EMBO Molecular Medicine

A commercially available antibody, Cox mAB 31A2, raised against the VP1 protein of coxsackievirus B3 (CVB3) has been reported as suitable for the detection of CVB3 in diagnostic samples (Ettischer-Schmid 2016). The authors compared this antibody with the widely used, multi-specific, monoclonal anti-VP1 antibody marketed by Dako (clone 5D8/1) and concluded that clone 5D8/1 should not be used to identify enterovirus infections in diagnostic samples. Rather they suggested that Cox mAB 31A2 is prefe...

Thioredoxin interacting protein, encoded by TXNIP, is a key mediator of glucose and lipid metabolism in preclinical models. However, its role in human metabolism is not well understood. We have characterized a cohort of individuals with biallelic pathogenic variants in TXNIP who exhibit lactic acidosis, dyslipidemia, adult-onset severe cardiomyopathy, hypoglycemia, and skeletal muscle weakness. Mechanistically, TXNIP dysfunction was associated with increased fatty acid synthesis and complex rear...

SARS-CoV-2 directly damages lung tissue via its infection and replication process and indirectly due to systemic effects of the host immune system. There are few systems-wide, untargeted studies of these effects on the different tissues of the human body and nearly all of them base their conclusions on the transcriptome. Here we developed a parallelized mass spectrometry (MS)-based proteomics workflow allowing the rapid, quantitative analysis of hundreds of virus-infected and FFPE preserved tiss...

During muscle contraction, increased influx of mitochondrial calcium (mtCa{superscript 2}) from the myocyte cytosol through the mitochondrial calcium uniporter (MCU) couples calcium homeostasis with high ATP provision. The mitochondrial calcium uniporter regulator 1 (MCUR1) is an integral membrane protein that promotes MCU activity. Although its function has been studied in cell models, mutations in MCUR1 have not yet been associated with human disease. Here, we present a case study of a patient...

BackgroundWhy some individuals experience severe neuropathy following infection is unknown. Nucleocytoplasmic trafficking (NCT) is an essential process in nucleated cells, and its disruption has been implicated in many neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. MethodsWe performed genomic and clinical studies in 24 individuals from 12 families with acute onset axonal neuropathy. Genetic variants were characterized by thermal stability...

BackgroundBarth syndrome is an inherited disorder that results from pathogenic mutations in TAZ, the gene responsible for encoding tafazzin, an enzyme that remodels the mitochondrial phospholipid cardiolipin. Barth syndrome is characterized by heart and skeletal muscle myopathy, growth delay, and neutropenia among other features. The TAZPOWER clinical trial investigated the effects of the mitochondria-targeting peptide elamipretide in patients with Barth syndrome. Methods and findingsTAZPOWER i...

ObjectiveWolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome. MethodsWe propose a novel clinical trial design with three ...

Diabetes mellitus (DM) complicates wound healing, partly due to excessive neutrophil extracellular trap (NET) formation, a process regulated by the enzyme peptidyl-arginine deiminase 4 (PADI4). Circulating NET markers can predict the healing outcome of chronic wounds, but may not allow enough time for intervention as the accumulated NETs may have already damaged the tissue. In search for an early detectable risk marker, this study aimed at relating PADI4 haplotype, to PADI4 expression, NET forma...

Diabetes is associated with an increased risk of Coronavirus disease 2019 (COVID-19) vulnerability and mortality. COVID-19 vaccines significantly reduce the risks of serious COVID-19 outcomes, but the impact of COVID-19 vaccines including their effectiveness and adverse effects in patients with diabetes are not well known yet. Here, we showed that 61.1% patients with type 2 diabetes, but not healthy controls, exhibited aggravated insulin resistance towards the booster shots of the COVID-19 vacci...

BackgroundCirculating tumor DNA (ctDNA) is a non-invasive biomarker that can be used as a tool to detect minimal residual disease (MRD). MRD can provide important prognostic information in diffuse large B-cell lymphomas (DLBCL). Here, we present an MRD assay with an improved detection method for ctDNA, Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) which leverages phased variants (PVs) to detect ctDNA. MethodsPlasma samples from non-cancer controls were used to assess assay spe...

Digital assays are in wide development for biomarker quantification at the single-molecule level, but the common use of surface-pulldown steps limits both analytical sensitivity and throughput. Here, we develop surface-free, wash-free, in-solution assays with a sensitivity slope approaching unity for sequence-specific counting of microRNAs (miRs) relevant to metastatic castration-resistant prostate cancer (mCRPC). These assays are enabled by DNA nanoflowers (DNFs) densely encoded with [~]200 flu...

Extrachromosomal circular DNA (eccDNA) is gaining substantial attention in basic and clinical research for its contribution to tumor heterogeneity, biogenesis, and evolution. However, its presence and molecular features in peripheral blood from cancer patients are poorly understood. Here, we demonstrated the existence of eccDNA molecules in cancer patients plasma using atomic-force microscopy and high throughput sequencing technology. We then developed a method named ScanTecc (Screening cancer T...

BackgroundPlasma-separating dried blood spots (psDBS) allow measurement of cancer biomarkers such as cell-free DNA concentration, enabling distributed sample collection, as well as ambient storage and shipment. However, unlike volumetric blood tube collections, blood volume collected using psDBS can vary between individuals. We evaluated whether analysis of psDBS mass, area, and color can be used to infer blood volume, and enable downstream measurement of circulating analyte concentrations. Met...

Type 2 diabetes mellitus is associated with impaired wound healing, which contributes substantially to patient morbidity and mortality. Glucocorticoid (stress hormone) excess is also known to delay wound repair. Optical coherence tomography (OCT) is an emerging tool for monitoring healing by "virtual biopsy", but largely requires manual analysis, which is labour-intensive and restricts data volume processing. This limits the capability of OCT in clinical research. Using OCT data from the GC-SHE...

ABSTRACTO_ST_ABSPurposeC_ST_ABSPlasma cell-free nucleosome (cf-nucleosome) measurements are used in veterinary, but not human medicine, to identify asymptomatic subjects at high risk of cancer. Uniquely among plasma sandwich immunoassay tests, cf-nucleosomes are nucleoproteins with a complex electrochemistry. Formaldehyde crosslinking is common in the investigation of cellular nucleoproteins by chromatin immunoprecipitation. cf-nucleosome sandwich immunoassay similarly involves isolation from pl...

BackgroundEarly in the COVID-19 pandemic type 2 diabetes (T2D) was marked as a risk factor of severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses have the potential to mitigate or aggravate disease course. Identifying at risk groups based on immuno-inflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. MethodsThis study characterised immunophenotypic var...

IntroductionThe current healthcare system relies largely on a passive approach toward disease detection, which typically involves patients presenting a "chief complaint" linked to a particular set of symptoms for diagnosis. Since all degenerative diseases occur slowly and initiate as changes in the regulation of individual cells within our organs and tissues, it is inevitable that with the current approach to medical care we are bound to discover some illnesses at a point in time when the damage...

1) ObjectivesTo establish adaptive immune cells specifically T helpers as mediators of meta-inflammation in Type 2 Diabetes Mellitus, correlate biochemical and immunological parameters and delineate the specific signaling proteins responsible for it. 2) Research Design and Methods100 T2DM patients with no other clinical disease, autoimmunity or infection were recruited and analyzed for their biochemical and immune parameters. Bioplexing and flow cytometry was employed to analyse total and cell ...

Sex bias is well documented in autoimmune diseases, cancer and immune responses to infectious agents. Here, we investigated if pre-treatment risk factors that influence the survival of B-cell non-Hodgkin lymphoma (NHL) patients after anti-CD19 CAR T-cell therapy are sexually dimorphic. We measured pre-leukapheresis tumor burden (lactate dehydrogenase levels), C-reactive protein (CRP) and serum cytokine and chemokine concentration in 67 B-cell NHL patients treated with axicabtagene ciloleucel (ax...

Robust cost effective and high-throughput tests for early detection of cancer in otherwise healthy people could potentially revolutionize public-health and the heavy personal and public burden of the morbidity and mortality from cancer. Several studies have delineated tumor specific DNA methylation profiles that could serve as biomarkers for early detection of Hepatocellular Carcinoma (HCC) as well as other cancers in liquid biopsies. Several published DNA methylation markers fail to distinguish...