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There is a strong tradition of viewing these two school subjects as mutually enhancing, but aesthetic aspects of this interplay are less studied. In this paper we define disciplinary aesthetics as appreciation and enjoyment of the what and how of learning within and across both subjects. Drawing on Peirce’s semiotic theory of signs, we claim that meaning-making from, with and through signs and sign systems (a) is fundamental to learning in both subjects and (b) constitutes a key feature of valuing and contributing to an aesthetic taste for both subjects. We illustrate these claims through examples drawn from secondary and tertiary learning.

BackgroundLimited research suggests that non-occupational health doctors rarely discuss occupation with their patients. There is a gap in research regarding the attitudes and practices of doctors towards discussing patient occupation and return to work. The aim of this work was to explore the attitudes of ophthalmology doctors towards work as a clinical outcome and assess the need for occupational health training among participants (doctors).MethodsA cross-sectional survey among doctors working in ophthalmology in two London teaching hospitals. The survey focused on the attitudes of doctors towards 'work' as a clinical outcome, their practices of asking patients about occupation, their perceived level of competency in this area of clinical practice and the level of training doctors had received in this field. Descriptive data analysis was undertaken and results presented as frequencies and proportions.ResultsThe response rate was 30/72 (42%). Approximately a quarter (8/30;27%) of doctors 'always' discussed return to work during care planning whilst the majority (25/30;87%) of doctors agreed or strongly agreed that this should always be the case. Over half of the doctors had received no formal OH training on how to discuss or assess the impact of health on work and only 17/30 (57%) considered themselves competent in discussing these work outcomes with patients. Over half agreed that additional training would be useful, with the majority believing that it would be most useful at all stages of medical training.ConclusionWe found the majority of ophthalmology doctors regard 'return to work' as an important clinical outcome yet most do not routinely discuss work outcomes with patients to inform care planning. Majority of doctors lack training in how to discuss issues relating to work and would benefit from additional OH training.

Abstract Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.

Abstract The impact of ocean warming on fish and fisheries is vigorously debated. Leading theories project limited adaptive capacity of tropical fishes and 14-39% size reductions by 2050 due to mass-scaling limitations of oxygen supply in larger individuals. Using the world’s hottest coral reefs in the Persian/Arabian Gulf as a natural laboratory for ocean warming - where species have survived >35.0 °C summer temperatures for over 6000 years and are 14-40% smaller at maximum size compared to cooler locations - we identified two adaptive pathways that enhance survival at elevated temperatures across 10 metabolic and swimming performance metrics. Comparing Lutjanus ehrenbergii and Scolopsis ghanam from reefs both inside and outside the Persian/Arabian Gulf across temperatures of 27.0 °C, 31.5 °C and 35.5 °C, we reveal that these species show a lower-than-expected rise in basal metabolic demands and a right-shifted thermal window, which aids in maintaining oxygen supply and aerobic performance to 35.5 °C. Importantly, our findings challenge traditional oxygen-limitation theories, suggesting a mismatch in energy acquisition and demand as the primary driver of size reductions. Our data support a modified resource-acquisition theory to explain how ocean warming leads to species-specific size reductions and why smaller individuals are evolutionarily favored under elevated temperatures.

Abstract Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

Abstract Obesity and food addiction are associated with distinct brain signatures related to reward processing, and early life adversity (ELA) also increases alterations in these same reward regions. However, the neural mechanisms underlying the effect of early life adversity on food addiction are unknown. Therefore, the aim of this study was to examine the interactions between ELA, food addiction, and brain morphometry in individuals with obesity. 114 participants with high body mass index (BMI) underwent structural MRIs, and completed several questionnaires (e.g., Yale Food Addiction Scale (YFAS), Brief Resilience Scale (BRS), Early Traumatic Inventory (ETI)). Freesurfer 6 was applied to generate the morphometry of brain regions. A multivariate pattern analysis was used to derive brain morphometry patterns associated with food addiction. General linear modeling and mediation analyses were conducted to examine the effects of ELA and resilience on food addiction in individuals with obesity. Statistical significance was determined at a level of p

Abstract Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing ‘M1-like’ macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.

Abstract Worms create complex paths when moving through sediment to feed. This research applies computer simulation models to provide a unique approach to visualise and quantify the process by which complex worm paths can emerge from simple local movement decisions. A grid environment is proposed in which worms can move with choice of up to 8 directions at each step. This uses a square grid with diagonal paths which has not been investigated before and the resulting number of complex paths is increased compared to triangular grids. Results identify many novel worm paths. Some of the resulting paths are symmetrical, others produce repetitive looping paths, others return to the origin. Interesting worm paths are identified with chaotic movement. Some include oscillating between chaotic and ordered movement for which the outcome is still unknown after millions of steps. A conclusion that may be extrapolated to other creatures is that local movement decisions of a species substantially determine the overall global search strategy that emerges.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Abstract The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.

Abstract Dietary restriction has shown benefits in physiological, metabolic, and molecular signatures associated with aging but is a difficult lifestyle to maintain for most individuals. In mice, a less restrictive diet that allows for cyclical periods of reduced calories mitigates aging phenotypes, yet the effects of such an intervention in a genetically heterogenous, higher-order mammal has not been examined. Here, using middle-aged rhesus macaques matched for age and sex, we show that a regimen of 4 days of low-calorie intake followed by 10 days of ad libitum feeding (4:10 diet) performed in repeating cycles over 12 weeks led to significant loss of weight and fat percentage, despite the free access to food for most of the study duration. We show the 4-day restriction period is sufficient to drive alterations to the serum metabolome characterized by substantial differences in lipid classes. These phenotypes were paralleled by changes in the gut microbiome of restricted monkeys that highlight the involvement of a microbiome-metabolome axis. This regimen shows promising phenotypes, with some sex-dimorphic responses, including residual memory of the diet. As many calorie restriction interventions are difficult to sustain, we propose that this short-term diet may be easier to adhere to and have benefits directly relevant to human aging.

Abstract Plasmids carry genes conferring antimicrobial resistance and other clinically important traits, and contribute to the rapid dissemination of such genes. Previous studies using complete plasmid assemblies, which are essential for reliable inference, have been small and/or limited to plasmids carrying antimicrobial resistance genes (ARGs). In this study, we sequenced 1,880 complete plasmids from 738 isolates from bloodstream infections in Oxfordshire, UK. The bacteria had been originally isolated in 2009 (194 isolates) and 2018 (368 isolates), plus a stratified selection from intervening years (176 isolates). We demonstrate that plasmids are largely, but not entirely, constrained to a single host species, although there is substantial overlap between species of plasmid gene-repertoire. Most ARGs are carried by a relatively small number of plasmid groups with biological features that are predictable. Plasmids carrying ARGs (including those encoding carbapenemases) share a putative ‘backbone’ of core genes with those carrying no such genes. These findings suggest that future surveillance should, in addition to tracking plasmids currently associated with clinically important genes, focus on identifying and monitoring the dissemination of high-risk plasmid groups with the potential to rapidly acquire and disseminate these genes.

Abstract Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.

Abstract Quantitative muscle MRI is increasingly important in the non-invasive evaluation of neuromuscular disorders and their progression. Underlying histopathotological alterations, leading to changes in qMRI parameters are incompletely unraveled. Early microstructural differences of unknown origin reflected by Diffusion MRI in non-fat infiltrated muscles were detected in Pompe patients. This study employed a longitudinal approach with a Pompe disease mouse model to investigate the histopathological basis of these changes. Monthly scans of Pompe (Gaa6neo/6neo) and wildtype mice (age 1–8 months) were conducted using diffusion MRI, T2-mapping, and Dixon-based water-fat imaging on a 7 T scanner. Immunofluorescence studies on quadriceps muscles were analyzed for lysosomal accumulations and autophagic buildup and correlated with MRI outcome measures. Fat fraction and water-T2 did not differ between groups and remained stable over time. In Pompe mice, fractional anisotropy increased, while mean diffusivity (MD) and radial diffusivity (RD) decreased in all observed muscles. Autophagic marker and muscle fibre diameter revealed significant negative correlations with reduced RD and MD, while lysosomal marker did not show any change or correlation. Using qMRI, we showed diffusion changes in muscles of presymptomatic Pompe mice without fat-infiltrated muscles and correlated them to autophagic markers and fibre diameter, indicating diffusion MRI reveals autophagic buildup.

Abstract Gametogenesis in Plasmodium spp. occurs within the Anopheles mosquito and is essential for sexual reproduction / differentiation and onwards transmission to mammalian hosts. To better understand the 3D organisation of male gametogenesis, we used serial block face scanning electron microscopy (SBF-SEM) and serial-section cellular electron tomography (ssET) of P. berghei microgametocytes to examine key structures during male gamete formation. Our data reveals an elaborate organisation of axonemes coiling around the nucleus in opposite directions forming a central axonemal band in microgametocytes. Furthermore, we discover the nucleus of microgametes to be tightly coiled around the axoneme in a complex structure whose formation starts before microgamete emergence during exflagellation. Our discoveries of the detailed 3D organisation of the flagellated microgamete and the haploid genome highlight some of the atypical mechanisms of axoneme assembly and haploid genome organisation during male gamete formation in the malaria parasite.

Summary: Visual responses of the primary visual cortex (V1) are altered by sound. Sound-driven behavioral arousal suggests that, in addition to direct inputs from the primary auditory cortex (A1), multiple other sources may shape V1 responses to sound. Here, we show in anesthetized mice that sound (white noise, ≥70dB) drives a biphasic modulation of V1 visually driven gamma-band activity, comprising fast-transient inhibitory and slow, prolonged excitatory (A1-independent) arousal-driven components. An analogous yet quicker modulation of the visual response also occurred earlier in the visual pathway, at the level of the dorsolateral geniculate nucleus (dLGN), where sound transiently inhibited the early phasic visual response and subsequently induced a prolonged increase in tonic spiking activity and gamma rhythmicity. Our results demonstrate that sound-driven modulations of visual activity are not exclusive to V1 and suggest that thalamocortical inputs from the dLGN to V1 contribute to shaping V1 visual response to sound.

Abstract Methane is the second most important greenhouse gas contributor to climate change; at the same time its reduction has been denoted as one of the fastest pathways to preventing temperature growth due to its short atmospheric lifetime. In particular, the mitigation of active point-sources associated with the fossil fuel industry has a strong and cost-effective mitigation potential. Detection of methane plumes in remote sensing data is possible, but the existing approaches exhibit high false positive rates and need manual intervention. Machine learning research in this area is limited due to the lack of large real-world annotated datasets. In this work, we are publicly releasing a machine learning ready dataset with manually refined annotation of methane plumes. We present labelled hyperspectral data from the AVIRIS-NG sensor and provide simulated multispectral WorldView-3 views of the same data to allow for model benchmarking across hyperspectral and multispectral sensors. We propose sensor agnostic machine learning architectures, using classical methane enhancement products as input features. Our HyperSTARCOP model outperforms strong matched filter baseline by over 25% in F1 score, while reducing its false positive rate per classified tile by over 41.83%. Additionally, we demonstrate zero-shot generalisation of our trained model on data from the EMIT hyperspectral instrument, despite the differences in the spectral and spatial resolution between the two sensors: in an annotated subset of EMIT images HyperSTARCOP achieves a 40% gain in F1 score over the baseline.

Abstract Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.

Abstract Residual stresses affect the performance and reliability of most manufactured goods and are prevalent in casting, welding, and additive manufacturing (AM, 3D printing). Residual stresses are associated with plastic strain gradients accrued due to transient thermal stress. Complex thermal conditions in AM produce similarly complex residual stress patterns. However, measuring real-time effects of processing on stress evolution is not possible with conventional techniques. Here we use operando neutron diffraction to characterize transient phase transformations and lattice strain evolution during AM of a low-temperature transformation steel. Combining diffraction, infrared and simulation data reveals that elastic and plastic strain distributions are controlled by motion of the face-centered cubic and body-centered cubic phase boundary. Our results provide a new pathway to design residual stress states and property distributions within additively manufactured components. These findings will enable control of residual stress distributions for advantages such as improved fatigue life or resistance to stress-corrosion cracking.

Abstract Obesity contributes to physical comorbidities and mental health consequences. We explored whether physical activity could influence more than metabolic regulation and result in psychological benefits through the brain-gut microbiome (BGM) system in a population with high BMI. Fecal samples were obtained for 16 s rRNA profiling and fecal metabolomics, along with psychological and physical activity questionnaires. Whole brain resting-state functional MRI was acquired, and brain connectivity metrics were calculated. Higher physical activity was significantly associated with increased connectivity in inhibitory appetite control brain regions, while lower physical activity was associated with increased emotional regulation network connections. Higher physical activity was also associated with microbiome and metabolite signatures protective towards mental health and metabolic derangements. The greater resilience and coping, and lower levels of food addiction seen with higher physical activity, may be explained by BGM system differences. These novel findings provide an emphasis on the psychological and resilience benefits of physical activity, beyond metabolic regulation and these influences seem to be related to BGM interactions.

Abstract Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M−1 s−1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 × 107 M−1 s−1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

Laboratory animal research with nonhuman primates (NHPs) requires anesthesia for most procedures to ensure safety and consistency in sample collection. However, anesthesia drugs can have adverse effects on the physiological measures of interest. Alfaxalone, most notably used in dogs and cats, offers rapid onset, short duration of action, and has a high safety margin. Here, we compared our current anesthesia protocol using Telazol, to three different doses of alfaxalone during a one-hour intravenous glucose tolerance test, the standard evaluation of glucose metabolism in NHPs. Results indicate there are no differences in the rate of glucose metabolism, anesthesia depth measurements, or total duration of sedation, but induction, number of supplemental doses required, and recovery time to eating were affected by the different doses of alfaxalone. Cardiovascular measures showed variability between the four protocols in respiratory rate and systolic blood pressure rates only. These results indicate that alfaxalone can produce a reliable state of anesthesia, similar to our current protocol, and confers minimal cardiovascular or metabolic disturbance, as well as enhanced recovery characteristics. As such, alfaxalone is a promising anesthetic for use in laboratory animals and further investigation is warranted.

Introduction. Exercise is beneficial for improving general health, wellbeing, and specific medical conditions. In musculoskeletal conditions such as chronic low back and neck pain, prescribed exercise has been found to be moderately effective in decreasing pain and improving function. Osteopaths are primary contact health professionals who manage predominantly musculoskeletal complaints. This work presents a secondary data analysis of the Australian osteopathy practice-based research network and profiles the characteristics of osteopaths who often use exercise prescription in patient care. Methodology. Secondary analysis of a cross-sectional survey of 992 osteopaths was registered with the Osteopathy Research and Innovation Network, an Australian practice-based research network. Demographics, practice, and treatment characteristics of Australian osteopaths who “often” use exercise prescription in patient care were examined. Results. Seven-hundred and thirty-three Australian osteopaths (74%) indicated that they use exercise prescription “often” in patient care. Australian osteopaths who often use exercise prescription are more likely to be colocated with another osteopath (ORa 1.54) and send referrals to an exercise physiologist (ORa 1.94) and a specialist medical practitioner (ORa 1.72). Those osteopaths who often used exercise prescription were also more likely to discuss physical activity (ORa 5.61) and nutrition (ORa 1.90). Australian osteopaths who use exercise prescription often were more likely to treat patients with sports injuries (ORa 2.43) and use soft tissue techniques (ORa 1.92), trigger point techniques (ORa 2.72), and sports taping (ORa 1.78). Conclusion. Osteopaths who utilise exercise prescription were more likely to discuss physical activity, diet, and nutrition and utilise referral networks with specialist medical practitioners and exercise physiologists. Australian osteopaths who often use exercise prescriptions were also more likely to treat patients with sport injury. The results suggest that most Australian osteopaths use exercise prescription and have referral networks with other health professionals for patient management. Further work is required to explore the type of exercise prescription used and for what conditions.

How do author perceptions match up to the outcomes of the peer-review process and perceptions of others? In a top-tier computer science conference (NeurIPS 2021) with more than 23,000 submitting authors and 9,000 submitted papers, we surveyed the authors on three questions: (i) their predicted probability of acceptance for each of their papers, (ii) their perceived ranking of their own papers based on scientific contribution, and (iii) the change in their perception about their own papers after seeing the reviews. The salient results are: (1) Authors had roughly a three-fold overestimate of the acceptance probability of their papers: The median prediction was 70% for an approximately 25% acceptance rate. (2) Female authors exhibited a marginally higher (statistically significant) miscalibration than male authors; predictions of authors invited to serve as meta-reviewers or reviewers were similarly calibrated, but better than authors who were not invited to review. (3) Authors' relative ranking of scientific contribution of two submissions they made generally agreed with their predicted acceptance probabilities (93% agreement), but there was a notable 7% responses where authors predicted a worse outcome for their better paper. (4) The author-provided rankings disagreed with the peer-review decisions about a third of the time; when co-authors ranked their jointly authored papers, co-authors disagreed at a similar rate-about a third of the time. (5) At least 30% of respondents of both accepted and rejected papers said that their perception of their own paper improved after the review process. The stakeholders in peer review should take these findings into account in setting their expectations from peer review.

IntroductionEarly in the COVID-19 pandemic, Canadian primary care practices rapidly adapted to provide care virtually. Most family physicians lacked prior training or expertise with virtual care. In the absence of formal guidance, they made individual decisions about in-person versus remote care based on clinical judgement, their longitudinal relationships with patients, and personal risk assessments. Our objective was to explore Canadian family physicians' perspectives on the strengths and limitations of virtual care implementation for their patient populations during the COVID-19 pandemic and implications for the integration of virtual care into broader primary care practice.MethodsWe conducted semi-structured qualitative interviews with family physicians working in four Canadian jurisdictions (Vancouver Coastal health region, British Columbia; Southwestern Ontario; the province of Nova Scotia; and Eastern Health region, Newfoundland and Labrador). We analyzed interview data using a structured applied thematic approach.ResultsWe interviewed 68 family physicians and identified four distinct themes during our analysis related to experiences with and perspectives on virtual care: (1) changes in access to primary care; (2) quality and efficacy of care provided virtually; (3) patient and provider comfort with virtual modalities; and (4) necessary supports for virtual care moving forward.ConclusionsThe move to virtual care enhanced access to care for select patients and was helpful for family physicians to better manage their panels. However, virtual care also created access challenges for some patients (e.g., people who are underhoused or living in areas without good phone or internet access) and for some types of care (e.g., care that required access to medical devices). Family physicians are optimistic about the ongoing integration of virtual care into broader primary care delivery, but guidance, regulations, and infrastructure investments are needed to ensure equitable access and to maximize quality of care.

Abstract Cork laser induced graphene (cork‐LIG) electrochemical sensors are fabricated by direct laser writing of natural cork sheets. Laser writing is performed with a hobbyist visible laser. The obtained cork‐LIG structures display graphene‐like Raman signatures, high conductivity, and fast electron‐transfer rates. After a 10 min electrochemical pretreatment, electrodes are used for detection of Tyrosine (Tyr) in the presence of uric acid, dopamine, ascorbic acid, urea, and glucose. linear detection of tyrosine is achieved in the 5–150 µm range with a limit of detection (LOD) of 3.03 µm. Calibration of dopamine detection is achieved with a LOD of 1.1 µm. Finally, the cork‐LIG electrochemical sensors show linear response of Tyr in artificial sweat in the relevant physiological range of 5–250 μm (sensitivity, 1.8×10−2 A m−1). The LOD is calculated as 3.75 μm. These results open the door to the exploitation of renewable materials such as cork for the development of high‐quality, green sensors for the monitoring of health and wellbeing parameters.

Abstract It is unclear whether the high burden of COPD in rural areas is related to worse outcomes in patients with COPD or is because the prevalence of COPD is higher in rural areas. We assessed the association of rural living with acute exacerbations of COPD (AECOPDs)-related hospitalization and mortality. We retrospectively analyzed Veterans Affairs (VA) and Medicare data of a nationwide cohort of veterans with COPD aged ≥ 65 years with COPD diagnosis between 2011 and 2014 that had follow-up data until 2017. Patients were categorized based on residential location into urban, rural, and isolated rural. We used generalized linear and Cox proportional hazards models to assess the association of residential location with AECOPD-related hospitalizations and long-term mortality. Of 152,065 patients, 80,162 (52.7%) experienced at least one AECOPD-related hospitalization. After adjusting for demographics and comorbidities, rural living was associated with fewer hospitalizations (relative risk-RR = 0.90; 95% CI: 0.89–0.91; P

Abstract We recently introduced an absolute and physical quantitative scale for chromatin immunoprecipitation followed by sequencing (ChIP-seq). The scale itself was determined directly from measurements routinely made on sequencing samples without additional reagents or spike-ins. We called this approach sans spike-in quantitative ChIP, or siQ-ChIP. Herein, we extend those results in several ways. First, we simplified the calculations defining the quantitative scale, reducing practitioner burden. Second, we reveal a normalization constraint implied by the quantitative scale and introduce a new scheme for generating ‘tracks’. The constraint requires that tracks are probability distributions so that quantified ChIP-seq is analogous to a mass distribution. Third, we introduce some whole-genome analyses that allow us, for example, to project the IP mass (immunoprecipitated mass) onto the genome to evaluate how much of any genomic interval was captured in the IP. We applied siQ-ChIP to p300/CBP inhibition and compare our results to those of others. We detail how the same data-level observations are misinterpreted in the literature when tracks are not understood as probability densities and are compared without correct quantitative scaling, and we offer new interpretations of p300/CBP inhibition outcomes.

Abstract To conduct a systematic review of the comparative efficacy of various psychotropic medications for the treatment of disruptive behavior (DBs) in youths. To this aim, we systematically reviewed randomized clinical trials (RCTs) of various psychotropic medications targeting symptoms of DBs and applied network meta-analysis to investigate their relative efficacy. Fifty-five RCTs meeting the inclusion criteria were selected. To predict and interpret relative treatment efficacy, we compared the efficacy of various psychotropic medications prescribed for DB symptoms based on their mechanism of action. Network meta-analysis revealed that for reducing DBs, second-generation antipsychotics, stimulants, and non-stimulant ADHD medications were more efficacious than placebo, and second-generation antipsychotics were the most efficacious. The dopaminergic modulation of top-down inhibitory process by these medications is discussed in this review. This study offers information on the relative efficacy of various psychotropic medications for the treatment of DB, and insight into a potential neurobiological underpinning for those symptoms. It also illustrates the potential utility of these neurobiological mechanisms as a target for future treatment studies.

Abstract Both sharks and humans present a potentially lethal threat to mesopredatory fishes in coral reef systems, with implications for both population dynamics and the role of mesopredatory fishes in reef ecosystems. This study quantifies the antipredator behaviours mesopredatory fishes exhibit towards the presence of large coral reef carnivores and compares these behavioural responses to those elicited by the presence of snorkelers. Here, we used snorkelers and animated life-size models of the blacktip reef shark (Carcharhinus melanopterus) to simulate potential predatory threats to mesopredatory reef fishes (lethrinids, lutjanids, haemulids and serranids). The responses of these reef fishes to the models and the snorkelers were compared to those generated by three non-threatening controls (life-size models of a green turtle [Chelonia mydas], a PVC-pipe [an object control] and a Perspex shape [a second object control]). A Remote Underwater Stereo-Video System (Stereo-RUV) recorded the approach of the different treatments and controls and allowed accurate measurement of Flight Initiation Distance (FID) and categorization of the type of flight response by fishes. We found that mesopredatory reef fishes had greater FIDs in response to the approach of threatening models (1402 ± 402–1533 ± 171 mm; mean ± SE) compared to the controls (706 ± 151–896 ± 8963 mm). There was no significant difference in FID of mesopredatory fishes between the shark model and the snorkeler, suggesting that these treatments provoked similar levels of predator avoidance behaviour. This has implications for researchers monitoring behaviour in situ or using underwater census as a technique to estimate the abundance of reef fishes. Our study suggests that, irrespective of the degree to which sharks actually consume these mesopredatory reef fishes, they still elicit a predictable and consistent antipredator response that has the potential to create risk effects.

Abstract Strontium isotopes analysis is a powerful tool in the study of past animal movements, notably the sequential analysis of tooth enamel to reconstruct individual movements in a time-series. Compared to traditional solution analysis, high resolution sampling using laser-ablation multi-collector inductively coupled plasma mass spectrometry (LA-MC-ICP-MS) has the potential to reflect fine scale mobility. However, the averaging of the 87Sr/86Sr intake during the enamel mineralization process may limit fine scale inferences. We compared solution and LA-MC-ICP-MS 87Sr/86Sr intra-tooth profiles from the second and third molars of 5 caribou from the Western Arctic herd, Alaska. Profiles from both methods showed similar trends, reflecting the seasonal migratory movements, but LA-MC-ICP-MS profiles showed a less damped 87Sr/86Sr signal than solution profiles. Geographic assignments of the profile endmembers to the known summer and winter ranges were consistent between methods and with the expected timing of enamel formation but showed discrepancy at a finer scale. Variations on LA-MC-ICP-MS profiles, consistent with expected seasonal movements, suggested more than an admixture of the endmember values. However, more work in understanding enamel formation in Rangifer, and other ungulates, and how 87Sr/86Sr daily intake translates into enamel are needed to assess the real resolution that can be achieved with LA-MC-ICP-MS.

TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.

Abstract A growing number of studies have shown a connection between rhythmic processing and language skill. It has been proposed that domain-general rhythm abilities might help children to tap into the rhythm of speech (prosody), cueing them to prosodic markers of grammatical (syntactic) information during language acquisition, thus underlying the observed correlations between rhythm and language. Working memory processes common to task demands for musical rhythm discrimination and spoken language paradigms are another possible source of individual variance observed in musical rhythm and language abilities. To investigate the nature of the relationship between musical rhythm and expressive grammar skills, we adopted an individual differences approach in N = 132 elementary school-aged children ages 5–7, with typical language development, and investigated prosodic perception and working memory skills as possible mediators. Aligning with the literature, musical rhythm was correlated with expressive grammar performance (r = 0.41, p

Measurement(s) COVID-19 Protocols, Restrictions • Health Behaviors • Personality and Behavioral Change, CTCAE • Emotion • Message Framing • Self-Determination Technology Type(s) Survey • Experiment Design Type Factor Type(s) COVID-19 Protocols, Restrictions • Health Behaviors • Loss-Gain Framing • Cognitive Reappraisal • Self-Determination Messaging Sample Characteristic - Organism Homo Sample Characteristic - Environment Daily Life Sample Characteristic - Location North America • South America • Africa • Australia • Europe • United Kingdom • Asia

Abstract Applications such as disaster management enormously benefit from rapid availability of satellite observations. Traditionally, data analysis is performed on the ground after being transferred—downlinked—to a ground station. Constraints on the downlink capabilities, both in terms of data volume and timing, therefore heavily affect the response delay of any downstream application. In this paper, we introduce RaVÆn, a lightweight, unsupervised approach for change detection in satellite data based on Variational Auto-Encoders (VAEs), with the specific purpose of on-board deployment. RaVÆn pre-processes the sampled data directly on the satellite and flags changed areas to prioritise for downlink, shortening the response time. We verified the efficacy of our system on a dataset—which we release alongside this publication—composed of time series containing a catastrophic event, demonstrating that RaVÆn outperforms pixel-wise baselines. Finally, we tested our approach on resource-limited hardware for assessing computational and memory limitations, simulating deployment on real hardware.

The onset of stress triggers sympathetic arousal (SA), which causes detectable changes to physiological parameters such as heart rate, blood pressure, dilation of the pupils and sweat release. The objective quantification of SA has tremendous potential to prevent and manage psychological disorders. Photoplethysmography (PPG), a non-invasive method to measure skin blood flow changes, has been used to estimate SA indirectly. However, the impact of various wavelengths of the PPG signal has not been investigated for estimating SA. In this study, we explore the feasibility of using various statistical and nonlinear features derived from peak-to-peak (AC) values of PPG signals of different wavelengths (green, blue, infrared and red) to estimate stress-induced changes in SA and compare their performances. The impact of two physical stressors: and Hand Grip are studied on 32 healthy individuals. Linear (Mean, s.d.) and nonlinear (Katz, Petrosian, Higuchi, SampEn, TotalSampEn) features are extracted from the PPG signal’s AC amplitudes to identify the onset, continuation and recovery phases of those stressors. The results show that the nonlinear features are the most promising in detecting stress-induced sympathetic activity. TotalSampEn feature was capable of detecting stress-induced changes in SA for all wavelengths, whereas other features (Petrosian, AvgSampEn) are significant (AUC ≥ 0.8) only for IR and Red wavelengths. The outcomes of this study can be used to make device design decisions as well as develop stress detection algorithms.

Summary: Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.

Abstract The cell cycle is tightly regulated by protein phosphorylation and ubiquitylation events. During mitosis, the multi-subunit cullin-RING E3 ubiquitin ligase APC/c functions as a molecular switch which signals for one cell to divide into two daughter cells, through the ubiquitylation and proteasomal degradation of mitotic cyclins. The contributions of other E3 ligase families during cell cycle progression remain less well understood. Similarly, the roles of ubiquitin chain types beyond homotypic K48 chains in S-phase or branched K11/K48 chains during mitosis, also remain to be fully determined. Our recent findings that HECTD1 ubiquitin ligase activity assembles branched K29/K48 ubiquitin linkages prompted us to evaluate HECTD1 function during the cell cycle. We used transient knockdown and genetic knockout to show that HECTD1 depletion in HEK293T and HeLa cells decreases cell number and we established that this is mediated through loss of ubiquitin ligase activity. Interestingly, we found that HECTD1 depletion increases the proportion of cells with aligned chromosomes (Prometa/Metaphase) and we confirmed this molecularly using phospho-Histone H3 (Ser28) as a marker of mitosis. Time-lapse microscopy of NEBD to anaphase onset established that HECTD1-depleted cells take on average longer to go through mitosis. In line with this data, HECTD1 depletion reduced the activity of the Spindle Assembly Checkpoint, and BUB3, a component of the Mitosis Checkpoint Complex, was identified as novel HECTD1 interactor. BUB3, BUBR1 or MAD2 protein levels remained unchanged in HECTD1-depleted cells. Overall, this study reveals a novel putative role for HECTD1 during mitosis and warrants further work to elucidate the mechanisms involved.

Abstract Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression network analysis (WGCNA). One module (blue) included 19 trans-eQTL targets and was correlated with POU2AF2 expression only. Following unsupervised clustering of single cells, the expression of 19 trans-eQTL targets was greatest and most variable in cluster number 11, which transcriptionally resembled tuft cells. 14 trans-eQTL targets were found to demarcate this cluster, 11 of which were corroborated in a second dataset. Intra-cluster WGCNA and module preservation analysis then identified twelve 11q23.1 trans-eQTL targets to comprise a network that was specific to cluster 11. Finally, linear modelling and differential abundance testing showed 11q23.1 trans-eQTL target expression was predictive of cluster 11 abundance. Our findings suggest 11q23.1 trans-eQTL targets comprise a POU2AF2-related network that is likely tuft cell-specific and reduced expression of these genes correlates with reduced tuft cell abundance in silico.

Measurement(s) Picture naming norms • Picture familiarity ratings Technology Type(s) Online experiment

Abstract In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex and hippocampus occurs. Two fundamental characteristics comprise widespread changes in the relative expression of GABA and glutamate receptors and debilitation of hippocampal synaptic plasticity. Here, we explored whether recovery from adaptive changes in the expression of plasticity-related neurotransmitter receptors and hippocampal synaptic plasticity occurs in the time-period of up to 12 months after onset of sensory loss. We compared receptor expression in CBA/J mice that develop hereditary blindness, with CBA/CaOlaHsd mice that have intact vision and no deficits in other sensory modalities throughout adulthood. GluN1-subunit expression was reduced and the GluN2A:GluN2B ratio was persistently altered in cortex and hippocampus. GABA-receptor expression was decreased and metabotropic glutamate receptor expression was altered. Hippocampal synaptic plasticity was persistently compromised in vivo. But although LTP in blind mice was chronically impaired throughout adulthood, a recovery of the early phase of LTP became apparent when the animals reached 12 months of age. These data show that cortical and hippocampal adaptation to early postnatal blindness progresses into advanced adulthood and is a process that compromises hippocampal function. A partial recovery of hippocampal synaptic plasticity emerges in advanced adulthood, however.

Knowledge of diet and dietary selectivity is vital, especially for the conservation of declining species. Accurately obtaining this information, however, is difficult, especially if the study species feeds on a wide range of food items within heterogeneous and inaccessible environments, such as the tree canopy. Hawfinches (Coccothraustes coccothraustes), like many woodland birds, are declining for reasons that are unclear. We investigated the possible role that dietary selection may have in these declines in the UK. Here, we used a combination of high-throughput sequencing of 261 hawfinch faecal samples assessed against tree occurrence data from quadrats sampled in three hawfinch population strongholds in the UK to test for evidence of selective foraging. This revealed that hawfinches show selective feeding and consume certain tree genera disproportionally to availability. Positive selection was shown for beech (Fagus), cherry (Prunus), hornbeam (Carpinus), maples (Acer) and oak (Quercus), while Hawfinch avoided ash (Fraxinus), birch (Betula), chestnut (Castanea), fir (Abies), hazel (Corylus), rowan (Sorbus) and lime (Tilia). This approach provided detailed information on hawfinch dietary choice and may be used to predict the effects of changing food resources on other declining passerines populations in the future.

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Abstract Bees are important pollinators in wild and agricultural ecosystems, and understanding the factors driving their global declines is key to maintaining these pollination services. Learning, which has been a focus of previous ecotoxicological studies in bees, may play a key role in driving colony fitness. Here we move beyond the standard single-stressor approach to ask how multiple stressors, an agrochemical (sulfoxaflor, a relatively new insecticide) and a parasite (Crithidia bombi, a prevalent gut parasite of bumblebees), impact learning in the bumblebee Bombus terrestris. We developed a modified version of the classic proboscis extension reflex assay to assess the combined effects of acute oral sulfoxaflor exposure and infection by C. bombi on olfactory learning of bumblebee workers. We found no evidence that either sulfoxaflor, C. bombi, or their combination had any significant effect on bumblebee olfactory learning, despite their known negative impacts on other aspects of bumblebee health. This suggests that losses in cognitive ability, as measured here, are unlikely to explain the impacts of sulfoxaflor and its interactions with other stressors on bumblebees. Our novel methodology provides a model system within which to test interactive effects of other key stressors on bee health.

Abstract Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have become a premier neuroscience research tool for enabling reversible manipulations of cellular activity following experimenter-controlled delivery of a DREADD-specific ligand. However, several DREADD ligands, e.g., clozapine-N-oxide (CNO), have metabolic and off-target effects that may confound experimental findings. New DREADD ligands aim to reduce metabolic and potential off-target effects while maintaining strong efficacy for the designer receptors. Recently a novel DREADD ligand, deschloroclozapine (DCZ), was shown to induce chemogenetic-mediated cellular and behavioral effects in mice and monkeys without detectable side effects. The goal of the present study was to examine the effectiveness of systemic DCZ for DREADD-based chemogenetic manipulations in behavioral and slice electrophysiological applications in rats. We demonstrate that a relatively low dose of DCZ (0.1 mg/kg) supports excitatory DREADD-mediated cFos induction, DREADD-mediated inhibition of a central amygdala-dependent behavior, and DREADD-mediated inhibition of neuronal activity in a slice electrophysiology preparation. In addition, we show that this dose of DCZ does not alter gross locomotor activity or induce a place preference/aversion in control rats without DREADD expression. Together, our findings support the use of systemic DCZ for DREADD-based manipulaations in rats, and provide evidence that DCZ is a superior alternative to CNO.

Abstract The nutritional integrity of wheat is jeopardized by rapidly rising atmospheric carbon dioxide (CO2) and the associated emergence and enhanced virulence of plant pathogens. To evaluate how disease resistance traits may impact wheat climate resilience, 15 wheat cultivars with varying levels of resistance to Fusarium Head Blight (FHB) were grown at ambient and elevated CO2. Although all wheat cultivars had increased yield when grown at elevated CO2, the nutritional contents of FHB moderately resistant (MR) cultivars were impacted more than susceptible cultivars. At elevated CO2, the MR cultivars had more significant differences in plant growth, grain protein, starch, fructan, and macro and micro-nutrient content compared with susceptible wheat. Furthermore, changes in protein, starch, phosphorus, and magnesium content were correlated with the cultivar FHB resistance rating, with more FHB resistant cultivars having greater changes in nutrient content. This is the first report of a correlation between the degree of plant pathogen resistance and grain nutritional content loss in response to elevated CO2. Our results demonstrate the importance of identifying wheat cultivars that can maintain nutritional integrity and FHB resistance in future atmospheric CO2 conditions.

Abstract Quantifying the drivers of population size in reef sharks is critical for the development of appropriate conservation strategies. In north-west Australia, shark populations inhabit coral reefs that border growing centres of human population, industry, and tourism. However, we lack baseline data on reef sharks at large spatial scales (hundreds of km) that might enable managers to assess the status of shark populations in the face of future development in this region. Here, we examined the occurrence, abundance and behaviour of apex (Galeocerdo cuvier, Carcharhinus plumbeus) and reef (C. amblyrhynchos, C. melanopterus, Triaenodon obesus) sharks using > 1200 deployments of baited remote underwater stereo-video systems (stereo-BRUVs) across > 500 km of coastline. We found evidence for species-specific influences of habitat and fishing activities on the occurrence (probability of observation), abundance (MaxN) and behaviour of sharks (time of arrival to the stereo-BRUVs and likelihood of feeding). Although the presence of management zoning (No-take areas) made little difference to most species, C. amblyrhynchos were more common further from boat ramps (a proxy of recreational fishing pressure). Time of arrival for all species was also influenced by distance to boat ramp, although patterns varied among species. Our results demonstrate the capacity for behavioural metrics to complement existing measures of occurrence and abundance in assessing the potential impact of human activities on shark populations.