APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice.

Reduced cerebral blood flow occurs early in the development of Alzheimer's disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD-the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity-can together produce this reduction in cerebral blood flow which leads eventually to AD. Using in vivo two-photon microscopy and haemodynamic measures, we record neurovascular function from the visual cortex of physically active or sedentary mice expressing APOE3 and APOE4 in place of murine APOE.

Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition.

Resolving the molecular basis of a Mendelian condition remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion and structural variant calling and diploid de novo genome assembly. This permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility and full-length transcript information in a single long-read sequencing run.

Genetic ancestry concordant RNA splicing in prostate cancer involves oncogenic genes and associates with recurrence.

Black men suffer disproportionately from prostate cancer (PCa) compared to men of other races and ethnicities. Comparing the molecular landscape of PCa among Black and White patients has the potential to identify targets for development of new precision medicine interventions. Herein, we conducted transcriptomic analysis of prostate tumors and paired tumor-adjacent normals from self-reported Black and White PCa patients and estimated patient genetic ancestry.

TERT-TP53 mutations: a novel biomarker pair for hepatocellular carcinoma recurrence and prognosis.

Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, and ranks among the most lethal malignancies globally, primarily due to its high rates of recurrence and metastasis. Despite the urgency, no reliable biomarkers currently exist for predicting tumor recurrence in HCC. Telomerase reverse transcriptase (TERT) promoter mutations (TERTpm) and cellular tumor antigen p53 mutations (TP53m) have been frequently documented in HCC, but their combined clinical significance remains undefined.

Pivotal roles of Plasmodium falciparum lysophospholipid acyltransferase 1 in cell cycle progression and cytostome internalization.

The rapid intraerythrocytic replication of Plasmodium falciparum, a deadly species of malaria parasite, requires a quick but constant supply of phospholipids to support marked cell membrane expansion. In the malarial parasite, many enzymes functioning in phospholipid synthesis pathway have not been identified or characterized. Here, we identify P.

Genetic associations between orexin genes and phenotypes related to behavioral regulation in humans, including substance use.

The hypothalamic neuropeptide system of orexin (hypocretin) neurons provides projections throughout the neuraxis and has been linked to sleep regulation, feeding and motivation for salient rewards including drugs of abuse. However, relatively little has been done to examine genes associated with orexin signaling and specific behavioral phenotypes in humans. Here, we tested for association of twenty-seven genes involved in orexin signaling with behavioral phenotypes in humans.

The genetics of neurodegenerative diseases is the genetics of age-related damage clearance failure.

In this perspective we draw together the data from the genome wide association studies for Alzheimer's disease, Parkinson's disease and the tauopathies and reach the conclusion that in each case, most of the risk loci are involved in the clearance of the deposited proteins: in Alzheimer's disease, the microglial removal of Aβ, in the synucleinopathies, the lysosomal clearance of synuclein and in the tauopathies, the removal of tau protein by the ubiquitin proteasome. We make the point that most loci identified through genome wide association studies are not strictly pathogenic but rather relate to failures to remove age related damage. We discuss these issues in the context of copathologies in elderly individuals and the prediction of disease through polygenic risk score analysis at different ages.

Development and validation of a prognostic model for critically ill type 2 diabetes patients in ICU based on composite inflammatory indicators.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder, and critically ill patients with T2DM in intensive care unit (ICU) have an increased risk of mortality. In this study, we investigated the relationship between nine inflammatory indicators and prognosis in critically ill patients with T2DM to provide a clinical reference for assessing the prognosis of patients admitted to the ICU. Critically ill patients with T2DM were extracted from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and divided into training and testing sets (7:3 ratio).

Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis.

Blood transfusion plays a vital role in modern medicine, but frequent shortages occur. Ex vivo manufacturing of red blood cells (RBCs) from universal donor cells offers a potential solution, yet the high cost of recombinant cytokines remains a barrier. Erythropoietin (EPO) signaling is crucial for RBC development, and EPO is among the most expensive media components.

Identification of heat tolerant lentil genotypes through stress tolerance indices.

With climate change projections indicating an increase in the frequency of extreme heat events and irregular rainfall patterns globally, the threat to global food security looms large. Terminal heat stress, which occurs during the critical reproductive stage, significantly limits lentil productivity. Therefore, there is an urgent need to improve lentil's resilience to heat stress to sustain production.

VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.

Ferroptosis is a form of iron-dependent programmed cell death, which is distinct from apoptosis, necrosis, and autophagy. Mitochondria play a critical role in initiating and amplifying ferroptosis in cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded in the mitochondrial outer membrane, exerts roles in regulation of ferroptosis.

Salicylic acid confers cadmium tolerance in wheat by regulating photosynthesis, yield and ionic homeostasis.

Wheat (Triticum aestivum L.) productivity and quality can be threatened by soil cadmium (Cd) contamination, posing a concern to food security. Salicylic acid (SA) is an endogenously produced signaling molecule that activates the defense system imparting abiotic stress tolerance in plants.

Time-resolved compositional and dynamics analysis of biofilm maturation and dispersal via solid-state NMR spectroscopy.

Dispersal plays a crucial role in the development and ecology of biofilms. While extensive studies focused on elucidating the molecular mechanisms governing this process, few have characterized the associated temporal changes in composition and structure. Here, we employed solid-state nuclear magnetic resonance (NMR) techniques to achieve time-resolved characterization of Bacillus subtilis biofilms over a 5-day period.

Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukemia (ALL) associated with favorable prognosis, but the optimal therapy for this subtype remains unclear. Profiling the genomic and pharmacological landscape of 194 pediatric ETV6::RUNX1 ALL cases, we uncover two transcriptomic clusters, C1 (61%) and C2 (39%). Compared to C1, the C2 subtype features higher white blood cell counts and younger age at diagnosis, as well as better early treatment responses.

Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma.

Isocitrate dehydrogenase 1/2 mutant (IDHmt) astrocytoma is considered a T cell-deprived tumor, yet little is known regarding the phenotypes underlying T cell exclusion. Using bulk, single nucleus and spatial RNA and protein profiling, we demonstrate that a distinct spatial organization underlies T cell confinement to the perivascular space (T cell cuff) in IDHmt astrocytoma. T cell cuffs are uniquely characterized by a high abundance of gemistocytic tumor cells (GTC) in the surrounding stroma.

Sucrose-preferring gut microbes prevent host obesity by producing exopolysaccharides.

Commensal bacteria affect host health by producing various metabolites from dietary carbohydrates via bacterial glycometabolism; however, the underlying mechanism of action remains unclear. Here, we identified Streptococcus salivarius as a unique anti-obesity commensal bacterium. We found that S.

Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting.

Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments.

Comparison of mNGS with conventional methods for diagnosis of cryptococcal meningitis: a retrospective study.

The application of metagenomic next-generation sequencing (mNGS) in the diagnosis of cryptococcal meningitis is relatively under characterized. Here, we retrospectively evaluated data from cryptococcal meningitis patients who were tested using mNGS and/or routine testing, including fungal culture, India ink staining, and cryptococcal antigen (CrAg) testing. The performance of mNGS was then assessed.

The mycobacterial ABC transporter IrtAB employs a membrane-facing crevice for siderophore-mediated iron uptake.

The mycobacterial ABC transporter IrtAB features an ABC exporter fold, yet it imports iron-charged siderophores called mycobactins. Here, we present extensive cryo-EM analyses and DEER measurements, revealing that IrtAB alternates between an inward-facing and an outward-occluded conformation, but does not sample an outward-facing conformation. When IrtAB is locked in its outward-occluded conformation in nanodiscs, mycobactin is bound in the middle of the lipid bilayer at a membrane-facing crevice opening at the heterodimeric interface.

Genetically-encoded targeted protein degradation technology to remove endogenous condensation-prone proteins and improve crop performance.

Effective modulation of gene expression in plants is achievable through tools like CRISPR and RNA interference, yet methods for directly modifying endogenous proteins remain lacking. Here, we identify the E3 ubiquitin ligase E3TCD1 and develope a Targeted Condensation-prone-protein Degradation (TCD) strategy. The X-E3TCD1 fusion protein acts as a genetically engineered degrader, selectively targeting endogenous proteins prone to condensation.

In situ osteogenic activation of mesenchymal stem cells by the blood clot biomimetic mechanical microenvironment.

Blood clots (BCs) play a crucial biomechanical role in promoting osteogenesis and regulating mesenchymal stem cell (MSC) function and fate. This study shows that BC formation enhances MSC osteogenesis by activating Itgb1/Fak-mediated focal adhesion and subsequent Runx2-mediated bone regeneration. Notably, BC viscoelasticity regulates this effect by modulating Runx2 nuclear translocation.

Categorization of 34 computational methods to detect spatially variable genes from spatially resolved transcriptomics data.

In the analysis of spatially resolved transcriptomics data, detecting spatially variable genes (SVGs) is crucial. Numerous computational methods exist, but varying SVG definitions and methodologies lead to incomparable results. We review 34 state-of-the-art methods, classifying SVGs into three categories: overall, cell-type-specific, and spatial-domain-marker SVGs.

Chromosome-level genome assembly of the sweet potato rot nematode Ditylenchus destructor.

Ditylenchus destructor, commonly known as the potato rot nematode, is a significant plant-parasitic pathogen affecting over 120 plant species globally. Effective control measures for D. destructor are limited, underscoring the need a high-quality reference genome to understand its pathogenic mechanisms.

Thyroid cancer.

In recent decades, the diagnosis of thyroid cancer, especially the papillary type, has increased significantly due to the use of imaging techniques such as ultrasound. For this reason, it is essential to rationalize diagnosis and treatment, since the behavior of thyroid cancer varies from slow-progressing tumors to highly aggressive ones. The application of risk assessment systems for ultrasound images and the optimization of cytology incorporating molecular studies allows cases to be stratified in order to select therapy on an individual basis.

Cancer evolution: from Darwin to the Extended Evolutionary Synthesis.

The fundamental evolutionary nature of cancer has been recognized for decades. Increasingly powerful genetic and single cell sequencing technologies, as well as preclinical models, continue to unravel the evolution of premalignant cells, and progression to metastatic stages and to drug-resistant end-stage disease. Here, we summarize recent advances and distil evolutionary principles and their relevance for the clinic.