EXTOD-Immune: a randomised controlled trial to investigate whether a remotely monitored, home-based exercise intervention can reduce disease activity in people with type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease in which the adaptive immune system targets insulin-producing ß-cells of pancreatic islets, leading to dependence on exogenous insulin therapy. Cytotoxic (CD8+) T-cells specific for islet antigens are major players in T1D autoimmunity. Data indicate that regular exercise may preserve ß-cell function in people recently diagnosed with T1D, but the role of islet-reactive CD8+ T-cells is unclear. In a randomised crossover design, this study will determine the impact of a 12-week exercise programme on the frequency and proliferative state of islet-reactive CD8+ T-cells in the peripheral blood of 20 adults diagnosed with T1D within the past 3 years. The exercise intervention will consist of three high-intensity interval training sessions per week (6-10 1 min intervals >80% maximum heart rate, with 1 min rest), the duration of which will incrementally increase from 14 to 22 min. Habitual physical activity and diet will be maintained during control and washout periods. At weeks 0, 12, 24 and 36, a fasting blood sample will be collected to quantify the frequency, phenotype and proliferative activity of islet-reactive CD8+ T-cells (primary outcome) and various clinical parameters. Glycaemic control will also be evaluated using 14-day continuous glucose monitoring at the start and end of each study arm. Findings may provide a rationale for conducting large-scale trials to evaluate the implementation of exercise into routine clinical care, particularly for people recently diagnosed with T1D when maintenance of ß-cell function is critical to counteract disease progression. Trial registration number: ISRCTN79006041.

Rehabilitation and Return to Sports after Achilles Tendon Repair.

Rehabilitation protocols post-Achilles tendon repair vary widely, particularly regarding weight bearing (WB) and immobilization duration, impacting recovery trajectories significantly. This commentary focuses on rehabilitation strategies following acute Achilles tendon repair (ATR), emphasizing early mobilization and progressive loading. Techniques such as blood flow restriction training (BFRT) and progressive loading to restore strength and tendon mechanical properties are discussed in the context of optimizing recovery, minimizing tendon elongation and facilitating safe return to sport (RTS). This manuscript highlights current evidence and clinical insights to guide practitioners in optimizing rehabilitation protocols for athletes recovering from ATR, aiming to improve functional outcomes and support safe return to athletic activity.

Waldenström Macroglobulinaemia lymphoma patients have impaired platelet and coagulation function.

Clinical features in patients with the B-cell lymphoma, Waldenström Macroglobulinaemia (WM), include cytopenias, IgM-mediated hyperviscosity, fatigue, bleeding and bruising. Therapeutics such as Bruton's tyrosine kinase inhibitors (BTKis) exacerbate bleeding risk. Abnormal haemostasis arising from platelet dysfunction, altered coagulation or vascular impairment have not been investigated in WM patients. To evaluate haemostatic dysfunction in samples from WM patients. Whole blood (WB) samples were collected from 14 WM patients not receiving therapy, 5 patients receiving BTKis and 15 healthy donors (HDs). Platelet receptor levels and reticulation were measured by flow cytometry, plasma thrombin generation ± platelets by FRET assay, WB clotting potential by rotational thromboelastometry (ROTEM), and plasma soluble glycoprotein VI (sGPVI) and serum thrombopoietin (TPO) by ELISA. Donor platelet spreading, aggregation and ability to accelerate thrombin generation in the presence of WM-derived IgM were assessed. WM platelet receptor levels, responses to physiological agonists and plasma sGPVI were within normal ranges. WM platelets had reduced reticulation (p=0.0012) while serum TPO levels were increased (p=0.0040). WM plasma displayed slower thrombin generation (p=0.0080) and WM platelets contributed less to endogenous thrombin potential (ETP, p=0.0312). HD plasma or platelets incubated with IgM (50-60 mg/mL) displayed reduced spreading (p=0.0002), aggregation (p<0.0001) and ETP (p=0.0081). Alterations to thrombin potential and WB coagulation were detected in WM samples. WM IgM significantly impaired haemostasis in vitro. Platelet and coagulation properties are disturbed in well-managed WM patients.

Throwing Injuries and Prevention Strategies in Youth Baseball.

The prevalence and severity of baseball-related injuries in the youth athlete population continue to escalate, despite efforts by health care professionals and sports organizations to quell this trend. This article reviews current research that has investigated the risk factors and possible prevention strategies for the most common injuries in young baseball players, including strengthening programs, pitch count guidelines, and throwing analysis.

IL-21 conditions antigen-presenting human γδ T-cells to promote IL-10 expression in naïve and memory CD4+ T-cells.

Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in 'unconventional' lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2+ γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4+ T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4+ T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4+ T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4+ T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease.

Notch1 regulates hepatic thrombopoietin production.

ABSTRACT: Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, the role of Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO messenger RNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-sequencing analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR), a heterodimer of asialoglycoprotein receptor 1 [ASGR1] and ASGR2, physically associates with Notch1, and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Delta-like 4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation, and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

Practical considerations for continuous glucose monitoring in elite athletes with type 1 diabetes mellitus: A narrative review.

Type 1 diabetes mellitus (T1DM) refers to a metabolic condition where a lack of insulin impairs the usual homeostatic mechanisms to control blood glucose levels. Historically, participation in competitive sport has posed a challenge for those with T1DM, where the dynamic changes in blood glucose during exercise can result in dangerously high (hyperglycaemia) or low blood glucoses (hypoglycaemia) levels. Over the last decade, research and technological development has enhanced the methods of monitoring and managing blood glucose levels, thus reducing the chances of experiencing hyper- or hypoglycaemia during exercise. The introduction of continuous glucose monitoring (CGM) systems means that glucose can be monitored conveniently, without the need for frequent fingerpick glucose checks. CGM devices include a fine sensor inserted under the skin, measuring levels of glucose in the interstitial fluid. Readings can be synchronized to a reader or mobile phone app as often as every 1-5 min. Use of CGM devices is associated with lower HbA1c and a reduction in hypoglycaemic events, promoting overall health and athletic performance. However, there are limitations to CGM, which must be considered when being used by an athlete with T1DM. These limitations can be addressed by individualized education plans, using protective equipment to prevent sensor dislodgement, as well as further research aiming to: (i) account for disparities between CGM and true blood glucose levels during vigorous exercise; (ii) investigate the effects of temperature and altitude on CGM accuracy, and (iii) explore of the sociological impact of CGM use amongst sportspeople without diabetes on those with T1DM.

Tissue-specific transcriptional programming of macrophages controls the microRNA transcriptome targeting multiple functional pathways.

Recent interest in the biology and function of peritoneal tissue resident macrophages (pMΦ) has led to a better understanding of their cellular origin, programming, and renewal. The programming of pMΦ is dependent on microenvironmental cues and tissue-specific transcription factors, including GATA6. However, the contribution of microRNAs remains poorly defined. We conducted a detailed analysis of the impact of GATA6 deficiency on microRNA expression in mouse pMΦ. Our data suggest that for many of the pMΦ, microRNA composition may be established during tissue specialization and that the effect of GATA6 knockout is largely unable to be rescued in the adult by exogenous GATA6. The data are consistent with GATA6 modulating the expression pattern of specific microRNAs, directly or indirectly, and including miR-146a, miR-223, and miR-203 established by the lineage-determining transcription factor PU.1, to achieve a differentiated pMΦ phenotype. Lastly, we showed a significant dysregulation of miR-708 in pMΦ in the absence of GATA6 during homeostasis and in response to LPS/IFN-γ stimulation. Overexpression of miR-708 in mouse pMΦ in vivo altered 167 mRNA species demonstrating functional downregulation of predicted targets, including cell immune responses and cell cycle regulation. In conclusion, we demonstrate dependence of the microRNA transcriptome on tissue-specific programming of tissue macrophages as exemplified by the role of GATA6 in pMΦ specialization.

Impaired oxysterol-liver X receptor signaling underlies aberrant cortical neurogenesis in a stem cell model of neurodevelopmental disorder.

The mechanisms by which genomic risks contribute to the onset of neuropsychiatric conditions remain a key challenge and a prerequisite for successful development of effective therapies. 15q11.2 copy number variation (CNV) containing the CYFIP1 gene is associated with autism and schizophrenia. Using stem cell models, we show that 15q11.2 deletion (15q11.2del) and CYFIP1 loss of function (CYFIP1-LoF) lead to premature neuronal differentiation, while CYFIP1 gain of function (CYFIP1-GoF) favors neural progenitor maintenance. CYFIP1 dosage changes led to dysregulated cholesterol metabolism and altered levels of 24S,25-epoxycholesterol, which can mimic the 15q11.2del and CYFIP1-LoF phenotypes by promoting cortical neuronal differentiation and can restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of liver X receptor (LXRß), while compound deletion of LXRß in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR-mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying 15q11.2 CNV and provides a potential target for therapeutic strategies for associated disorders.

Participatory community action research in homeless shelters: Outcomes for shelter residents and service-learning research assistants.

The article reports empirical outcomes of an ongoing transdisciplinary participatory community action research project that implements behavioral activation in homeless shelters. The overall goal of this Project is twofold: (1) to improve psychosocial functioning of shelter residents and enhance their opportunities to overcome homelessness; and (2) to enhance civic development of service-learning students who assist in Project implementation. Two studies are reported, representing these goals. Study 1 found that residents of a men's shelter (n = 892), women's shelter (n = 433), and transitional housing (n = 40) perceived behavioral activation sessions as immediately beneficial (i.e., important, meaningful, worthy of repeating, and enjoyable), and over the course of shelter stay, they perceived behavioral activation as contributing to their hope, empowerment/self-sufficiency, quality of life, purpose/meaning in life, wellbeing, social support, shelter social climate, and relationships with staff. Quantitative findings are supported by qualitative data (comments by residents on forms). Study 2, which replicates and extends past research on civic-development in service-learning students, used a new quasi-experimental design to compare service-learning students (n = 41) in an interdisciplinary course on homelessness versus non-service-learning students (n = 16) in a psychology course. Service-learning students showed pre- to post-semester improvements in community service self-efficacy, decreases in stigmatizing attitudes, and increases in awareness of privilege and oppression, but students not engaged in service-learning did not show these civic-related changes. These quantitative results are supported by qualitative data (written reflections by students). Results and implications are discussed within the context of the concept of psychopolitical validity.

Colonisation of hospital surfaces from low- and middle-income countries by extended spectrum ß-lactamase- and carbapenemase-producing bacteria.

Hospital surfaces can harbour bacterial pathogens, which may disseminate and cause nosocomial infections, contributing towards mortality in low- and middle-income countries (LMICs). During the BARNARDS study, hospital surfaces from neonatal wards were sampled to assess the degree of environmental surface and patient care equipment colonisation by Gram-negative bacteria (GNB) carrying antibiotic resistance genes (ARGs). Here, we perform PCR screening for extended-spectrum ß-lactamases (blaCTX-M-15) and carbapenemases (blaNDM, blaOXA-48-like and blaKPC), MALDI-TOF MS identification of GNB carrying ARGs, and further analysis by whole genome sequencing of bacterial isolates. We determine presence of consistently dominant clones and their relatedness to strains causing neonatal sepsis. Higher prevalence of carbapenemases is observed in Pakistan, Bangladesh, and Ethiopia, compared to other countries, and are mostly found in surfaces near the sink drain. Klebsiella pneumoniae, Enterobacter hormaechei, Acinetobacter baumannii, Serratia marcescens and Leclercia adecarboxylata are dominant; ST15 K. pneumoniae is identified from the same ward on multiple occasions suggesting clonal persistence within the same environment, and is found to be identical to isolates causing neonatal sepsis in Pakistan over similar time periods. Our data suggests persistence of dominant clones across multiple time points, highlighting the need for assessment of Infection Prevention and Control guidelines.

The Need to Prioritize Education and Resources to Support Exercise in Type 1 Diabetes: Results of an Australian Survey of Adults With Type 1 Diabetes and Health Providers.

OBJECTIVES: Regular exercise is recommended for people with type 1 diabetes (PWD) to improve their health, but many do not meet recommended exercise targets. Educational resources supporting PWD to exercise exist, but their value is unclear. To determine the need for improved exercise resources in Australia, we surveyed adult PWD and health providers (HPs) about their confidence in managing type 1 diabetes (T1D) around exercise, barriers to exercise, and the adequacy of current resources. METHODS: Australian adult PWD and HPs completed surveys to rate the importance of exercise in T1D management, confidence in managing T1D around exercise, barriers to giving and receiving education, resources used, and what form new resources should take. RESULTS: Responses were received from 128 PWD and 122 HPs. Both groups considered exercise to be important for diabetes management. PWD cited time constraints (57%) and concern about dysglycemia (43%) as barriers to exercise, and many lacked confidence in managing T1D around exercise. HPs were more confident, but experienced barriers to providing advice, and PWD did not tend to rely on this advice. Instead, 72% of PWD found continuous glucose monitoring most helpful. Both groups desired better resources to support exercise in T1D, with PWD preferring to obtain information through a structured education program and HPs through eLearning. CONCLUSIONS: Australian HPs and PWD appreciate the importance of exercise in T1D management and express a clear desire for improved educational resources. Our findings provide a basis for developing a comprehensive package of resources for both adult PWD and HPs, to support exercise in PWD.

LIPID MAPS: update to databases and tools for the lipidomics community.

LIPID MAPS (LIPID Metabolites and Pathways Strategy), www.lipidmaps.org, provides a systematic and standardized approach to organizing lipid structural and biochemical data. Founded 20 years ago, the LIPID MAPS nomenclature and classification has become the accepted community standard. LIPID MAPS provides databases for cataloging and identifying lipids at varying levels of characterization in addition to numerous software tools and educational resources, and became an ELIXIR-UK data resource in 2020. This paper describes the expansion of existing databases in LIPID MAPS, including richer metadata with literature provenance, taxonomic data and improved interoperability to facilitate FAIR compliance. A joint project funded by ELIXIR-UK, in collaboration with WikiPathways, curates and hosts pathway data, and annotates lipids in the context of their biochemical pathways. Updated features of the search infrastructure are described along with implementation of programmatic access via API and SPARQL. New lipid-specific databases have been developed and provision of lipidomics tools to the community has been updated. Training and engagement have been expanded with webinars, podcasts and an online training school.

Kinematic metrics and surgeon experience in robotic cholecystectomies: a pilot study on breaking down technical performance.

BACKGROUND: Recent studies have correlated surgical skill measured by video-based assessment with improved clinical outcomes. Certain automated measures of operative performance in robotic surgery can be gathered beyond video review called objective performance indicators (OPIs). We explore the relationship between OPIs, surgeon experience, and postoperative recovery, hypothesizing that more efficient dissection will be associated with experience. METHODS: Fifty-six robotic cholecystectomies between February 2022 and March 2023 were recorded at a large tertiary referral center. Surgeon experience and clinical outcomes data from the EMR were obtained for all 56 cases with 10 completing the QOL survey. Two steps of robotic cholecystectomies were reviewed: dissection of Calot's triangle (DCT) and dissection of the gallbladder from the liver (DGL). Postoperative recovery was measured using the SF-36 well-being survey. Univariate analysis was conducted using Pearson's coefficient. RESULTS: Increased operative experience was associated with more efficient camera and instrument movements. DCT had 7 and DGL had 31 of 41 OPIs that correlated with experience. With respect to DGL, more experienced surgeons had reduced step duration and instrument path length and increased camera and instrument speeds. CONCLUSIONS: Several OPIs correlate with surgical experience and may form the basis of more instructive feedback for trainees and less experienced surgeons in improving intraoperative technique.

Assessment of Biofilm Growth on Microplastics in Freshwaters Using a Passive Flow-Through System.

Biofilms that colonize on the surface of microplastics (MPs) in freshwaters may pose a potential health risk. This study examined factors that influence MP-associated biofilm growth, including polymer type, degree of weathering, and source water quality. Weathered MPs produced in-lab were employed in biofilm trials conducted on site using a passive flow-through system with raw water at drinking water treatment facility intakes. Adenosine triphosphate (ATP) was used to quantify biofilm abundance; biofilm composition was assessed via metagenomic sequencing. Biofilm growth was observed on all polymer types examined and most prevalent on polyvinyl chloride (PVC), where ATP levels were 6 to 12 times higher when compared to other polymers. Pathogen-containing species including Salmonella enterica and Escherichia coli were present on all polymers with relative abundance up to 13.7%. S. enterica was selectively enriched on weathered MPs in specific water matrices. These findings support the need to research the potential accumulation of pathogenic organisms on microplastic surfaces.

Tissue inhibitors of metalloproteinases (TIMPs) modulate platelet ADAM10 activity.

Platelet-specific collagen receptor glycoprotein (GP)VI is stable on the surface of circulating platelets but undergoes ectodomain cleavage on activated platelets. Activation-dependent GPVI metalloproteolysis is primarily mediated by A Disintegrin And Metalloproteinase (ADAM) 10. Regulation of platelet ADAMs activity is not well-defined however Tissue Inhibitors of Metalloproteinases (TIMPs) may play a role. As levels of TIMPs on platelets and the control of ADAMs-mediated shedding by TIMPs has not been evaluated, we quantified the levels of TIMPs on the surface of resting and activated platelets from healthy donors by flow cytometry and multiplex ELISA. Variable levels of all TIMPs could be detected on platelets. Plasma contained significant quantities of TIMP1 and TIMP2, but only trace amounts of TIMP3 and TIMP4. Recombinant TIMP3 strongly ablated resting and activated platelet ADAM10 activity, when monitored using a quenched fluorogenic peptide substrate with ADAM10 specificity. Whilst ADAM10-specific inhibitor GI254023X or ethylenediamine tetraacetic acid (EDTA) could modulate ligand-initiated shedding of GPVI, only recombinant TIMP2 achieved a modest (~20%) inhibition. We conclude that some platelet TIMPs are able to modulate platelet ADAM10 activity but none strongly regulate ligand-dependent shedding of GPVI. Our findings provide new insights into the regulation of platelet receptor sheddase activity.

What do we know? Platelet receptor GPVI initiates platelet adhesion and aggregation and is proteolytically cleaved from the activated platelet surfaceThe metalloproteinases responsible belong to the ADAMs family of enzymes which are inhibited by TIMPsWhat did we discover? Plasma contains significant amounts of TIMP1 and TIMP2Circulating platelets bear significant amounts of TIMPs 1, 2, and 3Recombinant TIMP3 strongly inhibits resting and activated platelet ADAM10 activityExogenous addition of TIMP2 mildly blocked ligand-initiated shedding of GPVIWhat is the impact? TIMPs may modulate ADAM10 activity under resting conditions and stabilize GPVI levels in response to platelet activationAnti-GPVI agents are being evaluated as anti-thrombotic agents, however, acute loss of GPVI in trauma or settings of thrombocytopenia is linked with clinical bleedingUnderstanding how GPVI levels are regulated is important as agents that modulate GPVI function are emerging as important therapeutics for clinical applications in Thrombosis and Hemostasis fields.

Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans.

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.

Adsorption of Per- and Polyfluoroalkyl Substances (PFAS) and Microcystins by Virgin and Weathered Microplastics in Freshwater Matrices.

Microplastics and per- and polyfluoroalkyl substances (PFAS) both represent persistent groups of environmental contaminants that have been associated with human health risks. Microcystin toxins are produced and stored in the cells of cyanobacteria and may be released into sources of drinking water. Recent concerns have emerged regarding the ability of microplastics to adsorb a range of organic contaminants, including PFAS and microcystins. This study examined the adsorption of two long-chain and two short-chain PFAS, as well as two common microcystins, by both virgin and weathered microplastics in freshwater. Natural weathering of microplastic surfaces may decrease adsorption by introducing hydrophilic oxygen-containing functional groups. Up to 50% adsorption of perfluorooctanesulfonic acid (PFOS) was observed for virgin PVC compared to 38% for weathered PVC. In contrast, adsorption capacities for microcystins by virgin LDPE were approximately 5.0 µg/g whereas no adsorption was observed following weathering. These results suggest that adsorption is driven by specific polymer types and dominated by hydrophobic interactions. This is the first known study to quantify PFAS and microcystins adsorption when considering environmentally relevant concentrations as well as weathered microplastics.

MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis.

Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collagen-related peptide (CRP) along with decreased mitochondrial ATP production. Thrombin but not CRP induced Ca2+-dependent mitochondria reactive oxygen species generation. Mechanistically, MTH1 deficiency caused mitochondrial DNA oxidative damage and reduced the expression of cytochrome c oxidase 1. Furthermore, MTH1 exerts a similar role in human platelet function. Our study suggests that MTH1 exerts a protective function against oxidative stress in platelets and indicates that MTH1 could be a potential therapeutic target for the prevention of thrombotic diseases.