Molecular organization of fibroin heavy chain and mechanism of fibre formation in Bombyx mori.

Fibroins' transition from liquid to solid is fundamental to spinning and underpins the impressive native properties of silk. Herein, we establish a fibroin heavy chain fold for the Silk-I polymorph, which could be relevant for other similar proteins, and explains mechanistically the liquid-to-solid transition of this silk, driven by pH reduction and flow stress. Combining spectroscopy and modelling we propose that the liquid Silk-I fibroin heavy chain (FibH) from the silkworm, Bombyx mori, adopts a newly reported ß-solenoid structure. Similarly, using rheology we propose that FibH N-terminal domain (NTD) templates reversible higher-order oligomerization driven by pH reduction. Our integrated approach bridges the gap in understanding FibH structure and provides insight into the spatial and temporal hierarchical self-assembly across length scales. Our findings elucidate the complex rheological behaviour of Silk-I, solutions and gels, and the observed liquid crystalline textures within the silk gland. We also find that the NTD undergoes hydrolysis during standard regeneration, explaining key differences between native and regenerated silk feedstocks. In general, in this study we emphasize the unique characteristics of native and native-like silks, offering a fresh perspective on our fundamental understanding of silk-fibre production and applications.

The DNA methyltransferase inhibitor 5-aza-4'-thio-2'-deoxycytidine induces C>G transversions and acute lymphoid leukemia development.

DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza TdCyd or ATC) is a recently described thiol substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. Here, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed thousands of acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC.

Transcriptional regulation and therapeutic potential of cyclin-dependent kinase 9 (CDK9) in sarcoma.

Sarcomas include various subtypes comprising two significant groups - soft tissue and bone sarcomas. Although the survival rate for some sarcoma subtypes has improved over time, the current methods of treatment remain efficaciously limited, as recurrent, and metastatic diseases remain a major obstacle. There is a need for better options and therapeutic strategies in treating sarcoma. Cyclin dependent kinase 9 (CDK9) is a transcriptional kinase and has emerged as a promising target for treating various cancers. The aberrant expression and activation of CDK9 have been observed in several sarcoma subtypes, including rhabdomyosarcoma, synovial sarcoma, osteosarcoma, Ewing sarcoma, and chordoma. Enhanced CDK9 expression has also been correlated with poorer prognosis in sarcoma patients. As a master regulator of transcription, CDK9 promotes transcription elongation by phosphorylation and releasing RNA polymerase II (RNAPII) from its promoter proximal pause. Release of RNAPII from this pause induces transcription of critical genes in the tumor cell. Overexpression and activation of CDK9 have been observed to lead to the expression of oncogenes, including MYC and MCL-1, that aid sarcoma development and progression. Inhibition of CDK9 in sarcoma has been proven to reduce these oncogenes' expression and decrease proliferation and growth in different sarcoma cells. Currently, there are several CDK9 inhibitors in preclinical and clinical investigations. This review aims to highlight the recent discovery and results on the transcriptional role and therapeutic potential of CDK9 in sarcoma.

Institutional complexity emerges from socioecological complexity in small-scale human societies.

Human lifestyles vary enormously over time and space and so understanding the origins of this diversity has always been a central focus of anthropology. A major source of this cultural variation is the variation in institutional complexity: the cultural packages of rules, norms, ontologies and expectations passed down through societies across generations. In this article, we study the emergence of institutions in small-scale societies. There are two primary schools of thought. The first is that institutions emerge top-down as rules are imposed by elites on their societies in order to gain asymmetrical access to power, resources and influence over others through coercion. The second is that institutions emerge bottom-up to facilitate interactions within populations as they seek collective solutions to adaptive problems. Here, we use Bayesian networks to infer the causal structure of institutional complexity in 172 small-scale societies across ethnohistoric western North America reflecting the wide diversity of indigenous lifestyles across this vast region immediately prior to European colonization. Our results suggest that institutional complexity emerges from underlying socioecological complexity because institutions are solutions to coordination problems in more complex environments where human-environment interactions require increased management.

"The worst thing is lying in bed thinking 'I want a cigarette'" a qualitative exploration of smoker's and ex-smoker's perceptions of sleep during a quit attempt and the use of cognitive behavioural therapy for insomnia to aid cessation.

Smokers report poorer sleep quality than non-smokers and sleep quality deteriorates further during cessation, increasing risk of smoking relapse. Despite the use of cognitive behavioural therapy for insomnia (CBT-I) to aid quit attempts emerging in the area, little is known about smokers and ex smoker's experiences of sleep during a quit attempt or their perceptions of CBT-I. This study addresses this gap by exploring smoker's and ex-smoker's experiences of the link between smoking and sleep and how this may change as a function of smoking/smoking abstinence. It also explores views of traditional CBT-I components (i.e., perceived feasibility, effectiveness, barriers of use). We conducted semi-structured interviews with current and recently quit smokers (n = 17) between January and September 2022. The framework method was used for analysis. Four themes addressing research questions were described. These included: 1) A viscous cycle; poor sleep quality and negative psychological state during cessation; 2) Perceived engagement and effectiveness; the importance of feasibility, experience, value, identity and psychological state in assessing CBT-I as a cessation tool; 3) Striking a balance; tailoring CBT-I to reduce psychological overload in a time of lifestyle transition; and 4) Personalisation and digital delivery helping overcome psychological barriers during cessation. The analysis suggested during quit attempts smokers experienced a range of sleep problems that could increase risk of relapse due to a negative impact on psychological state. It also revealed participants thought that CBT-I is something they would use during a quit attempt but suggested changes and additions that would improve engagement and be better tailored to quitting smokers. Key additions included the integration of smoking-based cognitive restructuring, starting the intervention prior to a quit attempt, and the need for personalisation and tailoring.

Cerebrospinal fluid galactomannan detection for the diagnosis of central nervous system aspergillosis: a diagnostic test accuracy systematic review and meta-analysis.

BACKGROUND: Cerebrospinal fluid (CSF) galactomannan is an adjunctive test for central nervous system (CNS) aspergillosis diagnosis with unclear diagnostic test characteristics. OBJECTIVES: To evaluate the diagnostic test characteristics of CSF galactomannan in CNS aspergillosis. METHODS: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, Web of Science, and Scopus, from inception to 24 February 2023. STUDY ELIGIBILITY CRITERIA: Prospective and retrospective studies with 1-group and 2-group designs using any galactomannan assay on CSF to diagnose CNS aspergillosis. PARTICIPANTS: Adult and/or paediatric patients with CNS aspergillosis. TEST(S): Galactomannan testing on CSF specimens. REFERENCE STANDARD: European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) diagnostic criteria, or equivalent. ASSESSMENT OF RISK OF BIAS: QUADAS-2 assessment in duplicate. METHODS OF DATA SYNTHESIS: Bivariate restricted maximum likelihood estimation random-effects meta-analysis, summarized using forest and summary receiver operating characteristic plots; bivariate meta-regression models to investigate heterogeneity; and subgroup and sensitivity analyses to explore subgroup effects and methodologic choices (PROSPERO registration: CRD42022296331; funding: none). RESULTS: We included eight studies (n = 342 participants). The summary estimates of CSF galactomannan sensitivity and specificity were 69.0% (95% CI, 57.2-78.7%) and 94.4% (95% CI, 82.8-98.3%), respectively. Using meta-regression, galactomannan cut-off (p = 0.38), EORTC/MSGERC criteria version (p = 0.48), or whether the reference standard was defined as both proven and probable or only proven aspergillosis (p = 0.48) did not explain observed heterogeneity. No subgroup effects were demonstrated by analysing the EORTC/MSGERC criteria reference standard used (e.g. 2002 vs. 2008 definitions) or whether paediatric patients were included. Diagnostic sensitivity was improved using a galactomannan cut-off of 1.0, and by excluding high risk of bias and 1-group design studies. DISCUSSION: CSF galactomannan is a highly specific but insensitive test for use as a component of CNS aspergillosis diagnosis. Few included studies, no prospective studies, and a high risk of bias are study limitations.

The impact of peritoneal dialysis on oxypurinol and urate elimination in people with gout.

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.

Autosomal dominant hypercalciuric hypocalcaemia: the calcium-sensing receptor in renal calcium homeostasis and the impact of renal transplantation.

Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation.

Australian and New Zealand Living Guideline cholesterol-lowering therapy for people with chronic kidney disease (CARI Guidelines): Reducing the evidence-practice gap.

AIM: People with chronic kidney disease experience high rates of cardiovascular disease. Cholesterol-lowering therapy is a mainstay in the management but there is uncertainty in the treatment effects on patient-important outcomes, such as fatigue and rhabdomyolysis. Here, we summarise the updated CARI Australian and New Zealand Living Guidelines on cholesterol-lowering therapy in chronic kidney disease. METHODS: We updated a Cochrane review and monitored newly published studies weekly to inform guideline development according to international standards. The Working Group included expertise from nephrology, cardiology, Indigenous Health, guideline development and people with lived experience of chronic kidney disease. RESULTS: The guideline recommends people with chronic kidney disease (eGFR ≥15 mL/min/1.73 m2) and an absolute cardiovascular risk of 10% or higher should receive statin therapy (with or without ezetimibe) to reduce the risk of cardiovascular events and death (strong recommendation, moderate certainty evidence). The guidelines also recommends a lower absolute cardiovascular risk threshold (≥5%) for Aboriginal and Torres Strait Islander Peoples and Maori with chronic kidney disease to receive statin therapy (with or without ezetimibe) (strong recommendation, low certainty evidence). The evidence was actively surveyed from 2020-2023 and updated as required. No changes to guideline recommendations were made, with no new data on the balance and benefits of harms. CONCLUSIONS: The development of living guidelines was feasible and provided the opportunity to update recommendations to improve clinical decision-making in real-time. Living guidelines provide the opportunity to transform chronic kidney disease guidelines.

Bullet ricochet mark plan-view morphology in concrete: an experimental assessment of five bullet types and two distances using machine learning.

Bullet ricochets are common occurrences during shooting incidents and can provide a wealth of information useful for shooting incident reconstruction. However, there have only been a small number of studies that have systematically investigated bullet ricochet impact site morphology. Here, this study reports on an experiment that examined the plan-view morphology of 297 ricochet impact sites in concrete that were produced by five different bullet types shot from two distances. This study used a random forest machine learning algorithm to classify bullet types with morphological dimensions of the ricochet mark (impact) with length and perimeter-to-area ratio emerging as the top predictor variables. The 0.22 LR leaves the most distinctive impact mark on the concrete, and overall, the classification accuracy using leave-one-out cross-validation is 62%, considerably higher than a random classification accuracy of 20%. Adding in distance to the model as a predictor increases the classification accuracy to 66%. These initial results are promising, in that they suggest that an unknown bullet type can potentially be determined, or at least probabilistically assessed, from the morphology of the ricochet impact site alone. However, the substantial amount of overlap this study documented among distinct bullet types' ricochet mark morphologies under highly controlled conditions and with machine learning suggests that the human identification of ricochet marks in real-world shooting incident reconstructions may be on occasion, or perhaps regularly, in error. Key points: Bullet ricochet impact sites can help with shooting incident reconstruction.A random forest machine learning algorithm classified bullet type from ricochet morphology.Results suggest that unknown bullets can potentially be determined from ricochet impact site morphology.Human identification of bullet types from ricochet sites may be erroneous.

Examining the Feasibility, Acceptability, and Effectiveness of Remote Training on Community-Based Participatory Research: Single-Arm Pre-Post Pilot Study.

BACKGROUND: Over the past decade, a growing body of scientific evidence has demonstrated that community engagement in research leads to more relevant research, enhances the uptake of research findings, and improves clinical outcomes. Despite the increasing need for the integration of community engagement methodologies into the scientific inquiry, doctoral and master's level competencies in the field of psychiatry often lack dedicated training or coursework on community engagement methodologies. OBJECTIVE: A total of 13 service users, peer support specialists, caregivers of people with mental health challenges, and scientists (with specialties ranging from basic science to implementation science) aged 18 and older participated in remote training on community-based participatory research. Data were collected at baseline, 2 days, and 3 months. METHODS: A total of 13 service users, peer support specialists, caregivers of people with mental health challenges, and scientists (with specialties ranging from basic science to implementation science) aged 18 and older participated in remote training on community-based participatory research. Data were collected at baseline, 2 days, and 3 months. RESULTS: The pilot study demonstrated that a 3-month remote training on community-based participatory research ("Partnership Academy") was deemed feasible and acceptable by service users, peer support specialists, caregivers of people with mental health challenges, and scientists. Improvements were found in research engagement and the quality of partnership. A marked increase in distrust in the medical system was also found. Groups submitted 4 grant applications and published 1 peer-reviewed journal at a 3-month follow-up. CONCLUSIONS: This pre- and postpilot study demonstrated it is possible to train groups of service users, peer support specialists, caregivers of people with mental health challenges, and scientists in community-based participatory research. These findings provide preliminary evidence that a 3-month remote training on community-based participatory research ("Partnership Academy") is feasible, acceptable, and potentially associated with improvements in research engagement as well as the quality of partnership and output, such as manuscripts and grant applications.

Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.

BACKGROUND: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 µg SARS-CoV-2 recombinant spike protein and 50 µg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 µg of NVX-CoV2373 plus 2·5 µg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING: Novavax.

Getting around the roundworms: Identifying knowledge gaps and research priorities for the ascarids.

The ascarids are a large group of parasitic nematodes that infect a wide range of animal species. In humans, they cause neglected diseases of poverty; many animal parasites also cause zoonotic infections in people. Control measures include hygiene and anthelmintic treatments, but they are not always appropriate or effective and this creates a continuing need to search for better ways to reduce the human, welfare and economic costs of these infections. To this end, Le Studium Institute of Advanced Studies organized a two-day conference to identify major gaps in our understanding of ascarid parasites with a view to setting research priorities that would allow for improved control. The participants identified several key areas for future focus, comprising of advances in genomic analysis and the use of model organisms, especially Caenorhabditis elegans, a more thorough appreciation of the complexity of host-parasite (and parasite-parasite) communications, a search for novel anthelmintic drugs and the development of effective vaccines. The participants agreed to try and maintain informal links in the future that could form the basis for collaborative projects, and to co-operate to organize future meetings and workshops to promote ascarid research.

Exploring parents' physical activity motivation during the COVID-19 pandemic: a mixed-methods study from a self-determination theory perspective.

Background and objectives: The COVID-19 lockdowns impacted physical activity for all, but especially parents, because they had to balance home, work and leisure activities. Motivation for exercise is consistently shown to be associated with physical activity levels. Self-determination theory provides a framework through which the motivation for exercise and its social-contextual antecedents can be explored. The purpose of this study is to explore the role of motivation in determining physical activity in parents and carers of English primary school children before, during and after the COVID-19 lockdowns. Design, setting and participants: This study uses a mixed-methods design combining quantitative data and individual interviews. Participants were all parents/carers of children in year 6 (aged 10-11 years) at English primary schools in the United Kingdom. Methods: Quantitative data were collected on three occasions: between March 2017 and May 2018 (Wave 0, N = 1296), between May and December 2021 (Wave 1, N = 393) and between January and July 2022 (wave 2, N = 436). Motivation for exercise was assessed using the Behavioural Regulations in Exercise Questionnaire-2 and moderate-to-vigorous physical activity was estimated via waist-worn accelerometers. Data were analysed via regression models. Interviews with a subsample of parents (N = 43) were conducted on two occasions: between September and December 2021 and between February and July 2022. Interviews covered the impact of the pandemic on children and parents' physical activity and changes over time. This study focuses on discussions around the parents' own physical activity behaviour and their motivation. The framework method was used for analysis. Results: In separate linear regression models, intrinsic and identified regulation were associated with higher moderate-to-vigorous physical activity in waves 0 and 2. Amotivation was associated with lower moderate-to-vigorous physical activity in waves 0 and 2. In fully adjusted multivariable regression models, identified regulation was associated with a 4.9-minute increase in moderate-to-vigorous physical activity and introjected regulation was associated with a 2.3-minute decrease in moderate-to-vigorous physical activity at wave 0. Associations with moderate-to-vigorous physical activity were different in wave 2, with introjected regulation changing direction and a negative association with amotivation, although confidence intervals were wide due to smaller sample sizes. In the interviews, parents spoke of the effects that the COVID-19 lockdowns had on their motivation to be physically active in four theoretically driven themes: (1) motivation for physical activity, (2) perceived autonomy for physical activity, (3) perceived competence for physical activity and (4) perceived relatedness for physical activity. Limitations: The smaller sample sizes for waves 1 and 2 may have limited the ability to identify associations between behavioural regulations and moderate-to-vigorous physical activity post pandemic. Across all waves, parents were predominantly active, females, white and from higher socioeconomic areas and therefore may not reflect broader experiences. Conclusions and future work: Autonomous motivation, especially enjoyment and the importance for mental and physical well-being, was a key driver in keeping parents active during lockdowns and remains important for physical activity post lockdown, with introjected regulation potentially playing an increased role. Parents' interviews highlighted that while for some the lockdowns promoted autonomous motivation for exercise, others had enduring negative influences on their autonomy, competence and relatedness, which could be detrimental to their well-being. Strategies that focus on offering a range of novel activities for parents and that bring parent groups together may be effective. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131847.

The COVID-19 pandemic affected parents' ability to be active. Motivation is important for taking part in physical activity. We wanted to know how motivation for exercise had changed since before the pandemic and how it might still impact parents' physical activity. We asked groups of parents of children in year 6 (aged 10­11 years) to complete a questionnaire and wear a device that measures physical activity. One group did this before the pandemic and two groups did this after the lockdowns. We also spoke to parents two times after schools reopened. We asked about their physical activity, what they felt helped or stopped them being active and how this changed during the pandemic. Motivation plays a part in how much physical activity parents do. Enjoying activities, being active because it is part of your identity and being active due to health make parents more active. Some parents felt they were more active in the first lockdown, as they had more time, freedom and a choice of new and exciting activities, while others felt the lockdowns led to them being less active. This was due to a loss of connection with other people and feeling less confident in their physical activity. This means that it is important that parents are well-supported in their physical activity post pandemic efforts to help parents be active should focus on creating opportunities for parents to try new activities opportunities for parents to be active together might lead to more physical activity, improved connections with others and better well-being.

FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway.

Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-ß1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-ß1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-ß1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-ß1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-ß1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.

Physical activity interventions in European primary schools: a scoping review to create a framework for the design of tailored interventions in European countries.

Introduction: Schools provide a unique environment to facilitate physical activity for children. However, many school-based physical activity interventions have not been effective. We propose a new approach, which allows schools to tailor interventions to their specific context. This scoping review aimed to identify intervention components from previous school-based physical activity interventions to form the basis of a tailored approach in a European setting. Methods: Joanna Briggs Institute guidelines for conducting scoping reviews were followed. European school-based intervention studies aimed at increasing physical activity in children aged 7-11 years published in English since 2015 were included. Databases searched were Ovid Medline, Embase, PsycINFO, Web of Science Social Sciences Citation Index, ERIC and British Education Index. Data was extracted on intervention components, context-related factors (geographical location, school size, child socioeconomic status and ethnicity), feasibility, acceptability and cost-effectiveness. A data-driven framework was developed to summarize the identified intervention components. Results: 79 articles were included, constituting 45 intervention studies. We identified 177 intervention components, which were synthesized into a framework of 60 intervention component types across 11 activity opportunities: six within the school day, three within the extended school day and two within the wider school environment. Interventions most frequently targeted physical education (21%), active and outdoor learning (16%), active breaks (15%), and school-level environmewnt (12%). Of the intervention components, 41% were delivered by school staff, 31% by the research team, and 24% by external organizations. Only 19% of intervention studies reported geographical location and only 10% reported school size. Participant ethnicity and socioeconomic information was reported by 15% and 25%, respectively. Intervention acceptability was reported in 51% of studies, feasibility in 49%, and cost effectiveness in 2%. Discussion: This review offers a first step in developing a future framework to help schools to develop context-specific, tailored interventions. However, there was a lack of reporting of contextual factors within the included studies, making it difficult to understand the role of context. Future research should seek to measure and report contextual factors, and to better understand the important aspects of context within school-based physical activity.

The impact of the COVID-19 pandemic on the physical activity environment in English primary schools: a multi-perspective qualitative analysis.

Background: The COVID-19 lockdowns and social distancing measures, including school closures, had a major impact on children's physical activity in England, with data showing an initial reduction in activity in the short-term post-lockdown phase of the pandemic followed by a recovery on average in the medium-term post-lockdown period. The school environment is an important context for child physical activity. The purpose of this study is to understand the changes that took place to school physical activity environments once schools reopened after lockdowns. This information will improve understanding of why changes to children's physical activity have occurred over the course of the pandemic and the implications for future promotion of physical activity in schools. Methods: Interviews with parents (n = 43), school staff (n = 18) and focus groups with 10- to 11-year-old children (participant n = 92) were conducted at two time points: between September-December 2021 and February-July 2022. Interview and focus group guides covered the impact of the pandemic on child physical activity and changes to this over time. The framework method was used for analysis. Results: Three themes and three subthemes were generated: (1) the return to school; (2) over-pressured staff and environment and (3) the uneven impact of the pandemic. Theme 3 consists of three subthemes: (a) retained pandemic policies, (b) impact on physical activity culture and (c) different children need different things. Limitations and future work: Conducting this research in schools during ongoing COVID-19 disruptions was a challenge and may have limited school and participant participation, particularly school staff. The parent interview sample is predominantly female, active and of higher socioeconomic status, so the experiences of male, less active and lower socioeconomic parents are limited. This study suggests that the impact of COVID-19 on child physical activity is uneven, affecting some children more than others. Future work is therefore needed to explore the details of this potential diverging experience. Conclusion: The COVID-19 pandemic, school closures and post-lockdown school policies have impacted upon primary school physical activity environments. The post-lockdown school environment is highly pressured, impacting the extent to which schools can support and encourage child physical activity. Future research is needed to further explore the impact of post-lockdown changes on physical activity environments in schools, particularly over the longer term, as schools continue to adapt post lockdowns. Strategies required to support school physical activity environments must be context specific and sensitive to these changes, pressures and needs. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131847.

Schools are important spaces for children's physical activity. Children can be active in physical education lessons, break times, after-school clubs and travelling to school. School closures and other COVID-19 restrictions affected children's physical activity. We wanted to know how physical activity in primary schools might have changed since the pandemic. We spoke to school staff, pupils and parents two times after schools reopened. We asked about children's physical activity, and if or how this had changed over the course of the pandemic. We asked school staff about school policies around physical activity. When children went back to school, schools needed a 'recovery' approach. Children's academic, social and physical skills had been affected. For this time schools prioritised physical activity, but this was short-lived. Since then, schools have been highly pressured. They have had to 'catch up' on missed learning, staff are overloaded and some pupils are still affected by the lockdowns. Physical activity policies in schools have changed, but in many different ways. Some have kept social distancing policies; others feel their school culture has changed. Additionally, pupil ability and needs are more polarised. These factors have shaped, but are also shaped by, the high pressure in schools. Supporting changing child needs in highly pressured schools is hard for state primary schools. Changes to school physical activity policies need to be understood and evaluated. Strategies to ease pressure in schools are needed to support physical activity.

Modeling the social drivers of environmental sustainability among Amazonian indigenous lands using Bayesian networks.

Amazonia is an invaluable global asset for all its ecological and cultural significance. Indigenous peoples and their lands are pivotal in safeguarding this unique biodiversity and mitigating global climate change. Understanding the causal structure behind variation in the degree of environmental conservation across different indigenous lands-each with varying institutional, legal, and socioenvironmental conditions-is an essential source of information in the struggle for long-term sustainable management of Amazonian ecosystems. Here, we use data from the Instituto Socioambiental for 361 indigenous lands in the Brazilian Amazon coded for environmental integrity, territorial integrity, legal stability, indigenous governance, and threats due to infrastructure projects. Using Bayesian networks to learn the causal structure amongst these variables reveals two causal pathways leading to environmental integrity. One causal pathway starts with territorial integrity and is mediated by infrastructure projects, while the other is directly from legal stability. Hence, safeguarding indigenous lands from exploitation is best accomplished via legal land rights and stricter enforcement instead of placing the onus on indigenous governance, which is also a direct outcome of legal stability.

Nutrition and Isolation in a Rural US Population over 80 Years Old: A Descriptive Analysis of a Vulnerable Population.

Factors allowing rural, community-dwelling 80+ year-olds to thrive remain unexplored. Isolation can impact this vulnerable population. In this study, patients were prospectively surveyed for age, gender, cohabitation (self, spouse, family) and location (suburban, rural, and isolated). Mini-nutritional assessment short form (MNA-SF) and BMI were obtained. A p < 0.05 represented statistical significance. Patients (n = 167) were mostly female (120; 71.9%) with an average overweight BMI (26.5) and low-normal MNA-SF scores (11.8). Most live alone (49.7%), followed by spousal (31.7%) and family (18.6%) cohabitation. Over 80% are rural (71) or rural-isolated (67), and of these, 83% had normal nutrition. Self-habitation correlated with lower MNA-SF scores (p = 0.02). Normal BMIs correlated with family cohabitation (OR = 0.90 [CI: 0.82-0.99]) and nourished MNA-SF scores with spousal cohabitation (OR = 1.69; CI: 1.15-2.47) rather than living alone. Self-habitation increases vulnerability to obesity and malnutrition. Interventions should aim to maintain independence while improving the effects of habitation on nutrition.