Biology subjects

Mitchell, R. A.

Publications and source records attributed to Mitchell, R. A..

4 recordsLinked to original sources

bioRxiv2026

Genetic architecture of soluble arabinoxylan fibre in elite genotypes of bread wheat revealed by genome-wide association analysis

Dietary fibre intake remains below recommended levels, and increasing fibre content of widely consumed white wheat flour (derived from the starchy endosperm) represents a scalable strategy to improve public health. In wheat starchy endosperm, arabinoxylan (AX) is the dominant fibre component, with the water-extractable (WE) fraction being particularly beneficial to health. We assembled an Elite Fibre Panel (EFP) of 384 elite modern wheat genotypes from UK commercial breeding programmes and quantified the content of WE-AX in wholemeal, as a proxy for soluble AX in white flour, across two UK field environments. Wholemeal WE-AX, showed substantial quantitative variation and moderate genotype-by-environment interaction, with a broad-sense heritability of 0.68. Genome-wide association analyses using 6,791 SNPs identified seven loci associated with WE-AX content. The strongest and most stable effects were mapped to major loci on chromosomes 1B and 6B, previously implicated in AX regulation, while additional loci of smaller and sometimes environment-dependent effect were detected on chromosomes 3A, 5B, and 7A. Favourable alleles increased WE-AX content by [~]5-15% and combined additively. LD-defined intervals contained several high-confidence candidate genes involved in cell-wall biosynthesis, remodelling and post-depositional modification, including PER1, a validated regulator of arabinoxylan cross-linking, together with genes encoding a UTP-glucose-1-phosphate uridylyltransferase, trichome birefringence-like proteins and xyloglucan endotransglucosylase/hydrolases. These findings demonstrate that substantial gains in soluble AX can be achieved by pyramiding favourable alleles already segregating within elite germplasm, providing a practical route for breeding wheat with enhanced dietary fibre content and improved nutritional quality. Key messageMultiple additive loci controlling soluble arabinoxylan content were identified in elite wheat germplasm, enabling marker-assisted breeding for increased dietary fibre in white flour.

genomics↗

bioRxiv2026

Dietary fructose promotes MASH/HCC progression through enhanced intestinal HIF-2α-dependent iron absorption

Dietary fructose is a major risk factor driving the progression of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the underlying fructose-induced nutrient-sensing pathway remains unclear. Here, we report that fructose facilitates iron absorption through the (Ketohexokinase) KHK/PKM2/HIF-2 axis, driving MASH and HCC development. Fructose aberrantly stabilizes intestinal HIF-; this effect is abrogated by a KHK inhibitor and genetic Khk deletion. Mechanistically, fructose-induced metabolic reprogramming drives glutamine-dependent oxidative phosphorylation, leading to HIF- stabilization, which is mediated by pyruvate kinase M2 (PKM2). A selective PKM2 inhibitor rescues reduced intestinal HIF- stability in Khk-deficient mice. Furthermore, dietary fructose increases plasma iron levels. Conversely, Khk-deficient mice exhibit spontaneous systemic iron deficiency, characterized by hypochromic anemia. Moreover, Khk deficiency inhibits iron absorption in a HIF-2-dependent manner. Finally, fructose promotes MASH and HCC progression in an iron-dependent manner. This study reveals a unique, therapeutically targetable nutrient-sensing pathway utilized by dietary fructose. In briefMitchell et al. demonstrate that fructose consumption increases plasma iron levels, while KHK deficiency inhibits iron absorption in a HIF-2-dependent manner. Mechanistically, dietary fructose-induced metabolic reprogramming aberrantly stabilizes intestinal HIF-, which is mediated by PKM2. Fructose promotes MASH and HCC progression in an iron-dependent manner. HighlightsO_LIFructose aberrantly stabilizes intestinal HIF- C_LIO_LIKHK is required for intestinal HIF- stability C_LIO_LIKHK deficiency inhibits iron absorption in a HIF-2-dependent manner C_LIO_LIDietary fructose promotes MASH and HCC progression in an iron-dependent manner C_LI

physiology↗

bioRxiv2022

Tumor-educated monocytes suppress T cells via adenosine and depletion of adenosine in the tumor microenvironment with adenosine deaminase enzyme promotes response to immunotherapy

Although immune checkpoint inhibitor (ICI) therapy has provided robust results in many cancer types such as melanoma and lung cancer, a large percentage of patients remain unresponsive to this therapy. Emerging evidence strongly suggests that one of the contributing factors in ICI resistance is monocytic myeloid derived suppressor cells (M-MDSCs) that accumulate in late-stage cancer patients. These M-MDSCs are a subset of innate immune cells and possess potent immunosuppressive activity against T lymphocytes. Here we provide evidence of a mechanism by which CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function via adenosine. We show that tumor-derived PGE2, a prostaglandin frequently found at high levels in the TME, directly induces CD73 expression in M-MDSCs by initiating a signaling pathway that is mediated by both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with strong T cell suppressive activity, culminating in the suppression of CD8+ T cell-mediated anti-tumor responses. We also show that depletion of adenosine in the TME by the repurposed drug PEGylated Adenosine Deaminase (PEG-ADA) increases CD8+ T cell anti-tumor activity and enhances response to ICI therapy in preclinical models of cancer. Our results suggest that use of PEG-ADA is a viable therapeutic option to overcome ICI therapeutic resistance in advanced cancer patients.

cell biology↗

bioRxiv2021

Antibody Conversion rates to SARS-CoV-2 in Saliva from Children Attending Summer Schools in Barcelona, Spain

Surveillance tools to estimate infection rates in young populations are essential to guide recommendations for school reopening and management during viral epidemics. Ideally, field-deployable non-invasive, sensitive techniques are required to detect low viral load exposures among asymptomatic children. We determined SARS-CoV-2 antibody conversion by high-throughput Luminex assays in saliva samples collected weekly in 1,509 children and 396 adults in 22 Summer schools and 2 pre-schools in 27 venues in Barcelona, Spain, from June 29th to July 31st 2020, between the first and second COVID-19 pandemic waves. Saliva antibody conversion defined as [≥]4-fold increase in IgM, IgA and/or IgG levels to SARS-CoV-2 antigens between two visits over a 5-week period was 3.22% (49/1518), or 2.36% if accounting for potentially cross-reactive antibodies, six times higher than the cumulative infection rate (0.53%) by weekly saliva RT-PCR screening. IgG conversion was higher in adults (2.94%, 11/374) than children (1.31%, 15/1144) (p=0.035), IgG and IgA levels moderately increased with age, and antibodies were higher in females. Most antibody converters increased both IgG and IgA antibodies but some augmented either IgG or IgA, with a faster decay over time for IgA than IgG. Nucleocapsid rather than spike was the main antigen target. Anti-spike antibodies were significantly higher in individuals not reporting symptoms than symptomatic individuals, suggesting a protective role against COVID-19. To conclude, saliva antibody profiling including three isotypes and multiplexing antigens is a useful and more user-friendly tool for screening pediatric populations to determine SARS-CoV-2 exposure and guide public health policies during pandemics.

immunology↗