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Abstract Endothelial cells are integral components of all vasculature within complex organisms. As they line the blood vessel wall, endothelial cells are constantly exposed to a variety of molecular factors and shear force that can induce cellular damage and stress. However, how endothelial cells are removed or eliminate unwanted cellular contents, remains unclear. The generation of large extracellular vesicles (EVs) has emerged as a key mechanism for the removal of cellular waste from cells that are dying or stressed. Here, we used intravital microscopy of the bone marrow to directly measure the kinetics of EV formation from endothelial cells in vivo under homoeostatic and malignant conditions. These large EVs are mitochondria-rich, expose the ‘eat me’ signal phosphatidylserine, and can interact with immune cell populations as a potential clearance mechanism. Elevated levels of circulating EVs correlates with degradation of the bone marrow vasculature caused by acute myeloid leukaemia. Together, our study provides in vivo spatio-temporal characterization of EV formation in the murine vasculature and suggests that circulating, large endothelial cell-derived EVs can provide a snapshot of vascular damage at distal sites.

Working at home, rather than in the workplace, has been suggested to affect office-based workers’ health and wellbeing. This exploratory, cross-sectional study sought to identify discrete psychological responses to home-working practices and investigate their relationship with engagement in health-related behaviours and wellbeing. A sample of 491 home-workers completed a survey assessing ten psychological responses to home-working (e.g., the ability to ‘switch off’ from work), ten health behaviour indices (e.g., sleep trouble), and seven wellbeing indices. Network Analysis modelled relationships between these variables. Results showed four clusters of psychological responses to home-working practices (representing ‘home-working independence’, ‘home-work transition’, ‘daily work pressure’, and ‘work-day forecasting’). Variables within these clusters linked to health behaviour and wellbeing: perceptions of workload manageability, ability to switch off from work, homeworking autonomy, and planning and organising a home-working day had cascading influences on indicators of health, health behaviours, and wellbeing. The findings point to a complex system of potential health and wellbeing consequences of working from home. Further evidence is needed to establish truly causal relationships; nonetheless, our findings call for the development of public health initiatives and organisational policies to support the adoption of home-working practices to benefit the health and wellbeing of home-workers.

Degraded peatlands are significant sources of carbon greenhouse gases (CGHG), and their recovery can make significant contributions to climate change mitigation as well as deliver biodiversity benefits. Sphagnum mosses are key species for northern peatland formation and re-introduction is often needed for successful ecohydrological restoration of degraded bogs, but natural sources are scarce and often protected. Micropropagated Sphagnum moss products (BeadaMoss®) were developed to alleviate this constraint. This research explored in detail, for the first time, the CGHG fluxes on a cut-over lowland peatland restoration site where micropropagated Sphagnum was introduced to an existing ‘nurse crop’ of Eriophorum angustifolium, and tested the influence of vegetation maturity. Ecosystem CGHG flux was measured using closed chambers at plot scale in areas of both mature and immature E. angustifolium with and without application of BeadaGel™ Sphagnum, with control plots on bare peat. Studies were conducted over two years of contrasting weather patterns. In Year 1, mean net (CO2e) CGHG uptake on vegetated plots was -2.33 (minimum 1.55, maximum 5.55) t ha-1 yr-1 with increasing CGHG uptake as vegetation matured. In Year 2, gross photosynthesis reduced significantly during the 2018 summer drought resulting in a small mean net CGHG emission of 0.11 (minimum 2.21 maximum -1.22) t ha-1 yr-1. Sphagnum application within immature vegetation resulted in greater CGHG uptake in both years, but was not as beneficial within mature vegetation. CGHG emission from bare peat (3.79 t ha-1 yr-1 overall) showed the magnitude of avoided losses. Methane flux contributed significantly to CGHG emission but was not closely related to water table depth. Application of Sphagnum within E. angustifolium can deliver good CGHG flux results in the early stages of degraded lowland bog recovery but cannot fully mitigate vulnerability to climate change scenarios.

Lecture capture is popular within Higher Education, but previous research suggests that students do not always optimally select content to review, nor do they make the most of specific functions. In the current study conducted in the 2019/20 academic year, we used a repeated-measures crossover design to establish the effects of transcripts with closed captioning, and email reminders, on use (self-reported and system analytics), perceptions of lecture capture and student performance, as measured by multiple-choice question (MCQ) tests designed to assess the module learning outcomes. System analytics (N = 129) and survey data (N = 42) were collected from students alongside qualitative data from semi-structured interviews (N = 8). We found that students value lecture capture highly, but do not access it extensively during the teaching period. The availability of transcripts and closed captions did not impact the amount of capture use or performance on MCQ tests, but did result in more positive perceptions of capture, including increased likelihood of recommending it to others. The use of email reminders referring students to specific segments of capture and reminding them of the functionality had no impact on any measure, although qualitative data suggested that the content of reminders may be used in revision rather than during the teaching period, which fell outside the period we investigated. Collectively, these data suggest that the use of captions and transcripts may be beneficial to students by allowing dual processing of visual and audio content, and a searchable resource to help consolidate their learning but there is little evidence to support reminders.

Abstract Background In the wake of Covid-19, the prevalence of working from home (‘home-working’) is expected to rise. Yet, working from home can have negative health and wellbeing impacts. Interventions are needed to promote effective ways of working that also protect workers’ health and wellbeing. This study explored the feasibility and acceptability of an intervention intended to promote home-working practices that would protect and promote health behaviour and wellbeing. Methods An uncontrolled, single-arm mixed-methods trial design was employed. Forty-two normally-office-based UK workers, working from home between January–February 2021 (during the Covid pandemic), consented to receive the intervention. The intervention: a digital document offering evidence-based recommendations for home-working in ways conducive to health behaviour and wellbeing. Feasibility and acceptability were quantitatively indexed by: expressions of interest within 1 week (target threshold ≥ 35); attrition across the one-week study period (threshold ≤ 20%); and the absence of any apparent detriments in self-reported physical activity, sedentary behaviour, snacking, and work-related wellbeing prior to and one week after receiving the intervention. Qualitative think-aloud data, obtained while participants read through the intervention, and analysed using reflexive thematic analysis, explored acceptability. Semi-structured interviews conducted one week after intervention exposure were content-analysed to identify whether and which behaviour changes were adopted. Results Two feasibility criteria were met: 85 expressions of interest indicated satisfactory intervention demand, and no detriments were observed in health behaviours or wellbeing. Forty-two participants (i.e., maximum capacity for the study; 26 females, 16 males, aged 22–63) consented to take part. 31% dropped out over the one-week study period leaving a final sample of 29 (18 females, 11 males, aged 22–63), exceeding identified attrition thresholds. Think-aloud data showed that participants concurred with intervention guidance, but felt it lacked novelty and practicality. Follow-up interviews produced 18 (62%) participant reports of intervention adherence, where nine recommendations reportedly prompted behaviour change in at least one participant. Conclusions Mixed evidence was found for intervention feasibility and acceptability. Whilst the information was deemed relevant and of value, further development is required to increase its novelty. It may also be more fruitful to provide this information via employers, to encourage and emphasise employer endorsement.

Abstract Background The retinal pigment epithelium (RPE), a layer of pigmented cells that lies between the neurosensory retina and the underlying choroid, plays a critical role in maintaining the functional integrity of photoreceptor cells and in mediating communication between the neurosensory retina and choroid. Prior studies have demonstrated neurotrophic effects of select steroids that mitigate the development and progression of retinal degenerative diseases via an array of distinct mechanisms of action. Methods Here, we identified major steroid hormone signaling pathways and their key functional protein constituents controlling steroid hormone signaling, which are potentially involved in the mitigation or propagation of retinal degenerative processes, from human proteome datasets with respect to their relative abundances in the retinal periphery, macula, and fovea. Results Androgen, glucocorticoid, and progesterone signaling networks were identified and displayed differential distribution patterns within these three anatomically distinct regions of the choroid-retinal pigment epithelial complex. Classical and non-classical estrogen and mineralocorticoid receptors were not identified. Conclusion Identified differential distribution patterns suggest both selective susceptibility to chronic neurodegenerative disease processes, as well as potential substrates for drug target discovery and novel drug development focused on steroid signaling pathways in the choroid-RPE.

Age related macular degeneration (AMD) is the most common cause of blindness in the elderly. Oxidative stress contributes to retinal pigment epithelium (RPE) dysfunction and cell death thereby leading to AMD. Using improved RPE cell model systems, such as human telomerase transcriptase-overexpressing (hTERT) RPE cells (hTERT-RPE), pathophysiological changes in RPE during oxidative stress can be better understood. Using this model system, we identified changes in the expression of proteins involved in the cellular antioxidant responses after induction of oxidative stress. Some antioxidants such as vitamin E (tocopherols and tocotrienols) are powerful antioxidants that can reduce oxidative damage in cells. Alpha-tocopherol (α-Toc or αT) and gamma-tocopherol (γ-Toc or γT) are well-studied tocopherols, but signaling mechanisms underlying their respective cytoprotective properties may be distinct. Here, we determined what effect oxidative stress, induced by extracellularly applied tBHP in the presence and absence of αT and/or γT, has on the expression of antioxidant proteins and related signaling networks. Using proteomics approaches, we identified differential protein expression in cellular antioxidant response pathways during oxidative stress and after tocopherol treatment. We identified three groups of proteins based on biochemical function: glutathione metabolism/transfer, peroxidases and redox-sensitive proteins involved in cytoprotective signaling. We found that oxidative stress and tocopherol treatment resulted in unique changes in these three groups of antioxidant proteins indicate that αT and γT independently and by themselves can induce the expression of antioxidant proteins in RPE cells. These results provide novel rationales for potential therapeutic strategies to protect RPE cells from oxidative stress.

Purpose: The COVID-19 pandemic has caused 1.4 million deaths globally and is associated with a 3–4 times increase in 30-day mortality after a fragility hip fracture with concurrent COVID-19 infection. Typically, death from COVID-19 infection occurs between 15 and 22 days after the onset of symptoms, but this period can extend up to 8 weeks. This study aimed to assess the impact of concurrent COVID-19 infection on 120-day mortality after a fragility hip fracture. Methods: A multi-centre prospective study across 10 hospitals treating 8% of the annual burden of hip fractures in England between 1st March and 30th April, 2020 was performed. Patients whose surgical treatment was payable through the National Health Service Best Practice Tariff mechanism for “fragility hip fractures” were included in the study. Patients’ 120-day mortality was assessed relative to their peri-operative COVID-19 status. Statistical analysis was performed using SPSS version 27. Results: A total of 746 patients were included in this study, of which 87 (11.7%) were COVID-19 positive. Mortality rates at 30- and 120-day were significantly higher for COVID-19 positive patients relative to COVID-19 negative patients (p

Abstract Lecture capture is popular within Higher Education, but previous research suggests that students do not always optimally select content to review, nor do they make the most of specific functions. In the current study conducted in the 2019/20 academic year, we used a repeated-measures crossover design to establish the effects of transcripts with closed captioning, and email reminders, on use (self-reported and system analytics), perceptions of lecture capture and student performance, as measured by multiple-choice question (MCQ) tests designed to assess the module learning outcomes. System analytics (N = 129) and survey data (N = 42) were collected from students alongside qualitative data from semi-structured interviews (N = 8). We found that students value lecture capture highly, but do not access it extensively during the teaching period. The availability of transcripts and closed captions did not impact the amount of capture use or performance on MCQ tests, but did result in more positive perceptions of capture, including increased likelihood of recommending it to others. The use of email reminders referring students to specific segments of capture and reminding them of the functionality had no impact on any measure, although qualitative data suggested that the content of reminders may be used in revision rather than during the teaching period, which fell outside the period we investigated. Collectively, these data suggest that the use of captions and transcripts may be beneficial to students by allowing dual processing of visual and audio content, and a searchable resource to help consolidate their learning but there is little evidence to support reminders.

Working at home, rather than in the workplace, has been suggested to affect office-based workers' health and wellbeing. This exploratory, cross-sectional study sought to identify discrete psychological responses to home-working practices and investigate their relationship with engagement in health-related behaviours and wellbeing. A sample of 491 home-workers completed a survey assessing ten psychological responses to home-working (e.g., the ability to 'switch off' from work), ten health behaviour indices (e.g., sleep trouble), and seven wellbeing indices. Network Analysis modelled relationships between these variables. Results showed four clusters of psychological responses to home-working practices (representing 'home-working independence', 'home-work transition', 'daily work pressure', and 'work-day forecasting'). Variables within these clusters linked to health behaviour and wellbeing: perceptions of workload manageability, ability to switch off from work, homeworking autonomy, and planning and organising a home-working day had cascading influences on indicators of health, health behaviours, and wellbeing. The findings point to a complex system of potential health and wellbeing consequences of working from home. Further evidence is needed to establish truly causal relationships; nonetheless, our findings call for the development of public health initiatives and organisational policies to support the adoption of home-working practices to benefit the health and wellbeing of home-workers. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the most prevalent ocular disease in the elderly, resulting in blindness. Oxidative stress plays a role in retinal pigment epithelium (RPE) pathology observed in AMD. Tocopherols are potent antioxidants that prevent cellular oxidative damage and have been shown to upregulate the expression of cellular antioxidant proteins. Here, we determined whether oxidative stress and tocopherols, using either normal cellular conditions or conditions of sublethal cellular oxidative stress, alter the expression of proteins mediating sterol uptake, transport, and metabolism. Human telomerase transcriptase-overexpressing RPE cells (hTERT-RPE) were used to identify differential expression of proteins resulting from treatments. We utilized a proteomics strategy to identify protein expression changes in treated cells. After the identification and organization of data, we divided the identified proteins into groups related to biological function: cellular sterol uptake, sterol transport and sterol metabolism. Exposure of cells to conditions of oxidative stress and exposure to tocopherols led to similar protein expression changes within these three groups, suggesting that α-tocopherol (αT) and γ-tocopherol (γT) can regulate the expression of sterol uptake, transport and metabolic proteins in RPE cells. These data suggest that proteins involved in sterol transport and metabolism may be important for RPE adaptation to oxidative stress, and these proteins represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract The speed of pellet propulsion through the isolated guinea pig distal colon in vitro significantly exceeds in vivo measurements, suggesting a role for inhibitory mechanisms from sources outside the gut. The aim of this study was to investigate the effects of sympathetic nerve stimulation on three different neurogenic motor behaviors of the distal colon: transient neural events (TNEs), colonic motor complexes (CMCs), and pellet propulsion. To do this, segments of guinea pig distal colon with intact connections to the inferior mesenteric ganglion (IMG) were set up in organ baths allowing for simultaneous extracellular suction electrode recordings from smooth muscle, video recordings for diameter mapping, and intraluminal manometry. Electrical stimulation (1–20 Hz) of colonic nerves surrounding the inferior mesenteric artery caused a statistically significant, frequency‐dependent inhibition of TNEs, as well as single pellet propulsion, from frequencies of 5 Hz and greater. Significant inhibition of CMCs required stimulation frequencies of 10 Hz and greater. Phentolamine (3.6 μM) abolished effects of colonic nerve stimulation, consistent with a sympathetic noradrenergic mechanism. Sympathetic inhibition was constrained to regions with intact extrinsic nerve pathways, allowing normal motor behaviors to continue without modulation in adjacent extrinsically denervated regions of the same colonic segments. The results demonstrate differential sensitivities to sympathetic input among distinct neurogenic motor behaviors of the colon. Together with findings indicating CMCs activate colo‐colonic sympathetic reflexes through the IMG, these results raise the possibility that CMCs may paradoxically facilitate suppression of pellet movement in vivo, through peripheral sympathetic reflex circuits.

In response to infection and injury, the neutrophil population rapidly expands and then quickly re-establishes the basal state when inflammation resolves. The exact pathways governing neutrophil/macrophage lineage outputs from a common granulocyte-macrophage progenitor are still not completely understood. From a forward genetic screen in zebrafish, we identify the transcriptional repressor, ZBTB11, as critical for basal and emergency granulopoiesis. ZBTB11 sits in a pathway directly downstream of master myeloid regulators including PU.1, and TP53 is one direct ZBTB11 transcriptional target. TP53 repression is dependent on ZBTB11 cys116, which is a functionally critical, metal ion-coordinating residue within a novel viral integrase-like zinc finger domain. To our knowledge, this is the first description of a function for this domain in a cellular protein. We demonstrate that the PU.1-ZBTB11-TP53 pathway is conserved from fish to mammals. Finally, Zbtb11 mutant rescue experiments point to a ZBTB11-regulated TP53 requirement in development of other organs.

In 2013 the University of Canberra (UC) initiated a program of peer-assisted academic skills help, the Academic Skills Rovers program, with the goal of providing drop-in peer learning support to students at campus locations where they congregate to study. The Academic Skills Rovers were initially recruited from the teacher education discipline, but the pool was subsequently extended to include students with high-level literacy skills from other fields. The program has proven to be a successful addition to the scope of learning development support offered at UC, as measured by a rapid increase in the number and reach of consultations, enthusiastic evaluations by students, and the positive experiences of the Rovers themselves. This article outlines and analyses the features of the program to provide a road map for other institutions contemplating the introduction of a similar service and proposes possible further directions for the future. [This program was pioneered by the following Academic Skills Rovers: Sarah Crawford, Lucy Ellen, Reuben Fox, Tania Hadlow, Kimberley Hall, Sharee Hodge, Katherine Kemp, Jayde Kominiarski, Alidia Lee, Kirra Lehman, Lisa Parsonage, Kentaro Takagi, and Rebecca Tedeschi.]

Plasticity allows organisms to respond to environmental change. Here the authors compare the distribution of cis-regulatory variants in the transcriptomes of Arabidopsis lyrata and A. halleriafter exposure to stress, to trace the role of polygenic selection in the evolution of gene expression plasticity.

Each generation, spontaneous mutations introduce heritable changes that tend to reduce fitness in populations of highly adapted living organisms. This erosion of fitness is countered by natural selection, which keeps deleterious mutations at low frequencies and ultimately removes most of them from the population. The classical way of studying the impact of spontaneous mutations is via mutation accumulation (MA) experiments, where lines of small effective population size are bred for many generations in conditions where natural selection is largely removed. Such experiments in microbes, invertebrates, and plants have generally demonstrated that fitness decays as a result of MA. However, the phenotypic consequences of MA in vertebrates are largely unknown, because no replicated MA experiment has previously been carried out. This gap in our knowledge is relevant for human populations, where societal changes have reduced the strength of natural selection, potentially allowing deleterious mutations to accumulate. Here, we study the impact of spontaneous MA on the mean and genetic variation for quantitative and fitness-related traits in the house mouse using the MA experimental design, with a cryopreserved control to account for environmental influences. We show that variation for morphological and life history traits accumulates at a sufficiently high rate to maintain genetic variation and selection response. Weight and tail length measures decrease significantly between 0.04% and 0.3% per generation with narrow confidence intervals. Fitness proxy measures (litter size and surviving offspring) decrease on average by about 0.2% per generation, but with confidence intervals overlapping zero. When extrapolated to humans, our results imply that the rate of fitness loss should not be of concern in the foreseeable future. Spontaneous mutations tend to reduce fitness in populations of living organisms, but this erosion of fitness is countered by natural selection. This study uses the first mutation accumulation experiment in a mammal to show that even in the absence of natural selection, the rate of fitness loss should not be of concern, which is reassuring for humans. [ABSTRACT FROM AUTHOR]