Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping.

Fibrotic diseases affect multiple organs and are associated with morbidity and mortality. To examine organ-specific and shared biologic mechanisms that underlie fibrosis in different organs, we developed machine learning models to quantify T1 time, a marker of interstitial fibrosis, in the liver, pancreas, heart and kidney among 43,881 UK Biobank participants who underwent magnetic resonance imaging. In phenome-wide association analyses, we demonstrate the association of increased organ-specific T1 time, reflecting increased interstitial fibrosis, with prevalent diseases across multiple organ systems. In genome-wide association analyses, we identified 27, 18, 11 and 10 independent genetic loci associated with liver, pancreas, myocardial and renal cortex T1 time, respectively. There was a modest genetic correlation between the examined organs. Several loci overlapped across the examined organs implicating genes involved in a myriad of biologic pathways including metal ion transport (SLC39A8, HFE and TMPRSS6), glucose metabolism (PCK2), blood group antigens (ABO and FUT2), immune function (BANK1 and PPP3CA), inflammation (NFKB1) and mitosis (CENPE). Finally, we found that an increasing number of organs with T1 time falling in the top quintile was associated with increased mortality in the population. Individuals with a high burden of fibrosis in ≥3 organs had a 3-fold increase in mortality compared to those with a low burden of fibrosis across all examined organs in multivariable-adjusted analysis (hazard ratio = 3.31, 95% confidence interval 1.77-6.19; P = 1.78 × 10-4). By leveraging machine learning to quantify T1 time across multiple organs at scale, we uncovered new organ-specific and shared biologic pathways underlying fibrosis that may provide therapeutic targets.

Unlocking Direct Lithium Extraction in Harsh Conditions through Thiol-Functionalized Metal-Organic Framework Subnanofluidic Membranes.

Metal-organic framework (MOF) membranes with high ion selectivity are highly desirable for direct lithium-ion (Li+) separation from industrial brines. However, very few MOF membranes can efficiently separate Li+ from brines of high Mg2+/Li+ concentration ratios and keep stable in ultrahigh Mg2+-concentrated brines. This work reports a type of MOF-channel membranes (MOFCMs) by growing UiO-66-(SH)2 into the nanochannels of polymer substrates to improve the efficiency of MOF membranes for challenging Li+ extraction. The resulting membranes demonstrate excellent monovalent metal ion selectivity over divalent metal ions, with Li+/Mg2+ selectivity up to 103 since Mg2+ should overcome a higher energy barrier than Li+ when transported through the MOF pores, as confirmed by molecular dynamics simulations. Under dual-ion diffusion, as the Mg2+/Li+ mole ratio of the feed solution increases from 0.2 to 30, the membrane Li+/Mg2+ selectivity decreases from 1516 to 19, corresponding to the purity of lithium products between 99.9 and 95.0%. Further research on multi-ion diffusion that involves Mg2+ and three monovalent metal ions (K+, Na+, and Li+, referred to as M+) in the feed solutions shows a significant improvement in Li+/Mg2+ separation efficiency. The Li+/Mg2+ selectivity can go up to 1114 when the Mg2+/M+ molar concentration ratio is 1:1, and it remains at 19 when the ratio is 30:1. The membrane selectivity is also stable for 30 days in a highly concentrated solution with a high Mg2+/Li+ concentration ratio. These results indicate the feasibility of the MOFCMs for direct lithium extraction from brines with Mg2+ concentrations up to 3.5 M. This study provides an alternative strategy for designing efficient MOF membranes in extracting valuable minerals in the future.

A Homochiral Porous Organic Cage-Polymer Membrane for Enantioselective Resolution.

Membrane-based enantioselective separation is a promising method for chiral resolution due to its low cost and high efficiency. However, scalable fabrication of chiral separation membranes displaying both high enantioselectivity and high flux of enantiomers is still a challenge. Here, the authors report the preparation of homochiral porous organic cage (Covalent cage 3 (CC3)-R)-based enantioselective thin-film-composite membranes using polyamide (PA) as the matrix, where fully organic and solvent-processable cage crystals have good compatibility with the polymer scaffold. The hierarchical CC3-R channels consist of chiral selective windows and inner cavities, leading to favorable chiral resolution and permeation of enantiomers; the CC3-R/PA composite membranes display an enantiomeric excess of 95.2% for R-(+)-limonene over S-(-)-limonene and a high flux of 99.9 mg h-1 m-2. This work sheds light on the use of homochiral porous organic cages for preparing enantioselective membranes and demonstrates a new route for the development of next-generation chiral separation membranes.

Chronic Stress Indicator: A Novel Tool for Comprehensive Stress Analysis.

Extensive research has highlighted the strong association between chronic stress and negative health outcomes. This relationship is influenced by various factors, including sociobehavioral, environmental, and genetic and epigenomic forces. To comprehensively assess an individual's stress levels, we propose the development of the Chronic Stress Indicator (CSI), a novel comprehensive multifaceted tool that incorporates key biological, anthropometric, behavioral, and socioeconomic factors. The objective of this study is to assess the effectiveness of the CSI compared to Allostatic Load (AL), a type of chronic stress, in identifying health issues related to stress. The objective of this research is to evaluate the performance of the Chronic Stress Indicator (CSI) versus Allostatic Load (AL) in detecting adverse health outcomes within the U.S. demographic aged 20-49. The information used for this study was sourced from the National Health and Nutrition Examination Survey (NHANES), carried out from 2001 to 2004. Logistic regression modeling was employed to calculate odds ratios and confidence intervals. The Wilcoxon rank-sum test was employed to assess differences in means, whereas the chi-square test, accompanied by Cramer's V statistic, was used to examine the association among categorical variables. Additionally, the relationship between continuous variables was analyzed using Pearson's correlation coefficient. Our association tests show that the length of occupation activity and health status were among the strongest associations to CSI risk. Based on our logistic regression models, age and sex were found to be significant factors in determining AL. We also found that age, smoking, and longest occupation activity were significant factors of CSI risk. These findings suggest a need for individuals to limit smoking as it may lead to higher overall stress despite its common use as a coping mechanism for stress. We should also review the level of occupational activity a job has before continuously working on it as this may also lead to higher cumulative stress.

Effects of prenatal THC vapor exposure on body weight, glucose metabolism, and feeding behaviors in chow and high-fat diet fed rats.

BACKGROUND: 4-20% of people report using cannabis during pregnancy, thereby it is essential to assess the associated risks. There is some evidence that prenatal cannabis exposure (PCE) may be associated with increased risk for developing of obesity and diabetes later in life, however this has not been well explored under controlled conditions. The aim of this study was to use a translational THC vapor model in rodents to characterize the effects of PCE on adiposity, glucose metabolism, and feeding patterns in adulthood, with focus on potential sex differences. METHODS: Pregnant Sprague Dawley rats were exposed to vaporized THC (100 mg/ml) or control (polyethylene glycol vehicle) across the entire gestational period. Adult offspring from PCE (n = 24) or control (n = 24) litters were subjected to measures of adiposity, glucose metabolism and feeding behavior. Rats were then placed onto special diets (60% high-fat diet [HFD] or control 10% low fat diet [LFD]) for 4-months, then re-subjected to adiposity, glucose metabolism and feeding behavior measurements. RESULTS: PCE did not influence maternal weight or food consumption but was associated with transient decreased pup weight. PCE did not initially influence bodyweight or adiposity, but PCE did significantly reduce the rate of bodyweight gain when on HFD/LFD, regardless of which diet. Further, PCE had complex effects on glucose metabolism and feeding behavior that were both sex and diet dependent. No effects of PCE were found on plasma leptin or insulin, or white adipose tissue mass. CONCLUSIONS: PCE may not promote obesity development but may increase risk for diabetes and abnormal eating habits under certain biological and environmental conditions. Overall, this data enhances current understanding of the potential impacts of PCE.

Treatment of a contained rupture of a splenic artery pseudoaneurysm with direct thrombin injection.

Splenic artery pseudoaneurysm is a rare and potentially fatal condition. In the present report, we describe the case of a 50-year-old woman with chronic pancreatitis who presented with worsening abdominal pain. Computed tomography demonstrated a 3.5-cm splenic artery pseudoaneurysm of the mid-splenic artery. The patient underwent attempted endovascular repair of the pseudoaneurysm that was unsuccessful. Open conversion revealed an inaccessible splenic artery due to chronic pancreatitis that resulted in dense retroperitoneal fibrosis, and repair was achieved via direct thrombin injection under ultrasound guidance of the pseudoaneurysm and splenectomy. The patient recovered well, and computed tomography at 3 days postoperatively revealed complete thrombosis of the pseudoaneurysm.

Synthesizing Hypercrosslinked Polymers with Deep Eutectic Solvents to Enhance CO2 /N2 Selectivity.

Hypercrosslinked polymers (HCPs) are widely used in ion exchange, water purification, and gas separation. However, HCP synthesis typically requires hazardous halogenated solvents e. g., dichloroethane, dichloromethane and chloroform which are toxic to human health and environment. Herein we hypothesize that the use of halogenated solvents in HCP synthesis can be overcome with deep eutectic solvents (DES) comprising metal halides-FeCl3 , ZnCl2 that can act as both the solvent hydrogen bond donor and catalyst for polymer crosslinking via Friedel Crafts alkylation. We validated our hypothesis by synthesizing HCPs in DESs via internal and external crosslinking strategies. [ChCl][ZnCl2 ]2 and [ChCl][FeCl3 ]2 was more suitable for internal and external hypercrosslinking, respectively. The specific surface areas of HCPs synthesized in DES were 20-60 % lower than those from halogenated solvents, but their CO2 /N2 selectivities were up to 453 % higher (CO2 /N2 selectivity of poly-α,α'-dichloro-p-xylene synthesized in [ChCl][ZnCl2 ]2 via internal crosslinking reached a value of 105). This was attributed to the narrower pore size distributions of HCPs synthesized in DESs.

MMCT-Loop: a mix model-based pipeline for calling targeted 3D chromatin loops.

Protein-specific Chromatin Conformation Capture (3C)-based technologies have become essential for identifying distal genomic interactions with critical roles in gene regulation. The standard techniques include Chromatin Interaction Analysis by Paired-End Tag (ChIA-PET), in situ Hi-C followed by chromatin immunoprecipitation (HiChIP) also known as PLAC-seq. To identify chromatin interactions from these data, a variety of computational methods have emerged. Although these state-of-art methods address many issues with loop calling, only few methods can fit different data types simultaneously, and the accuracy as well as the efficiency these approaches remains limited. Here we have generated a pipeline, MMCT-Loop, which ensures the accurate identification of strong loops as well as dynamic or weak loops through a mixed model. MMCT-Loop outperforms existing methods in accuracy, and the detected loops show higher activation functionality. To highlight the utility of MMCT-Loop, we applied it to conformational data derived from neural stem cell (NSCs) and uncovered several previously unidentified regulatory regions for key master regulators of stem cell identity. MMCT-Loop is an accurate and efficient loop caller for targeted conformation capture data, which supports raw data or pre-processed valid pairs as input, the output interactions are formatted and easily uploaded to a genome browser for visualization.

Secondary traumatic stress in partners of paramedics: A scoping review.

BACKGROUND: Paramedics experience post-traumatic stress in their work, and many paramedics turn to their intimate partner for support. However, exposure to traumatic event details can leave partners vulnerable to secondary traumatic stress. Despite substantial research into reducing stress and improving support for paramedics, few studies have investigated their partners' trauma experiences and support needs. This scoping review aimed to examine evidence regarding secondary traumatic stress in paramedic partners. METHODS: The MEDLINE, PsychINFO, CINAHL, EMCare, and Sociology Source Ultimate databases were searched up to November 9, 2022. The results sections of studies published in English involving a sample of paramedic partners that examined the impact of paramedics' work-related exposure to trauma on their intimate partner were extracted for analysis. This scoping review was guided by the Joanna Briggs Institute methodology. Key themes were generated using a framework synthesis approach. RESULTS: Five qualitative studies and one quantitative study were included, indicating a paucity of literature regarding secondary traumatic stress in paramedic partners. Post-traumatic stress experienced by paramedics can crossover to paramedic partners in the form of secondary traumatic stress; furthermore, it can have widespread effects on couple functioning. While paramedic partners appear to recognise the need for effective coping strategies, they perceive that little support is available to them. Notably, effective strategies aimed at reducing secondary traumatic stress in paramedic partners are limited. CONCLUSION: Further research is required to quantify secondary traumatic stress severity in paramedic partners and explore relationships between post-traumatic stress, secondary traumatic stress, and couple functioning. Further, evaluation of partner support needs and barriers to accessing support is warranted.

Understanding temporal variability across trophic levels and spatial scales in freshwater ecosystems.

A tenet of ecology is that temporal variability in ecological structure and processes tends to decrease with increasing spatial scales (from locales to regions) and levels of biological organization (from populations to communities). However, patterns in temporal variability across trophic levels and the mechanisms that produce them remain poorly understood. Here we analyzed the abundance time series of spatially structured communities (i.e., metacommunities) spanning basal resources to top predators from 355 freshwater sites across three continents. Specifically, we used a hierarchical partitioning method to disentangle the propagation of temporal variability in abundance across spatial scales and trophic levels. We then used structural equation modeling to determine if the strength and direction of relationships between temporal variability, synchrony, biodiversity, and environmental and spatial settings depended on trophic level and spatial scale. We found that temporal variability in abundance decreased from producers to tertiary consumers but did so mainly at the local scale. Species population synchrony within sites increased with trophic level, whereas synchrony among communities decreased. At the local scale, temporal variability in precipitation and species diversity were associated with population variability (linear partial coefficient, ß = 0.23) and population synchrony (ß = -0.39) similarly across trophic levels, respectively. At the regional scale, community synchrony was not related to climatic or spatial predictors, but the strength of relationships between metacommunity variability and community synchrony decreased systematically from top predators (ß = 0.73) to secondary consumers (ß = 0.54), to primary consumers (ß = 0.30) to producers (ß = 0). Our results suggest that mobile predators may often stabilize metacommunities by buffering variability that originates at the base of food webs. This finding illustrates that the trophic structure of metacommunities, which integrates variation in organismal body size and its correlates, should be considered when investigating ecological stability in natural systems. More broadly, our work advances the notion that temporal stability is an emergent property of ecosystems that may be threatened in complex ways by biodiversity loss and habitat fragmentation.

Circadian Influence on Acute Stress-induced Changes in Cortico-limbic Endocannabinoid Levels in Adult Male Rats.

The endocannabinoid (eCB) system plays an important role in regulating the stress response, including glucocorticoid release and the generation of avoidance behaviour. Its two major ligands, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), are dynamically influenced by psychological stress to gate the generation of the stress response and facilitate recovery upon stress termination. Many biological systems exhibit circadian "daily" rhythms, including glucocorticoids and endocannabinoids, and the behavioural and endocrine impact of stress is modulated by the time of day. Nonetheless, most preclinical experiments investigating the interaction between stress and endocannabinoids occur in the light, "inactive" phase. We therefore tested if circadian phase influences stress-induced changes in eCB levels in the hippocampus (HIP), prefrontal cortex (PFC), and amygdala (AMY). Adult male rats were exposed to 15 min swim stress or immediately euthanized, and brains were collected. Testing occurred either early in the light or early in the dark phase of their cycle to compare circadian effects. We found that overall, stress decreased AEA in the AMY and HIP, with an effect in the PFC dependent on the time of day. Conversely, stress increased 2-AG in the AMY, with an effect in the PFC and HIP dependent on the time of day. This suggests that stress has a similar overall impact on eCB levels regardless of circadian phase, but that subtle differences may occur depending on the brain region, especially the PFC.

The First "Hit" to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children.

Background: Cannabis is the most used federally illicit substance among pregnant people in the United States. However, emerging preclinical data show that a significant portion of cannabis constituents, such as Δ9-tetrahydrocannabinol and its bioactive metabolites, readily cross the placenta and accumulate in the fetal brain, disrupting neurodevelopment. Recent research using the Adolescent Brain Cognitive Development (ABCD) Study cohort has linked prenatal cannabis exposure (PCE) to greater neurobehavioral problems and lower total gray and white matter volume in children. Here, we examined the impact of PCE on frontolimbic white matter pathways that are critical for cognitive- and emotion-related functioning, show a high density of cannabinoid receptors, and are susceptible to cannabis exposure during other periods of rapid neurodevelopment (e.g., adolescence). Methods: This study included 11,530 children (mean ± SD age = 118.99 ± 7.49 months; 47% female) from the ABCD Study cohort. Linear mixed-effects models were used to examine the effects of caregiver-reported PCE on fractional anisotropy of 10 frontolimbic pathways (5 per hemisphere). Results: PCE was associated with lower fractional anisotropy of the right (ß = -0.005, p < .001) and left (ß = -0.003, p = .007) fornix, and these results remained significant after adjusting for a variety of covariates, multiple comparisons, fractional anisotropy of all fibers, and using a quality-control cohort only. Conclusions: In sum, we demonstrated small, yet reliable, effects of PCE on white matter integrity during childhood, particularly in the fornix, which plays a crucial role in emotion- and memory-related processes. Future studies are needed to understand the impacts of small changes in brain structure or function on neurodevelopment and risk of neurobehavioral problems.

Seasonal variability of lotic macroinvertebrate communities at the habitat scale demonstrates the value of discriminating fine sediment fractions in ecological assessments.

Despite lotic systems demonstrating high levels of seasonal and spatial variability, most research and biomonitoring practices do not consider seasonality when interpreting results and are typically focused at the meso-scale (combined pool/riffle samples) rather than considering habitat patch dynamics. We therefore sought to determine if the sampling season (spring, summer and autumn) influenced observed macroinvertebrate biodiversity, structure and function at the habitat unit scale (determined by substrate composition), and if this in turn influenced the assessment of fine sediment (sand and silt) pressures. We found that biodiversity supported at the habitat level was not seasonally consistent with the contribution of nestedness and turnover in structuring communities varying seasonally. Habitat differences in community composition were evident for taxonomic communities regardless of the season but were not seasonally consistent for functional communities, and, notably, season explained a greater amount of variance in functional community composition than the habitat unit. Macroinvertebrate biodiversity supported by silt habitats demonstrated strong seasonal differences and communities were functionally comparable to sand habitats in spring and to gravel habitats in autumn. Sand communities were impoverished compared to other habitats regardless of the season. Silt habitats demonstrated a strong increase in Ephemeroptera, Plecoptera and Trichoptera (EPT) taxa and functional richness from spring into autumn, while vegetation habitats displayed a peak in EPT abundance in summer. Only silt and sand habitats demonstrated temporal variability in functional evenness suggesting that these habitats are different in terms of their resource partitioning and productivity over time compared to other habitats. Gravel and vegetation habitats appeared to be more stable over time with functional richness and evenness remaining consistent. To accurately evaluate the influence of fine sediment on lotic ecosystems, it is imperative that routine biomonitoring and scientific research discriminate between sand and silt fractions, given they support different biodiversity, particularly during summer and autumn months.

Challenges and considerations for treating PTSD with medicinal cannabis: the Australian clinician's perspective.

INTRODUCTION: Preclinical and experimental research have provided promising evidence that medicinal cannabis may be efficacious in the treatment of posttraumatic stress disorder (PTSD). However, implementation of medicinal cannabis into routine clinical therapies may not be straightforward. AREAS COVERED: In this review, we describe some of the clinical, practical, and safety challenges that must be addressed for cannabis-based treatment of PTSD to be feasible in a real-world setting. These issues are especially prevalent if medicinal cannabis is to be combined with trauma-focused psychotherapy. EXPERT OPINION: Future consideration of the clinical and practical considerations of cannabis use in PTSD therapy will be essential to both the efficacy and safety of the treatment protocols that are being developed. These issues include dose timing and titration, potential for addiction, product formulation, windows of intervention, and route of administration. In particular, exposure therapy for PTSD involves recall of intense emotions, and the interaction between cannabis use and reliving of trauma memories must be explored in terms of patient safety and impact on therapeutic outcomes.

Sex Differences in Plasma, Adipose Tissue, and Central Accumulation of Cannabinoids, and Behavioral Effects of Oral Cannabis Consumption in Male and Female C57BL/6 Mice.

BACKGROUND: Cannabis edibles are an increasingly popular form of cannabis consumption. Oral consumption of cannabis has distinct physiological and behavioral effects compared with injection or inhalation. An animal model is needed to understand the pharmacokinetics and physiological effects of oral cannabis consumption in rodents as a model for human cannabis edible use. METHODS: Adult male and female C57BL/6 mice received a single dose of commercially available cannabis oil (5 mg/kg Δ9-tetrahydrocannabinol [THC]) by oral gavage. At 0.5, 1, 2, 3, and 6 hours post exposure, plasma, hippocampus, and adipose tissue were collected for THC, 11-OH-THC, and THC-COOH measures. RESULTS: We report delayed time to peak THC and 11-OH-THC concentrations in plasma, brain, and adipose tissue, which is consistent with human pharmacokinetics studies. We also found sex differences in the cannabis tetrad: (1) female mice had a delayed hypothermic effect 6 hours post consumption, which was not present in males; (2) females had stronger catalepsy than males; (3) males were less mobile following cannabis exposure, whereas female mice showed no difference in locomotion but an anxiogenic effect at 3 hours post exposure; and (4) male mice displayed a longer-lasting antinociceptive effect of oral cannabis. CONCLUSIONS: Oral cannabis consumption is a translationally relevant form of administration that produces similar physiological effects as injection or vaping administration and thus should be considered as a viable approach for examining the physiological effects of cannabis moving forward. Furthermore, given the strong sex differences in metabolism of oral cannabis, these factors should be carefully considered when designing animal studies on the effects of cannabis.

The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses.

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.

The Association of Cytomegalovirus and Allostatic Load by Country of Birth and Length of Time in the United States.

BACKGROUND: Cytomegalovirus (CMV) is a highly prevalent virus with a worldwide distribution. It typically remains dormant in most individuals until reactivation. Immunocompromised states are known to be potential causes for CMV reactivation. Current research has shown a link in the decline of immigrant health among those living in the US for an extended period, though the impact of CMV on this is not clear. METHODS: This study investigated the association between country of birth, duration of US residency, allostatic load, and latent cytomegalovirus infection (CMV IgG) in a sample of US adults aged 20-49. The data utilized for our analysis was obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2001 and 2004. Allostatic load, an index measuring the cumulative physiological strain on the body as it strives to regain stability in the presence of chronic stress, provided a valuable approach to assess stress within the context of CMV exposure. Logistic regression modeling was employed to estimate odds ratios and confidence intervals for the analysis. The chi-square test of association and Cramer's V statistic were used to assess the correlation among categorical variables, while Pearson's correlation coefficient was applied to evaluate the relationship between continuous variables. The results revealed that individuals born outside the US and those with less than 20 years of residency in the US exhibited significantly higher proportions of positive CMV IgG compared to individuals born in the US. Specifically, individuals born outside the US had more than triple the odds of CMV IgG when adjusting for the AL index (OR = 3.69, p-value = 0.0063). A similar trend was observed when examining AL risk based on the duration of US residency. Furthermore, age and sex were identified as significant predictors (p-value < 0.05) of AL risk, considering the individual's country of birth. In summary, the findings of this study significantly enhance our comprehension of the intricate interplay between cytomegalovirus (CMV) and allostatic load (AL). The investigation sheds light on how CMV and AL interact within specific demographic contexts, providing valuable insights into the underlying risk factors for CMV infection.

Loss of the Atrial Fibrillation-Related Gene, Zfhx3, Results in Atrial Dilation and Arrhythmias.

BACKGROUND: ZFHX3 (zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. METHODS: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 loss (Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. RESULTS: We found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Zfhx3 Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. CONCLUSIONS: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.