Recent ucr_som_ccr items

Exploring Space‐Time Interactions in Fatal Opioid Overdoses

Thu, 29 Jan 2026 00:00:00 +0000

ABSTRACT This study investigates fatal opioid overdoses in Riverside County, California, between January 2020 and March 2023, employing advanced spatial‐temporal analysis methods to uncover significant clusters and their underlying contexts. By integrating global and local Knox tests, the research identifies both broad trends and specific hotspots of fatal overdoses. The findings reveal substantial spatial disparities, with higher overdose rates in rural areas and neighborhoods characterized by lower socioeconomic status and larger Hispanic populations. Despite a lower overall overdose risk among Hispanics, their neighborhoods exhibit a higher occurrence of fatal overdoses, highlighting complex interactions between individual and environmental factors. These insights underscore the need for targeted, contextually informed public health interventions and policies to effectively address the opioid crisis.

Durable humoral immunity and long-term protection induced by a Crimean-Congo hemorrhagic fever virus replicon particle vaccine in mice

Mon, 8 Dec 2025 00:00:00 +0000

A Crimean-Congo hemorrhagic fever virus replicon particle vaccine was evaluated for long-term immunity and efficacy in mice. IgG responses persisted up to 18 months, with similar titers across dosing strategies through 12 months. Protective efficacy reached ≥75% at 6 months (prime-only) and up to 12 months (prime-boost). Booster dosing enhanced antibody avidity, effector function, and improved long-term protection. These findings support durable immunity from single or boosted vaccination.

The I-ACTED study (investigating action civics training through an experimental design): a cluster randomized controlled trial of a school-based action civics education intervention on adolescent wellbeing

Thu, 6 Nov 2025 00:00:00 +0000

BackgroundObservational studies have found that youth civic engagement is associated with positive mental health, education, and socioeconomic outcomes. However, access to civic opportunities is not evenly distributed. Many classrooms in the United States of America (USA) do not have access to high-quality civics education. Action civics approaches to civic education prepare students for civic engagement by developing the necessary civic skills, knowledge, and character. Through action civics, classes take action on a real-world issue students choose together. Some evidence suggests that action civics may positively affect participants’ wellbeing through the feelings of civic connection and empowerment. The aim of this study is to investigate, through a randomized controlled trial, the impact of a school-based action civics education intervention on civic and wellbeing outcomes, and the mechanisms of any impact observed, among middle and high school students in the USA.MethodsThis...

Rapid, sensitive, and species-independent detection of Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 antibodies

Thu, 14 Aug 2025 00:00:00 +0000

BACKGROUND: Crimean-Congo hemorrhagic fever virus (CCHFV), a zoonotic agent in the Nairoviridae family (genus Orthonairovirus), is a high-priority pathogen. CCHFV infection causes Crimean-Congo hemorrhagic fever (CCHF), a human disease with case fatality rates of up to 40%. Serological surveillance of CCHFV in animals and humans is crucial for ecological studies and public health. METHODS: We developed CCHFV mix-and-read assays utilizing split-NanoLuc technology (NanoBiT) to detect anti-CCHFV antibodies against the nucleoprotein (NP) stalk region and the GP38 glycoprotein. These species- and isotype-agnostic assays provide results in ∼30 min. Using serum samples from RT-PCR-confirmed CCHF cases collected during and after hospitalization, we investigated anti-NP and anti-GP38 antibody development. The performance of the mix-and-read assays was compared to the NP-based IDScreen® CCHF commercial assay using human sera, and cross-reactivity potential was evaluated using a diverse...

Long-Term Effects of Moderate Concussive Brain Injury During Adolescence on Synaptic and Tonic GABA Currents in Dentate Granule Cells and Semilunar Granule Cells

Thu, 14 Aug 2025 00:00:00 +0000

Progressive physiological changes in the hippocampal dentate gyrus circuits following traumatic brain injury (TBI) contribute to temporal evolution of neurological sequelae. Although early posttraumatic changes in dentate synaptic and extrasynaptic GABA currents have been reported, and whether they evolve over time and remain distinct between the two projection neuron classes, granule cells and semilunar granule cells, have not been evaluated. We examined long-term changes in tonic GABA currents and spontaneous inhibitory postsynaptic currents (sIPSCs) and in dentate projection neurons 3 months after moderate concussive fluid percussion injury (FPI) in adolescent rats. Granule cell tonic GABA current amplitude remained elevated up to 1 month after FPI, but decreased to levels comparable with age-matched controls by 3 months postinjury. Granule cell sIPSC frequency, which we previously reported to be increased 1 week after FPI, remained higher than in age-matched controls at 1...

Understanding Opioid Use from Retrospective Accounts of Young Adults in Recovery: Motives, Experiences, and Implications for Prevention

Thu, 17 Jul 2025 00:00:00 +0000

Opioid use disorder is a public health problem with disastrous effects for young people and their families. Opioid use shares risk factors with other substances; there may be additional unique motives and experiences associated with opioid use with potential implications for improving prevention. The present study used surveys and interviews to elicit retrospective accounts of 30 young adults (19 female) in recovery from opioid use disorder to examine (1) self-reported motives for opioid use, and (2) experiences and factors that participants associate with opioid use as compared to other substances. Motives reported for past opioid use on surveys were enhancement (i.e., fun or excitement) and coping (i.e., to forget worries or cheer up when in a bad mood), followed by conformity and social motives. Through analysis of interview data, we found that: experiences of opioid use differed from experiences associated with other substances, with effects described in terms of escape and...

PTPN2 Regulates Iron Handling Protein Expression in Inflammatory Bowel Disease Patients and Prevents Iron Deficiency in Mice

Sat, 26 Apr 2025 00:00:00 +0000

Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), in regulating iron homeostasis. Proteomic analyses were performed on serum from IBD patients genotyped for the IBD-associated loss-of-function rs1893217 PTPN2 variant. Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) mice were analyzed for iron content, blood parameters, and expression of iron handling proteins. Iron absorption was assessed through radiotracer assays. Serum proteomic analyses revealed that the "iron homeostasis signaling pathway" was the main pathway downregulated in Crohn's disease (CD) patients carrying the PTPN2 risk allele, independent of disease activity. Ptpn2-KO mice showed...

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene

Fri, 11 Apr 2025 00:00:00 +0000

BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated...

Chronic, Low-Dose Methamphetamine Reveals Sexual Dimorphism of Memory Performance, Histopathology, and Gene Expression Affected by HIV-1 Tat Protein in a Transgenic Model of NeuroHIV

Thu, 13 Mar 2025 00:00:00 +0000

Methamphetamine (METH) use is frequent among people with HIV (PWH) and appears to increase the risk of neuronal injury and neurocognitive impairment (NCI). This study explored in vivo the effects of a 12 week (long-term), low-dose METH regimen in a transgenic animal model of neuroHIV with inducible expression of HIV-1 transactivator of transcription (Tat). Seven months after transient Tat induction and five months after METH exposure ended, we detected behavioral changes in the Barnes maze (BM) spatial memory task in the Tat and METH groups but not the combined Tat + METH group. The novel object recognition (NOR) task revealed that Tat extinguished discrimination in female animals with and without METH, although METH alone slightly improved NOR. In contrast, in males, Tat, METH, and Tat + METH all compromised NOR. Neuropathological examination detected sex-dependent and brain region-specific changes of pre-synaptic terminals, neurites, and activation of astrocytes and microglia....

Can a Hybrid Line Break a Selection Limit on Behavioral Evolution in Mice?

Mon, 17 Feb 2025 00:00:00 +0000

Artificial selection yielded four replicate high runner (HR) lines of mice that reached apparent selection limits (~ threefold increase in wheel revolutions per day vs. four control lines), despite maintenance of additive genetic variance. After 68 generations, we used animal models to test for changes in additive-genetic variances and covariance of the two measured components (average speed and duration) of running distance. We also attempted to break the selection limit by crossing two HR lines, then continuing directional selection on this hybrid line and on the two parental lines for nine generations. The genetic correlation between speed and duration was positive in the base population, but evolved to be negative in the two parental HR lines. Although heritability for both speed and duration (but not distance) increased in the hybrid line, their genetic correlation remained negative. Hybrid F1 mice from generation 68 parents showed heterosis for running distance, which was...

“Violence and love and drugs…it all goes hand in hand”: A mixed methods analysis of the substance abuse, violence, and HIV/AIDS syndemic among women who use methamphetamine

Fri, 14 Feb 2025 00:00:00 +0000

Background: The synergistic epidemics of substance use, violence, and HIV/AIDS, also known as the SAVA syndemic, disproportionately affects vulnerable women in the United States. Methamphetamine use is closely linked with physical and sexual violence, including intimate partner violence (IPV), which heightens women's vulnerability to HIV. This mixed methods study examined the prevalence and correlates of violence among women who use methamphetamine, (n = 209) enrolled in an HIV intervention study in San Diego, California. Methods: At baseline, 209 women completed an interviewer-administered computer-assisted survey. A sub set of women who reported lifetime IPV (n = 18) also participated in qualitative interviews to contextualize our understanding of patterns of violence over time. Results: In the overall cohort, reports of lifetime (66.0%) and past 2-month (19.6%) IPV were prevalent. Moreover, women reported lifetime physical only (27.3%), sexual...

Synthesis and Molecular Properties of Nerve Agent Reactivator HLö‑7 Dimethanesulfonate

Tue, 24 Dec 2024 00:00:00 +0000

The threat of a deliberate release of chemical nerve agents has underscored the need to continually improve field effective treatments for these types of poisonings. The oxime containing HLö-7 is a potential second-generation therapeutic reactivator. A synthetic process for HLö-7 is detailed with improvements to the DIBAL reduction and ion exchange steps. HLö-7 was visualized for the first time within the active site of human acetylcholinesterase and its relative ex vivo potency confirmed against various nerve agents using a phrenic nerve hemidiaphragm assay.

A Sexually Dimorphic Role for Intestinal Cannabinoid Receptor Subtype-1 in the Behavioral Expression of Anxiety

Fri, 13 Dec 2024 00:00:00 +0000

Background: Increasing evidence suggests that the endocannabinoid system (ECS) in the brain controls anxiety and may be a therapeutic target for the treatment of anxiety disorders. For example, both pharmacological and genetic disruption of cannabinoid receptor subtype-1 (CB₁R) signaling in the central nervous system is associated with increased anxiety-like behaviors in rodents, while activating the system is anxiolytic. Sex is also a critical factor that controls the behavioral expression of anxiety; however, roles for the ECS in the gut in these processes and possible differences between sexes are largely unknown. Objective: In this study, we aimed to determine if CB₁Rs in the intestinal epithelium exert control over anxiety-like behaviors in a sex-dependent manner. Methods: We subjected male and female mice with conditional deletion of CB₁Rs in the intestinal epithelium (intCB₁^-/-) and controls (intCB₁^+/+)...

Replicon particle vaccination induces non-neutralizing anti-nucleoprotein antibody-mediated control of Crimean-Congo hemorrhagic fever virus

Mon, 9 Dec 2024 00:00:00 +0000

Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe human disease and is considered a WHO priority pathogen due to the lack of efficacious vaccines and antivirals. A CCHF virus replicon particle (VRP) has previously shown protective efficacy in a lethal Ifnar-/- mouse model when administered as a single dose at least 3 days prior to challenge. Here, we determine that non-specific immune responses are not sufficient to confer short-term protection, since Lassa virus VRP vaccination 3 days prior to CCHFV challenge was not protective. We also investigate how CCHF VRP vaccination confers protective efficacy by examining viral kinetics, histopathology, clinical analytes and immunity early after challenge (3 and 6 days post infection) and compare to unvaccinated controls. We characterize how these effects differ based on vaccination period and correspond to previously reported CCHF VRP-mediated protection. Vaccinating Ifnar-/- mice with CCHF VRP 28, 14, 7, or 3 days prior...

Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus

Mon, 9 Dec 2024 00:00:00 +0000

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) causes a life-threatening disease with up to a 40% mortality rate. With no approved medical countermeasures, CCHFV is considered a public health priority agent. The non-neutralizing mouse monoclonal antibody (mAb) 13G8 targets CCHFV glycoprotein GP38 and protects mice from lethal CCHFV challenge when administered prophylactically or therapeutically. Here, we reveal the structures of GP38 bound with a human chimeric 13G8 mAb and a newly isolated CC5-17 mAb from a human survivor. These mAbs bind overlapping epitopes with a shifted angle. The broad-spectrum potential of c13G8 and CC5-17 and the practicality of using them against Aigai virus, a closely related nairovirus were examined. Binding studies demonstrate that the presence of non-conserved amino acids in Aigai virus corresponding region prevent CCHFV mAbs from binding Aigai virus GP38. This information, coupled with in vivo efficacy, paves the way for future mAb therapeutics effective...

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses

Sat, 7 Dec 2024 00:00:00 +0000

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for...

Polyphenols as alternative treatments of COVID-19

Sat, 7 Dec 2024 00:00:00 +0000

Although scientists around the world have put lots of effort into the development of new treatments for COVID-19 since the outbreak, no drugs except Veklury (remdesivir) have been approved by FDA. There is an urgent need to discover some alternative antiviral treatment for COVID-19. Because polyphenols have been shown to possess antiviral activities, here we conducted a large-scale virtual screening for more than 400 polyphenols. Several lead compounds such as Petunidin 3-O-(6″-p-coumaroyl-glucoside) were identified to have promising binding affinities and convincing binding mechanisms. Analyzing the docking results and ADME properties sheds light on the potential efficacy of the top-ranked drug candidates and pinpoints the key residues on the target proteins for the future of drug development.

The structural and biochemical impacts of monomerizing human acetylcholinesterase

Fri, 6 Dec 2024 00:00:00 +0000

Serving a critical role in neurotransmission, human acetylcholinesterase (hAChE) is the target of organophosphate nerve agents. Hence, there is an active interest in studying the mechanism of inhibition and recovery of enzymatic activity, which could lead to better countermeasures against nerve agents. As hAChE is found in different oligomeric assemblies, certain approaches to studying it have been problematic. Herein, we examine the biochemical and structural impact of monomerizing hAChE by using two mutations: L380R/F535K. The activities of monomeric hAChE L380R/F535K and dimeric hAChE were determined to be comparable utilizing a modified Ellman's assay. To investigate the influence of subunit-subunit interactions on the structure of hAChE, a 2.1 Å X-ray crystallographic structure was determined. Apart from minor shifts along the dimer interface, the overall structure of the hAChE L380R/F535K mutant is similar to that of dimeric hAChE. To probe whether the plasticity of the...

Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening

Fri, 6 Dec 2024 00:00:00 +0000

Papain-like protease (PL^pro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PL^pro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PL^pro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC₅₀ values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment.

The SARS-CoV‑2 SSHHPS Recognized by the Papain-like Protease

Fri, 6 Dec 2024 00:00:00 +0000

Viral proteases are highly specific and recognize conserved cleavage site sequences of ∼6-8 amino acids. Short stretches of homologous host-pathogen sequences (SSHHPS) can be found spanning the viral protease cleavage sites. We hypothesized that these sequences corresponded to specific host protein targets since >40 host proteins have been shown to be cleaved by Group IV viral proteases and one Group VI viral protease. Using PHI-BLAST and the viral protease cleavage site sequences, we searched the human proteome for host targets and analyzed the hit results. Although the polyprotein and host proteins related to the suppression of the innate immune responses may be the primary targets of these viral proteases, we identified other cleavable host proteins. These proteins appear to be related to the virus-induced phenotype associated with Group IV viruses, suggesting that information about viral pathogenesis may be extractable directly from the viral genome sequence. Here we identify...

Inflammation associated with monocyte/macrophage activation and recruitment corresponds with lethal outcome in a mouse model of Crimean-Congo haemorrhagic fever

Fri, 6 Dec 2024 00:00:00 +0000

Crimean-Congo haemorrhagic fever virus (CCHFV) causes human disease ranging from subclinical to a fatal haemorrhagic syndrome. Determinants of CCHF pathogenesis are largely unknown and animal models that recapitulate human disease are limited. A recently described mouse model uses a monoclonal antibody (mAb 5A3) targeting the interferon (IFN) alpha/beta receptor to suppress type I IFN responses, making animals transiently susceptible to infection. To advance utility of this model, we investigated effects of challenge route, timing of 5A3 delivery, mouse sex and age, and virus strain on clinical course and outcome. C57BL/6J mice received mAb 5A3 -1, 0, or -1/+1 days post-infection (dpi). Subsets were challenged with CCHFV strain Turkey04 or IbAr10200 subcutaneously or intraperitoneally, and serially euthanized 3- and 7-dpi, when meeting euthanasia criteria or at study completion (14 dpi). CCHFV-IbAr10200-infected mice almost uniformly succumbed to infection, whereas CCHFV-Turkey04-infected...

Early deficits in dentate circuit and behavioral pattern separation after concussive brain injury

Thu, 5 Dec 2024 00:00:00 +0000

Traumatic brain injury leads to cellular and circuit changes in the dentate gyrus, a gateway to hippocampal information processing. Intrinsic granule cell firing properties and strong feedback inhibition in the dentate are proposed as critical to its ability to generate unique representation of similar inputs by a process known as pattern separation. Here we evaluate the impact of brain injury on cellular decorrelation of temporally patterned inputs in slices and behavioral discrimination of spatial locations in vivo one week after concussive lateral fluid percussion injury (FPI) in mice. Despite posttraumatic increases in perforant path evoked excitatory drive to granule cells and enhanced ΔFosB labeling, indicating sustained increase in excitability, the reliability of granule cell spiking was not compromised after FPI. Although granule cells continued to effectively decorrelate output spike trains recorded in response to similar temporally patterned input sets after FPI, their...

Editorial: Neuroinflammation in acquired epilepsy

Thu, 5 Dec 2024 00:00:00 +0000

Editorial: Neuroinflammation in acquired epilepsy

EphB2 Signaling Is Implicated in Astrocyte-Mediated Parvalbumin Inhibitory Synapse Development

Thu, 7 Nov 2024 00:00:00 +0000

Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch-clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV→PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV→PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore...

Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 subunit vaccine combination prevents morbidity in mice

Thu, 19 Sep 2024 00:00:00 +0000

Immunizing mice with Crimean-Congo hemorrhagic fever virus (CCHFV) nucleoprotein (NP), glycoprotein precursor (GPC), or with the GP38 domain of GPC, can be protective when the proteins are delivered with viral vectors or as a DNA or RNA vaccine. Subunit vaccines are a safe and cost-effective alternative to some vaccine platforms, but Gc and Gn glycoprotein subunit vaccines for CCHFV fail to protect despite eliciting high levels of neutralizing antibodies. Here, we investigated humoral and cellular immune responses and the protective efficacy of recombinant NP, GP38, and GP38 forms (GP85 and GP160) associated with the highly glycosylated mucin-like (MLD) domain, as well as the NP + GP38 combination. Vaccination with GP160, GP85, or GP38 did not confer protection, and vaccination with the MLD-associated GP38 forms blunted the humoral immune responses to GP38, worsened clinical chemistry, and increased viral RNA in the blood compared to the GP38 vaccination. In contrast, NP vaccination...

A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the Mini-Muscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice

Fri, 30 Aug 2024 00:00:00 +0000

Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g., larger hearts, reduced total body mass and fat mass, longer hind-limb bones) of this hypothesized adaptive allele include functional characteristics that facilitate high levels of voluntary wheel running (e.g., doubling of mass-specific muscle aerobic capacity, increased fatigue resistance of isolated muscles, longer hind-limb bones). Previously, we created a backcross population suitable for mapping the responsible locus. We phenotypically characterized the population and mapped the Minimsc locus to a 2.6-Mb interval on MMU11, a region containing ∼100 known or predicted genes. Here, we present a novel strategy to identify the genetic variant causing the mini-muscle phenotype. Using...

Island tameness: living on islands reduces flight initiation distance

Fri, 30 Aug 2024 00:00:00 +0000

One of Darwin's most widely known conjectures is that prey are tame on remote islands, where mammalian predators are absent. Many species appear to permit close approach on such islands, but no comparative studies have demonstrated reduced wariness quantified as flight initiation distance (FID; i.e. predator-prey distance when the prey begins to flee) in comparison with mainland relatives. We used the phylogenetic comparative method to assess influence of distance from the mainland and island area on FID of 66 lizard species. Because body size and predator approach speed affect predation risk, we included these as independent variables. Multiple regression showed that FID decreases as distance from mainland increases and is shorter in island than mainland populations. Although FID increased as area increased in some models, collinearity made it difficult to separate effects of area from distance and island occupancy. FID increases as SVL increases and approach speed increases;...

Large changes in detected selection signatures after a selection limit in mice bred for voluntary wheel-running behavior

Fri, 30 Aug 2024 00:00:00 +0000

In various organisms, sequencing of selectively bred lines at apparent selection limits has demonstrated that genetic variation can remain at many loci, implying that evolution at the genetic level may continue even if the population mean phenotype remains constant. We compared selection signatures at generations 22 and 61 of the "High Runner" mouse experiment, which includes 4 replicate lines bred for voluntary wheel-running behavior (HR) and 4 non-selected control (C) lines. Previously, we reported multiple regions of differentiation between the HR and C lines, based on whole-genome sequence data for 10 mice from each line at generation 61, which was >31 generations after selection limits had been reached in all HR lines. Here, we analyzed pooled sequencing data from ~20 mice for each of the 8 lines at generation 22, around when HR lines were reaching limits. Differentiation analyses of allele frequencies at ~4.4 million SNP loci used the regularized T-test and detected 258...

DNA methylation in AgRP neurons regulates voluntary exercise behavior in mice

Fri, 30 Aug 2024 00:00:00 +0000

DNA methylation regulates cell type-specific gene expression. Here, in a transgenic mouse model, we show that deletion of the gene encoding DNA methyltransferase Dnmt3a in hypothalamic AgRP neurons causes a sedentary phenotype characterized by reduced voluntary exercise and increased adiposity. Whole-genome bisulfite sequencing (WGBS) and transcriptional profiling in neuronal nuclei from the arcuate nucleus of the hypothalamus (ARH) reveal differentially methylated genomic regions and reduced expression of AgRP neuron-associated genes in knockout mice. We use read-level analysis of WGBS data to infer putative ARH neural cell types affected by the knockout, and to localize promoter hypomethylation and increased expression of the growth factor Bmp7 to AgRP neurons, suggesting a role for aberrant TGF-β signaling in the development of this phenotype. Together, these data demonstrate that DNA methylation in AgRP neurons is required for their normal epigenetic development and neuron-specific...

R2d2 Drives Selfish Sweeps in the House Mouse

Fri, 30 Aug 2024 00:00:00 +0000

A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds...

Early-Life Effects on Adult Physical Activity: Concepts, Relevance, and Experimental Approaches.

Fri, 30 Aug 2024 00:00:00 +0000

Locomotion is a defining characteristic of animal life and plays a crucial role in most behaviors. Locomotion involves physical activity, which can have far-reaching effects on physiology and neurobiology, both acutely and chronically. In human populations and in laboratory rodents, higher levels of physical activity are generally associated with positive health outcomes, although excessive exercise can have adverse consequences. Whether and how such relationships occur in wild animals is unknown. Behavioral variation among individuals arises from genetic and environmental factors and their interactions as well as from developmental programming (persistent effects of early-life environment). Although tremendous progress has been made in identifying genetic and environmental influences on individual differences in behavior, early-life effects are not well understood. Early-life effects can in some cases persist across multiple generations following a single exposure and, in principle,...

Still little evidence sex differences in spatial navigation are evolutionary adaptations

Fri, 30 Aug 2024 00:00:00 +0000

A putative male advantage in wayfinding ability is the most widely documented sex difference in human cognition and has also been observed in other animals. The common interpretation, the sex-specific adaptation hypothesis, posits that this male advantage evolved as an adaptive response to sex differences in home range size. A previous study a decade ago tested this hypothesis by comparing sex differences in home range size and spatial ability among 11 species and found no relationship. However, the study was limited by the small sample size, the lack of species with a larger female home range and the lack of non-Western human data. The present study represents an update that addresses all of these limitations, including data from 10 more species and from human subsistence cultures. Consistent with the previous result, we found little evidence that sex differences in spatial navigation and home range size are related. We conclude that sex differences in spatial ability are more...

Locomotor kinematics on sand vs. vinyl flooring in the sidewinder rattlesnake Crotalus cerastes

Fri, 30 Aug 2024 00:00:00 +0000

For terrestrial locomotion of animals and machines, physical characteristics of the substrate can strongly impact kinematics and performance. Snakes are an especially interesting system for studying substrate effects because their gait depends more on the environment than on their speed. We tested sidewinder rattlesnakes (Crotalus cerastes) on two surfaces: sand collected from their natural environment and vinyl tile flooring, an artificial surface often used to elicit sidewinding in laboratory settings. Of ten kinematic variables examined, two differed significantly between the substrates: the body's waveform had an average of ∼17% longer wavelength on vinyl flooring (measured in body lengths), and snakes lifted their bodies an average of ∼40% higher on sand (measured in body lengths). Sidewinding may also differ among substrates in ways we did not measure (e.g. ground reaction forces and energetics), leaving open clear directions for future study.

Multiple solutions at the genomic level in response to selective breeding for high locomotor activity

Fri, 30 Aug 2024 00:00:00 +0000

Replicate lines under uniform selection often evolve in different ways. Previously, analyses using whole-genome sequence data for individual mice (Mus musculus) from 4 replicate High Runner lines and 4 nonselected control lines demonstrated genomic regions that have responded consistently to selection for voluntary wheel-running behavior. Here, we ask whether the High Runner lines have evolved differently from each other, even though they reached selection limits at similar levels. We focus on 1 High Runner line (HR3) that became fixed for a mutation at a gene of major effect (Myh4Minimsc) that, in the homozygous condition, causes a 50% reduction in hindlimb muscle mass and many pleiotropic effects. We excluded HR3 from SNP analyses and identified 19 regions not consistently identified in analyses with all 4 lines. Repeating analyses while dropping each of the other High Runner lines identified 12, 8, and 6 such regions. (Of these 45 regions, 37 were unique.) These results suggest...

A Multi-Megabase Copy Number Gain Causes Maternal Transmission Ratio Distortion on Mouse Chromosome 2

Fri, 30 Aug 2024 00:00:00 +0000

Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 - 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using...

Treatment Referrals Post-prohibition of Alcohol Exclusion Laws: Evidence from Colorado and Illinois

Wed, 24 Jul 2024 00:00:00 +0000

BackgroundIndividuals with alcohol-related disorders often encounter barriers to accessing treatment. One potential barrier is the state alcohol exclusion laws (AELs) that allow insurers to deny coverage for injuries or illnesses caused by alcohol intoxication. Several states have repealed AELs by prohibiting them completely, including banning exclusions in health and accident insurance policies, limiting their scope, or creating exemptions.ObjectivesTo examine whether prohibiting alcohol exclusions in health and accident insurance policies is associated with alcohol-related treatment admissions.DesignWe used the 2002 to 2017 Treatment Episode Data Set and obtained data from several sources to control for state-level factors. We employed a heterogeneous difference-in-differences method and an event study to compare the treatment admissions in Colorado and Illinois, two states that uniquely repealed AELs, with control states that allowed or had no AELs.Main MeasuresWe used aggregated...

Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood

Sat, 20 Jul 2024 00:00:00 +0000

One of cannabis' most iconic effects is the stimulation of hedonic high-calorie eating-the "munchies"-yet habitual cannabis users are, on average, leaner than non-users. We asked whether this phenotype might result from lasting changes in energy balance established during adolescence, when use of the drug often begins. We found that daily low-dose administration of cannabis' intoxicating constituent, Δ⁹-tetrahydrocannabinol (THC), to adolescent male mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, enhanced thermogenesis, and impaired cold- and β-adrenergic receptor-stimulated lipolysis. Further analyses revealed that this phenotype is associated with molecular anomalies in the adipose organ, including ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote...

Deciphering Abnormal Platelet Subpopulations in COVID-19, Sepsis and Systemic Lupus Erythematosus through Machine Learning and Single-Cell Transcriptomics

Sat, 6 Jul 2024 00:00:00 +0000

This study focuses on understanding the transcriptional heterogeneity of activated platelets and its impact on diseases such as sepsis, COVID-19, and systemic lupus erythematosus (SLE). Recognizing the limited knowledge in this area, our research aims to dissect the complex transcriptional profiles of activated platelets to aid in developing targeted therapies for abnormal and pathogenic platelet subtypes. We analyzed single-cell transcriptional profiles from 47,977 platelets derived from 413 samples of patients with these diseases, utilizing Deep Neural Network (DNN) and eXtreme Gradient Boosting (XGB) to distinguish transcriptomic signatures predictive of fatal or survival outcomes. Our approach included source data annotations and platelet markers, along with SingleR and Seurat for comprehensive profiling. Additionally, we employed Uniform Manifold Approximation and Projection (UMAP) for effective dimensionality reduction and visualization, aiding in the identification of various...

Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV

Sat, 29 Jun 2024 00:00:00 +0000

Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced...

Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection

Mon, 24 Jun 2024 00:00:00 +0000

Crimean-Congo hemorrhagic fever virus (CCHFV) infection can result in a severe hemorrhagic syndrome for which there are no antiviral interventions available to date. Certain RNA viruses, such as CCHFV, encode cysteine proteases of the ovarian tumor (OTU) family that antagonize interferon (IFN) production by deconjugating ubiquitin (Ub). The OTU of CCHFV, a negative-strand RNA virus, is dispensable for replication of the viral genome, despite being part of the large viral RNA polymerase. Here, we show that mutations that prevent binding of the OTU to cellular ubiquitin are required for the generation of recombinant CCHFV containing a mutated catalytic cysteine. Similarly, the high-affinity binding of a synthetic ubiquitin variant (UbV-CC4) to CCHFV OTU strongly inhibits viral growth. UbV-CC4 inhibits CCHFV infection even in the absence of intact IFN signaling, suggesting that its antiviral activity is not due to blocking the OTU's immunosuppressive function. Instead, the prolonged...

Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species

Mon, 24 Jun 2024 00:00:00 +0000

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and antagonize the host innate immune response. The latter function involves reversing the post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like interferon-stimulated gene product 15 (ISG15). Ub is known to be highly conserved among eukaryotes, but surprisingly, ISG15 is highly divergent among animals. The ramifications of this sequence divergence to the recognition of ISG15 by coronavirus PLPs at a structural and biochemical level are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS-CoV, and mouse hepatitis virus was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly,...

Structural insights into the interaction of papain-like protease 2 from the alphacoronavirus porcine epidemic diarrhea virus and ubiquitin

Mon, 24 Jun 2024 00:00:00 +0000

Porcine epidemic diarrhea is a devastating porcine disease that is caused by the alphacoronavirus porcine epidemic diarrhea virus (PEDV). Like other members of the Coronaviridae family, PEDV encodes a multifunctional papain-like protease 2 (PLP2) that has the ability to process the coronavirus viral polyprotein to aid in RNA replication and antagonize the host innate immune response through cleavage of the regulatory proteins ubiquitin (Ub) and/or interferon-stimulated gene product 15 (ISG15) (deubiquitination and deISGylation, respectively). Because Betacoronavirus PLPs have been well characterized, it was sought to determine how PLP2 from the alphacoronavirus PEDV differentiates itself from its related counterparts. PEDV PLP2 was first biochemically characterized, and a 3.1 Å resolution crystal structure of PEDV PLP2 bound to Ub was then solved, providing insight into how Alphacoronavirus PLPs bind to their preferred substrate, Ub. It was found that PEDV PLP2 is a deubiquitinase...

Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease

Mon, 24 Jun 2024 00:00:00 +0000

Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights...

ISG15: It's Complicated

Mon, 24 Jun 2024 00:00:00 +0000

Interferon-stimulated gene product 15 (ISG15) is a key component of host responses to microbial infection. Despite having been known for four decades, grasping the functions and features of ISG15 has been a slow and elusive process. Substantial work over the past two decades has greatly enhanced this understanding, revealing the complex and variable nature of this protein. This has unveiled multiple mechanisms of action that are only now beginning to be understood. In addition, it has uncovered diversity not only between how ISG15 affects different pathogens but also between the function and structure of ISG15 itself between different host species. Here we review the complexity of ISG15 within the context of viral infection, focusing primarily on its antiviral function and the mechanisms viruses employ to thwart its effects. We highlight what is known regarding the impact of ISG15 sequence and structural diversity on these interactions and discuss the aspects presenting the next...

Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity

Mon, 24 Jun 2024 00:00:00 +0000

Post-translational modification of host and viral proteins by ubiquitin (Ub) and Ub-like proteins, such as interferon stimulated gene product 15 (ISG15), plays a key role in response to infection. Viruses have been increasingly identified that contain proteases possessing deubiquitinase (DUB) and/or deISGylase functions. This includes viruses in the Nairoviridae family that encode a viral homologue of the ovarian tumor protease (vOTU). vOTU activity was recently demonstrated to be critical for replication of the often-fatal Crimean-Congo hemorrhagic fever virus, with DUB activity suppressing the type I interferon responses and deISGylase activity broadly removing ISG15 conjugated proteins. There are currently about 40 known nairoviruses classified into fourteen species. Recent genomic characterization has revealed a high degree of diversity, with vOTUs showing less than 25% amino acids identities within the family. Previous investigations have been limited to only a few closely...

Determining the molecular drivers of species-specific interferon-stimulated gene product 15 interactions with nairovirus ovarian tumor domain proteases

Mon, 24 Jun 2024 00:00:00 +0000

Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species' ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species' ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in general, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe...

Structure of interferon-stimulated gene product 15 (ISG15) from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement

Mon, 24 Jun 2024 00:00:00 +0000

Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of these interferon responses. Within these pathways, ISG15 can serve to stabilize host proteins modulating innate immune responses and act as a cytokine. Post-translational modifications of viral proteins introduced by ISG15 have also been observed to directly affect the function of numerous viral proteins. Unlike ubiquitin, which is virtually identical across all animals, comparison of ISG15s across species reveals that they are relatively divergent, with sequence identity dropping to as low as ∼58% among mammals. In addition to serving as an obstacle to the zoonotic transmission of influenza, these ISG15 species-species differences have also long been shown...

Biochemical and Structural Insights into the Preference of Nairoviral DeISGylases for Interferon-Stimulated Gene Product 15 Originating from Certain Species

Mon, 24 Jun 2024 00:00:00 +0000

The regulation of the interferon type I (IFN-I) response has been shown to rely on posttranslational modification by ubiquitin (Ub) and Ub-like interferon-stimulated gene product 15 (ISG15) to stabilize, or activate, a variety of IFN-I signaling and downstream effector proteins. Unlike Ub, which is almost perfectly conserved among eukaryotes, ISG15 is highly divergent, even among mammals. Since zoonotic viruses rely on viral proteins to recognize, or cleave, ISG15 conjugates in order to evade, or suppress, innate immunity, the impact of ISG15 biodiversity on deISGylating proteases of the ovarian tumor family (vOTU) from nairoviruses was evaluated. The enzymatic activities of vOTUs originating from the Crimean-Congo hemorrhagic fever virus, Erve virus, and Nairobi sheep disease virus were tested against ISG15s from humans, mice, shrews, sheep, bats, and camels, which are mammalian species known to be infected by nairoviruses. This along with investigation of binding by isothermal...

Point-of-Sale Health Communication Campaigns for Cigarillos and Waterpipe Tobacco: Effects and Lessons Learned from Two Cluster Randomized Trials

Wed, 15 May 2024 00:00:00 +0000

Many adolescents and young adults hold erroneous beliefs that cigarillos and waterpipe tobacco (WT) are safer than cigarettes, contributing to use. Communication campaigns can correct misperceptions and increase risk beliefs. We tested point-of-sale (POS) communication campaigns focused on chemical exposure for cigarillos and WT. We conducted two cluster randomized trials at 20 gas stations with convenience stores (10 stores for cigarillos, 10 for WT) in North Carolina between June and November 2017. Within each trial, stores were randomly assigned to either the intervention (campaign messages displayed) or a no message control condition. We conducted intercept surveys with repeated cross-sectional samples of 50 adolescents and young adults (ages 16-25) per store, at baseline and follow-up. There were 978 participants (mean age = 20.9 years) in the cigarillo trial, and 998 participants (mean age = 21.0 years) in the WT trial. Rates of campaign exposure...

Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review

Sat, 11 May 2024 00:00:00 +0000

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones' role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because...

Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management

Sat, 11 May 2024 00:00:00 +0000

People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather...

Development and validation of an electronic health records‐based opioid use disorder algorithm by expert clinical adjudication among patients with prescribed opioids

Mon, 6 May 2024 00:00:00 +0000

BACKGROUND: In the US, over 200 lives are lost from opioid overdoses each day. Accurate and prompt diagnosis of opioid use disorders (OUD) may help prevent overdose deaths. However, international classification of disease (ICD) codes for OUD are known to underestimate prevalence, and their specificity and sensitivity are unknown. We developed and validated algorithms to identify OUD in electronic health records (EHR) and examined the validity of OUD ICD codes. METHODS: Through four iterations, we developed EHR-based OUD identification algorithms among patients who were prescribed opioids from 2014 to 2017. The algorithms and OUD ICD codes were validated against 169 independent "gold standard" EHR chart reviews conducted by an expert adjudication panel across four healthcare systems. After using 2014-2020 EHR for validating iteration 1, the experts were advised to use 2014-2017 EHR thereafter. RESULTS: Of the 169 EHR charts, 81 (48%) were reviewed by more than one expert and exhibited...

Cholinergic Neurotransmission Controls Orexigenic Endocannabinoid Signaling in the Gut in Diet-Induced Obesity.

Thu, 25 Apr 2024 00:00:00 +0000

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB₁Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the...

A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury

Thu, 21 Mar 2024 00:00:00 +0000

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal...

Reclusive chandeliers: Functional isolation of dentate axo-axonic cells after experimental status epilepticus

Tue, 13 Feb 2024 00:00:00 +0000

Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells...

Pathways to opioid use and implications for prevention: voices of young adults in recovery

Fri, 2 Feb 2024 00:00:00 +0000

BackgroundOpioid use remains a major public health issue, especially among young adults. Despite investment in harm reduction and supply-side strategies such as reducing overprescribing and safe medication disposal, little is known about demand-side issues, such as reasons for use and pathways to opioid use. Adolescents and young adults who struggle with opioid use disorder (OUD) are multifaceted individuals with varied individual histories, experiences, challenges, skills, relationships, and lives. MethodsTo inform the development of prevention strategies that hold promise for addressing opioid use, this study employs brief structured surveys and semi-structured in-depth interviews with 30 young adults (ages 18–29; 19 female, 23 White, 16 from Suburban areas) in recovery from OUD. For survey data, we used descriptive statistics to summarize the means and variance of retrospectively reported risk and protective factors associated with opioid use. For in-depth interview...

Trends in Opioid Misuse among Marijuana Users and Non-Users in the U.S. from 2007–2017