Incretin hormone responses to carbohydrate and protein/fat are preserved in adults with sulfonylurea-treated KCNJ11 neonatal diabetes.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings.

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression.

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood.

MASH Native: a unified solution for native top-down proteomics data processing.

Motivation: Native top-down proteomics (nTDP) integrates native mass spectrometry (nMS) with top-down proteomics (TDP) to provide comprehensive analysis of protein complexes together with proteoform identification and characterization. Despite significant advances in nMS and TDP software developments, a unified and user-friendly software package for analysis of nTDP data remains lacking.

Results: We have developed MASH Native to provide a unified solution for nTDP to process complex datasets with database searching capabilities in a user-friendly interface.

Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth.

Prostate cancer is the most common cancer in men and it is estimated that over 350,000 men worldwide die of prostate cancer every year. There remains an unmet clinical need to improve how clinically significant prostate cancer is diagnosed and develop new treatments for advanced disease. Aberrant glycosylation is a hallmark of cancer implicated in tumour growth, metastasis, and immune evasion.

MASH Native: A Unified Solution for Native Top-Down Proteomics Data Processing.

Native top-down proteomics (nTDP) integrates native mass spectrometry (nMS) with top-down proteomics (TDP) to provide comprehensive analysis of protein complexes together with proteoform identification and characterization. Despite significant advances in nMS and TDP software developments, a unified and user-friendly software package for analysis of nTDP data remains lacking. Herein, we have developed MASH Native to provide a unified solution for nTDP to process complex datasets with database searching capabilities in a user-friendly interface.

Validity and repeatability of cardiopulmonary exercise testing in interstitial lung disease.

Background: Cardiopulmonary exercise testing (CPET), and its primary outcome of peak oxygen uptake (VO), are acknowledged as biomarkers in the diagnostic and prognostic management of interstitial lung disease (ILD). However, the validity and repeatability of CPET in those with ILD has yet to be fully characterised, and this study fills this evidence gap.

Methods: Twenty-six people with ILD were recruited, and 21 successfully completed three CPETs.

Routine Islet Autoantibody Testing in Clinically Diagnosed Adult-Onset Type 1 Diabetes Can Help Identify Misclassification and the Possibility of Successful Insulin Cessation.

Objective: Recent joint American Diabetes Association and European Association for the Study of Diabetes guidelines recommend routine islet autoantibody testing in all adults newly diagnosed with type 1 diabetes. We aimed to assess the impact of routine islet autoantibody testing in this population.

Research Design And Methods: We prospectively assessed the relationship between islet autoantibody status (GADA, IA-2A, and ZNT8A), clinical and genetic characteristics, and progression (annual change in urine C-peptide-to-creatinine ratio [UCPCR]) in 722 adults (≥18 years old at diagnosis) with clinically diagnosed type 1 diabetes and diabetes duration <12 months.

Gene expression analysis reveals a 5-gene signature for progression-free survival in prostate cancer.

Prostate cancer (PCa) is the second most common male cancer worldwide, but effective biomarkers for the presence or progression risk of disease are currently elusive. In a series of nine matched histologically confirmed PCa and benign samples, we carried out an integrated transcriptome-wide gene expression analysis, including differential gene expression analysis and weighted gene co-expression network analysis (WGCNA), which identified a set of potential gene markers highly associated with tumour status (malignant . benign).

Assessing whether genetic scores explain extra variation in birthweight, when added to clinical and anthropometric measures.

Background: Human birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants.

efficacy of antibiotic loaded calcium sulfate beads (Stimulan Rapid Cure) against polymicrobial communities and individual bacterial strains derived from diabetic foot infections.

Diabetic foot infection (DFI) is the main reason for diabetes-related hospitalisation and is a major cause of diabetes-related amputation. DFIs are often complicated by ischaemia in the affected limb, the presence of polymicrobial biofilms and increasingly the occurrence of antibiotic resistant bacteria. Antibiotic loaded beads could inhibit the growth of polymicrobial DFI communities with differing compositions .

Babies of South Asian and European Ancestry Show Similar Associations With Genetic Risk Score for Birth Weight Despite the Smaller Size of South Asian Newborns.

Size at birth is known to be influenced by various fetal and maternal factors, including genetic effects. South Asians have a high burden of low birth weight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic scores (fGSs) and maternal genetic scores (mGSs) from 196 birth weight-associated variants identified in Europeans and conducted an association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6-year intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry.

Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight.

Background: Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown.

Persistence of clinically relevant levels of SARS-CoV2 envelope gene subgenomic RNAs in non-immunocompromised individuals.

Objectives: This study aimed to evaluate the associations between COVID-19 severity and active viral load, and to characterize the dynamics of active SARS-CoV-2 clearance in a series of archival samples taken from patients in the first wave of COVID-19 infection in the South West of the UK.

Methods: Subgenomic RNA (sgRNA) and E-gene genomic sequences were measured in a retrospective collection of PCR-confirmed SARS-CoV-2-positive samples from 176 individuals, and related to disease severity. Viral clearance dynamics were then assessed in relation to symptom onset and last positive test.

Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile.

Aims/hypothesis: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors.

Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels.

The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice.

Feasibility of cardiopulmonary exercise testing in interstitial lung disease: the PETFIB study.

Introduction: Cardiopulmonary exercise testing (CPET) provides a series of biomarkers, such as peak oxygen uptake, which could assess the development of disease status in interstitial lung disease (ILD). However, despite use in research and clinical settings, the feasibility of CPET in this patient group has yet to be established.

Methods: Twenty-six patients with ILD (19 male) were recruited to this study.

Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies.

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear.

Parental experiences of a diagnosis of neonatal diabetes and perceptions of newborn screening for glucose: a qualitative study.

Unlabelled: Neonatal diabetes presents <6 months of life but delays in recognition result in presentation with life-threatening hyperglycaemia/diabetic ketoacidosis. Early identification and rapid genetic diagnosis is crucial and ensures correct treatment/management. Adding 'glucose' to newborn bloodspot screening (NBS) could aid prompt detection but requires evidence of parental acceptance.

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses.

Noninvasive Fetal Genotyping by Droplet Digital PCR to Identify Maternally Inherited Monogenic Diabetes Variants.

Background: Babies of women with heterozygous pathogenic glucokinase (GCK) variants causing mild fasting hyperglycemia are at risk of macrosomia if they do not inherit the variant. Conversely, babies who inherit a pathogenic hepatocyte nuclear factor 4α (HNF4A) diabetes variant are at increased risk of high birth weight. Noninvasive fetal genotyping for maternal pathogenic variants would inform pregnancy management.

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

Background: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight.

Major surgery induces acute changes in measured DNA methylation associated with immune response pathways.

Surgery is an invasive procedure evoking acute inflammatory and immune responses that can influence risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regulation of gene expression. We quantified genome-wide levels of DNA methylation in peripheral blood mononuclear cells (PBMCs) longitudinally collected from a cohort of elderly patients undergoing major surgery, comparing samples collected at baseline to those collected immediately post-operatively and at discharge from hospital.

Circulating and tissue specific transcription of angiopoietin-like protein 4 in human Type 2 diabetes.

Aims: Obesity is associated with adipose tissue (AT) dysfunction marked by cellular hypertrophy, inflammation, hypoxia and fibrosis. Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase which regulates triglyceride storage. Recently, inhibition of ANGPTL4 has been suggested as potential treatment for type 2 diabetes.

Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated neonatal diabetes show predominance of non-K-channel pathways.

Objective: Insulin secretion in sulfonylurea-treated permanent neonatal diabetes mellitus (PNDM) is thought to be mediated predominantly through amplifying non-K-channel pathways such as incretins. Affected individuals report symptoms of postprandial hypoglycemia after eating protein/fat-rich foods. We aimed to assess the physiological response to carbohydrate and protein/fat in people with sulfonylurea-treated PNDM.