Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors.

Radiotherapy (RT), a common cancer treatment, unintentionally harms surrounding tissues, including the skin, and hinders wound healing years after treatment. This study aims to understand the mechanisms behind these late-onset adverse effects. We compare skin biopsies from previously irradiated (RT) and non-irradiated (RT) sites in breast cancer survivors who underwent RT years ago.

Lentiviral Vector-Mediated Hematopoietic Stem Cell Gene Therapy for Mucopolysaccharidosis IVA Murine Model.

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disease caused by a mutation in the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) gene resulting in progressive systemic skeletal dysplasia. There is currently no effective treatment available for this skeletal condition. Thus, the development of a new therapy stands as an unmet challenge in reversing or alleviating the progression of the disease.

Molecular mechanisms underlying glucose-dependent insulinotropic polypeptide secretion in human duodenal organoids.

Aims/hypothesis: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine K cells in the proximal small intestine. This study aimed to explore the function of human K cells at the molecular and cellular levels.

Methods: CRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids.

Interpreting elevated liver blood test results through a genetic lens: A genome-wide association study.

Background And Aims: Individuals with genetic polymorphisms in UGT1A1 exhibit bilirubin levels that belie their risk of liver disease (Gilbert's syndrome) but it is not known if this phenomenon extends to other common liver blood tests (LBTs).

Methods: A genome-wide association analysis of 10 LBTs was conducted using the UK biobank. Polygenic scores (PGS) were created from discordant loci (e.

Immunometabolism and mitochondria in inflammatory bowel disease: a role for therapeutic intervention?

Inflammatory bowel diseases (IBDs), incurable conditions characterised by recurrent episodes of immune-mediated gut inflammation and damage of unknown aetiology, are common. Current advanced therapies target key leukocyte-trafficking and cytokine-signalling hubs but are only effective in 50% of patients. With growing evidence of mitochondrial dysfunction in IBD and advances in our understanding of the role of metabolism in inflammation, we provide an overview of novel metabolic approaches to IBD therapy, challenging the current 'therapeutic ceiling', identifying critical pathways for intervention and re-imagining metabolic biomarkers for the 21st century.

Combining human liver ECM with topographically featured electrospun scaffolds for engineering hepatic microenvironment.

Liver disease cases are rapidly expanding worldwide, and transplantation remains the only effective cure for end-stage disease. There is an increasing demand for developing potential drug treatments, and regenerative therapies using in-vitro culture platforms. Human decellularized extracellular matrix (dECM) is an appealing alternative to conventional animal tissues as it contains human-specific proteins and can serve as scaffolding materials.

Monocyte-driven inflamm-aging reduces intestinal barrier function in females.

Background: The intestinal barrier encompasses physical and immunological components that act to compartmentalize luminal contents, such as bacteria and endotoxins, from the host. It has been proposed that an age-related decline of intestinal barrier function may allow for the passage of luminal contents into the bloodstream, triggering a low-grade systemic inflammation termed inflamm-aging. Although there is mounting evidence to support this hypothesis in model species, it is unclear if this phenomenon occurs in humans.

How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia.

Most eukaryotes require oxygen for their survival and, with increasing multicellular complexity, oxygen availability and delivery rates vary across the tissues of complex organisms. In humans, healthy tissues have markedly different oxygen gradients, ranging from the hypoxic environment of the bone marrow (where our haematopoietic stem cells reside) to the lungs and their alveoli, which are among the most oxygenated areas of the body. Immune cells are therefore required to adapt to varying oxygen availability as they move from the bone marrow to peripheral organs to mediate their effector functions.

Utilising an in silico model to predict outcomes in senescence-driven acute liver injury.

Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone.

Liver type 1 innate lymphoid cells undergo apoptosis in murine models of macrophage activation syndrome and are dispensable for disease.

Macrophage activation syndrome (MAS) exemplifies a severe cytokine storm disorder with liver inflammation. In the liver, classical natural killer (cNK) cells and liver-resident type 1 innate lymphoid cells (ILC1s) dominate the ILC population. Thus far, research has primarily focused on the corresponding role of cNK cells.

Metformin use and preeclampsia risk in women with diabetes: a two-country cohort analysis.

Background: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy.

Methods: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019).

Revolutionizing Drug Discovery: The Impact of Distinct Designs and Biosensor Integration in Microfluidics-Based Organ-on-a-Chip Technology.

Traditional drug development is a long and expensive process with high rates of failure. This has prompted the pharmaceutical industry to seek more efficient drug development frameworks, driving the emergence of organ-on-a-chip (OOC) based on microfluidic technologies. Unlike traditional animal experiments, OOC systems provide a more accurate simulation of human organ microenvironments and physiological responses, therefore offering a cost-effective and efficient platform for biomedical research, particularly in the development of new medicines.

Screening a Compound Library to Identify Additives That Boost Cytochrome P450 Enzyme Function in Vascularised Liver Spheres.

To accurately study human organ function and disease 'in the dish', it is necessary to develop reliable cell-based models that closely track human physiology. Our interest lay with the liver, which is the largest solid organ in the body. The liver is a multifunctional and highly regenerative organ; however, severe liver damage can have dire consequences for human health.

An ILK/STAT3 pathway controls glioblastoma stem cell plasticity.

Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumor progression and therapeutic resistance. Here, we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) stimulates phenotypic plasticity and mesenchymal-like, invasive behavior in a murine GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss produces cells that are unresponsive to multiple cell state transition cues.

Innate immunity champions: The diverse functions of macrophages.

Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals.

Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children.

Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls.

Two-factor authentication underpins the precision of the piRNA pathway.

The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young, active transposons during germline development in male mice. piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript, resulting in DNA methylation through SPOCD1 (refs. ).

RNA lipid nanoparticles as efficient in vivo CRISPR-Cas9 gene editing tool for therapeutic target validation in glioblastoma cancer stem cells.

In vitro and ex-vivo target identification strategies often fail to predict in vivo efficacy, particularly for glioblastoma (GBM), a highly heterogenous tumor rich in resistant cancer stem cells (GSCs). An in vivo screening tool can improve prediction of therapeutic efficacy by considering the complex tumor microenvironment and the dynamic plasticity of GSCs driving therapy resistance and recurrence. This study proposes lipid nanoparticles (LNPs) as an efficient in vivo CRISPR-Cas9 gene editing tool for target validation in mesenchymal GSCs.