Inter-organ communication: pathways and targets to cardioprotection and neuro-protection. A report from the 12th Hatter Cardiovascular Institute workshop.

A long-standing aim in the setting of various pathologies including acute myocardial infarction, chronic kidney disease (CKD), and ischaemic stroke, has been to identify successful approaches to augment cellular and organ protection. Although the continual evolution and refinement of ideas over the past few decades has allowed the field to progress, we are yet to realise successful clinical translation of this concept. The 12th Hatter Cardiovascular Workshop identified a number of important points and key questions for future research relating to cardio- and neuro-protection and interorgan communication.

Is there reversible dimerization of albumin in blood plasma? And does it matter?

Most albumin in blood plasma is thought to be monomeric with some 5% covalently dimerized. However, many reports in the recent biophysics literature find that albumin is reversibly dimerized or even oligomerized. We review data on this from X-ray crystallography and diverse biophysical techniques.

National Unified Renal Translational Research Enterprise: Idiopathic Nephrotic Syndrome (NURTuRE-INS) study.

Background: Idiopathic nephrotic syndrome (INS) is a heterogenous disease and current classification is based on observational responses to therapies or kidney histology. The National Unified Renal Translational Research Enterprise (NURTuRE)-INS cohort aims to facilitate novel ways of stratifying INS patients to improve disease understanding, therapeutics and design of clinical trials.

Methods: NURTuRE-INS is a prospective cohort study of children and adults with INS in a linked biorepository.

Intrinsic PARG inhibitor sensitivity is mimicked by haploinsufficiency and rescued by nucleoside supplementation.

A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of , a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined.

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI.

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, expression was ablated in mouse kidney and HK-2 proximal tubule cells.

Extensive multiregional urea elevations in a case-control study of vascular dementia point toward a novel shared mechanism of disease amongst the age-related dementias.

Introduction: Vascular dementia (VaD) is one of the most common causes of dementia among the elderly. Despite this, the molecular basis of VaD remains poorly characterized when compared to other age-related dementias. Pervasive cerebral elevations of urea have recently been reported in several dementias; however, a similar analysis was not yet available for VaD.

Associations with age and glomerular filtration rate in a referred population with chronic kidney disease: methods and baseline data from a UK multicentre cohort study (NURTuRE-CKD).

Background: Chronic kidney disease (CKD) is common but heterogenous and is associated with multiple adverse outcomes. The National Unified Renal Translational Research Enterprise (NURTuRE)-CKD cohort was established to investigate risk factors for clinically important outcomes in persons with CKD referred to secondary care.

Methods: Eligible participants with CKD stages G3-4 or stages G1-2 plus albuminuria >30 mg/mmol were enrolled from 16 nephrology centres in England, Scotland and Wales from 2017 to 2019.

Multi-regional alterations in glucose and purine metabolic pathways in the Parkinson's disease dementia brain.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, most commonly characterised by motor dysfunction, but also with a high prevalence of cognitive decline in the decades following diagnosis-a condition known as Parkinson's disease dementia (PDD). Although several metabolic disruptions have been identified in PD, there has yet to be a multi-regional analysis of multiple metabolites conducted in PDD brains. This discovery study attempts to address this gap in knowledge.

The pathophysiology of distal renal tubular acidosis.

The kidneys have a central role in the control of acid-base homeostasis owing to bicarbonate reabsorption and production of ammonia and ammonium in the proximal tubule and active acid secretion along the collecting duct. Impaired acid excretion by the collecting duct system causes distal renal tubular acidosis (dRTA), which is characterized by the failure to acidify urine below pH 5.5.

Development of a sensitive biochemical assay for the detection of tofacitinib adherence.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Tofacitinib is a Janus Kinase inhibitor licensed for the treatment of RA that, unlike biologic anti-rheumatic drugs, is administered orally, but studies of long-term treatment adherence rates are lacking. The measurement of adherence, however, is challenging and there is currently no gold standard test for adherence.

Association of Complement and Coagulation Pathway Proteins With Treatment Response in First-Episode Psychosis: A Longitudinal Analysis of the OPTiMiSE Clinical Trial.

Background And Hypothesis: Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications.

Study Design: Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial.

Inflammation and kidney stones: cause and effect?

Purpose Of Review: This short review is intended to highlight the potential role of inflammation as a key pathological driver, rather than a mere consequence, of nephrolithiasis. Although there is clearly a strong likelihood that the relationship is bidirectional, and that kidney stone-triggered inflammation can establish a vicious cycle of tissue injury and stone formation.

Recent Findings: These consist of data from both recent preclinical and clinical studies demonstrating the importance of inflammation in models of stone disease and in kidney tissue from patients with nephrolithiasis, and as a potential driver of disease recurrence and a suitable treatment target.

Elevated hippocampal copper in cases of type 2 diabetes.

Background: Type-2 diabetes (T2D) is characterized by chronic hyperglycaemia and glucose-evoked organ damage, and displays systemic copper overload, elevated risk of impaired cognitive function, and epidemiological links to sporadic Alzheimer's disease (sAD). Contrastingly, sAD exhibits impaired cerebral-glucose uptake, elevation of cerebral glucose but not blood glucose levels, and widespread cerebral-copper deficiency. We hypothesized that sAD-like brain-metal perturbations would occur in T2D.

Levels of soluble complement regulators predict severity of COVID-19 symptoms.

The SARS-CoV-2 virus continues to cause significant morbidity and mortality worldwide from COVID-19. One of the major challenges of patient management is the broad range of symptoms observed. While the majority of individuals experience relatively mild disease, a significant minority of patients require hospitalisation, with COVID-19 still proving fatal for some.

Uncertainty-Aware Protein-Level Quantification and Differential Expression Analysis of Proteomics Data with seaMass.

seaMass is an R package for protein-level quantification, normalization, and differential expression analysis of proteomics mass spectrometry data after peptide identification, protein grouping, and feature-level quantification. Using the concept of a blocked experimental design, seaMass can analyze all common discovery proteomics paradigms, including label-free (e.g.

Physiological regulation of phosphate homeostasis.

Phosphate homeostasis is dependent on the interaction and coordination of four main organ systems: thyroid/parathyroids, gastrointestinal tract, bone and kidneys, and three key hormonal regulators, 1,25-hydroxyvitamin D3, parathyroid hormone and FGF23 with its co- factor klotho. Phosphorus is a critical nutritional element for normal cellular function, but in excess can be toxic to tissues, particularly the vasculature. As phosphate, it also has an important interaction and inter-dependence with calcium and calcium homeostasis sharing some of the same controlling hormones, although this is not covered in our article.

Pan-cerebral sodium elevations in vascular dementia: Evidence for disturbed brain-sodium homeostasis.

Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias.