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Abstract Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel “two-hit” model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. HFD-Renin (aka “HFpEF”) mice demonstrated obesity and insulin resistance, moderate left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by echocardiographic measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF. Treatment with empagliflozin, an effective but incompletely understood HFpEF therapy, improved multiple endpoints. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Additional preclinical HFpEF models allow for orthogonal studies to increase validity in assessment of interventions.

Abstract Background State primary schools present an opportunity to support children’s physical activity equitably, however, many school-based physical activity interventions have been unsuccessful. Many interventions have focused on school built environments to increase or measure the physical infrastructure a school has. Yet literature suggests that broader social and institutional factors, such as school policies and staffing, are equally crucial for supporting pupil’s physical activity. The aim of this study is to qualitatively explore and assess primary school staff perspectives on the role of school facilities and resources in supporting pupil physical activity and the factors that impact their use. Methods We conducted 33 semi-structured interviews with state primary school staff in the Bristol area, Southwest England, between November 2023 and January 2024. Staff roles included headteacher/principal (n = 5), deputy headteacher/principal (n = 6), class teacher (n = 7), teaching assistant (n = 2), Physical Education (PE) subject lead (n = 8), dedicated PE teachers (n = 4), and Parent Teacher Association chair (n = 1). Staff were recruited from 19 purposively-sampled schools with a range of school sizes, locations, and sociodemographic characteristics. Reflexive thematic analysis was used. Results Five themes were generated related to how school facilities and resources impact pupil physical activity: 1) Facilities and resources create potential for pupil physical activity, 2) A social context supportive of physical activity is needed to maximise this potential, 3) Logistical challenges undermine the potential of facilities and resources, 4) The potential of facilities and resources change throughout the school year, and 5) Facilities and resources are not always fit for purpose. Conclusion The presence of facilities or resources alone does not determine pupil physical activity at primary school. Factors such as the social context of the school, logistical and timetabling challenges, seasonality, and how fit for purpose facilities are for that school, are important factors in school staff and pupils’ use and management of these facilities, and whether their potential is maximised or undermined. Future research and policy must broaden the focus from the presence of facilities and resources for physical activity, to include a focus on how these are maintained and engaged with in a school’s specific context.

Abstract This study investigates the potential of Burnt Sawdust Ash (BSDA) from seven timber species (Wawa, Mansonia, Teak, Odum, Ceiba, Essah and Mahogany) as a partial cement replacement in laterite interlocking blocks (LIBs). Using a replacement level of 0–30 (BSDA) wt% and mix proportion of 1:6 (cement + BSDA: laterite) with a 0.60 water-to-cement ratio, 396 blocks or specimens of size 185 mm × 220 mm × 120 mm were produced and cured at normal temperature and humidity under shady and sunny conditions for 7, 14, 21 and 28 days as per the BS EN 771‑1:2011 + A1:2015. Soil characterization test, particle size distribution, bulk density, water absorption, and erosion resistance were tested. It was observed that, the lateritic soil that passed through 2.36 mm and the fineness of BSDA partially helped in better interlocking and strength gains.While replacing cement with BSDA generally increased erosion rates, wood type influenced both properties, with 10% of Wawa, Mansonia and Odum offering better water absorption and erosion resistance at higher sawdust compositions. A positive finding was the decrease in bulk density with increasing BSDA, making blocks lighter and easier to transport. The research findings have some impacts on environmental sustainability, speed construction, and construction cost reduction.

Abstract Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. Neurodegeneration begins however several years before clinical onset of motor, cognitive or autonomic symptoms. The isolated form of REM sleep behavior disorder (RBD), a parasomnia with dream enactment behaviors and excessive muscle activity during REM sleep, is an early stage synucleinopathy. The neurophysiological hallmark of RBD is REM sleep without atonia (RWSA), i.e. the loss of physiological muscle atonia during REM sleep. RBD pathophysiology is not fully clarified yet, but clinical and basic science suggest that ɑ-syn pathology begins in the lower brainstem where REM atonia circuits are located, including the sublaterodorsal tegmental/subcoeruleus nucleus and the ventral medulla, then propagates rostrally to brain regions such as the substantia nigra, limbic system, cortex. Genetically, there is only a partial overlap between RBD, PD and DLB, and individuals with iRBD may represent a specific subpopulation. A genome-wide association study identified five loci, which all seem to revolve around the GBA1 pathway. iRBD patients often show subtle motor, cognitive, autonomic and/or sensory signs, neuroimaging alterations as well as biofluid and tissue markers of neurodegeneration (in particular pathologic α-synuclein aggregates), which can be useful for risk stratification. Patients with iRBD represent thus the ideal population for neuroprotective/neuromodulating trials. This review provides insights into these aspects, highlighting and substantiating the central role of iRBD in treatment development strategies for synucleinopathies.

Abstract Previously, we reported final-instar lepidopteran larvae exposed to low doses of imidacloprid, clothianidin, and thiamethoxam had arrest in pupal ecdysis, which is a novel adverse outcome for neonicotinoid insecticides. Since neonicotinoids disrupt acetylcholine signaling, we hypothesized that the excitatory neurotransmitter acetylcholine plays a critical role in regulation of pupal ecdysis, likely by modulating the release of peptides from crustacean cardioactive peptide (CCAP) neurons. In this paper, using two lepidopteran species, we undertook studies with five additional nicotinic acetylcholine receptor (nAChR) agonists and three muscarinic acetylcholine receptor (mAChR) agonists to hypothesize the putative nAChR subunits that mediate pupal ecdysis. We also explored the potential role of mAChRs in regulation of pupal ecdysis. These findings, along with toxicokinetic analyses, suggest that pupal ecdysis may be mediated by the α1, β1, and β2 subunits of nAChRs without involvement of mAChRs. An analysis of ecdysis movements showed that neonicotinoid-treated lepidopteran larvae exhibited similar disruptions as observed in CCAP neuron-knockout Drosophila larvae. Based on findings to date, we hypothesize that acetylcholine regulates lepidopteran pupal ecdysis directly through CCAP neurons or by activating their upstream efferent inhibitory (likely GABA-releasing) neurons. Further studies are needed to elucidate the interplay between neuroendocrine hormones and neurotransmitters in lepidopteran pupal ecdysis.

Abstract Background Persistent pain is a complicated phenomenon associated with a wide array of complex pathologies and conditions (e.g., complex regional pain syndrome, non-freezing cold injury), leading to extensive disability and reduced physical function. Conventional resistance training is commonly contraindicated in load compromised and/or persistent pain populations, compromising rehabilitation progression and potentially leading to extensive pharmacological intervention, invasive procedures, and reduced occupational status. The management of persistent pain and utility of adjunct therapies has become a clinical and research priority within numerous healthcare settings, including defence medical services. Main Body Blood flow restriction (BFR) exercise has demonstrated beneficial morphological and physiological adaptions in load-compromised populations, as well as being able to elicit acute hypoalgesia. The aims of this narrative review are to: (1) explore the use of BFR exercise to elicit hypoalgesia; (2) briefly review the mechanisms of BFR-induced hypoalgesia; (3) discuss potential implications and applications of BFR during the rehabilitation of complex conditions where persistent pain is the primary limiting factor to progress, within defence rehabilitation healthcare settings. The review found BFR application is a feasible intervention across numerous load-compromised clinical populations (e.g., post-surgical, post-traumatic osteoarthritis), and there is mechanistic rationale for use in persistent pain pathologies. Utilisation may also be pleiotropic in nature by ameliorating pathological changes while also modulating pain response. Numerous application methods (e.g., with aerobic exercise, passive application, or resistance training) allow practitioners to cater for specific limitations (e.g., passive, or contralateral application with kinesiophobia) in clinical populations. Additionally, the low-mechanical load nature of BFR exercise may allow for high-frequency use within residential military rehabilitation, providing a platform for conventional resistance training thereafter. Conclusion Future research needs to examine the differences in pain modulation between persistent pain and pain-free populations with BFR application, supporting the investigation of mechanisms for BFR-induced hypoalgesia, the dose-response relationship between BFR-exercise and pain modulation, and the efficacy and effectiveness of BFR application in complex musculoskeletal and persistent pain populations.

Abstract Background Early childhood obesity prevention interventions that aim to change parent/caregiver practices related to infant (milk) feeding, food provision and parent feeding, movement (including activity, sedentary behaviour) and/or sleep health (i.e. target parental behaviour domains) are diverse and heterogeneously reported. We aimed to 1) systematically characterise the target behaviours, delivery features, and Behaviour Change Techniques (BCTs) used in interventions in the international Transforming Obesity Prevention for CHILDren (TOPCHILD) Collaboration, and 2) explore similarities and differences in BCTs used in interventions by target behaviour domains. Methods Annual systematic searches were performed in MEDLINE, Embase, Cochrane (CENTRAL), CINAHL, PsycINFO, and two clinical trial registries, from inception to February 2023. Trialists from eligible randomised controlled trials of parent-focused, behavioural early obesity prevention interventions shared unpublished intervention materials. Standardised approaches were used to code target behaviours, delivery features and BCTs in both published and unpublished intervention materials. Validation meetings confirmed coding with trialists. Narrative syntheses were performed. Results Thirty-two trials reporting 37 active intervention arms were included. Interventions targeted a range of behaviours. The most frequent combination was targeting all parental behaviour domains (infant [milk] feeding, food provision and parent feeding, movement, sleep health; n[intervention arms] = 15/37). Delivery features varied considerably. Most interventions were delivered by a health professional (n = 26/36), included facilitator training (n = 31/36), and were interactive (n = 28/36). Overall, 49 of 93 unique BCTs were coded to at least one target behaviour domain. The most frequently coded BCTs were: Instruction on how to perform a behaviour (n[intervention arms, separated by domain] = 102), Behavioural practice and rehearsal (n = 85), Information about health consequences (n = 85), Social support (unspecified) (n = 84), and Credible source (n = 77). Similar BCTs were often used for each target behaviour domain. Conclusions Our study provides the most comprehensive description of the behaviour change content of complex interventions targeting early childhood obesity prevention available to date. Our analysis revealed that interventions targeted multiple behaviour domains, with significant variation in delivery features. Despite the diverse range of BCTs coded, five BCTs were consistently identified across domains, though certain BCTs were more prevalent in specific domains. These findings can be used to examine effectiveness of components and inform intervention development and evaluation in future trials. Trial registration PROSPERO registration no. CRD42020177408.

Abstract Natural products have long been a viable source of therapeutic agents, providing unique structures and mechanisms that may be beneficial for cancer treatment. Herein we first report on the anticancer activity OST-01, a natural product from Baccharis Coridifolia, on breast cancer cells, including triple-negative breast cancer (TNBC). OST-01 significantly inhibited cell proliferation and oncogenic activities of TNBC cells in vitro. OST-01 also markedly inhibited TNBC tumor growth in vivo, with > 50% reduction in tumor size compared to vehicle control treatment in different in vivo models, i.e., cell line-derived (CDX), patient-derived (PDX), and mammary fat pad xenografts. Mechanistically, OST-01 induces ferroptosis by downregulating LRP8-regulated selenoproteins, i.e., GPX4. A shift from a basal-mesenchymal to a luminal-epithelial state of breast cancer stem cells (BCSCs) as supported by the downregulation of stemness (e.g., CD44) and mesenchymal (e.g., FN1 and vimentin) markers, along with the upregulation of differentiation markers (e.g., CD24) and luminal-epithelial markers (e.g., CK19), was also observed.

Abstract Aims Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross‐sectionally associated with left ventricular (LV) size and geometry in a diverse population‐based cohort without known cardiovascular disease (CVD). Methods and results Among participants of the Multi‐Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer‐based platform at exam 1 (2000–2002) and exam 5 (2010–2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points. We used multivariable linear regression with robust variance to assess cross‐sectional associations between plasma protein abundances and LV structural characteristics at exam 1, reproduced findings in later‐life at exam 5, and explored relationships of associated proteins using annotated enrichment analysis. We studied 763 participants (mean age 60 ± 10 years at exam 1; 53% female; 19% Black race; 31% Hispanic ethnicity). Following adjustment for renal function and traditional CVD risk factors, plasma levels of 3 proteins were associated with LV mass index at both time points with the same directionality (FDR

We present a 1-bit reconfigurable intelligent surface (RIS) operating at millimeter-wave frequencies that suppresses the undesired grating lobes encountered in binary phase modulation schemes and achieves high resolution beam steering. We incorporate fixed, random phase delays at each unit cell of the surface which breaks the periodicity of the phase quantization error and suppresses side lobes. Additionally, the random phase delays reduce the beam pointing error – a limitation of binary RISs - which can be beneficial in applications that require high resolution beam steering. The proposed topology allows for scalable RIS apertures that are compatible with printed circuit board (PCB) fabrication technology. It consists of four metasurface tiles of 256 radiating elements ( $16\times 16$ ) connected on a separate control board that houses the control unit and power supply. The prototype is designed to operate at 27.2 GHz and perform electronic beam steering in ±60° in both azimuth and elevations planes. A quantization lobe reduction of more than 10 dB is achieved with the proposed technique and the surface is well suited for mmWave 5G communication scenarios to enhance signal coverage and signal-to-noise ratio.

Abstract Purpose Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans. Methods 8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P

Abstract Racial/ethnic differences are associated with the symptoms and conditions of post-acute sequelae SARS-CoV-2 infection (PASC) in adults. These differences may exist among children and warrant further exploration. We conducted a retrospective cohort study with difference-in-differences analyzes to assess these differences in children and adolescents under the age of 21. The study utilized data from the RECOVER Initiative in the United States, which aims to learn about the long-term effects of COVID-19. The cohort included 225,723 patients with SARS-CoV-2 infection or COVID-19 diagnosis between March 2020 and October 2022. The study compared minority racial/ethnic groups to Non-Hispanic White (NHW) individuals, stratified by severity during the acute phase of COVID-19. Within the severe group, Asian American/Pacific Islanders (AAPI) had a higher prevalence of fever/chills and respiratory signs and symptoms, Hispanic patients showed greater hair loss prevalence in severe COVID-19 cases, while Non-Hispanic Black (NHB) patients had fewer skin symptoms in comparison to NHW patients. Within the non-severe group, AAPI patients had increased POTS/dysautonomia and respiratory symptoms, and NHB patients showed more cognitive symptoms than NHW patients. In conclusion, racial/ethnic differences related to COVID-19 exist among PASC symptoms and conditions in pediatrics, and these differences are associated with the severity of illness during acute COVID-19.

Abstract Background Implementation strategies are essential to deliver evidence-based programs that align with local context, resources, priorities, and preferences. However, it is not always clear how specific strategies are selected (vs. others) and strategies are not always operationalized clearly, distinctly, and dynamically. Implementation logic models provide one useful way to conceptualize the role and selection of implementation strategies, plan evaluation of their intended impacts on implementation and effectiveness outcomes, and to communicate key aspects of a project. Methods This paper describes our initial plans, experiences, and lessons learned from applying implementation logic models in the Quadruple Aim Quality Enhancement Research Initiative (QUERI) a large multi-study program funded by the Veterans Health Administration (VA). We began with two primary implementation strategies based on our earlier work (i.e., Iterative RE-AIM and Relational Facilitation) that were applied across three different health outcomes studies. Results Our implementation strategies evolved over time, and new strategies were added. This evolution and reasons for changes are summarized and illustrated with the resulting logic models, both for the overall Quadruple Aim QUERI and the three specific projects. We found that implementation strategies are often not discrete, and their delivery and adaptation is dynamic and should be guided by emerging data and evolving context. Review of logic models across projects was an efficient and useful approach for understanding similarities and differences across projects. Conclusions Implementation logic models are helpful for clarifying key objectives and issues for both study teams and implementation partners. There are challenges in logic model construction and presentation when multiple strategies are employed, and when strategies change over time. We recommend presentation of both original and periodically updated project models and provide recommendations for future use of implementation logic models.

Abstract Selecting appropriate buffers is crucial for evaluating the chemical durability of glass under controlled conditions such as in the EPA 1313 test designed to measure elemental release as a function of pH. The efficacy of two alkali-metal free buffers, TRIS (NH2C(CH2OH)3) and ammonium chloride—ammonia (NH3/NH4Cl), was investigated during EPA 1313 testing of a simulated Hanford low-activity waste borosilicate glass in the alkaline regime (pH 8.5–10.5) at varying temperatures (RT, 40 °C, and 60 °C). While both buffers maintained the desired pH at room temperature, and up to 40 °C, the effectiveness of TRIS decreased at elevated temperatures, particularly at pH 10.5. Although 11B NMR showed evidence of TRIS-B complexation, its effect on the rate of elemental release was found to be negligible under the test conditions. With ammonium buffer, the release of alkali cations was slightly elevated when compared to the same conditions with TRIS at early time points.

Abstract Background The rumen fluke, Calicophoron daubneyi, is the major paramphistome species infecting ruminants within Europe. Adult flukes reside within the rumen where they are in direct contact with a unique collection of microorganisms. Here, we report a 1.76-Gb draft genome for C. daubneyi, the first for any paramphistome species. Results Several gene families have undergone specific expansion in C. daubneyi, including the peptidoglycan-recognition proteins (PGRPs) and DM9 domain-containing proteins, which function as pattern-recognition receptors, as well as the saposin-like proteins with putative antibacterial properties, and are upregulated upon arrival of the fluke in the microbe-rich rumen. We describe the first characterisation of a helminth PGRP and show that a recombinant C. daubneyi PGRP binds to the surface of bacteria, including obligate anaerobes from the rumen, via specific interaction with cell wall peptidoglycan. We reveal that C. daubneyi eggshell proteins lack L-DOPA typically required for eggshell crosslinking in trematodes and propose that C. daubneyi employs atypical eggshell crosslinking chemistry that produces eggs with greater stability. Finally, although extracellular digestion of rumen ciliates occurs within the C. daubneyi gut, unique ultrastructural and biochemical adaptations of the gastrodermal cells suggest that adult flukes also acquire nutrients via uptake of volatile fatty acids from rumen fluid. Conclusions Our findings suggest that unique selective pressures, associated with inhabiting a host environment so rich in microbial diversity, have driven the evolution of molecular and morphological adaptations that enable C. daubneyi to defend itself against microorganisms, feed and reproduce within the rumen.

Abstract Background In England, 23% of children aged 11 start their teenage years living with obesity. An adolescent living with obesity is five times more likely to live with obesity in adult life. There is limited research and policy incorporating adolescents’ views on how they experience the commercial determinants of dietary behaviour and obesity, which misses an opportunity to improve services and policies that aim to influence the prevalence of childhood obesity. This study reports the findings from online Group Model Building system mapping workshops in which we explored the mechanisms by which commercial drivers influence adolescents’ dietary behaviour. Methods We ran a series of 3 online Group Model Building workshops with adolescents and one Group Model Building workshop with policymakers and public health practitioners. Adolescents portrayed their views on how food and beverage industries influence what they choose to buy and eat in a system map, and then proposed a set of policy actions to promote healthier food environments. We shared the system map created by adolescents with policymakers and public health practitioners to reflect on how current policy interventions match adolescents’ views on the most influential factors. Results The system map contains 37 elements connected by 70 hypothesised causal links and five feedback loops. These elements were grouped into six themes that portray the complexity of factors that influence adolescents’ food choices in their physical and digital environments, disproportionately encouraging the consumption of unhealthy products. Policymakers and public health practitioners reflected on the power and the deep level of influence food companies exert on adolescents’ behaviour. They recognised that the coexisting influence of food marketing and social media on mental health and body image is not well reflected in current policy and research efforts. Conclusions This study highlights the need for public health policymaking processes to provide youth with a space to voice influential elements and consequences, thereby co-creating policies and designing interventions to buffer risk factors and increase well-being in this critical transitional stage.

Abstract GaN is rapidly gaining attention for implementation in power electronics but is still impacted by its high density of threading dislocations (TDs), which have been shown to facilitate current leakage through devices limiting their performance and reliability. Here, we discuss a novel implementation of photoluminescence (PL) imaging to study TDs in regions within vertically structured p-i-n GaN (PIN) diodes consisting of metalorganic chemical vapor deposition (MOCVD) epitaxial layers grown on ammonothermal GaN (am-GaN) substrates. PL imaging with a sub-bandgap excitation energy (3.1 eV) reveals TDs with excellent clarity in three dimensions within the am-GaN substrate. Galvanometric-driven PL imaging allows the microstructure of hundreds of devices to be characterized in a single session, enhancing the screening process through the addition of device specific TD location tracking and density mapping. The visibility, structural characteristics, luminescent nature and evolution of TDs through the GaN growth process are described, potentially providing the ability to define TD structures associated with leakage current.

Abstract The placenta is the critical interface between mother and fetus, and consequently, placental dysfunction underlies many pregnancy complications. Placental formation requires an adequate expansion of trophoblast stem and progenitor cells followed by finely tuned lineage specification events. Here, using single-cell RNA sequencing of mouse trophoblast stem cells during the earliest phases of differentiation, we identify gatekeepers of the stem cell state, notably Nicol1, and uncover unsuspected trajectories of cell lineage diversification as well as regulators of lineage entry points. We show that junctional zone precursors and precursors of one of the two syncytial layers of the mouse placental labyrinth, the Syncytiotrophoblast-I lineage, initially share similar trajectories. Importantly, our functional analysis of one such lineage precursor marker, CXADR, demonstrates that this cell surface protein regulates the differentiation dynamics between the two syncytial layers of the mouse labyrinth, ensuring the correct establishment of the placental exchange surface. Deciphering the mechanisms underlying trophoblast lineage specification will inform our understanding of human pregnancy in health and disease.

Abstract Permafrost is a potentially important source of deglacial carbon release alongside deep-sea carbon outgassing. However, limited proxies have restricted our understanding in circumarctic regions and the last deglaciation. Tibetan Plateau (TP), the Earth’s largest low-latitude and alpine permafrost region, remains underexplored. Using speleothem growth phases, we reconstruct TP permafrost thawing history over the last 500,000 years, standardizing chronology to investigate Northern Hemisphere permafrost thawing patterns. We find that, unlike circumarctic permafrost, TP permafrost generally initiates thawing at the onset of deglaciations, coinciding with Weak Monsoon Intervals and sluggish Atlantic Meridional Overturning Circulation (AMOC) during Terminal Stadials. Modeling elaborates that the associated Asian monsoon weakening induces anomalous TP warming through local cloud–precipitation–soil moisture feedback. This, combined with high-latitude cooling, results in asynchronous boreal permafrost thawing. During the last deglaciation, however, anomalous AMOC variability delayed TP and advanced circumarctic permafrost thawing. Our results indicate that permafrost carbon release, influenced by millennial-scale AMOC variability, may have been a non-trivial contributor to deglacial CO2 rise.

Abstract Persistent shifts to undesired ecological states, such as shifts from coral to macroalgae, are becoming more common. This highlights the need to understand processes that can help restore affected ecosystems. Herbivory on coral reefs is widely recognized as a key interaction that can keep macroalgae from outcompeting coral. Most attention has been on the role ‘grazing’ herbivores play in preventing the establishment of macroalgae, while less research has focused on the role of ‘browsers’ in extirpating macroalgae. Here we explored patterns, environmental correlates and state shift consequences of spatial co-variation in grazing and browsing functions of herbivorous fishes. Grazing and browsing rates were not highly correlated across 20 lagoon sites in Moorea, French Polynesia, but did cluster into 3 (of 4) combinations of high and low consumption rates (no site had low grazing but high browsing). Consumption rates were not correlated with grazer or browser fish biomass, but both were predicted by specific environmental variables. Experiments revealed that reversibility of a macroalgal state shift was strongly related to spatial variation in browsing intensity. Our findings provide insights and simple diagnostic tools regarding heterogeneity in top-down forcing that influences the vulnerability to and reversibility of shifts to macroalgae on coral reefs.

Abstract Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC. The primary endpoint was the fraction of expanded tumor-associated T-cell receptor (TCR) clones in blood at day 21 as a surrogate measure of anti-tumor immune response. Secondary objectives were safety and feasibility, 2-year disease-free survival (DFS), and predictive value of PD-L1 expression. Forty patients were randomized, 36 received treatment, and 25 were evaluable for the primary endpoint. After cycle 1, there was peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B (p = 0.0025) that remained higher at day 21, meeting the pre-specified endpoint on two-sample T-test (p = 0.052), but not on sensitivity analysis by Wilcoxon test (p = 0.13). At the median follow up of 25.8 months, 2-year DFS was 76% in Arm A and 56% in Arm B (p = 0.28). There were no new safety signals. In conclusion, neoadjuvant ICB prior to CRT was safe and was associated with immunologically and clinically favorable outcomes, warranting larger confirmatory studies.

Abstract Aging increases the risk for Alzheimer’s disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions in laminar structure, and exposed AD-related shifts in layer-to-layer and cell-cell interactions. Notably, we identified genes highly upregulated in stressed neurons and nearby glial cells, where AD diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis highlighted three neuronal modules linked to neuroprotection, protein dephosphorylation, and Aβ regulation, with all modules downregulated as AD progresses. We identified ZNF460 as a transcription factor regulating these modules, offering a potential therapeutic target. In summary, this spatial transcriptome atlas provides valuable insight into AD’s molecular mechanisms.

In the medical diagnostics domain, pathology and histology are pivotal for the precise identification of diseases. Digital histopathology, enhanced by automation, facilitates the efficient analysis of massive amount of biopsy images produced on a daily basis, streamlining the evaluation process. This study focuses in Stain Color Normalization (SCN) within a Whole-Slide Image (WSI) cohort, aiming to reduce batch biases. Building on published graphical method, this research demonstrates a mathematical population or data-driven method that optimizes the dependency on the number of reference WSIs and corresponding aggregate sums, thereby increasing SCN process efficiency. This method expedites the analysis of color convergence 50-fold by using stain vector Euclidean distance analysis, slashing the requirement for reference WSIs by more than half. The approach is validated through a tripartite methodology: 1) Stain vector euclidean distances analysis, 2) Distance computation timing, and 3) Qualitative and quantitative assessments of SCN across cancer tumors regions of interest. The results validate the performance of data-driven SCN method, thus potential to enhance the precision and reliability of computational pathology analyses. This advancement is poised to enhance diagnostic processes, therapeutic strategies, and patient prognosis.

Abstract The healthcare sector contributes up to 4.6% of global greenhouse gas emissions. The surgical system contributes predominantly. Despite this, many hospitals have been slow to adopt sustainable practices. This editorial discusses strategies to incentivize surgical healthcare systems to prioritize more sustainable operations, using examples from other industries as well as healthcare systems from more sustainable nations.

Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored. Despite significant advances in therapeutic strategies, effective management of large chronic skin wounds remains a clinical challenge. Dermal fibroblasts are the primary cell type responsible for remodeling the extracellular matrix (ECM) in wound healing. Here, we investigated whether ECM derived from exogenous fibroblasts, in combination with keratinocytes, promoted scarless cutaneous wound healing. To overcome the limited lifespan of primary dermal fibroblasts, we established reversibly immortalized mouse dermal fibroblasts (imDFs), which were non-tumorigenic, expressed dermal fibroblast markers, and were responsive to TGF-β1 stimulation. The decellularized ECM prepared from both imDFs and primary dermal fibroblasts shared similar expression profiles of extracellular matrix proteins and promoted the proliferation of keratinocyte (iKera) cells. The imDFs-derived ECM solicited no local immune response. While the ECM and to a lesser extent imDFs enhanced skin wound healing with excessive fibrosis, a combination of imDFs-derived ECM and iKera cells effectively promoted the re-epithelization and scarless healing of full-thickness skin wounds. These findings strongly suggest that dermal fibroblast-derived ECM, not fibroblasts themselves, may synergize with keratinocytes in regulating scarless healing and re-epithelialization of skin wounds. Given its low immunogenic nature, imDFs-derived ECM should be a valuable resource of skin-specific biomaterial for wound healing and skin tissue engineering.

Summary: Background: Children from racial and ethnic minority groups are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they have increased risk for post-acute sequelae of SARS-CoV-2 (PASC). Our objectives were to assess whether the risk of respiratory and neurologic PASC differs by race/ethnicity and social drivers of health. Methods: We conducted a retrospective cohort study of individuals

Background: Diabetes mellitus (DM) is a group of chronic metabolic diseases that affect the body’s ability to produce insulin. It is one of the most common endocrine disorders. Objectives: This study aims to measure whether there was any association between alarin and some anthropometric measurements (AMs) such as waist/nick (W/N), waist/thoracic (W/T), waist/hip (W/H) in Iraqi type II diabetic patients. Materials and Methods: This study included 43 patients from Ramadi Teaching Hospitals, in addition to 43 healthy controls. Enzyme-linked immunosorbent assay was used to determine serum alarin level, while the fasting serum glucose (FSG) level was determined by enzymatic colorimetric methods. Results: Serum alarin (ng/mL) was higher in DM patients than in HCs (P < 0.0001), body mass index (BMI) was significantly higher in patients with T2DM, in addition, FSG) mg/dL (was higher in T2DM than HCs. Furthermore, alarin was positively associated with BMI (0.151), W/H (0.006), W/T (0.008), W/N (0.1260), and FSG (0.612). The receiver operating characteristic (ROC) curve indicates that alarin and FSG were excellent sensitive markers in the diagnosis of T2DM. Moreover, ROC indicated that W/N gave good sensitive signs. New values of the cutoff value for studied variables have been estimated as follows: alarin (>2.035 ng/mL), W/H (>0.9554), W/T (>0.9633), W/N (>2.665), H/T (>1.06), and FSG (>116.5 mg/dL). Conclusion: A very weak correlation appeared for alarin with AMs; the serum level of alarin was higher in T2DM than HCS; this means alarin may be used as a novel biomarker in the detection of T2DM and may be an effective biomarker in the diagnostic test for the disease.

Abstract Deviation from protocolized assessment times is commonplace in pragmatic randomized clinical trials. Working with a stakeholder advisory board for a Patient-Centered Outcomes Research Institute®-funded project on statistical methods for handling potential biases introduced by irregular assessment times, we identified reasons for off-schedule or missed assessments. We used the Consolidated Framework for Implementation Research 2.0 to organize our findings. We conjectured that timely completion of outcome assessments is a function of multiple determinants, only some related to participants’ health status. We identified potential determinants that can be modified during the protocol design stage and can be reassessed and mitigated during trial implementation stage. Research to more formally evaluate our findings is warranted as well as studies to evaluate multi-level strategies that reduce off-schedule or missed assessments.

Abstract Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia. This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors.

Self-Expanding Metallic (SEM) Y stents are a newer form of stent that is gaining popularity outside the USA, but still has limited data, especially in a community medicine setting. This study analyzed efficacy and complication rates in 14 patients who had a SEM Y stent placed between August 2022 and June 2024 at Harris Methodist Hospital in Fort Worth, Texas for either central airway obstruction (CAO) or fistulae. Of the 14 patients, 11 were requiring supplemental oxygen or mechanical ventilation prior to stent placement. Post-stenting 42.9% had decreased oxygen requirements, 21.4% unchanged, 14.3% increased, and 21.4% remained on room air. Complications included mucus plugging (42.9%), infection (35.7%), and granulation tissue (14.3%). There was no statistically significant correlation between gender/age and complications (p = 0.879/0.490, respectively). Complication rates were similar when compared to silicone Y stents based on literature review. In conclusion, SEM Y stents are a safe and effective alternative stent intended for palliative treatment with similar success and complications that can be easily and effectively implemented in a community hospital, with the added benefit of being able to be placed with flexible bronchoscopy.

Abstract Voltage-gated potassium channels (VGKCs) comprise the largest and most complex families of ion channels. Approximately 70 genes encode VGKC alpha subunits, which assemble into functional tetrameric channel complexes. These subunits can also combine to form heteromeric channels, significantly expanding the potential diversity of VGKCs. The functional expression and physiological role of heteromeric K-channels have remained largely unexplored due to the lack of tools to probe their functions. Conotoxins, from predatory cone snails, have high affinity and specificity for heteromeric combinations of K-channels and show great promise for defining their physiological roles. In this work, using conotoxin kM-RIIIJ as a pharmacological probe, we explore the expression and physiological functions of heteromeric Kv1.2 channels using constellation pharmacology platform. We report that heteromers of Kv1.2/1.1 are highly expressed in proprioceptive neurons found in the dorsal root ganglion (DRG). Inhibition of Kv1.2/1.1 heteromers leads to an influx of calcium ions, suggesting that these channels regulate neuronal excitability. We also present evidence that Kv1.2/1.1 heteromers counteract persistent sodium currents, and that inhibiting these channels leads to tonic firing of action potentials. Additionally, kM-RIIIJ impaired proprioception in mice, uncovering a previously unrecognized physiological function of heteromeric Kv1.2/1.1 channels in proprioceptive sensory neurons of the DRG.

Abstract Research has previously documented that across a range of Olympic combat sports, wearing red is associated with a higher probability of winning contests, especially when bouts are close. Yet, the hypothesis for a red advantage has not been systematically examined across multiple tournaments. Here, we report 6,589 contest outcomes for boxing, taekwondo, and wrestling from seven Summer Olympic Games (1996–2020) and nine World Boxing Championships (2005–2021). Using meta-analytic techniques, we found 50.5% wins by red for the overall data, which was not a statistically significant bias. Analyses of close contests resulted in 51.5% red wins, also not significantly different from the null expectation of equal proportions. Before 2005, however, when the red advantage was first reported and prior to changes in particular tournament rules, there was some support for a red advantage in close contests, with 56.8% of bouts won by red. It is possible that knowledge of the effect, as well as rule changes in each of the sports, have reduced the chances of a small effect being manifested, leading to the disappearance of the red advantage in competition results.

Abstract Background Designing for Dissemination and Sustainability (D4DS) principles and methods can support the development of research products (interventions, tools, findings) that match well with the needs and context of the intended audience and setting. D4DS principles and methods are not well-known or used during clinical and public health research; research teams would benefit from applying D4DS. This paper presents the development of a new digital platform for research teams to learn and apply a D4DS process to their work. Methods A user-centered design (UCD) approach engaged users (n = 14) and an expert panel (n = 6) in an iterative design process from discovery to prototyping and testing. We led five design sessions using Zoom and Figma software over a 5-month period. Users (71% academics; 29% practitioners) participated in at least 2 sessions. Following design sessions, feedback from users was summarized and discussed to generate design decisions. A prototype was then built and heuristically tested with 11 users who were asked to complete multiple tasks within the platform while verbalizing their decision-making using the ‘think aloud’ procedure. The System Usability Scale (SUS) was administered at the end of each testing session. After refinements to the platform were made, usability was reassessed with 7 of 11 same users to examine changes. Results The interactive digital platform (the D4DS Planner) has two main components: 1) the Education Hub (e.g., searchable platform with literature, videos, websites) and 2) the Action Planner. The Action Planner includes 7 interactive steps that walk users through a set of activities to generate a downloadable D4DS action plan for their project. Participants reported that the prototype tool was moderately usable (SUS = 66) but improved following refinements (SUS = 71). Conclusions This is a first of its kind tool that supports research teams in learning about and explicitly applying D4DS to their work. The use of this publicly available tool may increase the adoption, impact, and sustainment of a wide range of research products. The use of UCD yielded a tool that is easy to use. This tool's future use and impact will be evaluated with a broader sample of community partners and projects and the tool will continue to be refined and improved.

Abstract Background Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations. Methods We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these “zero–passage” organoids by withdrawing β-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial nutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing (RNA-seq), and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of volumetric growth rates. Results We achieved > 50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined. Conclusions Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.

Abstract Aims Intercellular adhesion molecule‐1 (ICAM‐1) facilitates inflammation via leucocyte recruitment and has been implicated in heart failure with preserved ejection fraction (HFpEF). Approximately 35% of African American individuals carry a copy of an ICAM1 missense variant (rs5491; p.K56M), which is associated with an increased risk of HFpEF. The pathways by which rs5491 increases HFpEF risk are not well defined. We evaluated the circulating immune cell profile of rs5491. Methods Among African American individuals in the Multi‐Ethnic Study of Atherosclerosis, we evaluated the associations of rs5491 with 29 circulating peripheral blood mononuclear cell subsets. The top immune cells were then related to echocardiographic measures of structure and function. Results Among 502 individuals with immune cell profiling (mean age 63 years, 51% female), 191 individuals (38%) had at least one copy of rs5491. Each additional rs5491 allele was significantly associated with higher proportions of Tc17 CD8+ cytotoxic T cells (β = 1.34, SE = 0.45, P = 9.5 × 10−5) and Tc2 CD8+ cytotoxic T cells (β = 1.19, SE = 0.44, P = 0.00012). There were no other associations noted between rs5491 and the remaining immune cells. A higher proportion of Tc17 cells was significantly associated with a higher left ventricular ejection fraction, E/e′ average and right ventricular systolic pressure (RVSP), while a higher proportion of Tc2 cells was significantly associated with a higher RVSP. Conclusions The ICAM1 p.K56M variant (rs5491) carries a distinct and inflammatory T‐cell subset profile. These cytotoxic T cells are in turn associated with alterations in cardiac function and adverse haemodynamics later in life, thus providing insight into pathways by which rs5491 may increase the risk of HFpEF.

Abstract Background Very large sample sizes are often needed to capture heterogeneity in autism, necessitating data sharing across multiple studies with diverse assessment instruments. In these cases, data harmonization can be a critical tool for deriving a single dataset for analysis. This can be done through computational approaches that enable the conversion of scores across various instruments. To this end, our study examined the use of analytical approaches for mapping scores on two measures of adaptive functioning, namely predicting the scores on the vineland adaptive behavior scales II (VABS) from the scores on the adaptive behavior assessment system II (ABAS). Methods Data from the province of Ontario neurodevelopmental disorders network were used. The dataset included scores VABS and the ABAS for 720 participants (autism n = 547, 433 male, age: 11.31 ± 3.63 years; neurotypical n = 173, 95 male, age: 12.53 ± 4.05 years). Six regression approaches (ordinary least squares (OLS) linear regression, ridge regression, ElasticNet, LASSO, AdaBoost, random forest) were used to predict VABS total scores from the ABAS scores, demographic variables (age, sex), and phenotypic measures (diagnosis; core and co-occurring features; IQ; internalizing and externalizing symptoms). Results The VABS scores were significantly higher than the ABAS scores in the autism group, but not the neurotypical group (median difference: 8, 95% CI = (7,9)). The difference was negatively associated with age (beta = -1.2 ± 0.12, t = -10.6, p

Abstract Background Ureteral stents are placed by urologists to ensure ureteral patency in the postoperative period following ureteroscopy to treat kidney stones, with the goal to reduce complications. However, ureteral stents themselves cause pain and urinary symptoms in many patients that can lead to morbidity. Professional society guidelines support stent omission after uncomplicated ureteroscopy, which represents most cases. Despite this, ureteral stents are utilized in more than 80% of all ureteroscopy procedures. One reason for guideline discordance is the low level of evidence supporting stent omission recommendations. Studies are inconclusive on whether stents increase pain and complications. A recent Cochrane review concluded higher quality and large trials are needed to inform decision-making. Furthermore, there is a lack of studies evaluating health-related quality of life (HRQOL), patient-reported outcomes (PROs), and unplanned healthcare utilization. Another factor is that prospective clinical trials are hindered by patient reluctance to be randomized to either stent placement or omission. The outcomes of patients who decline randomization have been ignored in trials, limiting the generalizability of the evidence. Methods Through collaboration with patient partners, we developed a pragmatic multi-center combined randomized and observational cohort study in a quality improvement collaborative. Patients will be prospectively enrolled into a randomized cohort in which assignment to ureteral stent omission (vs. placement) is determined in the operating room using a web-based randomization platform. Patients who decline randomization are invited to take part in an observational (real-world) cohort in which the determination of stent use is at the discretion of the urologist. Patients in both cohorts will complete preoperative and postoperative assessments of PROs including pain, urinary symptoms, interference with usual activities, time taken off work or school, and treatment satisfaction. Unplanned healthcare utilization within 30 days postoperatively will be assessed by review of the electronic health record. Severe adverse events will be recorded. A subgroup of patients and urologists will also participate in qualitative semi-structured interviews focusing on knowledge, preferences, and practice patterns regarding ureteral stenting. Interview transcripts will be thematically analyzed. Discussion This study is designed to evaluate the HRQOL and 30-day healthcare utilization of patients undergoing ureteral stent omission compared to stent placement following uncomplicated ureteroscopic treatment of upper urinary tract stones. Additionally, patient and urologist opinions and preferences related to ureteral stenting will be explored through qualitative interviews, with the aim of identifying key barriers and facilitators of practice change related to stenting practices. Trial registration ClinicalTrials.gov, NCT05866081. Registered on 19 May 2023.

Across many countries of Central and Eastern Europe the emigration of skilled professionals since 1990 has become a serious problem of the loss of specialised human capital. This paper on Albanian doctors is one of the first to study in depth an example of this broader phenomenon of brain drain from the CEE region. There is a global demand for medical doctors which exceeds supply, leading to international competition in which the richer countries, with higher salaries and better working conditions, attract medical graduates and trained doctors from poorer countries. The migration of doctors from Albania is set within this globalised and hierarchised market for medical expertise. On the one hand, the movement of doctors to richer countries helps to plug the deficit in their supply in such countries and enables the individuals concerned to improve their incomes and life conditions. On the other hand, the loss of medical professionals severely harms the structure and quality of the health service in the sending country. This paper addresses three main questions. First, what are the characteristics of the Albanian medical brain drain in terms of its size, socio-demographics and destination countries? Second, what are the causes and consequences of Albania’s loss of medical doctors? Third, what are the prospects of the migrant doctors returning to Albania or contributing their expertise from abroad? Answers are provided via a dual methodology of an online survey of Albanian doctors currently working abroad (N=301) and follow-up interviews with 25 of them. More than half of the survey respondents do not intend to return to Albania and a further third are undecided. Interview data indicate that the doctors are well-integrated abroad and see ‘no future’ for themselves and their families in Albania. There is, however, a greater willingness to share expertise with the home country via cooperation and short visits. Obstacles to return are partly income-related but, to a greater extent, reflect the poor working conditions and career prospects in Albania, including endemic corruption – the same factors that caused emigration in the first place. The policy implications of our findings are challenging; one solution is to mandate a period of work in Albania for newly qualified doctors before they are allowed to go abroad.

Abstract αB-crystallin is an archetypical member of the small heat shock proteins (sHSPs) vital for cellular proteostasis and mitigating protein misfolding diseases. Gaining insights into the principles defining their molecular organization and chaperone function have been hindered by intrinsic dynamic properties and limited high-resolution structural analysis. To disentangle the mechanistic underpinnings of these dynamical properties, we ablate a conserved IXI-motif located within the N-terminal (NT) domain of human αB-crystallin implicated in subunit exchange dynamics and client sequestration. This results in a profound structural transformation, from highly polydispersed caged-like native assemblies into an elongated fibril state amenable to high-resolution cryo-EM analysis. The reversible nature of this variant facilitates interrogation of functional effects due to perturbation of the NT-IXI motif in both the native-like oligomer and fibril states. Together, our investigations unveil several features thought to be key mechanistic attributes to sHSPs and point to a critical significance of the NT-IXI motif in αB-crystallin assembly, polydispersity, and chaperone activity.

Abstract Background As dissemination and implementation (D&I) research increases, we must continue to expand training capacity and research networks. Documenting, understanding, and enhancing advice networks identifies key connectors and areas where networks are less established. In 2012 Norton et al. mapped D&I science advice and collaboration networks. The current study builds on this work and aims to map current D&I research advice networks. Methods D&I researchers in the United States (US) and Canada were identified through a combination of publication metrics, and key persons identified networks and were invited to participate (n = 1,576). In this social network analysis study, participants completed an online survey identifying up to 10 people from whom they sought and/or gave advice on D&I research. Participants identified four types of advice received: research methods, grant, career, or another type (e.g., work/life balance). We used descriptive statistics to characterize the sample and network metrics and visualizations to describe the composition of advice networks. Results A total of 482 individuals completed the survey. Eighty-six (18%) worked in Canada and 396 (82%) in the US. Respondents had varying D&I research expertise levels; 14% beginner expertise, 45% intermediate, 29% advanced, and 12% expert. The advice network included 978 connected nodes/individuals. For all research types, out-degree, or advice giving, was higher for those with advanced or expert-level expertise (6.9 and 11.9, respectively) than those with beginner or intermediate expertise (0.8 and 2.2, respectively). Respondents reporting White race reported giving (out-degree = 5.2) and receiving (in-degree = 6.1) more advice compared to individuals reporting Asian (out-degree = 2.9, in-degree = 5.3), Black (out-degree = 2.3, in-degree = 5.2), or other races (out-degree = 2.5, in-degree = 5.4). Assortativity analyses revealed 98% of network ties came from individuals within the same country. The top two reasons for advice seeking were trusting the individual to give good advice (78%) and the individual’s knowledge/experience in specific D&I content (69%). Conclusions The D&I research network is becoming more dispersed as the field expands. Findings highlight opportunities to further connect D&I researchers in the US and Canada, individuals with emerging skills in D&I research, and minoritized racial groups. Expanding peer mentoring opportunities, especially for minoritized groups, can enhance the field’s capacity for growth.

Background: The prevalence of mental health disorders calls for valid and reliable instruments that are easy to administer and assess for clinicians and researchers. The Depression Anxiety Stress Scale-21 (DASS-21) is a commonly used instrument to assess psychological distress; however, model fit and internal reliability issues have been reported. Our objective was to assess the factorial and structural validity of the DASS-21. Methods: A confirmatory factor analysis (CFA) was conducted on the full sample (n = 1036) to assess the proposed three-factor DASS-21 using a priori cut-off values. Because model fit indices were not met, an exploratory factor analysis (EFA) was conducted to identify a parsimonious model. The resulting three-factor structure (i.e., DASS-9) was then assessed using CFA and multigroup invariance testing procedures. Results: The proposed three-factor DASS-21 did not meet model fit criteria. The DASS-9 did meet recommended model fit criteria and was invariant between sex, injury status, mental health diagnosis, and activity level groups. Statistically different group means were found between mental health diagnosis and activity level groups, while no differences between sex or injury status groups were found. Conclusions: The current study provides support to use a condensed DASS-21 instrument, such as the DASS-9. Future research is necessary to establish the DASS-9 prior to its adoption in research and clinical practice. Additionally, there is a need to identify and review all condensed versions of the DASS-21, so individuals know which instrument can be used for clinical or research purposes.

Abstract We report the performance of a magnetically silent optically pumped cesium magnetometer with a statistical sensitivity of 3.5 pT/ $$\sqrt{\textrm{Hz}}$$ Hz at 1 Hz and a stability of 90 fT over 150 s of measurement. Optical pumping with coherent, linearly-polarized, resonant light leads to a relatively long-lived polarized ground state of the cesium vapour contained in a measurement cell. The state precesses at its Larmor frequency in the magnetic field to be measured. Nonlinear magneto-optical rotation then leads to the rotation of the plane of polarization of a linearly polarized probe laser beam. The rotation angle is modulated at twice the Larmor frequency. A measurement of this frequency constitutes an absolute measurement of the magnetic field magnitude. Featuring purely optical operation, non-magnetic construction, low noise floor, and high stability, this sensor will be used for the upcoming TUCAN electric dipole moment experiment and other highly sensitive magnetic applications. Novel aspects of the system include commercial construction and the ability to operate up to 24 sensors on a single probe laser diode.