Publications by authors named "Saeb-Parsy K"

Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility.

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DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium.

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The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood.

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Aging epithelia are colonized by somatic mutations, which are subjected to selection influenced by intrinsic and extrinsic factors. The lack of suitable culture systems has slowed the study of this and other long-term biological processes. Here, we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia.

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  • The Human Endometrial Cell Atlas (HECA) is a comprehensive single-cell reference atlas derived from 313,527 cells, profiling endometrial samples from 63 women, both with and without endometriosis.
  • HECA not only categorizes known cell types but also identifies new ones, utilizing advanced techniques like spatial transcriptomics and validation through an independent single-nuclei dataset.
  • The findings reveal significant cellular interactions in the endometrium, suggest potential dysregulation of specific cell types in endometriosis, and position HECA as a crucial tool for understanding endometrial health and related disorders.
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As the dimensionality, throughput and complexity of cytometry data increases, so does the demand for user-friendly, interactive analysis tools that leverage high-performance machine learning frameworks. Here we introduce FlowAtlas: an interactive web application that enables dimensionality reduction of cytometry data without down-sampling and that is compatible with datasets stained with non-identical panels. FlowAtlas bridges the user-friendly environment of FlowJo and computational tools in Julia developed by the scientific machine learning community, eliminating the need for coding and bioinformatics expertise.

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For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver.

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  • This research focuses on the aging of skeletal muscle, which contributes to frailty and sarcopenia in older adults, affecting global health significantly.
  • The study analyzed over 90,000 single cells and nuclei from 17 donors to discover how muscle stem cells change with age, revealing distinct aging traits and alterations in muscle structure.
  • The findings include new insights into muscle regeneration, the role of immune cells in the aging muscle environment, and the launch of a comprehensive muscle aging resource for further research in humans and mice.
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  • Despite advances in understanding kidney injury through lipids and metabolites, there's a lack of comprehensive data on the metabolic pathways involved in kidney impairment, partly due to limited kidney biopsy samples from living donors.
  • This study utilized kidneys from deceased transplant donors to investigate acute kidney injury, revealing common changes in injury and inflammation markers in those with reduced kidney function, along with various cellular interactions.
  • The research highlighted the role of arachidonic acid metabolism and other pathways linked to inflammation, showing that inhibiting certain lipid mediators can mitigate injury in kidney cells, suggesting potential therapeutic targets for kidney function recovery.
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  • The immune system is made up of various cell types that are found in blood and tissues, but research mostly focuses on blood samples, leaving gaps in our understanding of immune variation throughout the body and across different ages.
  • Researchers analyzed RNA and surface protein expression from over 1.25 million immune cells collected from various tissues of 24 organ donors aged 20-75 years to understand these variations better.
  • They discovered that immune cell composition and function varies significantly based on tissue type and age, providing insights into how immune responses can be linked to disease across the human lifespan.
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The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations.

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The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and immune cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (β2-AR) on CD4 T cells which, in turn, release acetylcholine (ACh). The binding of ACh to α7 acetylcholine receptors (α7-AChR) expressed by splenic macrophages inhibits the production of inflammatory cytokines, including tumor necrosis factor (TNF).

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Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells.

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Classic Hodgkin lymphoma (cHL) has a rich immune infiltrate, which is an intrinsic component of the neoplastic process. Malignant Hodgkin Reed-Sternberg cells (HRSCs) create an immunosuppressive microenvironment by the expression of regulatory molecules, preventing T-cell activation. It has also been demonstrated that mononuclear phagocytes (MNPs) in the vicinity of HRSCs express similar regulatory mechanisms in parallel, and their presence in tissue is associated with inferior patient outcomes.

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APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues.

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For decades, transplantation has been a life-saving treatment for those fortunate enough to gain access. Nevertheless, many patients die waiting for an organ and countless more never make it onto the waitlist because of a shortage of donor organs. Concurrently, thousands of donated organs are declined for transplant each year because of concerns about poor outcomes post-transplant.

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Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance.

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There is a significant need across multiple indications for an off-the-shelf bioengineered tubular graft which fulfils the mechanical and biological requirements for implantation and function but does not necessarily require cells for manufacture or deployment. Herein, we present a tissue-like tubular construct using a cell-free, materials-based method of manufacture, utilizing densified collagen hydrogel. Our tubular grafts are seamless, mechanically strong, customizable in terms of lumen diameter and wall thickness, and display a uniform fibril density across the wall thickness and along the tube length.

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  • Single-cell transcriptomics has advanced our understanding of cell types in the human lung, but how these cells are arranged in tissue is still being explored.
  • Researchers studied five locations in healthy human lungs, utilizing multi-omic techniques to uncover complex tissue structures and new cell types across different lung microenvironments.
  • They found that peribronchial fibroblasts are involved in lung disease and discovered a special niche in airway submucosal glands that helps IgA plasma cells thrive and produce antibodies, which is important for respiratory health.
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Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2), could represent a new chemoprophylactic approach for COVID-19 that complements vaccination. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems.

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The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution.

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Objectives: To determine if management of ureteric stones in the UK changed during the coronavirus disease 2019 (COVID-19) pandemic and whether this affected patient outcomes.

Patients And Methods: We conducted a multicentre retrospective study of adults with computed tomography-confirmed ureteric stone disease at 39 UK hospitals during a pre-pandemic period (23/3/2019-22/6/2019) and a period during the pandemic (the 3-month period after the first severe acute respiratory syndrome coronavirus-2 case at individual sites). The primary outcome was success of primary treatment modality, defined as no further treatment required for the index ureteric stone.

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Production of large quantities of hepatocytes remains a major challenge for a number of clinical applications in the biomedical field. Directed differentiation of human pluripotent stem cells (hPSCs) into hepatocyte-like cells (HLCs) provides an advantageous solution and a number of protocols have been developed for this purpose. However, these methods usually follow different steps of liver development in vitro, which is time consuming and requires complex culture conditions.

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The lymphocyte genome is prone to many threats, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life.

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