Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility.

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/-) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/- rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/- rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.

Simple autonomous agents can enhance creative semantic discovery by human groups.

Innovation is challenging, and theory and experiments indicate that groups may be better able to identify and preserve innovations than individuals. But innovation within groups faces its own challenges, including groupthink and truncated diffusion. We performed experiments involving a game in which people search for ideas in various conditions: alone, in networked social groups, or in networked groups featuring autonomous agents (bots). The objective was to search a semantic space of 20,000 nouns with defined similarities for an arbitrary noun with the highest point value. Participants (N = 1875) were embedded in networks (n = 125) of 15 nodes to which we sometimes added 2 bots. The bots had 3 possible strategies: they shared a random noun generated by their immediate neighbors, or a noun most similar from among those identified, or a noun least similar. We first confirm that groups are better able to explore a semantic space than isolated individuals. Then we show that when bots that share the most similar noun operate in groups facing a semantic space that is relatively easy to navigate, group performance is superior. Simple autonomous agents with interpretable behavior can affect the capacity for creative discovery of human groups.

Templated Synthesis of Copper Nanoclusters with a Hybrid Lysozyme-Polymer Material for Enhanced Fluorescence.

Hybrid materials that combine organic polymers and biomacromolecules offer unique opportunities for precisely controlling 3D chemical environments. Although biological or organic templates have been separately used to control the growth of inorganic nanoclusters, hybrid structures represent a relatively unexplored approach to tailoring nanocluster properties. Here, we demonstrate that a molecularly defined lysozyme-polymer resin material acts as a structural scaffold for the synthesis of copper nanoclusters (CuNCs) with well controlled size distributions. The resulting CuNCs have significantly enhanced fluorescence compared with syntheses based on polymeric or biological templates alone. The synergistic approach described here is appealing for the synthesis of biocompatible fluorescent labels with improved photostability.

Treatment of harmful gambling: a scoping review of United Kingdom-based intervention research.

BACKGROUND: Understanding and treating the harm caused by gambling is a growing international psychiatric and public health challenge. Treatment of gambling harm may involve psychological and pharmacological intervention, in conjunction with peer support. This scoping review was conducted to identify, for the first time, the characteristics and extent of United Kingdom (UK) based gambling treatment research. We reviewed studies conducted among people seeking treatment for disordered or harmful gambling in the UK, the settings, research designs, and outcome measures used, and to identify any treatment research gaps. METHODS: Systematic searches of PsycInfo, PsycArticles, Scopus, PubMed, and Web of Science databases were carried out for gambling treatment research or evaluation studies conducted in the UK. Studies were included if they evaluated the effectiveness of an intervention or treatment designed to improve symptoms of harmful or problematic gambling, reported outcomes of interventions on treatment adherence, gambling symptoms, or behaviours using standardised measures, were conducted in the UK, and were published since 2000. RESULTS: Eight studies met the inclusion criteria. Four were retrospective chart reviews, two were single-participant case reports, one described a retrospective case series, and one employed a cross-sectional design. None used an experimental design. CONCLUSION: The limited number of studies included in this review highlights a relative paucity of gambling treatment research conducted in UK settings. Further work should seek to identify potential barriers and obstacles to conducting gambling treatment research in the UK.

B cells in the pneumococcus-infected lung are heterogeneous and require CD4+ T cell help including CD40L to become resident memory B cells.

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

Care Quality and Equity in Health Centers During and After the COVID-19 Pandemic.

INTRODUCTION: Federally Qualified Community Health Centers (FQHCs) are on the frontline of efforts to improve healthcare equity and reduce disparities exacerbated by the COVID-19 pandemic. This study assesses the provision and equity of preventive care and chronic disease management by FQHCs before, during, and after the pandemic. METHODS: Using electronic health record data from 210 FQHCs nationwide and employing segmented regression in an interrupted time series design, preventive screening and chronic disease management were assessed for 939,053 patients from 2019 to 2022. Care measures included cancer screenings, blood pressure control, diabetes control, and childhood immunizations; patient-level factors including race and ethnicity, language preference, and multimorbidity status were analyzed for equitable care provision. Analyses were conducted in 2023-2024. RESULTS: Cancer screening rates and blood pressure control initially declined after the onset of the pandemic but later rebounded, while diabetes control showed a slight increase, later stabilizing. Racial and ethnic disparities persisted, with Asian individuals having a higher prevalence of screenings and blood pressure control, and Black/African American individuals facing a lower prevalence for most screenings but a higher prevalence for cervical cancer screening. Hispanic/Latino individuals had a higher prevalence of various screenings and diabetes control. Disparities persisted for Native Hawaiian/Other Pacific Islander and American Indian/Alaska Native individuals and were observed based on language and multimorbidity status. CONCLUSIONS: While preventive screening and chronic disease management in FQHCs have largely rebounded to pre-pandemic levels following an initial decline, persistent disparities highlight the need for targeted interventions to support FQHCs in addressing healthcare inequities.

Selective Macrocyclization of Unprotected Peptides with an Ex Situ Gaseous Linchpin Reagent.

Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride-derived reagent that achieves amine-amine, amine-phenol, and amine-aniline crosslinking via a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal-mediated, and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting-group strategies.

Electronic-Screening, Brief Intervention and Referral to Treatment (e-SBIRT) for Addictive Disorders: Systematic Review and Meta-Analysis.

BACKGROUND: Addictive disorders are significant global public health burdens. Treatment uptake with these disorders is low and outcomes can be mixed. Electronic screening, brief intervention, and referral to treatment (e-SBIRT) programs have potential to improve uptake and treatment outcomes. To date, however, no prior review of the literature has been conducted to gauge the effectiveness of e-SBIRT for addictive disorders. METHODS: We conducted a systematic review and meta-analysis of the literature concerning e-SBIRT for addictive disorders by surveying the MEDLINE, PubMed, Web of Science, Scopus, Embase, and PsycInfo databases on January 17, 2023. RESULTS: Ten articles were included at analysis reporting evaluation of e-SBIRT interventions for substance use disorders including alcohol use in a variety of settings. No articles were identified regarding treatment for behavioral addictions such as disordered/harmful gambling. Meta-analysis found e-SBIRT to be effective at reducing drinking frequency in the short term only. e-SBIRT was not found to be advantageous over control conditions for abstinence or other treatment outcomes. We identified and described common components of e-SBIRT programs and assessed the quality of available evidence, which was generally poor. CONCLUSION: The present findings suggest that research regarding e-SBIRT is concentrated exclusively on higher-risk substance use. There is a lack of consensus regarding the effectiveness of e-SBIRT for addictive disorders. Although common features exist, e-SBIRT designs are variable, which complicates identification of the most effective components. Overall, the quality of outcome evidence is low, and furthermore, high-quality experimental treatment evaluation research is needed.

PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors.

Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients' sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics.

Barriers and enablers to exercise adherence in people with nonspecific chronic low back pain: a systematic review of qualitative evidence.

ABSTRACT: Exercise is a first-line treatment for chronic low back pain (CLBP), reducing pain and disability in the short term. However, exercise benefits decrease over time, with a lack of long-term exercise adherence a potential reason for this. This study aimed to synthesize the perceptions and beliefs of individuals with CLBP and identify their barriers and enablers to exercise adherence. We searched CENTRAL, Embase, CINAHL, SPORTDiscus, PubMed, PsycINFO, and Scopus databases from inception to February 28, 2023, for qualitative studies that explored the factors influencing exercise adherence for people with CLBP. A hybrid approach combining thematic synthesis with the Theoretical Domains Framework was used to analyze data. We assessed methodological quality using the Critical Appraisal Skills Programme checklist and the level of confidence of the themes generated using the Confidence in the Evidence from Reviews of Qualitative Studies. Twenty-three papers (n = 21 studies) were included (n = 677 participants). Four main themes affected exercise adherence: (1) exercise, pain, and the body, (2) psychological factors, (3) social factors, and (4) external factors. These themes contained 16 subthemes that were predominantly both barriers and enablers to exercise adherence. The individual's experiences of barriers and enablers were most appropriately represented across a spectrum, where influencing factors could be a barrier or enabler to exercise adherence, and these could be specific to pre-exercise, during-exercise, and post-exercise situations. These findings may be used to improve exercise adherence and ultimately treatment outcomes in people with CLBP.

How and why do people with chronic low back pain modify their physical activity? A mixed-methods survey.

BACKGROUND: This study investigated the impact of Chronic Low Back Pain (CLBP) on individuals' physical activity (PA) behaviours, specifically, how they modify, cease, or continue PA when experiencing CLBP. The primary aim was to explore the relationship between CLBP and PA and how this is influenced in different contexts (e.g., necessity of a task). METHODS: A mixed-methods survey was administered to 220 participants, including self-reported outcomes, and capturing responses to three distinct questions related to PA and CLBP. The data was analysed via a content analysis. RESULTS: The findings revealed that individuals with CLBP are most likely to modify PA in work-related contexts and least likely to cease it in the same setting. Housework emerged as the most common domain for cessation of PA, while work/study activities were predominantly continued. Reasons for these trends were typically task-based rather than health or enjoyment based and influenced by the perceived necessity of the task in question. CONCLUSION: The study highlights the role of occupational and educational settings in individual responses to CLBP. The findings also highlight a gap in public awareness regarding effective CLBP management strategies, emphasising the need for increased education and awareness programs.

Investigative fatigue: how sleep-circadian factors shape criminal investigations.

Investigating criminal complaints and identifying culprits to be prosecuted in the court of law is an essential process for law-enforcement and public safety. However, law-enforcement investigators operate under very challenging conditions due to stressful environments, understaffing, and public scrutiny, which factors into investigative errors (e.g. uncleared cases). This paper argues that one contributing factor to investigative failures involves sleep and circadian disruption of investigators themselves, known to be prevalent among law-enforcement. By focusing on investigative interviewing, this analysis illustrates how sleep and circadian disruption could impact investigations by considering three broad phases of (1) preparation, (2) information elicitation, and (3) assessment and corroboration. These phases are organized in a framework that outlines theory-informed pathways in need of empirical attention, with special focus on effort and decision-making processes critical to investigations. While existing evidence is limited, preliminary findings support some elements of investigative fatigue. The paper concludes by placing investigative fatigue in a broader context of investigative work while providing recommendations for future research throughout. This paper is part of the Sleep and Circadian Health in the Justice System Collection.

The smallest worthwhile effect on pain intensity of exercise therapy for people with chronic low back pain: a discrete choice experiment study.

OBJECTIVE: To identify the smallest worthwhile effect (SWE) of exercise therapy for people with non-specific chronic low back pain (CLBP). DESIGN: Discrete choice experiment. METHODS: The SWE was estimated as the lowest reduction in pain that participants would consider exercising worthwhile, compared to not exercising i.e., effects due to natural history and other components (e.g., regression to the mean). We recruited English-speaking adults in Australia with non-specific CLBP to our online survey via email obtained from a registry of previous participants and advertisements on social media. We used discrete choice experiment to estimate the SWE of exercise compared to no exercise for pain intensity. We analysed the discrete choice experiment using a mixed logit model, and mitigated hypothetical bias through certainty calibration, with sensitivity analyses performed with different certainty calibration thresholds. RESULTS: Two-hundred and thirteen participants completed the survey. The mean age (±SD) was 50.7±16.5, median (IQR) pain duration 10 years (5-20), and mean pain intensity (±SD) was 5.8±2.3 on a 0-10 numerical rating scale. For people with CLBP the SWE of exercise was a between-group reduction in pain of 20%, compared to no exercise. In the sensitivity analyses, the SWE varied with different levels of certainty calibration; from 0% without certainty calibration to 60% with more extreme certainty calibration. CONCLUSION: This patient-informed threshold of clinical importance could guide the interpretation of findings from randomised trials and meta-analyses of exercise therapy compared to no exercise.

Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones.

High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment.

A Rare Case of Complete Inguinoscrotal Bladder Herniation With Ureteric Involvement: Assessing Diagnostic Challenges and Complex Surgical Management.

Inguinoscrotal hernias involving the urinary bladder are exceedingly rare, constituting a small subset of inguinal hernias. We present a case of a 47-year-old male with long-standing scrotal enlargement and obstructive uropathy due to complete herniation of the bladder with ureteric involvement. Diagnostic imaging confirmed the condition. Following an open laparotomy, the bladder was reduced, and a modified Bassini technique with orchiopexy was used for repair. Recurrence of the inguinoscrotal hernia with evidence of the bladder in the scrotal sac required additional surgery. This case underscores the rarity, diagnostic complexity, and potential complications of inguinoscrotal bladder hernias. Specialized surgical techniques and a multidisciplinary approach are crucial for successful management, especially in cases of complete bladder herniation. Future considerations should include innovative approaches to enhance primary repair outcomes for extensive hernias involving the bladder.

Alpha-mannosidase-2 modulates arbovirus infection in a pathogen- and Wolbachia-specific manner in Aedes aegypti mosquitoes.

Multiple Wolbachia strains can block pathogen infection, replication and/or transmission in Aedes aegypti mosquitoes under both laboratory and field conditions. However, Wolbachia effects on pathogens can be highly variable across systems and the factors governing this variability are not well understood. It is increasingly clear that the mosquito host is not a passive player in which Wolbachia governs pathogen transmission phenotypes; rather, the genetics of the host can significantly modulate Wolbachia-mediated pathogen blocking. Specifically, previous work linked variation in Wolbachia pathogen blocking to polymorphisms in the mosquito alpha-mannosidase-2 (αMan2) gene. Here we use CRISPR-Cas9 mutagenesis to functionally test this association. We developed αMan2 knockouts and examined effects on both Wolbachia and virus levels, using dengue virus (DENV; Flaviviridae) and Mayaro virus (MAYV; Togaviridae). Wolbachia titres were significantly elevated in αMan2 knockout (KO) mosquitoes, but there were complex interactions with virus infection and replication. In Wolbachia-uninfected mosquitoes, the αMan2 KO mutation was associated with decreased DENV titres, but in a Wolbachia-infected background, the αMan2 KO mutation significantly increased virus titres. In contrast, the αMan2 KO mutation significantly increased MAYV replication in Wolbachia-uninfected mosquitoes and did not affect Wolbachia-mediated virus blocking. These results demonstrate that αMan2 modulates arbovirus infection in A. aegypti mosquitoes in a pathogen- and Wolbachia-specific manner, and that Wolbachia-mediated pathogen blocking is a complex phenotype dependent on the mosquito host genotype and the pathogen. These results have a significant impact for the design and use of Wolbachia-based strategies to control vector-borne pathogens.

Influenza Induces Lung Lymphangiogenesis Independent of YAP/TAZ Activity in Lymphatic Endothelial Cells.

The lymphatic system consists of a vessel network lined by specialized lymphatic endothelial cells (LECs) that are responsible for tissue fluid homeostasis and immune cell trafficking. The mechanisms for organ-specific LEC responses to environmental cues are not well understood. We found robust lymphangiogenesis during influenza A virus infection in the adult mouse lung. We show that the number of LECs increases 2-fold at 7 days post-influenza infection (dpi) and 3-fold at 21 dpi, and that lymphangiogenesis is preceded by lymphatic dilation. We also show that the expanded lymphatic network enhances fluid drainage to mediastinal lymph nodes. Using EdU labeling, we found that a significantly higher number of pulmonary LECs are proliferating at 7 dpi compared to LECs in homeostatic conditions. Lineage tracing during influenza indicates that new pulmonary LECs are derived from preexisting LECs rather than non-LEC progenitors. Lastly, using a conditional LEC-specific YAP/TAZ knockout model, we established that lymphangiogenesis, fluid transport and the immune response to influenza are independent of YAP/TAZ activity in LECs. These findings were unexpected, as they indicate that YAP/TAZ signaling is not crucial for these processes.

Dermal absorption of high molecular weight parent and alkylated polycyclic aromatic hydrocarbons from manufactured gas plant soils using in vitro assessment.

An enhanced in vitro human dermal bioavailability method was developed to measure the release of twenty parent and seven alkylated high molecular weight (HMW) polycyclic aromatic hydrocarbons (PAHs) from contaminated soils collected from five former manufactured Gas Plants (MGP) in England. GC-MS/MS was used to quantify HMW PAHs in soil, Strat-M artificial membrane representing skin, and synthetic receptor solution (RS) representing systemic circulation at 1-h, 10-h, and 24-h timesteps. Fluoranthene and pyrene exhibited the highest fluxes from soils to membrane (ranging from 9.5 - 281 ng/cm2/h) and soil to RS (

Containing misinformation: Modeling spatial games of fake news.

The spread of fake news on social media is a pressing issue. Here, we develop a mathematical model on social networks in which news sharing is modeled as a coordination game. We use this model to study the effect of adding designated individuals who sanction fake news sharers (representing, for example, correction of false claims or public shaming of those who share such claims). By simulating our model on synthetic square lattices and small-world networks, we demonstrate that social network structure allows fake news spreaders to form echo chambers and more than doubles fake news' resistance to distributed sanctioning efforts. We confirm our results are robust to a wide range of coordination and sanctioning payoff parameters as well as initial conditions. Using a Twitter network dataset, we show that sanctioners can help contain fake news when placed strategically. Furthermore, we analytically determine the conditions required for peer sanctioning to be effective, including prevalence and enforcement levels. Our findings have implications for developing mitigation strategies to control misinformation and preserve the integrity of public discourse.

A Qualitative Study Identifying Barriers and Enablers to Exercise Adherence in People with Chronic Low Back Pain. "It's a personal journey".

Exercise leads to clinically meaningful pain reductions in people with chronic low back pain and is recommended as a first line treatment. The benefits of exercise for chronic low back pain decrease over time with a lack of long-term exercise adherence as a potential reason for this decreasing effect. We aimed to identify the barriers and enablers to exercise adherence from the perspective of people with chronic low back pain. This qualitative study was underpinned by a constructivist epistemology and used a critical realist ontological perspective. Adults (18-65 years) with chronic low back pain who had exercised since the onset of their back pain were recruited to participate in focus groups and individual interviews. Audio data were transcribed and then analysed in 2 stages 1) inductive coding using reflexive thematic analysis, followed by 2) deductive analysis through mapping codes onto the Theoretical Domains Framework. Five enablers and 3 barriers were identified across 6 of the 14 Theoretical Domain Framework domains. Exercise identity and confidence in deciding to self-manage pain were enablers, whereas beliefs about the consequences of exercise, exercise context, and relationships could function as either barriers or enablers. These barriers and enablers were complex and fluid, with participants reporting conflicting barriers and enablers that varied, depending on context. These findings improve our understanding of the barriers and enablers to exercise adherence from the individual perspective of people with chronic low back pain and can be utilised for more effective exercise treatment in this population. PERSPECTIVE: This article presents the barriers and enablers to exercise adherence from the perspective of people with chronic low back pain. These perspectives may aid to individualise and optimise exercise treatment, improve its long-term adherence and therefore its effectiveness for chronic low back pain.