The detection and consequences of association of two enzymes involved in catalysing consecutive reactions

A set of differential rate equations is formulated for a system wherein two enzymes catalyse consecutive reactions of a pathway and also interact to form a 1:1 complex. The effect of this interaction on the time-dependence of final product formation is explored in terms of explicit expressions obtained with the use of Maclaurin polynomials applied to the rate equations. It is shown with the aid of numerical examples that provided complex formation between the enzymes leads to a species possessing different activity toward either substrate the interaction may potentially be detected by steady-state kinetic measurements on the enzymes studied alone and in a coupled assay. The introduction of a sigmoidal regulatory response arising as a sole consequence of the enzyme-enzyme interaction is also discussed.     

Sex differences in lower urinary tract biology and physiology

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.     

L-dopa metabolism in genetically hypertensive mice: effect of pargyline

This study on the role of the sympathetic nervous system in the development of hypertension involves the measurement of dopamine and norepinephrine accumulation in various tissues of the hypertensive and random-bred normotensive strains of mice at basal levels, and following a pargyline-L-dopa treatment. Under such a treatment, designed to suppress the homeostatic action of monoamine oxidase and to better expose the relationship between dopamine and norepinephrine, the brain and heart of the hypertensive mice accumulated more dopamine than the normotensive mice. There was a significantly lower norepinephrine accumulation in the heart of the hypertensive mice in spite of comparable dopamine-beta-hydroxylase activity in this tissue between the two strains of mice. Under the pargyline-L-dopa treatment, the brain and heart of the older mice in both hypertensive and normotensive strains accumulated significantly (p less than 0.05) more dopamine than those of their younger counterparts, while their norepinephrine accumulation remained unchanged. The results demonstrated different patterns of response of dopamine and norepinephrine in the development of hypertension.     

Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues

The primary metabolic pathway required to produce ATP differs as a result of tissue type, developmental stage and substrate availability. We utilized molecular and histological techniques to define the metabolic status in foetal and adult, adipose and skeletal muscle tissues. Redox ratios of these tissues were also determined optically by two‐photon microscopy. Adult perirenal adipose tissue had a higher optical redox ratio than fetal perirenal adipose tissue, which aligned with glycolysis being used for ATP production; whereas adult skeletal muscle had a lower optical redox ratio than fetal skeletal muscle, which aligned with oxygen demanding oxidative phosphorylation activity being utilized for ATP production. We have compared traditional molecular and microscopy techniques of metabolic tissue characterization with optical redox ratios to provide a more comprehensive report on the dynamics of tissue metabolism.     

Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants

Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90–0.96, p = 3.37 × 10⁻⁷). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies.     

1H NMR spectroscopic survey of plasma and erythrocytes from selected marsupials and domestic animals of Australia.

1. 1H NMR spectra were acquired from whole plasma, intact erythrocytes, and ultrafiltrates of erythrocytes from nine native and eight introduced (domestic) Australian animals; single-pulse, spin-echo and 2-dimensional spectra were obtained. The aim was to detect and at least semi-quantify metabolites in the samples and compare the profiles amongst the species. 2. The Australian natives that were studied were all marsupials: greater brown bandicoot; bettong; eastern grey kangaroo; red kangaroo; koala; possum; red necked pademelon; Tammar wallaby; and wombat. The introduced mammals that were studied were: cat; cattle; dog; goat; horse; pig; rabbit; and sheep. 3. Because of the range of habitats and diets amongst the animals, it was postulated that the concentrations of the common metabolites in the blood would show marked differences and that there would also be some metabolites that were peculiar to a given animal. There were several major differences in the spectra: in the spectra of plasma, the glycoprotein and lipoprotein resonances showed the largest inter-species variation, whereas the most dramatic finding from the spectra of erythrocytes was a very high concentration of lysine in the cells from the Tammar wallaby.     

High salt intake-induced changes in atrial natriuretic factor kinetics are mediated by clearance receptors.

We have reported a paradoxical plasma atrial natriuretic factor (ANF) decline following prolonged high salt intake that was attributed to an increased tissue uptake of circulating ANF, leading to its augmented distribution volume (Vas) and metabolic clearance rate (MCR) as compared with control rats on a standard diet. To explore this phenomenon further, we evaluated possible chronic salt-loading-induced changes in ANF clearance (C-ANF) receptors, which appear to play a major role in ANF removal from the circulation. We studied changes in plasma [125I]ANF(1-28) and its pharmacokinetics after preoccupation of C-ANF receptors by its specific ligand, C-ANF(4-23), in high-salt-treated rats and their controls. Following C-ANF(4-23) administration, we detected significantly higher circulating [125I]ANF levels throughout the study period (8 min) in high-salt-fed rats compared with the controls (280-470% vs 100-215% increase of basal values, P less than 0.05). C-ANF(4-23) infusion caused a significantly greater decrease of the metabolic clearance rate and distribution volume of [125I]ANF in high-salt-fed rats than in control animals (74 +/- 6% vs 41 +/- 6% and 75 +/- 4% vs 50 +/- 5% of basal values, respectively; P less than 0.05). These data suggest that a prolonged high salt diet may increase the availability of C-ANF receptors and, through this mechanism, may negatively modulate plasma ANF concentrations. C-ANF receptors may thus fulfill a regulatory function on circulating ANF during prolonged salt loading in rats.     

Role of sulfate conjugation of catecholamines in blood pressure regulation

Catecholamine sulfates were found to be inactive at vascular receptor sites. Only at one nonvascular receptor site important for blood pressure (BP) regulation was dopamine-3-O-sulfate found to be an inhibitory modulator of the adrenocortical secretion of aldosterone in vitro. However, sulfation of catecholamines (CA) does play an important role in BP regulation, as shown by the following observations: Sulfoconjugated CA with a long half-life are sometimes better markers of CA release than free CA, which have short half-lives. This is particularly true of dopamine (DA) sulfate because free DA, being rapidly sulfoconjugated, is usually undetectable. This led to the recognition of a previously unsuspected role of DA in paroxysmal hypertension and orthostatic hypotension. Measurements of CA sulfates reveal potentially important storage functions for sulfoconjugation that can rapidly inactivate excessive circulating free CA and so mitigate their cardiovascular impact while building up a pool of conjugated CA. The possibility that free CA can be generated from this pool through deconjugation whenever a need for them arises should be further investigated. Reproducible individual differences in the velocity of the sulfoconjugation of infused free CA can be detected, which suggests a genetic control of certain components of the sulfoconjugating process. These differences in sulfoconjugation probably modulate the cardiovascular action of CA and of some drugs with similar structure that also undergo sulfoconjugation.