Anthracyclines disaggregate and restore mutant p63 function: a potential therapeutic approach for AEC syndrome.

Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome is a rare genetic disorder caused by mutations in the TP63 gene, which encodes a transcription factor essential for epidermal gene expression. A key feature of AEC syndrome is chronic skin erosion, for which no effective treatment currently exists. Our previous studies demonstrated that mutations associated with AEC syndrome lead to p63 protein misfolding and aggregation, exerting a dominant-negative effect.

Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.

More than 50% of families with suspected rare monogenic diseases remain unsolved after whole-genome analysis by short-read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare-disease cohort of 98 samples from 41 families, using nanopore sequencing, achieving per sample ∼36× average coverage and 32-kb read N50 from a single flow cell.

Rewiring cancer: 3D genome determinants of cancer hallmarks.

In modern cancer biology, Hanahan and Weinberg's classic depiction of the Hallmarks of Cancer serves as a heuristic for understanding malignant phenotypes [1]. Genetic determinants of these phenotypes promote cancer induction and progression, and these mutations drive current approaches to understanding and treating cancer. Meanwhile, for over a century, pathologists have noted that profound alterations of nuclear structure accompany transformation, integrating these changes into diagnostic classifications (Figure 1).

Viral Transcript and Tumor Immune Microenvironment-Based Transcriptomic Profiling of HPV-Associated Head and Neck Squamous Cell Carcinoma Identifies Subtypes Associated with Prognosis.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HPV-positive HNSCC) has distinct biological characteristics from HPV-negative HNSCC. Using an AI-based analytical platform on meta cohorts, we profiled expression patterns of viral transcripts and HPV viral genome integration, and classified the tumor microenvironment (TME). Unsupervised clustering analysis revealed five distinct and novel TME subtypes across patients (immune-enriched, highly immune and B-cell enriched, fibrotic, immune-desert, and immune-enriched luminal).

Missing Regulation Between Genetic Association and Transcriptional Abundance for Hypercholesterolemia Genes.

Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease, and it plays a causal role in the development of atherosclerosis. Genome-wide association studies (GWASs) have successfully identified hundreds of genetic variants associated with LDL-C. Most of these risk loci fall in non-coding regions of the genome, and it is unclear how these non-coding variants affect circulating lipid levels.

Exploring in Ischemic Stroke and Moyamoya Disease: From Cellular Models to Clinical Insights.

Advances in stroke genetics have highlighted the critical role of rare genetic variants in cerebrovascular diseases, with emerging as a key player in ischemic stroke and Moyamoya disease (MMD). Initially identified as the primary susceptibility gene for MMD, -notably the p.R4810K variant-has been strongly linked to intracranial artery stenosis (ICAS) and various ischemic stroke subtypes, particularly in East Asian populations.

Uniform volumetric single-cell processing for organ-scale molecular phenotyping.

Extending single-cell analysis to intact tissues while maintaining organ-scale spatial information poses a major challenge due to unequal chemical processing of densely packed cells. Here we introduce Continuous Redispersion of Volumetric Equilibrium (CuRVE) in nanoporous matrices, a framework to address this challenge. CuRVE ensures uniform processing of all cells in organ-scale tissues by perpetually maintaining dynamic equilibrium of the tissue's gradually shifting chemical environment.

Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, so together may provide a more complete picture of sleep health, while illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches.

Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease.

Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity strongly influences circulating protein levels, we investigated proteins mediating the effects of obesity on coronary artery disease, stroke and type 2 diabetes. By integrating two-step proteome-wide Mendelian randomization, colocalization, epigenomics and single-cell RNA sequencing, we identified five mediators and prioritized collagen type VI α3 (COL6A3).

Transposon mediated functional genomic screening for BRAF inhibitor resistance reveals convergent Hippo and MAPK pathway activation events.

Genotype-informed anticancer therapies such as BRAF inhibitors can show remarkable clinical efficacy in BRAF-mutant melanoma; however, drug resistance poses a major hurdle to successful cancer treatment. Many resistance events to targeted therapies have been identified, suggesting a complex path to improve therapeutics. Here, we showed the utility of a piggyBac transposon activation mutagenesis screen for the efficient identification of genes that are resistant to BRAF inhibition in melanoma.

Paediatric strategy forum for medicinal product development in diffuse midline gliomas in children and adolescents ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments.

Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy.

Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded CD8 cytotoxic T lymphocytes with in vitro specificity for patient-matched AML.

An alternatively translated isoform of PPARG proposes AF-1 domain inhibition as an insulin sensitization target.

PPARγ is the pharmacological target of thiazolidinediones (TZDs), potent insulin sensitizers that prevent metabolic disease morbidity but are accompanied by side effects such as weight gain, in part due to non-physiological transcriptional agonism. Using high throughput genome engineering, we targeted nonsense mutations to every exon of PPARG, finding an ATG in Exon 2 (chr3:12381414, CCDS2609 c.A403) that functions as an alternative translational start site.

Dynamic Importance of Genomic and Clinical Risk for Coronary Artery Disease Over the Life Course.

Background: Earlier identification of high coronary artery disease (CAD) risk individuals may enable more effective prevention strategies. However, existing 10-year risk frameworks are ineffective at earlier identification. We sought to understand how the variable importance of genomic and clinical factors across life stages may significantly improve lifelong CAD event prediction.

Machine learning for antimicrobial peptide identification and design.

Artificial intelligence (AI) and machine learning (ML) models are being deployed in many domains of society and have recently reached the field of drug discovery. Given the increasing prevalence of antimicrobial resistance, as well as the challenges intrinsic to antibiotic development, there is an urgent need to accelerate the design of new antimicrobial therapies. Antimicrobial peptides (AMPs) are therapeutic agents for treating bacterial infections, but their translation into the clinic has been slow owing to toxicity, poor stability, limited cellular penetration and high cost, among other issues.

Rapid human oogonia-like cell specification via transcription factor-directed differentiation.

The generation of germline cells from human induced pluripotent stem cells (hiPSCs) represents a milestone toward in vitro gametogenesis. Methods to recapitulate germline development beyond primordial germ cells in vitro have relied on long-term cell culture, such as 3-dimensional organoid co-culture for ~four months. Using a pipeline with highly parallelized screening, this study identifies combinations of TFs that directly and rapidly convert hiPSCs to induced oogonia-like cells (iOLCs).

Like, share, and spike: Glioblastoma progenitors influence neuronal excitability at the glioma-neural interface.

Writing in Neuron, Zhang et al. identify a subpopulation of glioblastoma cells from patient tumor samples with progenitor-like features that expresses the potassium ion channel KCND2. In mouse and organoid models, these cells enhance neural activity at the glioma-neural interface.

The architecture of theory and data in microbiome design: towards an S-matrix for microbiomes.

Designing microbiomes for applications in health, bioengineering, and sustainability is intrinsically linked to a fundamental theoretical understanding of the rules governing microbial community assembly. Microbial ecologists have used a range of mathematical models to understand, predict, and control microbiomes, ranging from mechanistic models, putting microbial populations and their interactions as the focus, to purely statistical approaches, searching for patterns in empirical and experimental data. We review the success and limitations of these modeling approaches when designing novel microbiomes, especially when guided by (inevitably) incomplete experimental data.

Highly multiplexed spatial transcriptomics in bacteria.

Single-cell decisions made in complex environments underlie many bacterial phenomena. Image-based transcriptomics approaches offer an avenue to study such behaviors, yet these approaches have been hindered by the massive density of bacterial messenger RNA. To overcome this challenge, we combined 1000-fold volumetric expansion with multiplexed error-robust fluorescence in situ hybridization (MERFISH) to create bacterial-MERFISH.

Quality of life disparities among Mexican people with systemic lupus erythematosus.

Higher prevalence and worst outcome have been reported among people with systemic lupus erythematosus with non-European ancestries, with both genetic and socioeconomic variables as contributing factors. In Mexico, studies assessing the inequities related to quality of life for Systemic Lupus Erythematosus patients remain sparse. This study aims to assess the inequities related to quality of life in a cohort of Mexican people with SLE.

Epstein-Barr virus BALF0/1 subverts the Caveolin and ERAD pathways to target B cell receptor complexes for degradation.

Epstein-Barr virus (EBV) establishes persistent infection, causes infectious mononucleosis, is a major trigger for multiple sclerosis and contributes to multiple cancers. Yet, knowledge remains incomplete about how the virus remodels host B cells to support lytic replication. We previously identified that EBV lytic replication results in selective depletion of plasma membrane (PM) B cell receptor (BCR) complexes, composed of immunoglobulin and the CD79A and CD79B signaling chains.

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.

Multiscale footprints reveal the organization of cis-regulatory elements.

Cis-regulatory elements (CREs) control gene expression and are dynamic in their structure and function, reflecting changes in the composition of diverse effector proteins over time. However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA-protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size.

RELMβ sets the threshold for microbiome-dependent oral tolerance.

Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule β (RELMβ) is a critical regulator of oral tolerance.

In vivo CRISPR-Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington's disease.

Huntington's disease, one of more than 50 inherited repeat expansion disorders, is a dominantly inherited neurodegenerative disease caused by a CAG expansion in HTT. Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the disease is driven by the CAG length-dependent propensity of the repeat to further expand in the brain. Routes to slowing somatic CAG expansion, therefore, hold promise for disease-modifying therapies.