Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5.

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified , a highly brain penetrant and selective mGlu NAM which displayed moderate potency against both human and rat mGlu.

Sodium oligomannate disrupts the adherence of Rib bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice.

Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer's disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.

Coordinated inheritance of extrachromosomal DNAs in cancer cells.

The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells.

Efficacy of Occupation-Based Intervention in Promoting Well-Being Among Occupational Therapy Graduate Students.

Background: Occupational therapy graduate students report poor well-being during their educational experience.

Objective: This convergent mixed-methods study (quantitative approach presented) examined the effectiveness of an occupation-based intervention in promoting well-being.

Methodology: Forty-one entry-level doctorate students (intervention = 18, control = 23) completed four standardized measures at three timepoints.

Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer.

Background: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes.

Methods: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group).

Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease.

Clinical, Cultural, Computational, and Regulatory Considerations to Deploy AI in Radiology: Perspectives of RSNA and MICCAI Experts.

The Radiological Society of North of America (RSNA) and the Medical Image Computing and Computer Assisted Intervention (MICCAI) Society have led a series of joint panels and seminars focused on the present impact and future directions of artificial intelligence (AI) in radiology. These conversations have collected viewpoints from multidisciplinary experts in radiology, medical imaging, and machine learning on the current clinical penetration of AI technology in radiology and how it is impacted by trust, reproducibility, explainability, and accountability. The collective points-both practical and philosophical-define the cultural changes for radiologists and AI scientists working together and describe the challenges ahead for AI technologies to meet broad approval.

Rational Protein Engineering to Enhance MHC-Independent T-cell Receptors.

Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T-cell activation causes T-cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T-cell response, we designed MHC-independent T-cell receptors (miTCR) by linking antibody variable domains to T-cell receptor constant chains.

Site-Selective Zn-Metalation in Poly-Triphenyl Amine-based Porous Organic Polymer for Solid-Gas Phase CO Photoreduction.

Harvesting solar energy to produce value-added chemicals from carbon dioxide (CO) presents a promising route for addressing the complexities of sustainable energy systems and environmental issues. In this context, the development of metal-coordinated porous organic polymers (POPs) offers a vital avenue for improving the photocatalytic performance of organic motifs. The current study presents a metal-integrated photocatalytic system (namely, ) developed via a one-pot Friedel-Crafts (F.

A Neuroradiologist's Guide to Operationalizing the Response Assessment in Neuro-Oncology (RANO) Criteria Version 2.0 for Gliomas in Adults.

Radiographic assessment plays a crucial role in the management of patients with central nervous system (CNS) tumors, aiding in treatment planning and evaluation of therapeutic efficacy by quantifying response. Recently, an updated version of the Response Assessment in Neuro-Oncology (RANO) criteria (RANO 2.0) was developed to improve upon prior criteria and provide an updated, standardized framework for assessing treatment response in clinical trials for gliomas in adults.

Distinct Longitudinal Trajectories of Symptom Burden Predict Clinical Outcomes in End-Stage Liver Disease.

Introduction: Little has been reported about the clinical relevance and trajectories of symptoms in end-stage liver disease (ESLD). The purpose of this prospective study was to identify trajectories of change in symptom burden over the course of 12 months in adults with ESLD.

Methods: Patients were recruited from hepatology clinics at 2 healthcare systems.

Territory-Related Functional Connectivity Changes Associated with Verbal Memory Decline in Patients with Unilateral Asymptomatic Internal Carotid Stenosis.

Background And Purpose: Verbal memory decline is a common complaint of patients with severe asymptomatic stenosis of the internal carotid artery (aICS). Previous publications explored the associations between verbal memory decline and altered functional connectivity (FC) after aICS. Patients with severe aICS may show reduced perfusion in the ipsilateral territory and redistribution of cerebral blood flow to compensate for the deficient regions, including expansion of the posterior and contralateral ICA territories via the circle of Willis.

Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension.

Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women.

A bilingual speech neuroprosthesis driven by cortical articulatory representations shared between languages.

Advancements in decoding speech from brain activity have focused on decoding a single language. Hence, the extent to which bilingual speech production relies on unique or shared cortical activity across languages has remained unclear. Here, we leveraged electrocorticography, along with deep-learning and statistical natural-language models of English and Spanish, to record and decode activity from speech-motor cortex of a Spanish-English bilingual with vocal-tract and limb paralysis into sentences in either language.

The speech neuroprosthesis.

Loss of speech after paralysis is devastating, but circumventing motor-pathway injury by directly decoding speech from intact cortical activity has the potential to restore natural communication and self-expression. Recent discoveries have defined how key features of speech production are facilitated by the coordinated activity of vocal-tract articulatory and motor-planning cortical representations. In this Review, we highlight such progress and how it has led to successful speech decoding, first in individuals implanted with intracranial electrodes for clinical epilepsy monitoring and subsequently in individuals with paralysis as part of early feasibility clinical trials to restore speech.

Decomposing and simplifying the Fracture Risk Assessment Tool-a module from the Taiwan-specific calculator.

The Fracture Risk Assessment Tool (FRAX®) is a widely utilized country-specific calculator for identifying individuals with high fracture risk; its score is calculated from 12 variables, but its formulation is not publicly disclosed. We aimed to decompose and simplify the FRAX® by utilizing a nationwide community survey database as a reference module for creating a local assessment tool for osteoporotic fracture community screening in any country. Participants ( = 16384; predominantly women (75%); mean age = 64.

Discovery, Pathogenesis, and Complete Genome Characterization of Herpesvirus.

In 2015 and 2016, two Barramundi () farms in Singapore reported a disease outbreak characterized by lethargic behavior, pronounced inappetence, generalized skin lesions, erosions of the fins and tail, and ultimately high mortality in their fish. Next-generation sequencing and PCR confirmed presence of a novel virus belonging to the family, herpesvirus (LCHV), which was subsequently isolated and cultured. We characterize, for the first time, the complete genome of two cultured LCHV isolates.

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET CC-96191.

Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells.

Assess Alzheimer's Disease via Plasma Extracellular Vesicle-derived mRNA.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder globally, has emerged as a significant health concern, particularly due to the increasing aging population. Recently, it has been revealed that extracellular vesicles (EVs) originating from neurons play a critical role in AD pathogenesis and progression. These neuronal EVs can cross the blood-brain barrier and enter peripheral circulation, offering a less invasive means for assessing blood-based AD biomarkers.