Carbonyl Reductase 1: a novel regulator of blood pressure in Down Syndrome.

Approximately one in every 800 children is born with the severe aneuploid condition of Down Syndrome, a trisomy of chromosome 21. Low blood pressure (hypotension) is a common condition associated with DS and can have a significant impact on exercise tolerance and quality of life. Little is known about the factors driving this hypotensive phenotype and therefore therapeutic interventions are limited.

A practical approach to supported liquid extraction and measurement of 18 steroids in plasma and serum by targeted liquid chromatography tandem mass spectrometry.

Chromatography combined with mass spectrometry is a gold standard technique for steroid measurement, however the type of sample preparation, the dynamic range and reliability of the calibration curve, the chromatographic separation and mass spectrometry settings ultimately determine the success of the method. The steroid biosynthetic pathway is conserved in higher mammals and literature demonstrates that the concentration ranges of different steroid groups are relatively comparable across species. We sought to develop a robust and reliable multi steroid targeted analysis method for blood that would have wide application across higher mammals.

Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

Objective: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies.

Design/patients: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study).

Using LC-MS/MS to Determine Salivary Steroid Reference Intervals in a European Older Adult Population.

A number of steroids, including glucocorticoids and sex hormones, have been associated with neurodegenerative and cardiovascular conditions common in aging populations. The application of liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid analysis offers an opportunity to conduct simultaneous multiplex steroid analysis within a given sample. In this paper, we describe the application of an LC-MS/MS steroid analysis method for the assessment of reference ranges of steroids in human saliva samples (200 µL) collected from older adults (age 50 years and above) enrolled in a European cohort investigating the risk for Alzheimer's dementia.

Increased Adipose Tissue Indices of Androgen Catabolism and Aromatization in Women With Metabolic Dysfunction.

Context: Body fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex difference in body fat distribution, and steroid hormones are known to regulate several cellular processes within adipose tissue.

Objective: Our aim was to investigate if intra-adipose steroid concentration and expression or activity of steroidogenic enzymes were associated with features of adipose tissue dysfunction in individuals with severe obesity.

The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range.

Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study.

Objectives: The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors.

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

Objective: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states.

Methods: The actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists.

Derivatization with 2-hydrazino-1-methylpyridine enhances sensitivity of analysis of 5α-dihydrotestosterone in human plasma by liquid chromatography tandem mass spectrometry.

Liquid Chromatography tandem mass spectrometry (LC-MS/MS) is the gold-standard approach for androgen analysis in biological fluids, superseding immunoassays in selectivity, particularly at low concentrations. While LC-MS/MS is established for analysis of testosterone and androstenedione, 5α-dihydrotestosterone (DHT) presents greater analytical challenges. DHT circulates at low nanomolar concentrations in men and lower in women, ionizing inefficiently and suffering from isobaric interference from other androgens.

Development and application of a LC-MS/MS assay for simultaneous analysis of 25-hydroxyvitamin-D and 3-epi-25-hydroxyvitamin-D metabolites in canine serum.

Hypovitaminosis D and hypervitaminosis D are well recognised disorders in dogs. Hypovitaminosis D can occur following consumption of a diet inadequately supplemented with vitamin D or as a sequelae of severe intestinal disease. Hypervitaminosis D may occur as a result of consuming proprietary dog foods over-supplemented with vitamin D or through ingestion of vitamin D containing medicinal products or rodenticides.

A mechanism for multidisciplinary dialogue: the memory & … series.

Neuroscientists have long explored the mechanisms of memory from molecular, physiological, cognitive, and social perspectives. Scholars from other disciplines such as history, sociology, literature, and cultural studies, that do not traditionally cross-pollinate ideas with neuroscientists, also study memory from a variety of angles. In this article, we describe the founding of a multidisciplinary discussion series in which faculty and staff from the arts, humanities, social sciences, and natural sciences come together to explain how memory is integral to their scholarship and teaching.

Modulation of oncogenic phenotype in human glioma cells by cytomegalovirus IE1-mediated mitogenicity.

Recent evidence indicates that human cytomegalovirus (HCMV) infection occurs in a high percentage of human malignant gliomas in vivo, as the HCMV immediate early-1 (IE1) protein is detected in >90% of these tumors. The HCMV IE1 protein is essential for viral infection and has potent trans-activating and oncomodulatory properties. To investigate a potential role of HCMV in glioma biology, we stably expressed the HCMV IE1 gene product in immortalized and malignant human glial cells.

Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness.

Given our previous findings that human cytomegalovirus (HCMV) nucleic acids and proteins are expressed in human malignant glioma in vivo, we investigated cellular signaling events associated with HCMV infection of human glioma and astroglial cells. HCMV infection caused rapid activation of the phosphatidylinositol-3 kinase (PI-3K) effector AKT kinase in human astro-glial and fibroblast cells, and induced tyrosine phosphorylation of phospholipase Cgamma (PLCgamma). Co-immunoprecipitation experiments revealed association of the p85 regulatory subunit of PI-3K with a high-molecular weight protein phosphorylated on tyrosine, following short-term exposure to HCMV.

Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission.

Heterosexual transmission accounts for the majority of human immunodeficiency virus-1 (HIV-1) infections worldwide, yet the viral properties that determine transmission fitness or outgrowth have not been elucidated. Here we show, for eight heterosexual transmission pairs, that recipient viruses were monophyletic, encoding compact, glycan-restricted envelope glycoproteins. These viruses were also uniquely sensitive to neutralization by antibody from the transmitting partner.