Structural pharmacology and therapeutic potential of 5-methoxytryptamines.

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ).

Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HTR and 5-HTR.

Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HTR have confirmed roles in native tissue and are validated drug targets. Despite 5-HTR's therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive.

Molecular basis of human trace amine-associated receptor 1 activation.

The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies.

A comparative effectiveness trial of functional behavioral assessment methods.

Clinicians report primarily using functional behavioral assessment (FBA) methods that do not include functional analyses. However, studies examining the correspondence between functional analyses and other types of FBAs have produced inconsistent results. In addition, although functional analyses are considered the gold standard, their contribution toward successful treatment compared with other FBA methods remains unclear.

Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR.

Serotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HTR have confirmed roles in native tissue and are validated drug targets. Despite 5-HTR's therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive.

Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation.

The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies.

Substrate binding and inhibition of the anion exchanger 1 transporter.

Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regulation. However, key questions remain regarding substrate binding and transport, mechanisms of drug inhibition and modulation by membrane components.

Patient Outcomes and Unit Composition With Transition to a High-Intensity ICU Staffing Model: A Before-and-After Study.

Unlabelled: Provider staffing models for ICUs are generally based on pragmatic necessities and historical norms at individual institutions. A better understanding of the role that provider staffing models play in determining patient outcomes and optimizing use of ICU resources is needed.

Objectives: To explore the impact of transitioning from a low- to high-intensity intensivist staffing model on patient outcomes and unit composition.

A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward.

Opioid analgesics exert their therapeutic and adverse effects by activating opioid receptors (MOPR); however, functional responses to MOPR activation are modulated by distinct signal transduction complexes within the brain. The ventrolateral periaqueductal gray (vlPAG) plays a critical role in modulation of nociception and analgesia, but the exact intracellular pathways associated with opioid responses in this region are not fully understood. We previously showed that knockout of the signal transduction modulator Regulator of G protein Signaling z1 (RGSz1) enhanced analgesic responses to opioids, whereas it decreased the rewarding efficacy of morphine.

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis.

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo.

Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial.

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed.

Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19.

Cinematic virtual reality for anxiety management in mechanically ventilated patients: a feasibility and pilot study.

Background: Mechanically ventilated patients experience anxiety for many reasons. Pharmacological treatments such as benzodiazepines are commonly employed to manage anxiety; however, these therapies often cause undesired side effects. Additional therapies for anxiety management are needed.

Evaluating Vitamin C in Septic Shock: A Randomized Controlled Trial of Vitamin C Monotherapy.

Objectives: To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock.

Design: Multicenter, double-blinded, randomized controlled trial.

Setting: One academic medical ICU and four community ICUs.

Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis.

Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis.

A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19.

Background: The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease.

Methods: This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.

Parent Ratings of Generalized and Indirect Effects of Functional Communication Training for Children with Autism Spectrum Disorder.

Functional communication training (FCT) is a behavioral treatment that has been shown to reduce problem behavior and increase appropriate communication in young children with autism spectrum disorder (ASD). In this study, we assessed the effects of FCT on targeted and nontargeted problem behaviors outside of the training context, as well as parent stress, for 30 young children with ASD and their parents. Indirect measures of generalization treatment effects were administered prior to and following FCT treatment delivered via telehealth.

Delivering Interventions Via Telehealth: Functional Communication Training with a Child with Autism as a Case Example.

In this article, we provide a case example of how telehealth can be used by care providers in their homes to access empirically validated procedures such as functional communication training. As shown in the case example, complex assessment and intervention procedures were implemented successfully by care providers in their homes while receiving real-time coaching by behavior analysts who were located in a hospital in a different city. This case example is representative of the results we obtained thus far; substantial improvements in challenging and adaptive behavior occurred.

Artificial intelligence and machine learning-aided drug discovery in central nervous system diseases: State-of-the-arts and future directions.

Neurological disorders significantly outnumber diseases in other therapeutic areas. However, developing drugs for central nervous system (CNS) disorders remains the most challenging area in drug discovery, accompanied with the long timelines and high attrition rates. With the rapid growth of biomedical data enabled by advanced experimental technologies, artificial intelligence (AI) and machine learning (ML) have emerged as an indispensable tool to draw meaningful insights and improve decision making in drug discovery.

Effects of the Minimal Extrathyroidal Extension on Early Response Rates after (Adjuvant) Initial Radioactive Iodine Therapy in PTC Patients.

Background: Extrathyroidal extension of differentiated thyroid cancer is a poor outcome factor but seems to be less significant in minimal extrathyroidal extension (mETE). However, the impact of mETE on response rate after (adjuvant) initial radioactive iodine (RAI) therapy remains unclear. We therefore compared response rates of patients with classical and follicular variants of papillary thyroid cancer (PTC) according to the updated eighth tumor-node-metastasis (TNM) classification to a control group.