Ligand Reorganization for End-Point Binding Free Energy Calculations: Identifying Preferred Poses of Fentanyls in the μ Opioid Receptor.

We have developed a method that uses energy landscapes of unbound and bound ligands to compute reorganization free energies for end-point binding free-energy calculations. The method is applied to our previous simulations of fentanyl derivatives bound to the μ opioid receptor in different orientations. Whereas the mean interaction energy provides an ambiguous ranking of binding poses, interaction entropy and ligand reorganization strongly penalize geometric decoys such that native poses observed in CryoEM structures are best ranked.

N-terminal fragment shedding contributes to signaling of the full-length adhesion receptor ADGRL3.

Most adhesion GPCRs undergo autoproteolytic cleavage during receptor biosynthesis, resulting in non-covalently bound N- and C-terminal fragments (NTF and CTF) that remain associated during receptor trafficking to the plasma membrane. While substantial evidence supports increased G protein signaling when just the CTF is expressed, there is an ongoing debate about whether NTF removal is required to initiate signaling in the context of the wild-type receptor. Here, we use adhesion GPCR latrophilin-3 (ADGRL3) as a model receptor to investigate tethered agonist-mediated activation.

Global Epidemiology of Alcohol-Related Liver Disease, Liver Cancer, and Alcohol Use Disorder, 2000-2021.

Background/aims: Alcohol represents a leading burden of disease worldwide, including alcohol use disorder (AUD) and alcohol-related liver disease (ALD). We aim to assess the global burden of AUD, ALD, and alcohol-attributable primary liver cancer between 2000-2021.

Methods: We registered the global and regional trends of AUD, ALD, and alcohol-related liver cancer using data from the Global Burden of Disease 2021 Study, the largest and most up-to-date global epidemiology database.

Bariatric surgery and alcohol and substance use: A case-control survey study.

Purpose: Studies suggest alcohol and/or other substance misuse may develop after bariatric surgery (BS), but findings are not consistent or conclusive.

Procedures: This cross-sectional online survey investigated alcohol and other substance use, via a modified version of the Alcohol Use Disorders Identification Test, before and after bariatric surgery, compared to a non-bariatric surgery sample. Data were anonymously collected via Qualtrics from adults who reported alcohol or substance use (BS, n = 328; non-BS, n = 292).

Longitudinal changes in reinforcement learning during smoking cessation: a computational analysis using a probabilistic reward task.

Despite progress in smoking reduction in the past several decades, cigarette smoking remains a significant public health concern world-wide, with many smokers attempting but ultimately failing to maintain abstinence. However, little is known about how decision-making evolves in quitting smokers. Based on preregistered hypotheses and analysis plan ( https://osf.

Increased mortality from alcohol use disorder, alcohol-associated liver disease, and liver cancer from alcohol among older adults in the United States: 2000 to 2021.

Background: To investigate the trends in alcohol-associated liver disease (ALD), liver cancer from alcohol, and alcohol use disorder (AUD) burden among older adults in the United States (US).

Methods: We gathered the ALD, liver cancer from alcohol, and AUD prevalence, mortality, and age-standardized rates (ASRs) from the Global Burden of Disease (GBD) Study 2021 between 2010 and 2021. We estimated the annual percent change (APC) with confidence intervals (CIs) for the burden of ALD, liver cancer from alcohol, and AUD in older adults (>70 years) in the United States.

In vitro safety evaluation of dopamine D3R antagonist, R-VK4-116, as a potential medication for the treatment of opioid use disorder.

R-VK4-116 is currently being developed as a medication to treat opioid use disorder (OUD). To characterize in vitro safety properties of R-VK4-116, metabolic stability in hepatocytes or liver microsomes, metabolite identification, metabolism/transporter-mediated drug interactions, lysosomal perturbation, mitochondrial toxicity, off-target enzyme effects, cellular and nuclear receptor functional assays, electrophysiological assays, CiPA, KINOMEscanTM, plasma protein binding, phospholipidosis and steatosis assays were performed. Overall, R-VK4-116 was metabolically stable in hepatocytes and microsomes.

Catecholaminergic Modulation of Large-Scale Network Dynamics Is Tied to the Reconfiguration of Corticostriatal Connectivity.

Large-scale brain network function is critical for healthy cognition, yet links between such network function, neurochemistry, and smaller-scale neurocircuitry are unclear. Here, we evaluated 59 healthy individuals using resting-state fMRI to determine how network-level temporal dynamics were impacted by two well-characterized pharmacotherapies targeting catecholamines: methylphenidate (20 mg) and haloperidol (2 mg)-administered via randomized, double-blind, placebo-controlled design. Network temporal dynamic changes were tested for links with drug-induced alterations in complex corticostriatal connections as this circuit is a primary site of action for both drugs.

Dysfunctional suction dynamics in newborns with ankyloglossia.

Purpose: Compare infant suction in babies with and without ankyloglossia using a microprocessor-controlled pressure sensor coupled to a pacifier.

Methods: Fifty-five infants from 0 to 2 months of age underwent clinical examination for ankyloglossia, after which they were offered a silicone pacifier connected to the pressure acquisitiondevice and suction activity was recorded. Thus, we extracted the frequency of sucks within a burst, the average suck duration, the burst duration, the number of sucks per burst, the maximum amplitude of sucks per burst and the inter-burst interval.

Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement.

Background: Although countless studies have aimed to identify and test novel therapeutics for stimulant misuse, there are still no FDA-approved pharmacotherapies for stimulant use disorders. One potential treatment target is the dopamine D3 receptor (D3R) and studies in rodents have suggested that the novel D3R partial agonist (±)VK4-40 may be effective at decreasing cocaine self-administration. However, no previous studies have examined the efficacy of (±)VK4-40 in reducing cocaine self-administration in nonhuman primates nor the generality of effects by examining self-administration of other stimulants using a within-subjects design.

Kratom (Mitragyna speciosa) use for self-management of pain: Insights from cross-sectional and ecological momentary assessment data.

Kratom (Mitragyna speciosa) is increasingly used in the US for self-management of pain, despite limited research on its efficacy and safety. To better understand how and why people use kratom for pain self-management, we analyzed baseline survey data (N = 395) and 15-day ecological momentary assessment (EMA) data (N = 357) from kratom consumers across the US. Although we recruited participants based on their kratom use, not on whether they used it for pain management, nearly half (49.

Time course of kratom effects via ecological momentary assessment, by product type, dose amount, and assayed alkaloid content.

Background And Aims: Using ecological momentary assessment (EMA), we undertook a natural experiment wherein kratom-product variability was a tool to assess kratom dose-response relationships based on product form and alkaloid level.

Methods: Between July-November 2022, 357 US kratom consumers (56.6 % male, 90.

The effect of alcohol, tobacco, and other drug use on vaccine acceptance, uptake, and adherence: a systematic review.

Background: Vaccine hesitancy is increasingly recognized as a health challenge affecting populations worldwide. Given the biological vulnerabilities and structural barriers people who use substances and/or have behavioral addictions face, this systematic review aims to evaluate whether this subpopulation is less prone to adhere to vaccination recommendations.

Methods: Electronic searches of published original research were conducted in PubMed, EMBASE, Scopus, and PsycINFO from database inception to December 2022.

Barriers to Alcohol Use Disorder Treatment in Patients with Alcohol-Associated Liver Disease.

The cornerstone in managing alcohol-associated liver disease is the treatment of alcohol use disorder (AUD). Several barriers prevent the implementation of adequate treatment and integrated care models. There are patient-level barriers, including the lack of self-awareness of AUD and being ashamed of AUD.