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.

Novel Application of Skills for Psychological Recovery as an Early Intervention for Posttraumatic Stress Disorder, Depression, and Alcohol Misuse in Survivors of Recent Sexual Assault: A Case Series.

Skills for Psychological Recovery (SPR) is an evidence-informed, early intervention for teaching survivors coping skills in the aftermath of recent disasters. Although SPR has not been tested following recent sexual assault, there is theoretical support for applying SPR to the needs of recent sexual assault survivors. The current study is the first to describe the application of SPR among survivors of recent sexual assault.

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.

Patient-derived response estimates from zero-passage organoids of luminal breast cancer.

Background: Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations.

An isothermal calorimetry assay for determining steady state kinetic and Ensitrelvir inhibition parameters for SARS-CoV-2 3CL-protease.

This manuscript details the application of Isothermal Titration Calorimetry (ITC) to characterize the kinetics of 3CL, the main protease from the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2), and its inhibition by Ensitrelvir, a known non-covalent inhibitor. 3CL is essential for producing the proteins necessary for viral infection, which led to the COVID-19 pandemic. The ITC-based assay provided rapid and reliable measurements of 3CL activity, allowing for the direct derivation of the kinetic enzymatic constants K and k by monitoring the thermal power required to maintain a constant temperature as the substrate is consumed.

Phthalimides as anti-inflammatory agents.

Isoindoline-1,3-dione, also referred as phthalimide, has gained recognition as promising pharmacophore due to the documented biological activities of its derivatives. Phthalimides are a family of synthetic molecules that exhibit notable bioactivity across various fields, particularly as anticancer and anti-inflammatory agents. This review focuses on syntheses and anti-inflammatory studies of the reported phthalimide derivatives.

Unsymmetric hydroxylamine and hydrazine BAM15 derivatives as potent mitochondrial uncouplers.

Chemical mitochondrial uncouplers are protonophoric, lipophilic small molecules that transport protons from the mitochondrial intermembrane space into the matrix independent of ATP synthase, thus uncoupling nutrient oxidation from ATP production. Our previous work identified BAM15 (IC 0.27 μM) as a potent and efficacious mitochondrial uncoupler with potential for obesity treatment.

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).

Structure-guided design and synthesis of C22- and C32-modified FK520 analogs with enhanced activity against human pathogenic fungi.

Invasive fungal infections are a leading cause of death worldwide. Translating molecular insights into clinical benefits is challenging because fungal pathogens and their hosts share similar eukaryotic physiology. Consequently, current antifungal treatments have limited efficacy, may be poorly fungicidal in the host, can exhibit toxicity, and are increasingly compromised by emerging resistance.

Rapid identification and phenotyping of nonalcoholic fatty liver disease patients using a machine-based approach in diverse healthcare systems.

Nonalcoholic fatty liver disease (NAFLD) is the most common global cause of chronic liver disease and remains under-recognized within healthcare systems. Therapeutic interventions are rapidly advancing for its inflammatory phenotype, nonalcoholic steatohepatitis (NASH) at all stages of disease. Diagnosis codes alone fail to recognize and stratify at-risk patients accurately.

US mortality trends from alcohol-associated hepatitis by sex, age, race, and ethnicity, 1999-2020.

Background: Alcohol-associated hepatitis (AH) is a subtype of alcohol-associated liver disease (ALD) resulting in severe acute liver inflammation. This study aims to examine longitudinal trends in mortality from AH in the United States (US) from 1999 to 2020, stratifying the data by sex, age, and racial/ethnic groups.

Methods: We performed a cross-sectional study using data from the US Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER) to determine annual AH-related mortality rates (MR) in adults ≥21 years between 1999 and 2020.

Oxidized phospholipid and transcriptomic signatures of THC-related vaping associated lung injury.

E-cigarette/vaping-associated lung injury (EVALI) is strongly associated with vitamin E acetate and often occurs with concomitant tetrahydrocannabinol (THC) use. To uncover pathways associated with EVALI, we examined cytokines, transcriptomic signatures, and lipidomic profiles in bronchoalveolar lavage fluid (BALF) from THC-EVALI patients. At a single center, we prospectively enrolled mechanically ventilated patients with EVALI from THC-containing products (N = 4) and patients with non-vaping acute lung injury and airway controls (N = 5).

Design of an equilibrative nucleoside transporter subtype 1 inhibitor for pain relief.

The current opioid crisis urgently calls for developing non-addictive pain medications. Progress has been slow, highlighting the need to uncover targets with unique mechanisms of action. Extracellular adenosine alleviates pain by activating the adenosine A1 receptor (A1R).

Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice.

Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low.

Examining social attention as a predictor of problem drinking behavior: A longitudinal study using eye-tracking.

Background: Researchers have long been interested in identifying objective markers for problem drinking susceptibility informed by the environments in which individuals drink. However, little is known of objective cognitive-behavioral indices relevant to the social contexts in which alcohol is typically consumed. Combining group-based alcohol administration, eye-tracking technology, and longitudinal follow-up over a 2-year span, the current study examined the role of social attention in predicting patterns of problem drinking over time.

Supplemental Intervention for Alcohol Use Disorder Treatment Patients With a Co-Occurring Anxiety Disorder: Technical Development and Functional Testing of an Autonomous Digital Program.

Background: Anxiety disorders are common in alcohol use disorder (AUD) treatment patients. Such co-occurring conditions ("comorbidity") have negative prognostic implications for AUD treatment outcomes, yet they commonly go unaddressed in standard AUD care. Over a decade ago, we developed and validated a cognitive behavioral therapy intervention to supplement standard AUD care that, when delivered by trained therapists, improves outcomes in comorbid patients.

Microstructural mapping of neural pathways in Alzheimer's disease using macrostructure-informed normative tractometry.

Introduction: Diffusion-weighted magnetic resonance imaging (dMRI) is sensitive to the microstructural properties of brain tissues and shows great promise in detecting the effects of degenerative diseases. However, many approaches analyze single measures averaged over regions of interest without considering the underlying fiber geometry.

Methods: We propose a novel macrostructure-informed normative tractometry (MINT) framework to investigate how white matter (WM) microstructure and macrostructure are jointly altered in mild cognitive impairment (MCI) and dementia.

Sex differences in the relationships between 24-h rest-activity patterns and plasma markers of Alzheimer's disease pathology.

Background: Although separate lines of research indicated a moderating role of sex in both sleep-wake disruption and in the interindividual vulnerability to Alzheimer's disease (AD)-related processes, the quantification of sex differences in the interplay between sleep-wake dysregulation and AD pathology remains critically overlooked. Here, we examined sex-specific associations between circadian rest-activity patterns and AD-related pathophysiological processes across the adult lifespan.

Methods: Ninety-two cognitively unimpaired adults (mean age = 59.

Total Serum Immunoglobulin E in a Cohort of Children with Food Allergy.

Background: Total serum immunoglobulin E (TsIgE) has not been examined in children with food allergy.

Objective: Evaluate associations of TsIgE with patient, household, environmental and community-level characteristics among children with food allergy.

Method: Linear mixed effect models of data from 398 Black and/or African American (B/AA) and White and/or European American (W/EA) children with allergist-diagnosed food allergy from the multi-center, observational cohort FORWARD; TsIgE in kU/L was the primary outcome measure.

Enhancing Data Science and Genomics Capacity of a Historically Black Medical College Through Interdisciplinary Training and Research Collaborations.

As data grows exponentially across diverse fields, effectively leveraging big data has become increasingly crucial. In data science and computational genomics, however, minority groups, including African Americans, are significantly underrepresented, coupled with the lack of resources and infrastructure in minority-serving institutions. This paper summarizes the second phase of our funded project that aims to enhance the data science capacity of Meharry Medical College (MMC), a Historically Black College/University (HBCU), by providing training and fostering collaborations between data scientists and researchers in basic science and biomedical fields.

Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease.

Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence and severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation is a well-established key factor, recent evidence highlights the critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced liver injury. This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD.

GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis.

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated at 32.4%, reflecting its growing clinical significance. MASLD, which includes MASLD and metabolic dysfunction-associated steatohepatitis (MASH) has been linked to increased metabolic, cardiovascular, and malignant morbidity.