Structural insights into the regulation of monomeric and dimeric apelin receptor.

The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi proteins as a monomer or dimer, the dynamic regulation within the APJR dimer during activation remains poorly understood. In this study, we present the structures of the APJR dimer and monomer complexed with its endogenous ligand apelin-13.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations.

Mosaic HIV-1 vaccine and SHIV challenge strain V2 loop sequence identity and protection in primates.

The failure of human vaccine efficacy trials assessing a mosaic HIV-1 vaccine calls into question the translatability of preclinical SHIV challenge studies that demonstrated high efficacy of this vaccine in primates. Here we present a post hoc immune correlates analysis of HIV-1 Env peptide-binding antibody responses from the NHP13-19 study identifying the V2 loop as the principal correlate of protection in primates. Moreover, we found high V2 loop sequence identity between the Mos1 vaccine component and the SHIV challenge strain, while the vaccine showed considerably lower V2 identity to globally circulating HIV-1 sequences.

Learning-based real-time imaging through dynamic scattering media.

Imaging through dynamic scattering media is one of the most challenging yet fascinating problems in optics, with applications spanning from biological detection to remote sensing. In this study, we propose a comprehensive learning-based technique that facilitates real-time, non-invasive, incoherent imaging of real-world objects through dense and dynamic scattering media. We conduct extensive experiments, demonstrating the capability of our technique to see through turbid water and natural fog.

Large Animal Translational Validation of 3 Mitral Valve Repair Operations for Mitral Regurgitation Using a Mitral Valve Prolapse Model: A Comprehensive In Vivo Biomechanical Engineering Analysis.

Background: Various mitral repair techniques have been described. Though these repair techniques can be highly effective when performed correctly in suitable patients, limited quantitative biomechanical data are available. Validation and thorough biomechanical evaluation of these repair techniques from translational large animal in vivo studies in a standardized, translatable fashion are lacking.

Nondestructive, quantitative viability analysis of 3D tissue cultures using machine learning image segmentation.

Ascertaining the collective viability of cells in different cell culture conditions has typically relied on averaging colorimetric indicators and is often reported out in simple binary readouts. Recent research has combined viability assessment techniques with image-based deep-learning models to automate the characterization of cellular properties. However, further development of viability measurements to assess the continuity of possible cellular states and responses to perturbation across cell culture conditions is needed.

Electric Field Characteristics of Rotating Permanent Magnet Stimulation.

Neurostimulation devices that use rotating permanent magnets are being explored for their potential therapeutic benefits in patients with psychiatric and neurological disorders. This study aims to characterize the electric field (E-field) for ten configurations of rotating magnets using finite element analysis and phantom measurements. Various configurations were modeled, including single or multiple magnets, and bipolar or multipolar magnets, rotated at 10, 13.

Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.

Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies.

Detecting Disruption of HER2 Membrane Protein Organization in Cell Membranes with Nanoscale Precision.

The spatiotemporal organization of proteins within the cell membrane can affect numerous biological functions, including cell signaling, communication, and transportation. Deviations from normal spatial arrangements have been observed in various diseases, and a better understanding of this process is a key stepping stone to advancing development of clinical interventions. However, given the nanometer length scales involved, detecting these subtle changes has primarily relied on complex super-resolution and single-molecule imaging methods.

Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.

Background: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

Methods: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles.

Algorithm for optimized mRNA design improves stability and immunogenicity.

Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. ), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products. Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression.

Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer's disease.

Complex diseases are characterized by spatiotemporal cellular and molecular changes that may be difficult to comprehensively capture. However, understanding the spatiotemporal dynamics underlying pathology can shed light on disease mechanisms and progression. Here we introduce STARmap PLUS, a method that combines high-resolution spatial transcriptomics with protein detection in the same tissue section.

Differential Impact of Coronary Revascularization on Long-Term Clinical Outcome According to Coronary Flow Characteristics: Analysis of the International ILIAS Registry.

Background: Coronary pressure indices such as fractional flow reserve are the standard for guiding elective revascularization. However, considering additional coronary flow parameters could further individualize and optimize the decision on revascularization. We aimed to investigate the potentially differential prognostic associations of elective percutaneous coronary intervention (PCI) according to coronary flow properties represented by coronary flow reserve (CFR), coronary flow capacity (CFC), and baseline CFC (bCFC).

Immune responses against SARS-CoV-2 variants after two and three doses of vaccine in B-cell malignancies: UK PROSECO study.

Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study ( NCT04858568 ) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment.

Prediction of the Acuity of Vertebral Compression Fractures on CT Using Radiologic and Radiomic Features.

Rationale And Objectives: To develop and validate prediction models to differentiate acute and chronic vertebral compression fractures based on radiologic and radiomic features on CT.

Materials And Methods: This study included acute and chronic compression fractures in patients who underwent both spine CT and MRI examinations. For each fractured vertebra, three CT findings ([1] cortical disruption, [2] hypoattenuating cleft or sclerotic line, and [3] relative bone marrow attenuation) were assessed by two radiologists.

Comparative effectiveness of mRNA-1273 and BNT162b2 against symptomatic SARS-CoV-2 infection.

Background: mRNA coronavirus disease 2019 (COVID-19) vaccines are safe and effective, but increasing reports of breakthrough infections highlight the need to vigilantly monitor and compare the effectiveness of these vaccines.

Methods: We retrospectively compared protection against symptomatic infection conferred by mRNA-1273 and BNT162b2 at Mayo Clinic sites from December 2020 to September 2021. We used a test-negative case-control design to estimate vaccine effectiveness (VE) and to compare the odds of symptomatic infection after full vaccination with mRNA-1273 versus BNT162b2, while adjusting for age, sex, race, ethnicity, geography, comorbidities, and calendar time of vaccination and testing.

Current strategies for intratumoural immunotherapy - Beyond immune checkpoint inhibition.

Immunotherapy has revolutionised cancer treatment through restoration of host antitumour immune response. Immune checkpoint inhibitors (ICIs) confer durable responses in only a subset of patients. Mechanisms of ICI resistance to improve durable response rates and overall survival are an area of intense clinical research.

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints.

Clinical Characteristics and Predictors of In-Hospital Mortality in Patients With Cardiogenic Shock: Results From the RESCUE Registry.

Background: In the current era of mechanical circulatory support, limited data are available on prognosis of cardiogenic shock (CS) caused by various diseases. We investigated the characteristics and predictors of in-hospital mortality in Korean patients with CS.

Methods: The RESCUE study (Retrospective and Prospective Observational Study to Investigate Clinical Outcomes and Efficacy of Left Ventricular Assist Device for Korean Patients With CS) is a multicenter, retrospective, and prospective registry of patients that presented with CS.

Exception Status Listing in the New Adult Heart Allocation System: A New Solution to an Old Problem?

Background: One of the goals of the revised 6-tiered US adult heart allocation policy was to improve risk stratification of patients to lower exception status utilization for transplant listing. We sought to define the characteristics and outcomes of waitlisted patients using exception status and to examine region- and center-level differences in utilization of exception status in the new heart allocation system.

Methods: This retrospective cohort analysis of the United Network for Organ Sharing database included adult waitlisted patients for heart transplant between October 18, 2018, and June 30, 2020, in the United States, stratified by use of exception status versus standard criteria.

Sex and the G Protein-Coupled Estrogen Receptor Impact Vascular Stiffness.

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Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

Background: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao) would result in lower mortality than using a higher target.

Methods: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.

Combined TCR Repertoire Profiles and Blood Cell Phenotypes Predict Melanoma Patient Response to Personalized Neoantigen Therapy plus Anti-PD-1.

T cells use highly diverse receptors (TCRs) to identify tumor cells presenting neoantigens arising from genetic mutations and establish anti-tumor activity. Immunotherapy harnessing neoantigen-specific T cells to target tumors has emerged as a promising clinical approach. To assess whether a comprehensive peripheral mononuclear blood cell analysis predicts responses to a personalized neoantigen cancer vaccine combined with anti-PD-1 therapy, we characterize the TCR repertoires and T and B cell frequencies in 21 patients with metastatic melanoma who received this regimen.