briggs Institute Critical Appraisal Checklist was used to assess study quality. Prevalence estimates disaggregated by type of sexual assault, gender identity, and world region were meta-analyzed using a random-effects model and reported following PRISMA guidance. We identified 131 articles, from 21 different countries. The meta-analyzed prevalence of sexual assault was 17.5% for women, 7.8% for men, and 18.1% for transgender and gender diverse people. Four types of sexual assault were identified: rape, attempted rape, forced sexual touching, and coercive sex. Forced sexual touching was the most common act experienced. The African Region had the highest prevalence estimates for women's sexual assault, and the Western Pacific region had the highest prevalence estimates for men's sexual assault. Higher education institutions, especially those outside of the United States, should commit to the implementation of surveys to monitor sexual assault prevalence and dedicate increased resources to supporting student survivors of sexual assault. [ABSTRACT FROM AUTHOR]

Background and Aims No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterized fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. Methods We undertook immunohistochemistry, metabolic, signalling pathway and epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/NSCD fibroblasts were cultured with TGFβ and valproic acid [VPA]. Results Stricturing CD was characterized by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1 , HDAC2 , and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFβ stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appeared 'metabolically primed' and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and TGFβ-independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. Conclusions Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype and metabolic priming characterize SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis. [ABSTRACT FROM AUTHOR]

Sexual violence (SV) experienced by higher education students is a prevalent public health problem. Collecting data on SV through self-report surveys in higher education institutions (HEIs) is essential for estimating the scope of the problem, the first step to adequately resourcing and implementing prevention and response programming and policies. However, in the United Kingdom, data is limited. We used data from the cross-sectional Oxford Understanding Relationships, Sex, Power, Abuse and Consent Experiences survey, administered to all students at a university in the United Kingdom in May 2021 (n = 25,820), to estimate the past year prevalence of SV. We analyzed data from respondents who answered at least one question on SV (n = 1,318) and found that 20.5% of respondents experienced at least one act of attempted or forced sexual touching or rape, and 52.7% of respondents experienced at least one act of sexual harassment (SH). We found that women experienced the highest rates of SV. Attempted forced sexual touching was far more common than forced sexual touching, or rape. Sexist remarks or jokes were the most common act of SH. Most acts of SV took place at the university. These findings reveal that the prevalence of SV in HEIs in the United Kingdom could be far higher than what is experienced in the general population. While this study reflects the context in only one institution, it underlines the need for continued monitoring to develop rigorous, evidence-based, and targeted prevention and response strategies. [ABSTRACT FROM AUTHOR]