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Abstract Galilean and Carrollian algebras acting on two-dimensional Newton-Cartan and Carrollian manifolds are isomorphic. A consequence of this property is a duality correspondence between one-dimensional Galilean and Carrollian fluids. We describe the dynamics of these systems as they emerge from the relevant limits of Lorentzian hydrodynamics, and explore the advertised duality relationship. This interchanges longitudinal and transverse directions with respect to the flow velocity, and permutes equilibrium and out-of-equilibrium observables, unveiling specific features of Carrollian physics. We investigate the action of local hydrodynamic-frame transformations in the Galilean and Carrollian configurations, i.e. dual Galilean and Carrollian local boosts, and comment on their potential breaking. Emphasis is laid on the additional geometric elements that are necessary to attain complete systems of hydrodynamic equations in Newton-Cartan and Carroll spacetimes. Our analysis is conducted in general Cartan frames as well as in more explicit coordinates, specifically suited to Galilean or Carrollian use.

Abstract Genome-wide association studies of primary sclerosing cholangitis have identified 23 susceptibility loci. The majority of these loci reside in non-coding regions of the genome and are thought to exert their effect by perturbing the regulation of nearby genes. Here, we aim to identify these genes to improve the biological understanding of primary sclerosing cholangitis, and nominate potential drug targets. We first build an eQTL map for six primary sclerosing cholangitis-relevant T-cell subsets obtained from the peripheral blood of primary sclerosing cholangitis and ulcerative colitis patients. These maps identify 10,459 unique eGenes, 87% of which are shared across all six primary sclerosing cholangitis T-cell types. We then search for colocalisations between primary sclerosing cholangitis loci and eQTLs and undertake Bayesian fine-mapping to identify disease-causing variants. In this work, colocalisation analyses nominate likely primary sclerosing cholangitis effector genes and biological mechanisms at five non-coding (UBASH3A, PRKD2, ETS2 and AP003774.1/CCDC88B) and one coding (SH2B3) primary sclerosing cholangitis loci. Through fine-mapping we identify likely causal variants for a third of all primary sclerosing cholangitis-associated loci, including two to single variant resolution.

Abstract The uptake and elimination of beta-lactam antibiotics in the human body are facilitated by the proton-coupled peptide transporters PepT1 (SLC15A1) and PepT2 (SLC15A2). The mechanism by which SLC15 family transporters recognize and discriminate between different drug classes and dietary peptides remains unclear, hampering efforts to improve antibiotic pharmacokinetics through targeted drug design and delivery. Here, we present cryo-EM structures of the proton-coupled peptide transporter, PepT2 from Rattus norvegicus, in complex with the widely used beta-lactam antibiotics cefadroxil, amoxicillin and cloxacillin. Our structures, combined with pharmacophore mapping, molecular dynamics simulations and biochemical assays, establish the mechanism of beta-lactam antibiotic recognition and the important role of protonation in drug binding and transport.

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Abstract Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone. Therefore, we adopted a combined in vivo-in silico approach and developed an ordinary differential equation model of acute liver disease able to predict the host response to injury and potential interventions. The Mdm2fl/fl mouse model of senescence-driven liver injury was used to generate a quantitative dynamic characterisation of the key cellular players (macrophages, endothelial cells, myofibroblasts) and extra cellular matrix involved in liver injury. This was qualitatively captured by the mathematical model. The mathematical model was then used to predict injury outcomes in response to milder and more severe levels of senescence-induced liver injury and validated with experimental in vivo data. In silico experiments using the validated model were then performed to interrogate potential approaches to enhance regeneration. These predicted that increasing the rate of macrophage phenotypic switch or increasing the number of pro-regenerative macrophages in the system will accelerate the rate of senescent cell clearance and resolution. These results showcase the potential benefits of mechanistic mathematical modelling for capturing the dynamics of complex biological systems and identifying therapeutic interventions that may enhance our understanding of injury-repair mechanisms and reduce translational bottlenecks.

Abstract Background Telemedicine allows delivery of healthcare to occur between parties that are not in the same location. As telemedicine users are not co-present, effective communication methods are crucial to the delivery and reception of information. The aim of this study was to explore perspectives of general practitioners (GPs) and patients on the interactional components of telemedicine consultations. Methods Semi-structured qualitative interviews were held with telemedicine users; 15 GPs and nine patients self-selected from a larger telemedicine study. Participants were asked about their preparation for telemedicine consultations, conducting telemedicine consultations and post-consultation activities. Deidentified transcripts from the interviews were analysed thematically. Results GPs and patients discussed factors they used to decide whether a consultation would be best conducted by telemedicine or in-person; the condition to be discussed, the existing doctor-patient relationship and whether physical examination was required. Participants also described how they prepared for their telemedicine consultations, gathering relevant documents, and reading previous notes. Participants described strategies they employed to optimise the telemedicine interaction; improving conversational flow and building rapport, as well as difficulties they experienced when trying to provide and receive care via telemedicine. Conclusions Patient factors including health literacy and familiarity with technology affect the transfer of information shared during telemedicine consultations and consideration of these factors when choosing patients for telemedicine is required. Many GPs and patients have innate communication skills to effectively deliver and receive care through telemedicine. However, they may not be aware of these subconscious techniques to use to optimise telemedicine consultations. Communication training could be delivered to increase conversational flow, build rapport, and establish safety netting.

University athletes have a limited time (usually four years) of eligibility to perform for their institutions. The dynamic nature of university athletics in the United States results in a continuous influx of newcomers to the various teams. Furthermore, athletes with diverse cultural backgrounds have to adapt to the team culture to be able to perform at their highest level. Considering that, the integration of new athletes is a process that happens on a large scale at the beginning of every season and can have an impact on their performance throughout the season and beyond. Delineating the tactics coaches employ to facilitate this process warrants considerable attention. In this study, the authors focused on the onboarding process of newcomer university athletes who have a significant difference between their culture and the team culture. The authors paid special attention to the university athlete's perception of the ability of their coach to structure the onboarding process. For this reason, the purpose of this study is to develop a valid and reliable instrument to measure athlete perceptions of tactics used by their coach during the onboarding process of newcomers into university athletics, based on Churchill (1979) and DeVellis’ (2016) scale development procedures.

ABSTRACTWork plays a central role in many men’s lives and can be a major contributor to mental health. The current study aim was to examine the prevalence and nature of Canadian men’s mental health challenges at work, including diverse indicators of mental health and workplace characteristics. Participants (N = 451) were men (M = 49.97 years; SD = 14.99) employed in British Columbia, Canada, who were recruited via a market research online panel. Questionnaires were used to collect men’s mental health data (e.g. depression, loneliness), work-related health (e.g. burnout, bullying), and workplace performance (e.g. presentism, absenteeism). Findings revealed high rates of hazardous drinking (36%), depression (22%), suicidal/self-injury ideation (18%), and anxiety (14%). Many participants reported that they frequently experienced occupational burnout, and 18% reported that personal problems significantly impaired their work. Of concern, approximately 53% indicated that they keep feelings to themselves and 45% reported that they would prefer not to talk about their problems. Important factors related to mental health symptoms were identified (e.g. age, distress concealment, male-dominated workplace). These findings highlight the need for policy makers and employers to take immediate action to address men’s mental health challenges by developing initiatives that promote men’s mental health in the workplace.

Abstract It has been shown that noise emissions from HV overhead line conductors can be reduced under rain conditions by making their surfaces superhydrophobic. The working environment makes ensuring the longevity of any treatment a major challenge. The degradation of various superhydrophobic surfaces generated by applying a superhydrophobic coating and patterning microscale channels is assessed under an AC electric field (18 kV/cm) with continuous water spray. By examining the droplet distribution on the surfaces during the degradation and the surface roughness before and after degradation, the authors demonstrate that no water droplets were found on the microscale patterned surface, but droplets were formed on the coated surface after degradation. The surface roughness reduction of the coated surface and microscale patterned surface was 29.8% and 11.3%, respectively, indicating that the microscale patterned surface has better durability than the superhydrophobic coating under the AC electric stress.

Abstract Background Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Results Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10 −/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10 −/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10 −/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10 −/− mice than the distinct microbiota reassembled in non-inflamed WT hosts. Conclusions Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract

Abstract Background Understanding connections between biodiversity and ecosystem services can be enhanced by shifting focus from species richness to functional trait-based approaches, that when paired with comparative phylogenetic methods can provide even deeper insights. We investigated the functional ecology and phylogenetic diversity of pollination services provided by hymenopteran insects visiting apple flowers in orchards surrounded by either ‘natural’ or ‘disturbed’ landscapes in New South Wales, Australia. We assessed whether morphological and behavioural traits (hairiness, body size, glossa length, pollen load purity, and probability of loose pollen) exhibited non-random phylogenetic patterns. Then, explored whether bees, the primary pollinators in this system, filled unique or overlapping functional entities (FEs). For each landscape, we calculated phylogenetic diversity and used FEs to assess functional richness, evenness, and diversion. Results A phylogenomic matrix based on ultraconserved elements (UCEs; 1,382,620 bp from 1,969 loci) was used to infer a fully-resolved and well-supported maximum likelihood phylogeny for 48 hymenopteran morphospecies. There was no significant difference in species richness between landscape categories. Pollinator communities at natural sites had higher phylogenetic complexity (X = 2.37) and functional divergence (x̄ = 0.74 ± 0.02 s.e.) than disturbed sites (X = 1.65 and x̄ = 0.6 ± 0.01 s.e.). Hairiness showed significant phylogenetic clustering (K = 0.94), whereas body size, glossa length, and loose pollen showed weaker non-random phylogenetic patterns (K between 0.3–0.5). Pollen load purity showed no association with phylogeny. The assemblage of 17 bee morphospecies comprised nine FEs: eight FEs consisted of native bees with three containing 65% of all native bee taxa. The introduced honey bee (Apis mellifera) occupied a unique FE, likely due to its different evolutionary history. Both landscape types supported six FEs each with three overlapping: two native bee FEs and the honey bee FE. Conclusions Bee hairiness was the only functional trait to exhibit demonstrable phylogenetic signal. Despite differences in species richness, and functional and phylogenetic diversity between orchard landscape types, both maintained equal bee FE numbers. While no native bee taxon was analogous to the honey bee FE, four native bee FEs shared the same hairiness level as honey bees. Health threats to honey bee populations in Australia will likely disrupt pollination services to apple, and other pollination-dependent food crops, given the low level of functional redundancy within the investigated pollinator assemblages.

Background: Preeclampsia has remained an important public health problem in the developing world where it is associated with a five-fold increase in perinatal morbidity and mortality. Objective: We set out to compare neonatal outcomes between women with preeclampsia and those with normal pregnancy. We also sought to evaluate factors associated with poor outcome in the neonates. Materials and Methods: This was a prospective cohort study that enrolled 90 women (45 with preeclampsia and 45 with normal pregnancy) after 20 weeks gestation. Maternal socio-demographic and clinical information was obtained at enrolment and delivery using questionnaire. Neonatal anthropometric and physiologic data was obtained at delivery and used for classifying the birth weight according to the WHO classification. APGAR score was used to evaluate the presence of birth asphyxia. We defined poor outcome as the presence of at least one of low birth weight, prematurity, birth asphyxia and need for admission. SPSS version 25 was used in all analysis. Significance testing was set at p=0.05. Results: The women with preeclampsia were significantly heavier at booking (BMI 29.0±6.9 Kg/ m2 vs 25.0±5.2. p=0.005), have higher mean booking systolic blood pressure (122.±22.6 mmHg vs 111.5±12.7mmHg, p=0.003) and diastolic blood pressure (79. 8 ± 1 4 . 3 mm Hgv s 68.8±9.0mmHg, p = 0.001). Neonates of women with preeclampsia were significantly more premature (m e a n g e s t a t i o n a l a g e = 3 6 . 8 ± 3 . 2 w e e k s v s 38.7±2.0weeks, p=0.001) and lighter (mean birth weight =2,529±817.5g vs 3,079.2±527.4g, p. 0.001 Overall, 22 (49.4%) of the neonates of women with preeclampsia had significantly poor outcome compared with 12(27.4%) of the neonates of women with normal pregnancy (p=0.01). Univariate logistic analysis showed only being a male neonate, maternal preeclampsia and admission in index pregnancy were significantly associated with poor outcome. Multivariable logistic regression showed only being a male neonate to be 3 times more likely to have a poor outcome (Wald=5.34. OR=3.2, p=0.02) Conclusions: Intrauterine exposure to preeclampsia is associated with poor neonatal outcomes especially in males

Abstract Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

Statement of the problem. The article discusses the manifestations and consequences of such conflicts, in particular their impact on the Pechenihy Reservoir. The study of the problem of water clashes and its exhaustive justification is an important step in the development of effective strategies for managing water resources and preventing the negative consequences of conflicts. Despite the generally defined interpretation of water conflicts, the term should be considered more thoroughly as a phenomenon, based on its duality, because such conflicts can be provoked by different reasons, and therefore their course and consequences may differ. The study of the problem of water clashes and its exhaustive justification is an important step in the development of effective strategies for managing water resources and preventing the negative consequences of conflicts. The study of the problems of water conflicts with the example of the Pechenihy reservoir is due to the novelty of the problem faced by this reservoir. For the first time, the Pechenihy reservoir witnessed large-scale hostilities and, accordingly, for the first time in the history of its existence, faced the devastating consequences of the war. A comprehensive characterization of the reservoir as a center of local water skirmish is necessary, especially in the context of determining the manifestations and classifications of water conflicts. The aim of the work is to set out the causes, classifications and consequences of water conflicts that arise in the context of the use of water resources based on the example of the Pechenihy reservoir. The article aims at a comprehensive analysis of the impact of these conflicts on the geo-ecological and social spheres. Methods. In addition to general scientific methods of analysis, synthesis and generalization, geographical methods of research were used. A special place was occupied by the methods of space hydrology (deciphering aerospace images of the reservoir). The applied method of system analysis helped to identify and clearly classify the situation around the studied reservoir as a local water conflict with the identification of the problem and the way of its course. Results. The study substantiates the phenomenon of water conflicts, highlighting their dual nature as both geo-ecological and social issues, exacerbated by military operations. The hydrological and technical characteristics of the Pechenihy reservoir were examined, revealing significant geo- and hydroecological problems due to nearby combat activities. The study provides a first-time analysis of local water conflict events from the onset of the Russian invasion to the Kharkiv counteroffensive, classifying the conflict around the Pechenihy reservoir as armed, with water serving as both a victim and weapon. The novelty of this article is manifested in an in-depth study of the specifics of hydroecological conflicts in the conditions of long-term hostilities around the Pechenihy reservoir, followed by a comprehensive analysis of the geoecological and social aspects of this problem.

Abstract Background The unprecedented increase in telehealth use due to COVID-19 has changed general practitioners’ (GP) and patients’ engagement in healthcare. There is limited specific advice for effective communication when using telehealth. Examining telehealth use in practice in conjunction with perspectives on telehealth as they relate to communication allows opportunities to produce evidence-based guidance for optimal use of telehealth, while also offering practitioners the opportunity to reflect on elements of their communicative practice common to both styles of consultation. The objective of this research was to develop evidence-based resources to support effective, person-centred communication when GPs and patients use telehealth. This included examination of interactional practices of recorded telehealth consultations, exploration of GP and patient perspectives relating to telehealth, and identifying priorities for guidance informed by these analyses as well as participant co-design. Methods This study involved recording telehealth consultations (n = 42), conducting patient surveys (n = 153), and interviewing patients (n = 9) and GPs (n = 15). These were examined using interaction analytic methods, quantitative analysis, and thematic analyses, to create a robust, integrated picture of telehealth practice and perspectives. The process of research translation involved a co-design approach, engaging with providers, patients, and policy makers to facilitate development of evidence-based principles that focus on supporting effective communication when using telehealth. Results Three key themes relating to communication in telehealth were identified across the different analyses. These were relationship building, conversational flow, and safety netting. The draft best practice principles drawn from these themes were modified based on co-design feedback into five Best Practice Principles for Communication between GPs and Patients using Telehealth. Conclusions Effective communication is supported through relationship building and attention to conversational flow in telehealth consultations, which in turn allows for safety netting to occur. In telehealth, GPs and patients recognise that not being co-present changes the consultation and use both intuitive and strategic interactional adjustments to support their exchange. The mixed-method examination of experiences through both a detailed analysis of telehealth consultations in practice and comparative exploration of GP and patient perspectives enabled the identification of principles that can support effective communication when using telehealth. Co-design helped ensure these principles are ready for implementation into practice.

Abstract Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer’s Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

IntroductionSegmentation of lung structures in medical imaging is crucial for the application of automated post-processing steps on lung diseases like cystic fibrosis (CF). Recently, machine learning methods, particularly neural networks, have demonstrated remarkable improvements, often outperforming conventional segmentation methods. Nonetheless, challenges still remain when attempting to segment various imaging modalities and diseases, especially when the visual characteristics of pathologic findings significantly deviate from healthy tissue.MethodsOur study focuses on imaging of pediatric CF patients [mean age, standard deviation (7.50 ± 4.6)], utilizing deep learning-based methods for automated lung segmentation from chest magnetic resonance imaging (MRI). A total of 165 standardized annual surveillance MRI scans from 84 patients with CF were segmented using the nnU-Net framework. Patient cases represented a range of disease severities and ages. The nnU-Net was trained and evaluated on three MRI sequences (BLADE, VIBE, and HASTE), which are highly relevant for the evaluation of CF induced lung changes. We utilized 40 cases for training per sequence, and tested with 15 cases per sequence, using the Sørensen-Dice-Score, Pearson’s correlation coefficient (r), a segmentation questionnaire, and slice-based analysis.ResultsThe results demonstrated a high level of segmentation performance across all sequences, with only minor differences observed in the mean Dice coefficient: BLADE (0.96 ± 0.05), VIBE (0.96 ± 0.04), and HASTE (0.95 ± 0.05). Additionally, the segmentation quality was consistent across different disease severities, patient ages, and sizes. Manual evaluation identified specific challenges, such as incomplete segmentations near the diaphragm and dorsal regions. Validation on a separate, external dataset of nine toddlers (2–24 months) demonstrated generalizability of the trained model achieving a Dice coefficient of 0.85 ± 0.03.Discussion and conclusionOverall, our study demonstrates the feasibility and effectiveness of using nnU-Net for automated segmentation of lung halves in pediatric CF patients, showing promising directions for advanced image analysis techniques to assist in clinical decision-making and monitoring of CF lung disease progression. Despite these achievements, further improvements are needed to address specific segmentation challenges and enhance generalizability.

Background & Aims: Senescence has been reported to have differential functions in cholangiocytes and hepatic stellate cells (HSCs) during human and murine cholestatic disease, being detrimental in biliary cells and anti-fibrotic in HSCs. Cholestatic liver disease is associated with loss of intestinal barrier function and changes in the microbiome, the mechanistic cause of which is undetermined. Methods: Intestinal samples were analysed from controls and patients with primary sclerosing cholangitis, as well as wild-type (WT) and p16-3MR transgenic mice. Cholestatic liver disease was induced by bile duct ligation (BDL) and DDC diet feeding. Fexaramine was used as an intestinal-restricted FXR agonist and antibiotics were given to eliminate the intestinal microbiome. Senescent cells were eliminated in p16-3MR mice with ganciclovir and in WT mice with the senolytic drug ABT-263. In vitro studies were done in intestinal CaCo-2 cells and organoids were generated from intestinal crypts isolated from mice. Results: Herein, we show increased senescence in intestinal epithelial cells (IECs) in patients with primary sclerosing cholangitis and in mice after BDL and DDC diet feeding. Intestinal senescence was increased in response to reduced exposure to bile acids and increased presence of lipopolysaccharide in vitro and in vivo during cholestatic liver disease. Senescence of IECs was associated with lower proliferation but increased intestinal stem cell activation, as supported by increased organoid growth from intestinal stem cells. Elimination of senescent cells with genetic and pharmacological approaches exacerbated liver injury and fibrosis during cholestatic liver disease, which was associated with increased IEC apoptosis and permeability. Conclusions: Senescence occurs in IECs during cholestatic disease and the elimination of senescent cells has a detrimental impact on the gut-liver axis. Our results point to cell-specific rather than systemic targeting of senescence as a therapeutic approach to treat cholestatic liver disease. Impact and implications:: Cholestatic liver disease associates with the dysregulation of intestinal barrier function, while the mechanisms mediating the disruption of the gut-liver axis remain largely undefined. Here, we demonstrate that senescence, a cellular response to stress, is activated in intestinal cells during cholestatic liver disease in humans and mice. Mechanistically, we demonstrate that the reduction of bile acids and the increased presence of bacterial products mediate the activation of intestinal senescence during cholestatic liver disease. Importantly, the elimination of these senescent cells promotes further damage to the intestine that aggravates liver disease, with increased tissue damage and fibrosis. Our results provide evidence that therapeutic strategies to treat cholestatic liver disease by eliminating senescent cells may have unwanted effects in the intestine and support the need to develop cell/organ-specific approaches.

The objectives of this study were to estimate genetic parameters for citric acid content (CA) and lactic acid content (LA) in sheep milk and to identify the associated candidate genes in a New Zealand dairy sheep flock. Records from 165 ewes were used. Heritability estimates based on pedigree records for CA and LA were 0.65 and 0.33, respectively. The genetic and phenotypic correlations between CA and LA were strong-moderate and negative. Estimates of genomic heritability for CA and LA were also high (0.85, 0.51) and the genomic correlation between CA and LA was strongly negative (-0.96 ± 0.11). No significant associations were found at the Bonferroni level. However, one intragenic SNP in C1QTNF1 (chromosome 11) was associated with CA, at the chromosomal significance threshold. Another SNP associated with CA was intergenic (chromosome 15). For LA, the most notable SNP was intragenic in CYTH1 (chromosome 11), the other two SNPs were intragenic in MGAT5B and TIMP2 (chromosome 11), and four SNPs were intergenic (chromosomes 1 and 24). The functions of candidate genes indicate that CA and LA could potentially be used as biomarkers for energy balance and clinical mastitis. Further research is recommended to validate the present results.

Lumpy skin disease (LSD) is an infectious disease currently spreading worldwide and poses a serious global threat. However, there is limited evidence and understanding to support the use of models to inform decision-making in LSD outbreak responses. This review aimed to identify modelling approaches that can be used before and during an outbreak of LSD, examining their characteristics and priorities, and proposing a structured workflow. We conducted a systematic review and identified 60 relevant publications on LSD outbreak modelling. The review identified six categories of question to be addressed following outbreak detection (origin, entry pathway, outbreak severity, risk factors, spread, and effectiveness of control measures), and five analytical techniques used to address them (descriptive epidemiology, risk factor analysis, spatiotemporal analysis, dynamic transmission modelling, and simulation modelling). We evaluated the questions each analytical technique can address, along with their data requirements and limitations, and accordingly assigned priorities to the modelling. Based on this, we propose a structured workflow for modelling during an LSD outbreak. Additionally, we emphasise the importance of pre-outbreak preparation and continuous updating of modelling post-outbreak for effective decision-making. This study also discusses the inherent limitations and uncertainties in the identified modelling approaches. To support this workflow, high-quality data must be collected in standardised formats, and efforts should be made to reduce inherent uncertainties of the models. The suggested modelling workflow can be used as a process to support rapid response for countries facing their first LSD occurrence and can be adapted to other transboundary diseases.

BackgroundDespite clinical suspicion, most non-invasive ischemia tests for coronary artery disease (CAD) reveal unremarkable results. Patients with a coronary artery calcium score (CACS) of zero rarely have an abnormal positron emission tomography (PET) and could be deferred from further testing. However, most patients have some extent of coronary calcification.ObjectivesCACS percentiles could be useful to exclude abnormal perfusion in patients with CACS >0, but data from patients with 82Rb PET are lacking. The aim of this study was to assess the diagnostic utility of CACS percentiles in comparison to zero calcium and absolute CACS classes.MethodsConsecutive patients with suspected CAD (n = 1,792) referred for 82Rb PET were included and analyzed for abnormal PET (SSS ≥4) and relevant ischemia (>10% myocardium). Test characteristics were calculated.ResultsThe mean age was 65 ± 11 years, 43% were female, and typical angina was reported in 21%. Abnormal PET/relevant ischemia (>10%) were observed in 19.8%/9.3%. Overall, the sensitivity/negative predictive value (NPV) of a 90.9% in all age groups.ConclusionIn patients >50 years, the 10%). They could be used to extend the scope of application of CACS 0 by 8%–10% to 32%–34% overall of patients who could be deferred from further testing.

IntroductionResolution of a child’s diagnosis, the process of accepting and adjusting to the reality of a child’s significant diagnosis, has been often associated with decreased parental stress. Hope, a potential buffer against psychological distress, has been suggested as a potential explanation for this relationship. However, the mediating role of hope in the relationship between resolution of diagnosis and parental stress has not been explored.MethodsThis study aimed to examine whether four types of hope (child, parental, societal, denial of diagnosis) mediated the relationship between resolution to an autism diagnosis and reduced parental stress. Participants included 73 parents (Mage = 43.22, SD = 7.69, female 97.3%) of autistic children (Mage = 11.15, SD = 4.56, male = 67.1%).ResultsResolution to diagnosis was negatively and significantly correlated with resolution to diagnosis, as well as child, parental and societal hope. These three hopes were also significantly and negatively correlated with parental stress. Importantly, when controlling for level of support and autism awareness, parental hope mediated the relationship between resolution to diagnosis and parental stress. Denial of diagnosis was not correlated with resolution or parental stress but did have significant but weak associate with the other hopes.DiscussionThese findings suggest that hope based on parent’s abilities to support their child and be supported themselves play an important role in parental stress once parents are more resolved to their child’s diagnosis. Supporting parents to manage factors associated with supporting their child’s needs, may benefit parents of autistic children.

BackgroundThe part played by oxytocin and oxytocin neurons in the regulation of food intake is controversial. There is much pharmacological data to support a role for oxytocin notably in regulating sugar consumption, however, several recent experiments have questioned the importance of oxytocin neurons themselves.MethodsHere we use a combination of histological and chemogenetic techniques to investigate the selective activation or inhibition of oxytocin neurons in the hypothalamic paraventricular nucleus (OxtPVH). We then identify a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis using the cell-selective expression of channel rhodopsin.ResultsOxtPVH neurons increase their expression of cFos after both physiological (fast-induced re-feeding or oral lipid) and pharmacological (systemic administration of cholecystokinin or lithium chloride) anorectic signals. Chemogenetic activation of OxtPVH neurons is sufficient to decrease free-feeding in OxtCre:hM3Dq mice, while inhibition in OxtCre:hM4Di mice attenuates the response to administration of cholecystokinin. Activation of OxtPVH neurons also increases energy expenditure and core-body temperature, without a significant effect on locomotor activity. Finally, the selective, optogenetic stimulation of a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis reduces the consumption of sucrose.ConclusionOur results support a role for oxytocin neurons in the regulation of whole-body metabolism, including a modulatory action on food intake and energy expenditure. Furthermore, we demonstrate that the pathway from OxtPVH neurons to the bed nucleus of the stria terminalis can regulate sugar consumption.

Abstract Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). We identify several positive local genetic correlations (negative for T2D – IBD) contributing to T2D’s relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D – IBD), thyroid, interferon, and notch signalling (T2D – IBS), abnormal circulating calcium (T2D – PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D – GI pairs, and identify targets for further investigation.

Abstract Zirconolite ceramics present a chemically durable host matrix for waste actinides, but zirconolite dissolution rates reported in the literature often vary significantly. Here, the release of Ca and Al from a hot isostatically pressed zirconolite (Ca0.8Zr0.9Ce0.3Ti1.6Al0.4O7.0) was shown to be predominantly driven by preferential dissolution of minor perovskite and alumina phases. Both phases were undetectable by XRD, and the perovskite was difficult to detect by SEM-EDS. Whilst the zirconolite phase exhibited no signs of alteration, dissolution of the perovskite proceeded congruently without forming a hydrated altered layer or diffusion of protons into the solid that would be indicative of an ion-exchange mechanism. The weak temperature dependence of dissolution (40, 90 and 150 °C) showed that kinetics were limited by transport and a mixed transport-surface controlled reaction for Ca and Al, respectively. A significant H2O-D2O isotope effect on dissolution was observed for Ca but not for Al at all temperatures. The former was consistent with an abated rate of hydrolysis in the absence of a contribution from diffusion, whilst the latter could be attributed to differences in the activated complex for Ca and Al release through hydrolysis. These results demonstrate the role of a secondary phase perovskite in the dissolution kinetics of zirconolite even when perovskite occurs at low concentration and evades detection by bulk techniques such as XRD. This study provides a potential explanation of variations in zirconolite ceramic dissolution rates present in the literature and provides a null result to tests of an incongruent Ca release mechanism from zirconolite.

Abstract Soil organic carbon (SOC) is a soil health indicator and understanding dynamics changing SOC stocks will help achieving net zero goals. Here we present four datasets featuring 11,750 data points covering co-located aboveground and below-ground metrics for exploring ecosystem SOC dynamics. Five sites across England with an established land use contrast, grassland and woodland next to each other, were rigorously sampled for aboveground (n = 109), surface (n = 33 soil water release curves), topsoil, and subsoil metrics. Commonly measured soil metrics were analysed in five soil increments for 0–1 metre (n = 4550). Less commonly measured soil metrics which were assumed to change across the soil profile were measured on a subset of samples only (n = 3762). Additionally, we developed a simple method for soil organic matter fractionation using density fractionation which is part of the less common metrics. Finally, soil metrics which may impact SOC dynamics, but with less confidence as to their importance across the soil profile were only measured on topsoil (~5–15 cm = mineral soil) and subsoil (below 50 cm) samples (n = 2567).

Abstract Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches. We discuss how in silico approaches, alongside complementary experimental approaches, can enhance our understanding of the mechanisms underlying successful cell delivery and engraftment. Furthermore, such combined theoretical-experimental approaches can be exploited to develop novel therapies, address safety and efficacy challenges, bridge the gap between in vitro and in vivo model systems, and compensate for the inherent differences between animal model systems and humans. We also highlight how in silico model development can result in fewer and more targeted in vivo experiments, thereby reducing preclinical costs and experimental animal numbers and potentially accelerating translation to the clinic. The development of biologically-accurate in silico models that capture the mechanisms underpinning the behaviour of these complex systems must be reinforced by quantitative methods to assess cell survival post-transplant, and we argue that non-invasive in vivo imaging strategies should be routinely integrated into transplant studies.

Abstract Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial protein biosynthesis by binding to the polypeptide exit tunnel (PET) near the peptidyl transferase center. Api137, an optimized derivative of honeybee PrAMP apidaecin, inhibits protein expression by trapping release factors (RFs), which interact with stop codons on ribosomes to terminate translation. This study uses cryo-EM, functional assays and molecular dynamic (MD) simulations to show that Api137 additionally occupies a second binding site near the exit of the PET and can repress translation independently of RF-trapping. Api88, a C-terminally amidated (-CONH2) analog of Api137 (-COOH), binds to the same sites, occupies a third binding pocket and interferes with the translation process presumably without RF-trapping. In conclusion, apidaecin-derived PrAMPs inhibit bacterial ribosomes by multimodal mechanisms caused by minor structural changes and thus represent a promising pool for drug development efforts.

This research aims to look at the impact and learning outcomes of using LMS and online learning platforms, so it is necessary to analyze learning outcomes and how they impact students, lecturers, and learning organizing institutions. This research shows that the LMS and online learning platforms used can improve student learning outcomes, which cannot be separated from the readiness of lecturers and students to implement it. This research used factor analysis (CFA), with a total of 150 respondents, students, and 15 lecturers. The impact provided by the use of LMS and online platforms in online learning is in the form of GPA and students' views on the learning process they have gone through. From the research results, several findings were obtained, including the ability to use LMS in online learning is not optimal, the GPA of learning outcomes is relatively high, and the readiness of lecturers and students to use LMS in online learning is still low.

Abstract Background The qualities of trainees play a key role in entrustment decisions by clinical supervisors for the assignments of professional tasks and levels of supervision. A recent body of qualitative research has shown that in addition to knowledge and skills, a number of personality traits are relevant in the workplace; however, the relevance of these traits has not been investigated empirically. The aim of this study was to analyse the workplace performance of final-year medical students using an Entrustable Professional Activity (EPA) framework in relation to their personality traits. Methods Medical students at the end of their final clerkship year were invited to participate in an online survey-based, cross-sectional field study. In the survey, the workplace performance was captured using a framework consisting of levels of experienced supervision and a defined set of 12 end-of-undergraduate medical training EPAs. The Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness) of the participating medical students were measured using the Big Five Inventory-SOEP (BFI-S), which consists of 15 items that are rated on a seven-point Likert scale. The data were analysed using descriptive and inferential statistics. Results The study included 880 final-year medical students (mean age: 27.2 years, SD = 3.0; 65% female). The levels of supervision under which the final-year clerkship students carried out the EPAs varied considerably. Significant correlations were found between the levels of experienced supervision and all Big Five dimensions The correlations with the dimensions of extraversion, agreeableness, conscientiousness and openness were positive, and that for the neuroticism dimension was negative (range r = 0.17 to r = − 0.23). Multiple regression analyses showed that the combination of the Big Five personality traits accounted for 0.8–7.5% of the variance in supervision levels on individual EPAs. Conclusions Using the BFI-S, we found that the levels of supervision on a set of end-of-undergraduate medical training EPAs were related to the personality traits of final-year medical students. The results of this study confirm the existing body of research on the role of conscientiousness and extraversion in entrustment decision-making and, in particular, add the personality trait of neuroticism as a new and relevant trainee quality to be considered.

Abstract Background In clinical trials and epidemiological research, mixed-effects models are commonly used to examine population-level and subject-specific trajectories of biomarkers over time. Despite their increasing popularity and application, the specification of these models necessitates a great deal of care when analysing longitudinal data with non-linear patterns and asymmetry. Parametric (linear) mixed-effect models may not capture these complexities flexibly and adequately. Additionally, assuming a Gaussian distribution for random effects and/or model errors may be overly restrictive, as it lacks robustness against deviations from symmetry. Methods This paper presents a semiparametric mixed-effects model with flexible distributions for complex longitudinal data in the Bayesian paradigm. The non-linear time effect on the longitudinal response was modelled using a spline approach. The multivariate skew-t distribution, which is a more flexible distribution, is utilized to relax the normality assumptions associated with both random-effects and model errors. Results To assess the effectiveness of the proposed methods in various model settings, simulation studies were conducted. We then applied these models on chronic kidney disease (CKD) data and assessed the relationship between covariates and estimated glomerular filtration rate (eGFR). First, we compared the proposed semiparametric partially linear mixed-effect (SPPLM) model with the fully parametric one (FPLM), and the results indicated that the SPPLM model outperformed the FPLM model. We then further compared four different SPPLM models, each assuming different distributions for the random effects and model errors. The model with a skew-t distribution exhibited a superior fit to the CKD data compared to the Gaussian model. The findings from the application revealed that hypertension, diabetes, and follow-up time had a substantial association with kidney function, specifically leading to a decrease in GFR estimates. Conclusions The application and simulation studies have demonstrated that our work has made a significant contribution towards a more robust and adaptable methodology for modeling intricate longitudinal data. We achieved this by proposing a semiparametric Bayesian modeling approach with a spline smoothing function and a skew-t distribution.

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyse a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behaviour to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

Vascular adhesion protein-1 (VAP-1) is a type 2 transmembrane sialoglycoprotein with oxidative deamination functionality, encoded by the amine oxidase copper-containing 3 (AOC3) gene. VAP-1 is widely expressed across various tissues, particularly in highly vascularized tissues and organs essential for lymphocyte circulation. In the vascular system, VAP-1 is predominantly found in vascular smooth muscle cells and endothelial cells, with higher expression levels in vascular smooth muscle cells. Under inflammatory conditions, VAP-1 rapidly translocates to the endothelial cell surface, facilitating leukocyte adhesion and migration through interactions with specific ligands, such as sialic acid-binding immunoglobulin-type lectins (Siglec)-9 on neutrophils and monocytes, and Siglec-10 on B cells, monocytes, and eosinophils. This interaction is crucial for leukocyte transmigration into inflamed tissues. Furthermore, VAP-1’s enzymatic activity generates hydrogen peroxide and advanced glycation end-products, contributing to cytotoxic damage and vascular inflammation. In this context, the soluble form of VAP-1 (sVAP-1), produced by matrix metalloproteinase cleavage from its membrane-bound counterpart, also significantly influences leukocyte migration. This review aims to elucidate the multifaceted pathophysiological roles of VAP-1 in vascular inflammation, particularly in giant cell arteritis (GCA) and associated polymyalgia rheumatica (PMR). By exploring its involvement in immune cell adhesion, migration, and its enzymatic contributions to oxidative stress and tissue damage, we investigate the importance of VAP-1 in GCA. Additionally, we discuss recent advancements in imaging techniques targeting VAP-1, such as [68Ga]Ga-DOTA-Siglec-9 PET/CT, which have provided new insights into VAP-1’s role in GCA and PMR. Overall, understanding VAP-1’s comprehensive roles could pave the way for improved strategies in managing these conditions.

Background: Age, gender and household infrastructure are important social determinants affecting health inequalities. This study aims to assess the ways that age and gender of the household head and household infrastructure intersect to create relative advantage and disadvantage in COVID-19 vulnerability. Methods: Using household primary care survey data from Mamelodi, Gauteng, headed households were sorted into three risk categories for each of the relevant infrastructural determinants of COVID-19. Bivariate ordinal logistic regression was used to determine the odds of households falling into each risk category. The proportion of high-risk (HR) categories and dwelling types was also calculated. Results: Households headed by someone ≥ 65 years were less likely to be in all HR categories and more frequently had formal houses. Male-head households were more likely to be HR for water, sanitation and hygiene infrastructure and indoor pollution; however, female-headed households (FHHs) were at higher risk for crowding. In Mamelodi, households headed by ≥ 65 years olds were relatively infrastructurally protected, likely because of pro-equity housing policy, as were FHHs, except for crowding. The care load on FHHs results in their infrastructural protection benefiting more community members, while simultaneously incurring risk. Conclusion: Infrastructural support based on the household head’s age and gender could improve targeting and the effectiveness of health interventions. These results demonstrate the importance of a contextual understanding of gender and age inequalities and tailoring public health support based on this understanding. Contribution: This research describes patterns of health-related infrastructural inequality, identifies ways to improve health interventions, and demonstrates the importance of equity-focused policy in an African context.

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT family are conserved across all phylogenetic kingdoms and function by coupling peptide uptake to the proton electrochemical gradient. Cryo-EM structures and alphafold models have recently provided new insights into different conformational states of two mammalian POTs, SLC15A1, and SLC15A2. Nevertheless, these studies leave open important questions regarding the mechanism of proton and substrate coupling, while simultaneously providing a unique opportunity to investigate these processes using molecular dynamics (MD) simulations. Here, we employ extensive unbiased and enhanced-sampling MD to map out the full SLC15A2 conformational cycle and its thermodynamic driving forces. By computing conformational free energy landscapes in different protonation states and in the absence or presence of peptide substrate, we identify a likely sequence of intermediate protonation steps that drive inward-directed alternating access. These simulations identify key differences in the extracellular gate between mammalian and bacterial POTs, which we validate experimentally in cell-based transport assays. Our results from constant-PH MD and absolute binding free energy (ABFE) calculations also establish a mechanistic link between proton binding and peptide recognition, revealing key details underpining secondary active transport in POTs. This study provides a vital step forward in understanding proton-coupled peptide and drug transport in mammals and pave the way to integrate knowledge of solute carrier structural biology with enhanced drug design to target tissue and organ bioavailability.

As Si electronics hits fundamental performance limits, oxide integration emerges as a solution to augment the next generation of electronic and optical devices. Specifically, oxide perovskites provide diverse functionalities with a potential to create, tune, and combine emergent phenomena at interfaces. High‐level crystalline order is needed to realize these functionalities, often achieved through epitaxy. However, large‐scale implementation in consumer devices faces challenges due to the need for high‐temperature deposition in complex vacuum systems. Herein, this challenge is addressed using atmospheric pressure spatial chemical vapor deposition, a thin‐film fabrication technique that can rapidly produce uniform films at sub‐400 °C temperatures under atmospheric conditions over ≈cm2 areas. Thus, the deposition of epitaxial perovskite tungsten trioxide, WO3, thin films is demonstrated at a rate of 5 nm min−2 on single‐crystal substrates at 350 °C in open‐air conditions enabling a high‐throughput process. The resulting films exhibit crystallographic and electronic properties comparable to vacuum‐based growth above 500 °C. The high‐quality epitaxy is attributed to the energetics of the exothermic decomposition reaction of the W[CO]6 precursors combined with the stabilization of a hot zone near the substrate surface. From this work, the way can be paved for low‐temperature atmospheric‐pressure epitaxy of a wide range of other perovskite thin films.

BackgroundComplex disorders, such as Alzheimer’s disease (AD), result from the combined influence of multiple biological and environmental factors. The integration of high-throughput data from multiple omics platforms can provide system overviews, improving our understanding of complex biological processes underlying human disease. In this study, integrated data from four omics platforms were used to characterise biological signatures of AD.MethodThe study cohort consists of 455 participants (Control:148, Cases:307) from the Religious Orders Study and Memory and Aging Project (ROSMAP). Genotype (SNP), methylation (CpG), RNA and proteomics data were collected, quality-controlled and pre-processed (SNP = 130; CpG = 83; RNA = 91; Proteomics = 119). Using a diagnosis of Mild Cognitive Impairment (MCI)/AD combined as the target phenotype, we first used Partial Least Squares Regression as an unsupervised classification framework to assess the prediction capabilities for each omics dataset individually. We then used a variation of the sparse generalized canonical correlation analysis (sGCCA) to assess predictions of the combined datasets and identify multi-omics signatures characterising each group of participants.ResultsAnalysing datasets individually we found methylation data provided the best predictions with an accuracy of 0.63 (95%CI = [0.54–0.71]), followed by RNA, 0.61 (95%CI = [0.52–0.69]), SNP, 0.59 (95%CI = [0.51–0.68]) and proteomics, 0.58 (95%CI = [0.51–0.67]). After integration of the four datasets, predictions were dramatically improved with a resulting accuracy of 0.95 (95% CI = [0.89–0.98]).ConclusionThe integration of data from multiple platforms is a powerful approach to explore biological systems and better characterise the biological signatures of AD. The results suggest that integrative methods can identify biomarker panels with improved predictive performance compared to individual platforms alone. Further validation in independent cohorts is required to validate and refine the results presented in this study.

Globally, there has been a substantial increase in the number of men being diagnosed with anxiety disorders. Despite this, men's mental health research often focusses on uncovering why men don't, rather than why they do, seek help. Within this context, men's help-seeking pathways for anxiety are poorly understood. This study mapped the help-seeking pathways of 419 Australian-based men for anxiety. Respondents 16 to 77 years-old (M = 40.92 years, SD = 15.36) reported multiple instances of help-seeking (n = 321, 77%) elaborating on their drivers for help-seeking via an open-text qualitative survey. Thematic analysis of men's responses was used to generate three themes, first detailing common tipping points of men's anxiety (namely relationship issues and work stress), and second, the reclusive causes and consequences of men's anxiety (burdensome symptoms and unmet expectations). These two themes converged into a third theme of help-seeking where defeatist (i.e., resigned abandonment self-management strategies) or defiant (proactive motivation in reaction to new events) motivations propelled men into either assisted or solitary help-seeking pathways. The current study findings afford important insights about the drivers that lead men to seek help for anxiety across the life course. Interventions targeting men's help-seeking for anxiety should accentuate the potential benefits of community-based mental health treatment within the context of men's social connectedness. Such interventions would also benefit from leveraging positive masculine ideals including strength, emotional-control and competition which can be both a barrier to, and driver for, help-seeking in the context of men's anxiety.

Abstract Background Elite-level coaches are exposed to multiple performance, organisational and personal stressors which may contribute to reduced mental health and wellbeing. This systematic scoping review examined the current body of evidence to explore what is known about the mental health of elite-level coaches (i.e. wellbeing and mental ill-health), the risk and protective factors that influence coach mental health, and the relationship between mental health and coaching effectiveness. Methods The review adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A systematic search was undertaken and updated in September 2022 using six electronic databases. Results 12,376 studies were identified and screened, with 42 studies satisfying the inclusion criteria. Despite the paucity of high-quality research, findings indicated that 40% of the included studies examined themes connected to wellbeing, with 76% assessing the nature or prevalence of mental ill-health in elite-level coaches. Among studies exploring mental ill-health, coach burnout was the primary focus, while scant research examined symptoms associated with clinical disorders (e.g. anxiety and depression). Overall, psychological outcomes for elite-level coaches were shaped by risk and protective factors operating at the individual, interpersonal, organisational and societal level. Preliminary evidence was also found to suggest that poor mental health may contribute to reduced coaching effectiveness. It is proposed that coaching effectiveness could therefore be employed as a ‘hook’ to engage elite-level coaches in greater consideration of their mental health needs. Conclusion Alongside the development of methodologically robust research, there is a need to examine dynamic individual (e.g. psychological skills), interpersonal (e.g. strong social supports) and organisational (e.g. workload) factors that aim to preserve the mental health and optimise the efficacy of elite-level coaches.

Abstract Membrane-camouflaged nanomedicines often suffer from reduced efficacy caused by membrane protein disintegration and spatial disorder caused by separation and reassembly of membrane fragments during the coating process. Here we show that intracellularly gelated macrophages (GMs) preserve cell membrane structures, including protein content, integration and fluidity, as well as the membrane lipid order. Consequently, in our testing GMs act as cellular sponges to efficiently neutralize various inflammatory cytokines via receptor-ligand interactions, and serve as immune cell-like carriers to selectively bind inflammatory cells in culture medium, even under a flow condition. In a rat model of collagen-induced arthritis, GMs alleviate the joint injury, and suppress the overall arthritis severity. Upon intravenous injection, GMs efficiently accumulate in the inflammatory lungs of acute pneumonia mice for anti-inflammatory therapy. Conveniently, GMs are amenable to lyophilization and can be stored at ambient temperatures for at least 1 month without loss of integrity and bio-activity. This intracellular gelation technology provides a universal platform for targeted inflammation neutralization treatment.

Abstract The increasing demand for cultivated lands driven by human population growth, escalating consumption and activities, combined with the vast area of uncultivated land, highlight the pressing need to better understand the biodiversity conservation implications of land use change in Sub-Saharan Africa. Land use change alters natural wildlife habitats with fundamental consequences for biodiversity. Consequently, species richness and diversity typically decline as land use changes from natural to disturbed. We assess how richness and diversity of avian species, grouped into feeding guilds, responded to land use changes, primarily expansion of settlements and cultivation at three sites in the Lake Victoria Basin in western Kenya, following tsetse control interventions. Each site consisted of a matched pair of spatially adjacent natural/semi-natural and settled/cultivated landscapes. Significant changes occurred in bird species richness and diversity in the disturbed relative to the natural landscape. Disturbed areas had fewer guilds and all guilds in disturbed areas also occurred in natural areas. Guilds had significantly more species in natural than in disturbed areas. The insectivore/granivore and insectivore/wax feeder guilds occurred only in natural areas. Whilst species diversity was far lower, a few species of estrildid finches were more common in the disturbed landscapes and were often observed on the scrubby edges of modified habitats. In contrast, the natural and less disturbed wooded areas had relatively fewer estrildid species and were completely devoid of several other species. In aggregate, land use changes significantly reduced bird species richness and diversity on the disturbed landscapes regardless of their breeding range size or foraging style (migratory or non-migratory) and posed greater risks to non-migratory species. Accordingly, land use planning should integrate conservation principles that preserve salient habitat qualities required by different bird species, such as adequate patch size and habitat connectivity, conserve viable bird populations and restore degraded habitats to alleviate adverse impacts of land use change on avian species richness and diversity.

Background and purpose: Stage at cancer diagnosis is an important predictor of cancer survival. TNM stage is constructed for anatomic solid cancer diagnoses from tumor size (T), nodal spread (N) and distant metastasis (M) and categorized in groups 0–I, II, II and IV. TNM stage is imperative in cancer diagnosis, management and control, and of high value in cancer surveillance, for example, monitoring of stage distributions. This study yields an overview of TNM availability and trends in stage distribution in the Nordic countries for future use in monitoring and epidemiologic studies. Material and methods: TNM information was acquired from the cancer registries in Denmark, Norway, Sweden, and Iceland during 2004–2016 for 26 cancer sites in the three former countries and four in Iceland. We studied availability, comparability, and distribution of TNM stage in three periods: 2004–2008, 2009–2013, and 2014–2016, applying a previously validated algorithm of ‘N0M0 for NXMX’. For cancers of colon, rectum, lung, breast, and kidney, we examined TNM stage-specific 1-year relative survival to evaluate the quality in registration of TNM between countries. Results: Denmark, Sweden, and Iceland exhibited available TNM stage proportions of 75–95% while proportions were lower in Norway. Proportions increased in Sweden over time but decreased in Denmark. One-year relative survival differed substantially more between TNM stages than between countries emphasizing that TNM stage is an important predictor for survival and that stage recording is performed similarly in the Nordic countries. Interpretation: Assessment and registration of TNM stage is an imperative tool in evaluations of trends in cancer survival between the Nordic countries.

IntroductionAntigen binding to the T cell antigen receptor (TCR) leads to the phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 complex, and thereby to T cell activation. The CD3ε subunit plays a unique role in TCR activation by recruiting the kinase LCK and the adaptor protein NCK prior to ITAM phosphorylation. Here, we aimed to investigate how phosphorylation of the individual CD3ε ITAM tyrosines impacts the CD3ε signalosome.MethodsWe mimicked irreversible tyrosine phosphorylation by substituting glutamic acid for the tyrosine residues in the CD3ε ITAM.ResultsIntegrating CD3ε phospho-mimetic variants into the complete TCR-CD3 complex resulted in reduced TCR signal transduction, which was partially compensated by the involvement of the other TCR-CD3 ITAMs. By using novel CD3ε phospho-mimetic Chimeric Antigen Receptor (CAR) variants, we avoided any compensatory effects of other ITAMs in the TCR-CD3 complex. We demonstrated that irreversible CD3ε phosphorylation prevented signal transduction upon CAR engagement. Mechanistically, we demonstrated that glutamic acid substitution at the N-terminal tyrosine residue of the CD3ε ITAM (Y39E) significantly reduces NCK binding to the TCR. In contrast, mutation at the C-terminal tyrosine of the CD3ε ITAM (Y50E) abolished LCK recruitment to the TCR, while increasing NCK binding. Double mutation at the C- and N-terminal tyrosines (Y39/50E) allowed ZAP70 to bind, but reduced the interaction with LCK and NCK.ConclusionsThe data demonstrate that the dynamic phosphorylation of the CD3ε ITAM tyrosines is essential for CD3ε to orchestrate optimal TCR and CAR signaling and highlights the key role of CD3ε signalosome to tune signal transduction.

Background: Since the early 2000s, overall and site-specific cancer survival have improved substantially in the Nordic countries. We evaluated whether the improvements have been similar across countries, major cancer types, and age groups. Material and methods: Using population-based data from the five Nordic cancer registries recorded in the NORDCAN database, we included a cohort of 1,525,854 men and 1,378,470 women diagnosed with cancer (except non-melanoma skin cancer) during 2002–2021, and followed for death until 2021. We estimated 5-year relative survival (RS) in 5-year calendar periods, and percentage points (pp) differences in 5-year RS from 2002–2006 until 2017–2021. Separate analyses were performed for eight cancer sites (i.e. colorectum, pancreas, lung, breast, cervix uteri, kidney, prostate, and melanoma of skin). Results: Five-year RS improved across nearly all cancer sites in all countries (except Iceland), with absolute differences across age groups ranging from 1 to 21 pp (all cancer sites), 2 to 20 pp (colorectum), -1 to 36 pp (pancreas), 2 to 28 pp (lung), 0 to 9 pp (breast), -11 to 26 pp (cervix uteri), 2 to 44 pp (kidney), -2 to 23 pp (prostate) and -3 to 30 pp (skin melanoma). The oldest patients (80–89 years) exhibited lower survival across all countries and sites, although with varying improvements over time. Interpretation: Nordic cancer patients have generally experienced substantial improvements in cancer survival during the last two decades, including major cancer sites and age groups. Although survival has improved over time, older patients remain at a lower cancer survival compared to younger patients.

Abstract INTRODUCTION This study investigated whether self‐reported sleep quality is associated with brain amyloid beta (Aβ) accumulation. METHODS Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean ± standard deviation 74.0 ± 6.2; 53.2% female), with baseline self‐reported sleep data, and positron emission tomography‐determined brain Aβ measured over a minimum of three time points (range 33.3–72.7 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status, and time, adjusting for sex and baseline age. RESULTS Sleep duration

IntroductionTo effectively regulate and reduce antibiotic use, in the livestock sector, a thorough understanding of the flow of veterinary antibiotics will help to identify key nodes in the chain for targeted interventions. The aim of this study was to understand the flow of antibiotics from import to end-user, and identify relevant governance mechanisms.MethodsA mixed methods approach was used to collect data in three Kenyan counties (Nairobi, Kiambu, and Kajiado). Focus group discussions (n = 23), individual interviews (n = 148), and key informant interviews (n = 10) were conducted.ResultsThe key actors identified include primary wholesalers, secondary wholesalers, retailers, animal health service providers (AHSPs), and farmers. Kenya imports 100% of its veterinary antibiotics: primary wholesalers legally import antibiotics as finished pharmaceutical products (90%) or active pharmaceutical ingredients (10%) after approval by the Veterinary Medicines Directorate. Secondary wholesalers play a major role in the distribution of antibiotics (60% of antibiotics) from importers to farmers, AHSPs, and retailers. Some of the illegal sources of antibiotics include unlicenced/unauthorized middlemen and online platforms that sell directly to retailers, AHSPs, and farmers.DiscussionDespite the presence of various laws and regulations governing the antibiotic value chain, implementation has been a challenge due to financial and human resource constraints. This contributes to over-the-counter sale of antibiotics without prescription, unlicensed businesses selling antibiotics, illegal importation, and presence of poor-quality drugs. There is a need to review the applicability of existing policies and address policy gaps (e.g., product containing antibiotic combinations, and use of human critically important antibiotics) to ensure the prudent sale and use of antibiotics, pharmacovigilance, antimicrobial use surveillance, and developing a business model that aligns with antibiotic stewardship. Additional interventions include awareness raising and capacity building of the different stakeholders along the antibiotic distribution chain to reduce antibiotic mis- and overuse.

Background: The Western Cape province in South Africa has a high age-standardised mortality from cancer. Most literature reports significantly poorer access to healthcare, more advanced cancers and worse survival for rural and remote populations. This study investigates if significant disparities exist with regard to stage at presentation and overall survival of patients with head and neck cancer (HNC) between geographical areas within the Western Cape province in South Africa. Methods: A retrospective chart review was conducted on all patients managed at the Combined ENT Head and Neck Oncology clinic at Groote Schuur from January 2010 to December 2014. Ethics approval was granted by the University of Cape Town Human Research Ethics Committee (HREC, 351-2017). Results: Although we observed no significant difference in TNM clinical stages or overall survival between metropolitan and remote patients, there were statistically and clinically significant differences in terms of both stages of HNC and overall survival between some individual metropolitan and remote areas. The remote area of Eden had a median overall survival of more than 6 months less than that of the Southern subdistrict of the City of Cape Town. Conclusion: Differences in HNC stages and overall survivals between some subdistricts of the City of Cape Town and remote areas are not only statistically significant but also clinically relevant. Contribution: This article highlights the need to improve on diagnostic and referral pathways for management of patients with HNC in the Western Cape.

The COVID-19 pandemic has presented substantial challenges to higher education, leading to economic loss and disruptions in STEM courses. This study addresses these issues through the successful implementation of a problem-based learning research project within the Instrumental Chemistry course at Georgia Gwinnett College (GGC). Focused on instrumental chemistry, the project spans various categories, requiring students to propose solutions to real-case scenarios using specific analytical instruments. Despite the shift to a hybrid teaching modality, students exhibited commendable preparation and investigation skills, as demonstrated by their projects. Assessment data, including a student survey and written report evaluations, underscore significant skill improvements in literature survey, instrument selection, experimental design, and data analysis. This problem-based learning approach not only mitigated the disruptions caused by the pandemic but also fostered enhanced capabilities and motivation among students. The study’s findings contribute insights into the adaptability and effectiveness of problem-based learning in analytical chemistry education within a hybrid teaching framework, offering valuable considerations for future educational strategies in STEM disciplines and beyond.

Abstract Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N = 103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N = 92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N = 33; controls: N = 43). In an additional analysis using 11C-ABP688 positron emission tomography (PET) in a male subsample (CU: N = 18; controls: N = 16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence.

Abstract Up to 25% of the US population harbor Clostridioides difficile in the gut. Following antibiotic disruption of the gut microbiota, C. difficile can act as an opportunistic pathogen and induce potentially lethal infections. Consequently, reducing the colonization of C. difficile in at-risk populations is warranted, prompting us to identify and characterize a probiotic candidate specifically targeting C. difficile colonization. We identified Bacillus velezensis DSM 33864 as a promising strain to reduce C. difficile levels in vitro. We further investigated the effects of B. velezensis DSM 33864 in an assay including human fecal medium and in healthy or clindamycin-treated mouse models of C. difficile colonization. The addition of B. velezensis DSM 33864 to human fecal samples was shown to reduce the colonization of C. difficile in vitro. This was supported in vivo where orally administered B. velezensis DSM 33864 spores reduced C. difficile levels in clindamycin-treated mice. The commensal microbiota composition or post-antibiotic reconstitution was not impacted by B. velezensis DSM 33864 in human fecal samples, short-, or long-term administration in mice. In conclusion, oral administration of B. velezensis DSM 33864 specifically reduced C. difficile colonization in vitro and in vivo without adversely impacting the commensal gut microbiota composition.