Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.

Evolution of the umbilical cord blood proteome across gestational development.

Neonatal health is dependent on early risk stratification, diagnosis, and timely management of potentially devastating conditions, particularly in the setting of prematurity. Many of these conditions are poorly predicted in real-time by clinical data and current diagnostics. Umbilical cord blood may represent a novel source of molecular signatures that provides a window into the state of the fetus at birth.

Proteomic dataset of sorghum leaf and root responses to single and combined drought and heat stress.

Drought and heat stress significantly limit crop growth and productivity. Their simultaneous occurrence, as often observed in summer crops, leads to larger yield losses. Sorghum is well adapted to dry and hot conditions.

Lipidic folding pathway of α-Synuclein via a toxic oligomer.

Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently determined by single-particle cryo-electron microscopy. By contrast, smaller pre-fibrillar α-Synuclein (αS) oligomers, crucial for initiating amyloidogenesis, remain largely uncharacterized.

Structure and catalytic activity of a dihydrofolate reductase-like enzyme from Leptospira interrogans.

A dihydrofolate reductase (DHFR)-like enzyme from Leptospira interrogans (LiDHFRL) was cloned and the recombinant protein was characterized. Sequence alignment suggested that the enzyme lacked the conserved catalytic residues found in DHFR. Indeed, LiDHFRL did not catalyze the reduction of dihydrofolate by either NADH or NADPH.

Exploring mimosamycin as a Janus kinase 2 inhibitor: A combined computational and experimental investigation.

Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play a crucial role in signal transduction pathways. JAK2 has been implicated in the pathogenesis of leukemia, making it a promising target for research aimed at reducing the risk of this disease. This study examined the potential of mimosamycin as a JAK2 inhibitor using both in vitro and in silico approaches.

Exercise Therapy Rescues Skeletal Muscle Dysfunction and Exercise Intolerance in Cardiometabolic HFpEF.

Exercise intolerance, a hallmark of heart failure with preserved ejection fraction (HFpEF) exacerbated by obesity, involves unclear mechanisms related to skeletal muscle metabolism. In a "2-hit" model of HFpEF, we investigated the ability of exercise therapy (voluntary wheel running) to reverse skeletal muscle dysfunction and exercise intolerance. Using state-of-the-art metabolic cages and a multiomic approach, we demonstrate exercise can rescue dysfunctional skeletal muscle lipid and branched-chain amino acid oxidation and restore exercise capacity in mice with cardiometabolic HFpEF.

Oxidised Apolipoprotein Peptidome Characterises Metabolic Dysfunction-Associated Steatotic Liver Disease.

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) encompasses a spectrum of histological conditions ranging from simple steatosis to fibrosing steatohepatitis, and is a risk factor for cardiovascular diseases (CVD). While oxidised apolipoproteins A and B have been linked to obesity and CVD, the association between other oxidised apolipoproteins and MASLD is yet to be established. To fill this gap, we characterised the circulating serum peptidome of patients with MASLD.

Anatomical mapping of neural lineages expressing the transient receptor potential vanilloid type 1 receptor using a modified and combined PACT and CUBIC protocol for rapid tissue clearance.

Aim: Tissue clearance is a rapidly evolving technology that allows for the three-dimensional imaging of intact biological tissues. Preexisting tissue-clearing techniques, such as Passive Clarity Technique (PACT) and Clear Unobstructed Brain Imaging Cocktails and Computational Analysis (CUBIC), clear tissues adequately but have distinct disadvantages, such as taking extensive time to clear tissues and degradation of endogenous tissue fluorescence. We developed a new tissue-clearing technique combining PACT and CUBIC protocols to map the neural lineages expressing the transient receptor potential vanilloid type 1 (TRPV1) receptor.

Unbiased identification of cell identity in dense mixed neural cultures.

Induced pluripotent stem cell (iPSC) technology is revolutionizing cell biology. However, the variability between individual iPSC lines and the lack of efficient technology to comprehensively characterize iPSC-derived cell types hinder its adoption in routine preclinical screening settings. To facilitate the validation of iPSC-derived cell culture composition, we have implemented an imaging assay based on cell painting and convolutional neural networks to recognize cell types in dense and mixed cultures with high fidelity.

Phenotyping and metabolomics insights into the effect of melatonin in lettuce under non-stress and salinity conditions.

Melatonin (MLT) is an indole derivative that exhibits hormone-like activities in plants, regulating multiple aspects of growth and development. Due to its role in mitigating oxidative stress and facilitating osmoprotectant accumulation, MLT enhances abiotic stress tolerance, although the pathways and metabolic mechanisms involved remain unclear despite being studied in various crops. This work aimed to investigate the changes elicited by the exogenous MLT application at different concentrations (10, 50, 150 μM) and its role in mitigating the salinity stress in Lactuca sativa L.

CD137 agonism enhances anti-PD1 induced activation of expanded CD8 T cell clones in a neoadjuvant pancreatic cancer clinical trial.

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist.

Increasing anthropogenic stressors influenced the water quality and shifted trophic status of northern Lake Tana Gulf, Ethiopia.

Nutrients in an aquatic system determine productivity, integrity and ecological status of the aquatic system. However, the excessive enrichment of these nutrients emanating from severe anthropogenic activity has substantially impacted water quality and biodiversity. There is diminutive information available on the water quality and trophic status of the northern Gulf of Lake Tana, Ethiopia due to accessibility difficulties.

Engineering Peptide-Based Molecular Baits for Targeted Fishing and Protein Profiling of Exosomes as a Liquid Biopsy for Gastrointestinal Adenocarcinoma.

High-performance isolation of exosomes as a promising liquid biopsy target is of great importance for both fundamental research and clinical applications. This is, however, challenged by the prevalent heterogeneity of exosomes and the highly complex nature of biosamples. Here, we introduce the use of a CD81-targeting peptide as a building block for tailoring molecular baits for exosome isolation and payload analysis in clinical biofluids.

Proteomic, metabolomic and lipidomic profiles in community acquired pneumonia for differentiating viral and bacterial infections.

Community-acquired pneumonia (CAP) has a significant impact on public health, especially in light of the recent SARS-CoV-2 pandemic. To enhance disease characterization and improve understanding of the underlying mechanisms, a comprehensive analysis of the plasma lipidome, metabolome and proteome was conducted in patients with viral and bacterial CAP infections, including those induced by SARS-CoV-2. Lipidomic, metabolomic and proteomic profiling were conducted on plasma samples of 69 patients suffering either from viral or bacterial CAP.

Standard: Human gastric organoids.

Organoid technology provides a transformative approach to understand human physiology and pathology, offering valuable insights for scientific research and therapeutic development. Human gastric organoids, in particular, have gained significant interest for applications in disease modeling, drug discovery, and studies of tissue regeneration and homeostasis. However, the lack of standardized quality control has limited their extensive clinical applications.

Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.

Members of the KMT2C/D-KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation.

A simple phylogenetic approach to analyze hypermutated HIV proviruses reveals insights into their dynamics and persistence during antiretroviral therapy.

Hypermutated proviruses, which arise in a single Human Immunodeficiency Virus (HIV) replication cycle when host antiviral APOBEC3 proteins introduce extensive guanine to adenine mutations throughout the viral genome, persist in all people living with HIV receiving antiretroviral therapy (ART). However, hypermutated sequences are routinely excluded from phylogenetic trees because their extensive mutations complicate phylogenetic inference, and as a result, we know relatively little about their within-host evolutionary origins and dynamics. Using >1400 longitudinal single-genome-amplified HIV sequences isolated from six women over a median of 18 years of follow-up-including plasma HIV RNA sequences collected over a median of 9 years between seroconversion and ART initiation, and >500 proviruses isolated over a median of 9 years on ART-we evaluated three approaches for masking hypermutation in nucleotide alignments.

HoloFood Data Portal: holo-omic datasets for analysing host-microbiota interactions in animal production.

The HoloFood project used a hologenomic approach to understand the impact of host-microbiota interactions on salmon and chicken production by analysing multiomic data, phenotypic characteristics, and associated metadata in response to novel feeds. The project's raw data, derived analyses, and metadata are deposited in public, open archives (BioSamples, European Nucleotide Archive, MetaboLights, and MGnify), so making use of these diverse data types may require access to multiple resources. This is especially complex where analysis pipelines produce derived outputs such as functional profiles or genome catalogues.

Chemoresistance in Pancreatic Cancer: The Role of Adipose-Derived Mesenchymal Stem Cells and Key Resistance Genes.

Drug resistance is a significant challenge in pancreatic ductal adenocarcinoma (PDAC), where stromal elements such as adipose-derived mesenchymal stem cells (ASCs) contribute to a chemoresistant tumor microenvironment (TME). This study explored the effects of oxaliplatin (OXP) and 5-fluorouracil (5-FU) on PDAC cells (Capan-1) and ASCs to investigate the mechanisms of chemoresistance. While OXP and 5-FU reduced Capan-1 viability in a dose- and time-dependent manner, ASCs demonstrated high resistance, maintaining > 90% viability even at cytotoxic doses.

Head-to-Head Comparison of Aptamer- and Antibody-Based Proteomic Platforms in Human Cerebrospinal Fluid Samples from a Real-World Memory Clinic Cohort.

High-throughput proteomic platforms are crucial to identify novel Alzheimer's disease (AD) biomarkers and pathways. In this study, we evaluated the reproducibility and reliability of aptamer-based (SomaScan 7k) and antibody-based (Olink Explore 3k) proteomic platforms in cerebrospinal fluid (CSF) samples from the Ace Alzheimer Center Barcelona real-world cohort. Intra- and inter-platform reproducibility were evaluated through correlations between two independent SomaScan assays analyzing the same samples, and between SomaScan and Olink results.

The efficacy of Lacticaseibacillus paracasei MSMC39-1 and Bifidobacterium animalis TA-1 probiotics in modulating gut microbiota and reducing the risk of the characteristics of metabolic syndrome: A randomized, double-blinded, placebo-controlled study.

Modern treatment, a healthy diet, and physical activity routines lower the risk factors for metabolic syndrome; however, this condition is associated with all-cause and cardiovascular mortality worldwide. This investigation involved a randomized controlled trial, double-blind, parallel study. Fifty-eight participants with risk factors of metabolic syndrome according to the inclusion criteria were randomized into two groups and given probiotics (Lacticaseibacillus paracasei MSMC39-1 and Bifidobacterium animalis TA-1) (n = 31) or a placebo (n = 27).

A Highly Divergent Mitochondrial Genome in Extant Cape Buffalo From Addo Elephant National Park, South Africa.

The reduced cost of next-generation sequencing (NGS) has allowed researchers to generate nuclear and mitochondrial genome data to gain deeper insights into the phylogeography, evolutionary history and biology of non-model species. While the Cape buffalo () has been well-studied across its range with traditional genetic markers over the last 25 years, researchers are building on this knowledge by generating whole genome, population-level data sets to improve understanding of the genetic composition and evolutionary history of the species. Using publicly available NGS data, we assembled 40 Cape buffalo mitochondrial genomes (mitogenomes) from four protected areas in South Africa, expanding the geographical range and almost doubling the number of mitogenomes available for this species.

Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.

Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study.

Uncovering genetic determinants of antioxidant properties in Thai landrace rice through genome-wide association analysis.

Pigmented rice (Oryza sativa L.) is recognized as a source of natural antioxidant compounds, such as flavonoids, oryzanol, tocopherol, and anthocyanin. Because of their nutritional benefits, anthocyanin-enriched or pigmented rice varieties are feasible alternatives for promoting human health.