FAIR sharing of Chromatin Tracing datasets using the newly developed 4DN FISH Omics Format.

A key output of the NIH-Common Fund 4D Nucleome (4DN) project is the open publication of datasets related to the structure of the human cell nucleus and the genome. Recent years have seen a rapid expansion of multiplexed Fluorescence In Situ Hybridization (FISH) or FISH-omics methods, which quantify the spatial organization of chromatin in single cells, sometimes together with RNA and protein measurements, and provide an expanded understanding of how 3D higher-order chromosome structure relates to transcriptional activity and cell development in both health and disease. Despite this progress, results from Chromatin Tracing FISH-omics experiments are difficult to share, reuse, and subject to third-party downstream analysis due to the lack of standard specifications for data exchange.

The impact of paternal body mass index on semen parameters and assisted reproductive outcomes in couples undergoing IVF/ICSI-ET treatment.

Purpose: To investigate the impact of paternal body mass index (BMI) on semen parameters and assisted reproductive outcomes in couples undergoing their first IVF/ICSI-ET cycle.

Materials And Methods: This retrospective study included 7618 couples undergoing IVF/ICSI-ET for maternal tubal/pelvic factors from 2017 to 2023. Paternal BMI was classified according to WHO criteria: normal weight (n = 3433), overweight (n = 3248), and obese (n = 937).

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation.

Solvent-Rich Pre-Coagulation Bath for Tunable Liquid-State Fusion Enables Robust Two-Step Polymer Embedded Printing.

Effective interlayer fusion is a critical step enabling a 3D printing process. For engineering polymer printing, interlayer fusion is usually either heat-enabled or binder-based, which may introduce thermal residual stress, warpage, and undesirable impurities. To overcome such challenges, a two-step immersion phase separation (IPS)-based room-temperature polymer fusion and solidification approach for self-supported engineering polymer printing, termed IPS-embedded 3D printing (IPS-E3DP) is introduced.

Comparative analysis of cumulative live birth rates in patients with recurrent pregnancy loss undergoing preimplantation genetic testing for aneuploidy versus conventional in vitro fertilisation/intracytoplasmic sperm injection: a retrospective study.

Background: Recurrent pregnancy loss (RPL) affects 1-2% of women worldwide and poses diagnostic and therapeutic challenges due to its multifactorial causes. Preimplantation genetic testing for aneuploidy (PGT-A) aims to improve outcomes by selecting euploid embryos, but its benefits in RPL patients remain uncertain. This study compared the effectiveness of PGT-A versus conventional in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) in improving cumulative live birth rates (CLBRs) and explored the effects of maternal age and miscarriage frequency on treatment efficacy.

Single-Cell Epigenomics Uncovers Heterochromatin Instability and Transcription Factor Dysfunction during Mouse Brain Aging.

The mechanisms regulating transcriptional changes in brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight brain regions in the mouse brain at 2, 9, and 18 months of age. In addition to a significant decline in progenitor cell populations involved in neurogenesis and myelination, we observed widespread and concordant changes of transcription and chromatin accessibility during aging in glial and neuronal cell types.

Anastrozole-induced autoimmune hepatitis: a rare case report and literature review.

Background: Anastrozole, an aromatase inhibitor (AI), has been used extensively for the treatment of estrogen receptor-positive breast cancer. Autoimmune hepatitis (AIH) is an extremely rare but serious complication of anastrozole treatment.

Case Description: We present the case of an 81-year-old female who presented with significantly elevated liver function test (LFTs) results 8 months after the initiation of anastrozole for early-stage breast cancer.

Evaluating methods for the prediction of cell-type-specific enhancers in the mammalian cortex.

Identifying cell-type-specific enhancers is critical for developing genetic tools to study the mammalian brain. We organized the "Brain Initiative Cell Census Network (BICCN) Challenge: Predicting Functional Cell Type-Specific Enhancers from Cross-Species Multi-Omics" to evaluate machine learning and feature-based methods for nominating enhancer sequences targeting mouse cortical cell types. Methods were assessed using in vivo data from hundreds of adeno-associated virus (AAV)-packaged, retro-orbitally delivered enhancers.

Specific targeting of brain endothelial cells using enhancer AAV vectors.

Brain endothelial cells (BECs) in brain vasculature are critical structural and functional components of the blood brain barrier (BBB). Adeno-associated virus (AAV) capsids have previously been genetically engineered to confer specificity to endothelial cells, but these capsids show limited endothelial cell specificity that varies by delivery conditions. We developed a set of new BEC-enhancer AAV vectors that specifically target BECs based on the cis-regulatory elements identified from single-cell epigenetic datasets.

Single cell multiomics reveals drivers of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has limited treatments, and cell type-specific regulatory networks driving MASLD represent therapeutic avenues. We assayed five transcriptomic and epigenomic modalities in 2.4M cells from 86 livers across MASLD stages.

Single cell multiomics and 3D genome architecture reveal novel pathways of human heart failure.

Heart failure is a leading cause of morbidity and mortality; yet gene regulatory mechanisms driving cell type-specific pathologic responses remain undefined. Here, we present the cell type-resolved transcriptomes, chromatin accessibility, histone modifications and chromatin organization of 36 non-failing and failing human hearts profiled from 776,479 cells spanning all cardiac chambers. Integrative analyses revealed dynamic changes in cell type composition, gene regulatory programs and chromatin organization, which expanded the annotation of cardiac -regulatory sequences by ten-fold and mapped cell type-specific enhancer-gene interactions.

Fate of polycyclic aromatic hydrocarbons in the phytoremediation of different hydrocarbon contaminated soils with cotton, ryegrass, tall fescue, and wheat.

Introduction: Phytoremediation is a promising strategy for cleaning up polycyclic aromatic hydrocarbon (PAH)-contaminated soils. This study investigated the effectiveness of four plant species-cotton, ryegrass, tall fescue, and wheat-in enhancing PAH removal from soils contaminated with diesel oil, PAHs, and aged oily sludge.

Methods: Aged oily sludge-contaminated soil was artificially prepared, and the selected plants were cultivated in different hydrocarbon-contaminated soils (diesel oil, PAHs, and oily sludge).

Extensive folding variability between homologous chromosomes in mammalian cells.

Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single-nucleotide polymorphisms (SNPs).

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.

Impaired differentiation is a hallmark of myeloid malignancies. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model.

Near-Infrared Light-Controlled Nitric Oxide Delivery Combined with In Situ Activated Chemotherapy for Enhanced Multimodal Therapy.

Development of nanoplatforms with in situ activation for chemotherapy represents a promising modality for biomedical application. Herein, a multifunctional nanoplatform, CMS@DTC@PDA@RuNO@FA (abbreviated as CDPNF NPs), was developed for highly efficient antitumor therapy, in which diethyldithiocarbamate (DTC)-loaded mesoporous CuMoS (CMS) nanoparticles were covered by polydopamine (PDA) layers and further covalently modified with a NO donor (RuNO) and a folic acid (FA)-directing moiety. Under the mild acidic tumor microenvironment (TME), the CDPNF NPs co-liberated DTC and Cu in the tumor site, where in situ formation of the highly cytotoxic Cu(DTC) complex effectively killed tumor cells.

Human Body Single-Cell Atlas of 3D Genome Organization and DNA Methylation.

Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multi-omic profiling of 3D genome structure and DNA methylation for 86,689 single nuclei across 16 human tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across almost all cell types and characterized 3D chromatin structure at an unprecedented cellular resolution.

The Farm Animal Genotype-Tissue Expression (FarmGTEx) Project.

Genetic mutation and drift, coupled with natural and human-mediated selection and migration, have produced a wide variety of genotypes and phenotypes in farmed animals. We here introduce the Farm Animal Genotype-Tissue Expression (FarmGTEx) Project, which aims to elucidate the genetic determinants of gene expression across 16 terrestrial and aquatic domestic species under diverse biological and environmental contexts. For each species, we aim to collect multiomics data, particularly genomics and transcriptomics, from 50 tissues of 1,000 healthy adults and 200 additional animals representing a specific context.

Context-Dependent and Gene-Specific Role of Chromatin Architecture Mediated by Histone Modifiers and Loop-extrusion Machinery.

Loop-extrusion machinery, comprising the cohesin complex and CCCTC-binding factor CTCF, organizes the interphase chromosomes into topologically associating domains (TADs) and loops, but acute depletion of components of this machinery results in variable transcriptional changes in different cell types, highlighting the complex relationship between chromatin organization and gene regulation. Here, we systematically investigated the role of 3D genome architecture in gene regulation in mouse embryonic stem cells under various perturbation conditions. We found that acute depletion of cohesin or CTCF disrupts the formation of TADs, but affects gene regulation in a gene-specific and context-dependent manner.

Sensory input, sex and function shape hypothalamic cell type development.

Mammalian behaviour and physiology undergo major changes in early life. Young animals rely on conspecifics to meet their needs and start showing nutritional independence and sex-specific social interactions at weaning and puberty, respectively. How neuronal populations regulating homeostatic functions and social behaviours develop during these transitions remains unclear.

Cell type-specific 3D-genome organization and transcription regulation in the brain.

3D organization of the genome plays a critical role in regulating gene expression. How 3D-genome organization differs among different cell types and relates to cell type-dependent transcriptional regulation remains unclear. Here, we used genome-scale DNA and RNA imaging to investigate 3D-genome organization in transcriptionally distinct cell types in the mouse cerebral cortex.

Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor.

Dosage-sensitive transcription factors (TFs) underlie altered gene regulation in human developmental disorders, and cell-type specific gene regulation is linked to the reorganization of 3D chromatin during cellular differentiation. Here, we show dose-dependent regulation of chromatin organization by the congenital heart disease (CHD)-linked, lineage-restricted TF TBX5 in human cardiomyocyte differentiation. Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reduced dosage in a human model of CHD, with variations in response across individual cells.

Deep Learning for Classification of Inflammatory Bowel Disease Activity in Whole Slide Images of Colonic Histopathology.

Grading activity of inflammatory bowel disease (IBD) using standardized histopathological scoring systems remains challenging due to limited availability of pathologists with IBD expertise and interobserver variability. In this study, a deep learning model was developed to classify activity grades in hematoxylin and eosin-stained whole slide images (WSIs) from patients with IBD, offering a robust approach for general pathologists. This study utilized 2077 WSIs from 636 patients who visited Dartmouth-Hitchcock Medical Center in 2018 and 2019, scanned at ×40 magnification (0.

Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina.

Most genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and retinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells.