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Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized "liver-on-a-chip" model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic "liquid biopsy" of human liver, relevant to biomarker discovery and mechanistic research applications., Competing Interests: Declaration of interests R.S., J.E.B., and A.S.P. have filed for a patent relevant to the findings in this manuscript. R.S. is supported in part by grants from the National Institutes of Health (NIH) and the American Heart Association (AHA). R.S. has equity ownership in Thryv Therapeutics and has served as a consultant for Amgen and Cytokinetics. R.S. is a co-inventor on a patent for ex-RNA signatures of cardiac remodeling (not relevant to the current work), and other patents on proteomic signatures of fitness and lung disease. A.S.P. and E.C. are supported by the AHA Strategically Focused Research Network in Cardiometabolic Disease. J.F.K.S. and G.M. are employees of Emulate, Inc. (a maker of the liver-on-a-chip) and may hold equity interest in Emulate, Inc. S.D. holds a research grant from Bristol Myers Squibb, is a founder and holds equity in Switch Therapeutics, and is a founder and consultant and holds equity for Thryv Therapeutics. J.K. has served as a consultant to Gilead, Merck, ViiV Healthcare, and Janssen and also received research support from Gilead Sciences and Merck. R.K. is supported in part by grants from the NIH; has received grants from AstraZeneca, PneumRx/BTG, and Spiration; has received consulting fees from CVS Caremark, AstraZeneca, GlaxoSmithKline, and CSA Medical; and has received speaking fees from GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. K.A. is supported by an AHA Career Development Award (#929347). J.A.F. serves as a consultant or advisory board member for Kynos Therapeutics, Resolution Therapeutics, Ipsen, River 2 Renal Corp., Stimuliver, Global Clinical Trial Partners, and Guidepoint and has received speaker’s fees from HistoIndex and research grant funding from GlaxoSmithKline, Intercept Pharmaceuticals, and Genentech. T.J.K. undertakes consultancy work for Perspectum, Clinnovate Health, Kynos Therapeutics, Fibrofind, HistoIndex, Concept Life Sciences, and Resolution Therapeutics and has received speaker’s fees from Incyte Corporation and Servier Laboratories. K.V.K.-J. is a member of the scientific advisory board at Dyrnamix. J.J.C. receives project funding from GE Healthcare, Siemens Healthineers, TheraTech, and the NIH. M.N. has received speaking honoraria from Cytokinetics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Get Sensible, a project by Canadian Students for Sensible Drug Policy (CSSDP), is an entirely youth-led cannabis education initiative funded by Health Canada that challenges traditional approaches to cannabis education by prioritizing harm reduction, evidence-based information, lived experience, and non-judgmental conversations through innovative peer-to-peer models. In this narrative reflection, the Get Sensible team explores the necessity of centering young people in the development and implementation of cannabis education initiatives, drawing on their experience developing and disseminating the "Sensible Cannabis Education Booklets", an illustrated series covering a range of cannabis topics in an accessible, intersectional and engaging manner. The positive reception and impact of this campaign is a reflection of the power of truly youth-led projects for authentically connecting with young people to mobilize information in language they relate to and through mediums that resonate with them. This work considers Get Sensible's outreach strategy and approach by evaluating the impact of meeting young people where they are at, whether through social media or pop-up tabling in novel settings (e.g. skateparks and beaches). This reflection details the value of hiring youth to lead every aspect of the project and highlights the benefits of youth-led project design and execution, including the development of print and digital resources, video series, social media content, focus groups and workshops. Through meaningful youth engagement, Get Sensible empowers young people to make informed choices about cannabis use and contribute to the development of effective, evidence-based cannabis education resources and policies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CSSDP would like to acknowledge an unrestricted grant provided by Canopy Growth Corp in 2017 during the initial development of the Sensible Cannabis Education Toolkit, prior to being funded by Health Canada's Substance Use and Addictions Program (SUAP) in 2020., (Copyright © 2024. Published by Elsevier B.V.)

Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated., Methods: We adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length., Results: The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY., Conclusion: Our study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

Alzheimer's disease (AD) is broadly characterized by neurodegeneration, pathology accumulation, and cognitive decline. There is considerable variation in the progression of clinical symptoms and pathology in humans, highlighting the importance of genetic diversity in the study of AD. To address this, we analyze cell composition and amyloid-beta deposition of 6- and 14-month-old AD-BXD mouse brains. We utilize the analytical QUINT workflow- a suite of software designed to support atlas-based quantification, which we expand to deliver a highly effective method for registering and quantifying cell and pathology changes in diverse disease models. In applying the expanded QUINT workflow, we quantify near-global age-related increases in microglia, astrocytes, and amyloid-beta, and we identify strain-specific regional variation in neuron load. To understand how individual differences in cell composition affect the interpretation of bulk gene expression in AD, we combine hippocampal immunohistochemistry analyses with bulk RNA-sequencing data. This approach allows us to categorize genes whose expression changes in response to AD in a cell and/or pathology load-dependent manner. Ultimately, our study demonstrates the use of the QUINT workflow to standardize the quantification of immunohistochemistry data in diverse mice, - providing valuable insights into regional variation in cellular load and amyloid deposition in the AD-BXD model., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of- onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity of human populations, we utilized the AD-BXD mouse panel. This genetically diverse resource combines AD genotypes with multiple BXD strains to discover new genetic drivers of AD resilience. Comparing AD-BXD carriers to noncarrier littermates, we computed a novel quantitative metric for resilience to cognitive decline in the AD-BXDs. Our quantitative AD resilience trait was heritable and genetic mapping identified a locus on chr8 associated with resilience to AD mutations that resulted in amyloid brain pathology. Using a hippocampus proteomics dataset, we nominated the mitochondrial glutathione S reductase protein (GR or GSHR) as a resilience factor, finding that the DBA/2J genotype was associated with substantially higher GR abundance. By mapping protein QTLs (pQTLs), we identified synaptic organization and mitochondrial proteins coregulated in trans with a cis-pQTL for GR. We found four coexpression modules correlated with the quantitative resilience score in aged 5XFAD mice using paracliques, which were related to cell structure, protein folding, and postsynaptic densities. Finally, we found significant positive associations between human GSR transcript abundance in the brain and better outcomes on AD-related cognitive and pathology traits in the Religious Orders Study/Memory and Aging project (ROSMAP). Taken together, these data support a framework for resilience in which neuronal antioxidant pathway activity provides for stability of synapses within the hippocampus.

Cortisol is a vital steroid hormone that has been known as the "stress hormone", which is elevated during times of high stress and anxiety and has a significant impact on neurochemistry and brain health. The improved detection of cortisol is critically important as it will help further our understanding of stress during several physiological states. Several methods exist to detect cortisol; however, they suffer from low biocompatibility and spatiotemporal resolution, and they are relatively slow. In this study, we developed an assay to measure cortisol with carbon fiber microelectrodes (CFMEs) and fast-scan cyclic voltammetry (FSCV). FSCV is typically utilized to measure small molecule neurotransmitters by producing a readout cyclic voltammogram (CV) for the specific detection of biomolecules on a fast, subsecond timescale with biocompatible CFMEs. It has seen enhanced utility in measuring peptides and other larger compounds. We developed a waveform that scanned from -0.5 to -1.2 V at 400 V/s to electro-reduce cortisol at the surface of CFMEs. The sensitivity of cortisol was found to be 0.87 ± 0.055 nA/μM (n = 5) and was found to be adsorption controlled on the surface of CFMEs and stable over several hours. Cortisol was co-detected with several other biomolecules such as dopamine, and the waveform was fouling resistant to repeated injections of cortisol on the surface of the CFMEs. Furthermore, we also measured exogenously applied cortisol into simulated urine to demonstrate biocompatibility and potential use in vivo . The specific and biocompatible detection of cortisol with high spatiotemporal resolution will help further elucidate its biological significance and further understand its physiological importance and impact on brain health.

Background: Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome is a disease composed of hypoparathyroidism, growth retardation, severe developmental delay, and typical dysmorphic features caused by the tubulin-specific chaperone E gene variant. Many patients succumb in infancy to HRD due to overwhelming infections mainly caused by Pneumococcus spp. Knowledge related to the immune system in these patients is scarce., Purpose: To define the immune phenotype of a cohort of HRD patients including their cellular, humoral, and neutrophil functions., Methods: The study included HRD patients followed at Soroka University Medical Center. Clinical and immunological data were obtained, including immunoglobulin concentrations, specific antibody titers, lymphocyte subpopulations, lymphocyte proliferation, and neutrophil functions., Results: Nine patients (5 females and 4 males) were enrolled, aged 6 months to 15 years. All received amoxicillin prophylaxis as part of a routine established previously. Three patients had bacteremia with Klebsiella, Shigella spp., and Candida. Three patients had confirmed coronavirus disease 19 (COVID-19), and two of them died from this infection. All patients had normal blood counts. Patients showed high total IgA and IgE levels, low anti-pneumococcal antibodies in spite of a routine vaccination schedule, and reduced frequency of naive B cells with increased frequency of CD21lowCD27- B cells. All patients had abnormal T-cell population distributions, including reduced terminally differentiated effector memory CD8, inverted CD4/CD8 ratios, and impaired phytohemagglutinin (PHA)-induced lymphocyte proliferation. Neutrophil superoxide production and chemotaxis were normal in all patients tested., Conclusion: HRD is a combined immunodeficiency disease with syndromic features, manifesting in severe invasive bacterial and viral infections., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls on Y-maze working memory (WM) and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging to recall of CFM. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with CFM outcomes in aged mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with the neuronal monocarboxylate transporter MCT2 encoded by Slc16a7 highlighted as novel target., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Excessive smartphone use leads to several physical and psychological disorders, particularly among young adults. This study aimed to investigate the prevalence and the associated factors of problematic smartphone use (PSU) among health sciences students in Jeddah, Saudi Arabia. During the 2019 academic year, a cross-sectional analytic study randomly recruited 408 health sciences students (67.5% were females), with a mean age of 20.5 ± 1.42. Data on sociodemographic and health profiles, smartphone usage patterns, and overuse symptoms were collected for each participant. The Smartphone Addiction Scale-Short Version (SAS-SV) and Generalized Anxiety Disorder 7-item (GAD-7) scale were used to assess PSU and anxiety levels. PSU was detected in 66.9% of the study participants. The prevalence is high among both females and males (69.5 and 61.7%, respectively). PSU was found to be associated with more years of use and frequent smartphone upgrading (aOR = 2.11, 95% CI: 1.12, 3.97) and (aOR = 1.69, 95% CI: 1.08, 2.65), respectively (p = 0.021 and 0.021, respectively). Participants with moderate and severe anxiety levels were found to be more likely to have PSU (aOR = 2.22, 95% CI: 1.21, 4.05) and (aOR = 5.97, 95% CI: 2.41, 14.78), respectively. (p = 0.010 and < 0.001, respectively). PSU is an emerging problem among health sciences students in Saudi Arabia with a high prevalence in both genders. Longer years of use, more frequent smartphone upgrades, and higher anxiety levels are associated with PSU among health sciences students. Special health education and psychological support programs are recommended to guide and support future healthcare providers against the consequences of PSU., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Common neurological disorders, like Alzheimer's disease (AD), multiple sclerosis (MS), and autism, display profound sex differences in prevalence and clinical presentation. However, sex differences in the brain with health and disease are often overlooked in experimental models. Sex effects originate, directly or indirectly, from hormonal or sex chromosomal mechanisms. To delineate the contributions of genetic sex (XX v. XY) versus gonadal sex (ovaries v. testes) to the epigenomic regulation of hippocampal sex differences, we used the Four Core Genotypes (FCG) mouse model which uncouples chromosomal and gonadal sex. Transcriptomic and epigenomic analyses of ~ 12-month-old FCG mouse hippocampus, revealed genomic context-specific regulatory effects of genotypic and gonadal sex on X- and autosome-encoded gene expression and DNA modification patterns. X-chromosomal epigenomic patterns, classically associated with X-inactivation, were established almost entirely by genotypic sex, independent of gonadal sex. Differences in X-chromosome methylation were primarily localized to gene regulatory regions including promoters, CpG islands, CTCF binding sites, and active/poised chromatin, with an inverse relationship between methylation and gene expression. Autosomal gene expression demonstrated regulation by both genotypic and gonadal sex, particularly in immune processes. These data demonstrate an important regulatory role of sex chromosomes, independent of gonadal sex, on sex-biased hippocampal transcriptomic and epigenomic profiles. Future studies will need to further interrogate specific CNS cell types, identify the mechanisms by which sex chromosomes regulate autosomes, and differentiate organizational from activational hormonal effects., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Previous studies have demonstrated that cytosolic phospholipase A 2 α (cPLA 2 α) is required for NOX2 NADPH oxidase activation in human and mouse phagocytes. Moreover, upon stimulation, cPLA 2 α translocates to the plasma membranes by binding to the assembled oxidase, forming a complex between its C2 domain and the PX domain of the cytosolic oxidase factor, p47 phox in human phagocytes. Intravenous administration of antisense against cPLA 2 α that significantly inhibited its expression in mouse peritoneal neutrophils and macrophages also inhibited superoxide production, in contrast to cPLA 2 α knockout mice that showed normal superoxide production. The present study aimed to determine whether there is a binding between cPLA 2 α-C2 domain and p47 phox -PX in mouse macrophages, to further support the role of cPLA 2 α in oxidase regulation also in mouse phagocytes., Methods and Results: A significant binding of mouse GST-p47 phox -PX domain fusion protein and cPLA 2 α in stimulated mouse phagocyte membranes was demonstrated by pull-down experiments, although lower than that detected by the human p47 phox -PX domain. Substituting the amino acids Phe98, Asn99, and Gly100 to Cys98, Ser99, and Thr100 in the mouse p47 phox -PX domain (present in the human p47 phox -PX domain) caused strong binding that was similar to that detected by the human p47 phox -PX domain CONCLUSIONS: The binding between cPLA 2 α-C2 and p47 phox -PX domains exists in mouse macrophages and is not unique to human phagocytes. The binding between the two proteins is lower in the mice, probably due to the absence of amino acids Cys98, Ser 99, and Thr100in the p47 phox -PX domain that facilitate the binding to cPLA 2 α., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)