Addressing the Pathophysiology of Venous Thrombosis and Chronic Kidney Disease in Sickle Cell Trait Using a Mouse Model.

Sickle cell trait (SCT) is present in subjects who possess a single copy of the bS-globin gene mutation. While most affected individuals are asymptomatic, SCT is a well-established risk factor for venous thrombosis and renal complications, including chronic and end-stage kidney disease. Following prolonged hypoxia, SCT red blood cells (RBCs) can undergo sickling, and hypoxia-mediated RBC sickling can be enhanced by cellular dehydration, hyperosmolarity and/or acidosis.

LILRB3 genetic variation is associated with kidney transplant failure in African American recipients.

African American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared with other racial and ethnic populations, highlighting the need to identify causative factors. Here, in the Genomics of Chronic Allograft Rejection cohort, pretransplant blood RNA sequencing revealed a cluster of four consecutive missense single-nucelotide polymorphisms (SNPs), within the leukocyte immunoglobulin-like receptor B3 (LILRB3) gene, strongly associated with death-censored graft loss. This SNP cluster (named LILRB3-4SNPs) encodes missense mutations at amino acids 617-618 proximal to a SHP1/2 phosphatase-binding immunoreceptor tyrosine-based inhibitory motif.

Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B.

Adolescent binge alcohol exposure accelerates Alzheimer's disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling.

Human studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer's disease (AD) neuropathology. Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including proinflammatory high-mobility group box 1 (HMGB1)-mediated neuroimmune signaling and basal forebrain cholinergic neuron degeneration. Adolescent onset of binge drinking represents a significant risk factor for later development of an AUD, and accumulating evidence suggests that adolescent initiation of heavy alcohol use induces HMGB1 signaling and causes degeneration of the basal forebrain cholinergic system that persists into adulthood.

Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans.

Candida albicans is the most common cause of life-threatening fungal infection in the developed world but remains a therapeutic challenge. Protein kinases have been rewarding drug targets across diverse indications but remain untapped for antifungal development. Previously, screening kinase inhibitors against C.

Greater alcohol intake predicts accelerated brain aging in humans, which mediates the relationship between alcohol intake and behavioral inflexibility.

Background: Hazardous use of alcohol is associated with cognitive-behavioral impairments and accelerated aging. To date, however, accelerated brain aging has not been tested as a mediating factor between alcohol use and associated task-based behavioral deficits, such as behavioral inflexibility. Here, we evaluated hazardous alcohol use as a predictor of machine learning-derived brain aging and tested if this measure accounted for the relationship between hazardous alcohol use and a task-based measure of behavioral flexibility.

Di-Tyrosine Cross-Linking of Elastin-Like Polypeptides through Ruthenium Photoreaction To Form Scaffolds: Fine Tuning Mechanical Properties and Improving Cytocompatibility.

Ensuring that the mechanical properties of tissue engineering scaffolds align with those of the target tissues is crucial for their successful integration and functional performance. Tyrosine-tyrosine cross-links are found in nature in numerous proteins including resilin that exhibit enhanced toughness and energy storage capacity. Herein, we investigated the potential of tuning the mechanical properties of scaffolds made from elastin-like polypeptides (ELPs) containing tyrosine residues.

Choline enhances elicited imitation memory performance in preschool children with prenatal alcohol exposure: a cumulative report of 3 randomized controlled trials.

Background: Fetal alcohol spectrum disorders (FASDs) are associated with neurocognitive deficits for which there are no biological treatments. Choline supplementation may attenuate these deficits.

Objectives: This study was aimed to evaluate choline as a neurodevelopmental intervention for preschool-aged children with FASD.

State Policy Variation in Implementation of Federal Drug and Child Abuse Laws and Stigmatization of Pregnant and Postpartum Individuals with Opioid Use Disorder.

Despite increased initiatives and funding to improve access to evidence-based treatments for opioid use disorder (OUD), including medications for OUD (mOUD), pregnant/postpartum individuals have significant obstacles to accessing these life-saving medications. Current legislation, specifically the , mandates that the Governor of each state has systems in place to identify and address the needs of substance-exposed infants. However, this legislation removed the word "illegal" when defining substance use and left other important words in the law up to each individual state to define.

Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity.

Introduction: Considering sex as a biological variable (SABV) in preclinical research can enhance understanding of the neurobiology of alcohol use disorder (AUD). However, the behavioral and neural mechanisms underlying sex-specific differences remain unclear. This study aims to elucidate SABV in ethanol (EtOH) consumption by evaluating its reinforcing effects and regulation by glutamate AMPA receptor activity in male and female mice.

Long-chain PUFA and painful temporomandibular disorder in the Hispanic Community Health Study/Study of Latinos.

Objective: -6 and -3 long-chain PUFA play opposing roles in inflammation, anxiety and nociception, all of which are closely associated with chronic pain. We hypothesised that diets high in -6 arachidonic acid (C20:4-6, AA) and low in combined -3 EPA (C20:5-3, EPA) and DHA (C22:6-3, DHA) would be associated with higher odds of painful temporomandibular disorder (TMD).

Design: We analysed baseline data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Repeated cycles of binge-like ethanol consumption and abstinence alter neuropeptide mRNA in prefrontal and insular cortex, amygdala, and lateral hypothalamus of male and female C57BL/6J mice.

Background: Binge drinking is a risky pattern of alcohol (ethanol) consumption associated with a variety of negative outcomes, including the development of alcohol use disorder (AUD). Many neuropeptide systems are thought to become dysregulated in AUD; however, whether repeated cycles of binge-like ethanol consumption and abstinence following binge-like drinking alter neuropeptide mRNA in key brain regions, such as the medial prefrontal cortex (mPFC), insular cortex (IC), amygdala, and lateral hypothalamus (LH), remains unknown.

Methods: Male and female mice underwent 0, 3, or 6 cycles of binge-like ethanol consumption using the "Drinking in the Dark" (DID) paradigm.

Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice.

Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimer's disease and frontotemporal dementia. Phosphorylated tau accumulates in the LC and results in inflammation, synaptic loss, and eventually cell death as the disease progresses. Loss of LC neurons and noradrenergic innervation is thought to contribute to the symptoms of cognitive decline later in disease.

Structure-guided optimization of small molecules targeting the yeast casein kinase, Yck2, as a therapeutic strategy to combat Candida albicans.

is the most common cause of life-threatening fungal infection in the developed world but remains a therapeutic challenge. Protein kinases have been rewarding drug targets across diverse indications but remain untapped for antifungal development. Previously, screening kinase inhibitors against revealed a 2,3-aryl-pyrazolopyridine, GW461484A (GW), which targets casein kinase 1 (CK1) family member Yck2.

Obsessive-compulsive symptoms in individuals with a history of eating disorders.

Background: OCD symptoms are well documented in anorexia nervosa (AN) and to a lesser extent in bulimia nervosa (BN), yet remain virtually unstudied in binge-eating disorder (BED).

Methods: In this cross-sectional observational study, 5927 participants with lifetime eating disorders (EDs) (i.e.

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.

Safety and Efficacy of Deutetrabenazine at High versus Lower Daily Dosages in the ARC-HD Study to Treat Chorea in Huntington Disease.

Background: Huntington disease (HD) is a progressive neurodegenerative disease that causes psychiatric and neurological symptoms, including involuntary and irregular muscle movements (chorea). Chorea can disrupt activities of daily living, pose safety issues, and may lead to social withdrawal. The vesicular monoamine transporter 2 inhibitors tetrabenazine, deutetrabenazine, and valbenazine are approved treatments that can reduce chorea.

Effect of nirmatrelvir/ritonavir (Paxlovid) on hospitalization among adults with COVID-19: An electronic health record-based target trial emulation from N3C.

Background: Nirmatrelvir with ritonavir (Paxlovid) is indicated for patients with Coronavirus Disease 2019 (COVID-19) who are at risk for progression to severe disease due to the presence of one or more risk factors. Millions of treatment courses have been prescribed in the United States alone. Paxlovid was highly effective at preventing hospitalization and death in clinical trials.

A Cross-Biomeasure Study to Optimize Antiretroviral Adherence Estimation.

Background: Incomplete adherence to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) reduces effectiveness. Adherence biomeasures (ie, drug concentrations in biological specimen) are more accurate than self-report. TDF/FTC's intracellular active metabolites (tenofovir-diphosphate; TFVdp and FTC-triphosphate; FTCtp) can be quantified in different types of blood samples to estimate adherence.

Targeting MAO-B with Small-Molecule Inhibitors: A Decade of Advances in Anticancer Research (2012-2024).

Monoamine oxidase B (MAO-B) is a key enzyme in the mitochondrial outer membrane, pivotal for the oxidative deamination of biogenic amines. Its overexpression has been implicated in the pathogenesis of several cancers, including glioblastoma and colorectal, lung, renal, and bladder cancers, primarily through the increased production of reactive oxygen species (ROS). Inhibition of MAO-B impedes cell proliferation, making it a potential therapeutic target.

Selective Mu-Opioid Receptor Imaging Using F-Labeled Carfentanils.

Carfentanil, a highly potent synthetic opioid, paradoxically serves as a crucial positron emission tomography (PET) imaging tool in neurobiological studies of the mu-opioid receptor (MOR) system when labeled with carbon-11 ([C]CFN). However, its clinical research use is hindered by extreme potency and the limited availability of short-lived carbon-11 ( = 20.4 min).

Sex-Specific Effects in Acute Nicotine Vapor Exposure on Binge Drinking and Activity in the Central Amygdala and Ventral Tegmental Area.

Introduction: The increasing prevalence of electronic nicotine delivery systems and alcohol drinking has led to increases in nicotine and alcohol co-use. However, the impact of ENDs on brain activity and binge drinking behavior is not fully understood.

Aims And Methods: We subjected female and male C57BL/6J mice to a voluntary drinking and electronic nicotine vapor exposure paradigm.

Oral fentanyl consumption and withdrawal impairs fear extinction learning and enhances basolateral amygdala principal neuron excitatory-inhibitory balance in male and female mice.

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks.

Dopamine D2 receptors in the bed nucleus of the stria terminalis modulate alcohol-related behaviors.

Dysregulation of the dopamine (DA) system is a hallmark of substance use disorders, including alcohol use disorder (AUD). Of the DA receptor subtypes, the DA D2 receptors (D2Rs) play a key role in the reinforcing effects of alcohol. D2Rs are expressed in numerous brain regions associated with the regulation of appetitive behaviors.

Associations of prenatal urinary melamine, melamine analogues, and aromatic amines with gestational duration and fetal growth in the ECHO Cohort.

Melamine, its analogues, and aromatic amines (AAs) were commonly detected in a previous study of pregnant women in the Environmental influences on Child Health Outcomes (ECHO) Cohort. While these chemicals have identified toxicities, little is known about their influences on fetal development. We measured these chemicals in gestational urine samples in 3 ECHO cohort sites to assess associations with birth outcomes (n = 1,231).