PlexinD1 is a driver and a therapeutic target in advanced prostate cancer.

Aggressive prostate cancer (PCa) variants associated with androgen receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of cancer aggressiveness in metastatic castration-resistant prostate cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes.

A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice.

: The periaqueductal gray (PAG) is a central hub for the regulation of aggression, whereas the circuitry and molecular mechanisms underlying this regulation remain uncharacterized. In this study, we investigate the role of a distinct cell type, -expressing (Tac2) neurons, located in the dorsomedial PAG (dmPAG) and their modulation of aggressive behavior in mice. : We combined activity mapping, Ca recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model.

The human zinc-binding cysteine proteome.

Zinc is an essential micronutrient that regulates a wide range of physiological processes, most often through zinc binding to protein cysteine residues. Despite being critical for modulation of protein function, the cysteine sites in the majority of the human proteome that are subject to zinc binding remain undefined. Here, we develop ZnCPT, a deep and quantitative mapping of the zinc-binding cysteine proteome.

Mechanisms of tandem duplication in the cancer genome.

Tandem duplications (TD) are among the most frequent type of structural variant (SV) in the cancer genome. They are characterized by a single breakpoint junction that defines the boundaries and the size of the duplicated segment. Cancer-associated TDs often increase oncogene copy number or disrupt tumor suppressor gene function, and thus have important roles in tumor evolution.

Cold-related mortality in U.S. state and private prisons: a case-crossover analysis.

Background: Cold temperatures are associated with increased risk for cardiovascular and respiratory disease mortality. Due to limited temperature regulation in prisons, incarcerated populations may be particularly vulnerable to cold-related mortality.

Methods: We analyzed mortality data in U.

SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection.

Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here, we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure.

Association of structured continuum emission with dynamic aurora.

Patterns of ionospheric luminosity provide a unique window into our complex, coupled space environment. The aurora, for example, indicates plasma processes occurring thousands of km away, depositing immense amounts of energy into our polar ionospheres. Here we show observations of structured continuum emission associated with the dynamic aurora.

microT-CNN: an avant-garde deep convolutional neural network unravels functional miRNA targets beyond canonical sites.

microRNAs (miRNAs) are central post-transcriptional gene expression regulators in healthy and diseased states. Despite decades of effort, deciphering miRNA targets remains challenging, leading to an incomplete miRNA interactome and partially elucidated miRNA functions. Here, we introduce microT-CNN, an avant-garde deep convolutional neural network model that moves the needle by integrating hundreds of tissue-matched (in-)direct experiments from 26 distinct cell types, corresponding to a unique training and evaluation set of >60 000 miRNA binding events and ~30 000 unique miRNA-gene target pairs.

Misfolding PRSS1 variant p.Ala61Val in a case of suspected intrauterine pancreatitis.

Background/objectives: Genetic variants in PRSS1 encoding human cationic trypsinogen are associated with hereditary pancreatitis. The clinically frequent variants exert their pathogenic effect by increasing intrapancreatic trypsin activity, while a distinct subset of variants causes disease via mutation-induced trypsinogen misfolding and endoplasmic reticulum (ER) stress. Here, we report a novel misfolding PRSS1 variant.

Controlling vaccine kinetics using tannic acid for enhanced humoral immunity.

Despite the success of global vaccination campaigns, vaccine access in low-resource settings is an ongoing challenge. Subunit vaccines are a well-established and clinically scalable intervention, yet they have achieved limited success for poorly immunogenic antigens such as those associated with SARS-CoV-2. Delivery strategies that promote gradual release of subunit vaccines from the injection site offer the potential to improve humoral immunity by enhancing lymph node exposure, however, clinical implementation of this strategy is challenging due to poor scalability and high costs.

Children's cost-benefit analysis about agents who act for the greater good.

Acting for the greater good often involves paying a personal cost to benefit the collective. In two studies, we investigate how children (N = 184, M = 8.02 years, SD = 1.

Disorder within order: identification of the disordered loop of STAS domain as the inhibitory domain in SLC26A9 chloride channel.

The chloride transporter-channel SLC26A9 is mediated by a reciprocal regulatory mechanism through the interaction between its cytoplasmic STAS domain and the R domain of CFTR. In vertebrate Slc26a9s, the STAS domain structures are interrupted by a disordered loop which is conserved in mammals but is variable in non-mammals. Despite the numerous studies involving the STAS domains in SLC26 proteins, the role of the disordered loop region has not been identified.

The Role of Podocytes in Lupus Pathology.

Purpose Of Review: Kidney injury due to lupus nephritis (LN) is a severe and sometimes life-threatening sequela of systemic lupus erythematosus. Autoimmune injury to podocytes has been increasingly demonstrated to be a key driver of LN-related kidney injury because these cells play key roles in glomerular filtration barrier homeostasis. Irreparable podocyte injury impairs these processes and can lead to proteinuria, which is an indicator of poor prognosis in LN.

Exploring the Unique Role of Specialized Pro-Resolving Mediators in Cancer Therapeutics.

Unresolved chronic inflammation, a hallmark of cancer, promotes tumor growth and metastasis in various cancer types. In contrast to blocking inflammation, stimulation of resolution of inflammation is an entirely novel approach to "resolve" inflammation. Resolution of inflammation mechanisms in cancer includes clearance of tumor debris, counter-regulation of pro-inflammatory eicosanoids and cytokines, and suppression of leukocyte infiltration.

Integrating Hydrogels and Biomedical Plastics via In Situ Physical Entanglements and Covalent Bonding.

Both rigid plastics and soft hydrogels find ample applications in engineering and medicine but bear their own disadvantages that limit their broader applications. Bonding these mechanically dissimilar materials may resolve these limitations, preserve their advantages, and offer new opportunities as biointerfaces. Here, a robust adhesion strategy is proposed to integrate highly entangled tough hydrogels and diverse plastics with high interfacial adhesion energy and strength.

Gaps in the management of adrenal insufficiency in melanoma survivors: a retrospective cohort study.

Background: Due to limited data on managing immunotherapy-induced secondary adrenal insufficiency (SAI) in melanoma survivors, this study investigated its management strategies and outcomes.

Methods: This retrospective cohort study analyzed melanoma patients treated with immune checkpoint inhibitors (ICIs) with SAI (Mel_SAI, n = 161), without SAI (Mel_CON, n = 168), and patients with pituitary adenoma-related SAI (Pit_SAI, n = 106) at our institution from January 2013 to November 2023. We compared glucocorticoid management patterns, quality of life using distress scores, and the impact of different glucocorticoid types on survival outcomes using Kaplan-Meier analysis.

Pregnancy- and lactation-related bone fragility: The hidden risk.

Pregnancy and lactation significantly alter bone homeostasis, potentially leading to impaired bone quality and mineralization due to the increased metabolic demands of the developing offspring. While most women with osteopenia during these periods experience a return to baseline bone density after weaning, some may remain at risk for fractures, particularly in cancellous bone. There are inconsistencies in current reports on fracture risk and appropriate treatment strategies.

Conformal Metamaterials with Active Tunability and Self-Adaptivity for Magnetic Resonance Imaging.

Metamaterials hold great potential to enhance the imaging performance of magnetic resonance imaging (MRI) as auxiliary devices, due to their unique ability to confine and enhance electromagnetic fields. Despite their promise, the current implementation of metamaterials faces obstacles for practical clinical adoption due to several notable limitations, including their bulky and rigid structures, deviations from optimal resonance frequency, and inevitable interference with the radiofrequency (RF) transmission field in MRI. Herein, we address these restrictions by introducing a flexible and smart metamaterial that enhances sensitivity by conforming to patient anatomies while ensuring comfort during MRI procedures.

HDI-STARR-seq: Condition-specific enhancer discovery in mouse liver in vivo.

Background: STARR-seq and other massively-parallel reporter assays are widely used to discover functional enhancers in transfected cell models, which can be confounded by plasmid vector-induced type-I interferon immune responses and lack the multicellular environment and endogenous chromatin state of complex mammalian tissues.

Results: We describe HDI-STARR-seq, which combines STARR-seq plasmid library delivery to the liver, by hydrodynamic tail vein injection (HDI), with reporter RNA transcriptional initiation driven by a minimal Albumin promoter, which we show is essential for mouse liver STARR-seq enhancer activity assayed 7 days after HDI. Importantly, little or no vector-induced innate type-I interferon responses were observed.

Design and fabrication of a parasite-inspired, millimeter-scale tissue anchoring mechanism.

Optimizing mechanical adhesion to specific human tissue types is a field of research that has gained increasing attention over the past two decades due to its utility for diagnostics, therapeutics, and surgical device design. This is especially relevent for medical devices, which could benefit from the presence of attachment mechanisms in order to better target-specific regions of the gastrointestinal (GI) tract or other soft tissues for sensing, sample collection, and drug release. In this work, and inspired by the tissue anchoring adaptations found in diverse parasitic taxa, we present a design and manufacturing platform for the production of a nonintuitive bioinspired millimeter-scale articulated attachment mechanism using laminate fabrication techniques.

Comparison of patient radiation exposure and procedure time between CT-fluoroscopy and spiral CT for lumbar epidural steroid injections.

Objective: To compare patient radiation exposure and procedure time for lumbar epidural steroid injections (ESIs) performed under CT-fluoroscopy (CTF) vs spiral CT-guidance.

Materials And Methods: A retrospective cohort study of 767 consecutive lumbar ESIs performed between 2015-2023 using CTF vs spiral CT-guidance was conducted. Patient characteristics (age, sex, weight), procedural characteristics (injection level, type of ESI, trainee participation), and outcomes (patient radiation exposure, procedure time, pain relief, complications) were compared.

Transcriptional profile of the rat cardiovascular system at single-cell resolution.

We sought to characterize cellular composition across the cardiovascular system of the healthy Wistar rat, an important model in preclinical cardiovascular research. We performed single-nucleus RNA sequencing (snRNA-seq) in 78 samples in 10 distinct regions, including the four chambers of the heart, ventricular septum, sinoatrial node, atrioventricular node, aorta, pulmonary artery, and pulmonary veins, which produced 505,835 nuclei. We identified 26 distinct cell types and additional subtypes, with different cellular composition across cardiac regions and tissue-specific transcription for each cell type.

Renin-independent aldosteronism and metabolic dysfunction-associated steatotic liver disease and cirrhosis: A genetic association study.

Background & Aims: Renin-independent aldosteronism (RIA) refers to a spectrum of autonomous aldosterone hypersecretion. We aimed to explore the genetical relationship between RIA and metabolic dysfunction-associated steatotic liver disease (MASLD) and cirrhosis.

Methods: We included 125357 participants from the cohort of United Kingdom Biobank.

Multi-omics approaches reveal that diffuse midline gliomas present altered DNA replication and are susceptible to replication stress therapy.

Background: The fatal diffuse midline gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3.