Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants.

Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, and as such this target holds significant therapeutic potential. However, over 5 years later, the function of 17B-HSD13 remains unknown. Structure-aided design enables the development of potent and selective sulfonamide-based 17B-HSD13 inhibitors.

Clinical and genetic drivers of oligo-metastatic disease in colon cancer.

Background: Oligo-metastatic disease (OMD) in colon cancer patients exhibits distinct clinical behavior compared to poly-metastatic disease (PMD), with a more responsive and indolent course. This study aims to identify clinical and biological factors uniquely associated with oligo-metastatic behavior.

Methods: Metastatic colon cancer patients from an academic center underwent genetic characterization.

Underappreciated Effects of Delayed Graft Function in Pediatric Kidney Transplantation.

Purpose: In kidney transplantation (KT), delayed graft function (DGF) is associated with worse outcomes. However, it is unclear what effect DGF plays in long-term survival compared to the impact of the various transplant, donor, and recipient risk factors associated with DGF. This study aims to determine the effect of DGF alone on long-term survival in pediatric deceased donor kidney transplant recipients (DDKTRs).

A Systematic Review of Social Support Instruments for Measurement-Based Care in Posttraumatic Stress Disorder.

Purpose: Social support is a treatment target for individuals with post-traumatic stress disorder (PTSD) but is not systematically assessed in clinical care. This review evaluated the quality of patient-reported social support instruments used in PTSD research to identify candidates for measurement-based care (MBC) with this population.

Method: A systematic review identified all validated measures of social support used in research with traumatized populations after 1990.

Measurement-Based Care: A Practical Strategy Toward Improving Behavioral Health Through Primary Care.

Behavioral health care access is inadequate and new primary care-based strategies are needed to meet the rising demand. Behavioral health integration (BHI) models, such as collaborative care (CoCM) or the primary care behavioral health (PCBH) model, are often touted as actionable and sustainable solutions. The intent of such models is to bring behavioral health expertise into medical settings with the aims of improving outcomes, increasing treatment capacity, and reducing stigma.

Ranolazine Unveiled: Rediscovering an Old Solution in a New Light.

Ranolazine is an anti-anginal medication that has demonstrated antiarrhythmic properties by inhibiting both late sodium and potassium currents. Studies have shown promising results for ranolazine in treating both atrial fibrillation and ventricular arrhythmias, particularly when used in combination with other medications. This review explores ranolazine's mechanisms of action and its potential role in cardiac arrhythmias treatment in light of previous clinical studies.

MI2AMI-CS: A meta-analysis comparing Impella and IABP outcomes in Acute Myocardial Infarction-related Cardiogenic Shock.

Background: Cardiogenic Shock (CS) complicating acute myocardial infarction (AMI) poses a significant mortality risk, suggesting the opportunity to implement effective mechanical circulatory support strategies. The comparative efficacy of Intra-Aortic Balloon Pump (IABP) and Impella in managing CS-AMI remains a subject of investigation.

Objective: This meta-analysis aims to evaluate the comparative effectiveness of Impella and IABP in managing CS-AMI, exploring mortality and adverse events.

In Vitro Biotechnology for Conservation and Sustainable Use of Plant Genetic Resources.

This Special Issue contains novel contributions related to the role and use of in vitro culture in the conservation and sustainable use of plant genetic resources [...

Model-Informed Reinforcement Learning for Enabling Precision Dosing Via Adaptive Dosing.

Precision dosing, the tailoring of drug doses to optimize therapeutic benefits and minimize risks in each patient, is essential for drugs with a narrow therapeutic window and severe adverse effects. Adaptive dosing strategies extend the precision dosing concept to time-varying treatments which require sequential dose adjustments based on evolving patient conditions. Reinforcement learning (RL) naturally fits this paradigm: it perfectly mimics the sequential decision-making process where clinicians adapt dose administration based on patient response and evolution monitoring.

Predicting ADMET Properties from Molecule SMILE: A Bottom-Up Approach Using Attention-Based Graph Neural Networks.

Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs).

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883.

Metal-Halide Perovskite Submicrometer-Thick Films for Ultra-Stable Self-Powered Direct X-Ray Detectors.

Metal-halide perovskites are revolutionizing the world of X-ray detectors, due to the development of sensitive, fast, and cost-effective devices. Self-powered operation, ensuring portability and low power consumption, has also been recently demonstrated in both bulk materials and thin films. However, the signal stability and repeatability under continuous X-ray exposure has only been tested up to a few hours, often reporting degradation of the detection performance.

Breaking the maternity mold: navigating the return to work and challenging rigid maternal beliefs through an online psychological intervention.

Working mothers must often balance work and family responsibilities which can be affected by rigid and irrational beliefs about motherhood. The present study had two aims: (a) to provide psychometric evidence for a shortened Italian version of the Rigid Maternal Beliefs Scale (RMBS) and (b) to facilitate mothers' return to work after maternity leave by reducing perceptions of anxiety and stress related to rigid maternal beliefs (i.e.

Flexible, Transparent, and Bifacial Perovskite Solar Cells and Modules Using the Wide-Band Gap FAPbBr Perovskite Absorber.

Perovskite solar cells (PSCs) offer impressive performance and flexibility, thanks to their simple, low-temperature deposition methods. Their band gap tunability allows for a wide range of applications, transitioning from opaque to transparent devices. This study introduces the first flexible, bifacial PSCs using the FAPbBr perovskite.

Characterization and Applications of Permeabilized Hepatocytes in Drug Discovery.

Hepatocytes are one of the most physiologically relevant in vitro liver systems for human translation of clearance and drug-drug interactions (DDI). However, the cell membranes of hepatocytes can limit the entry of certain compounds into the cells for metabolism and DDI. Passive permeability through hepatocytes can be different in vitro and in vivo, which complicates the human translation.

Novel Multiplexed High Throughput Screening of Selective Inhibitors for Drug-Metabolizing Enzymes Using Human Hepatocytes.

Selective chemical inhibitors are critical for reaction phenotyping to identify drug-metabolizing enzymes that are involved in the elimination of drug candidates. Although relatively selective inhibitors are available for the major cytochrome P450 enzymes (CYP), they are quite limited for the less common CYPs and non-CYPs. To address this gap, we developed a multiplexed high throughput screening (HTS) assay using 20 substrate reactions of multiple enzymes to simultaneously monitor the inhibition of enzymes in a 384-well format.

Replacement of Ascending Aortic Aneurysm with Anomalous Origin of the Right Coronary Artery: Multidisciplinary Imaging for the Diagnosis.

This case report presents a rare scenario involving a congenital anomaly of the right coronary artery's (RCA) origin in association with an ascending aortic aneurysm. While both anomalies are individually recognized in the literature, their coexistence and potential interplay remain understudied. The aim of this report is to emphasize the challenges and implications associated with such a combination.

Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancer.

Background: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response.