Physiological Point Research Articles

Abolition of Aorticorenal Ganglia Pacing Responses Improves Denervation Efficacy.

Transcatheter renal denervation (RDN) remains inconsistent despite developments in ablation technologies, due to the lack of an intraprocedural physiological end point. To identify whether aorticorenal ganglion (ARG) guided RDN using microwave (MW) catheter leads to more consistent denervation outcomes compared with empirical MW ablation. Pigs underwent sham procedure (n=8) or bilateral RDN using an in-house built open-irrigated MW catheter. Before denervation, ipsilateral ARG pacing was performed leading to renal artery vasoconstriction. MW ablation group (MW-group; n=7) received 1 ablation (100-120 W for 360 seconds) in the mid-main renal artery based on artery caliber. ARG-guided-MW ablation group (ARG-MW-group; n=7) was permitted an additional ablation more distally or at higher power until a vasoconstrictive response was abolished. Animals were euthanized at 4 to 5 weeks post-procedure. ARG pacing caused an ipsilateral reduction in renal artery caliber from 4.67 to 4 mm; P=0.0006 in MW-group and 4.8 to 3.9 mm; P=0.001 in ARG-MW-group. Repeat ARG pacing at euthanasia led to a reduction in renal artery caliber in MW-group from 5.1 to 4.8 mm; P=0.006, but not in ARG-MW-group from 4.88 to 4.55 mm; P=0.08. There were no differences in ablation injury volumes between the groups. Compared with undenervated sham controls, ARG-MW-RDN versus MW-RDN caused median reductions in viable nerve area (antityrosine hydroxylase staining) at 4 to 5 weeks by 92.6% (interquartile range, 0.94-19.59%; P<0.0001) versus 55.02% (interquartile range, 15.87-75.11%; P=0.006) and median renal cortical norepinephrine content by 68.06% (interquartile range, 27.16-38.39%; P<0.0001) versus 25.25% (interquartile range, 56.97-157.7%; P=NS). ARG pacing serves as a physiological procedural end point to guide MW denervation to improve denervation outcomes.

Mathematical Model of Bingham Fluid Inside Asymmetric Stenosed Artery and Its Applications

This study is to analysis the two-layered model of blood flow inside asymmetric stenosed artery with the consideration that blood behaves like a Newtonian and non-Newtonian fluid with different viscosities in the Peripheral layer and core regions. Further, in view of the existence of a velocity slip in blood flow regime, an axial slip condition as reported by many researchers is introduced at interface of the two-layers in the present analysis. The expressions for the flow characteristics namely the velocity profile, flow rate , the resistance to flow, the wall shear stress at the stenosis throat within the tube are obtained. Discussions are done from a physiological point of view with the help of graph.

GENESIS OF ARTICULATORY PRAXIS FROM BIRTH TO THREE YEARS

Articulatory praxis is a motor act consciously regulated by the subject based on the existing need and united by a single goal. It is not an innate ability and develops over time. Early age is included in the preparatory and pre-school stages of speech activity formation. The development of oral motor skills and the formation of articulato-ry praxis at this age can be divided into several periods. Each period has a number of changes. Screaming, cooing, babbling, modular babbling, imitation of adult words, first words and phrases appear. Eating behavior changes, the child moves from liquid food to denser and thicker textures, begins to chew. From a physiological point of view, the larynx changes, the muscles of the peripheral speech apparatus, facial muscles, neck muscles are strengthened, teeth appear. As the child grows, the organization of the brain changes, the ability to perform more differentiated movements appears, the work of the auditory, visual, kinesthetic analyzers develops, the tertiary fields of the fron-tal lobes of the brain are formed, this makes it possible to single out a word, sound in speech and exercise control when trying to pronounce them, adjust the articulatory structure to achieve the desired sound.

Normative values of non-radiological surface measurement of the lumbar lordosis curvature in the standing position and its association with age, sex, and body mass index: a cross-sectional study of 2,500 healthy individuals from Iran.

A cross-sectional study. This study aimed to define the normal values of the lumbar lordosis curve (LLC) and investigate its association with sex, age, and body mass index (BMI). The importance of the human spine's sagittal alignment, particularly in the lumbar region, has been argued from the physiological and pathophysiological points of view. The LLC size is an important predictor of lumbar pathologies. Lumbar curvature misalignment, particularly increased lumbar lordosis or hypolordosis, can, in the long term, lead to spinal instability and development of disorders such as low back pain and spondylolisthesis Therefore, knowledge about the normal LLC value and its association with age, sex, and BMI, appears crucial. The study recruited 2,497 asymptomatic volunteers (1,264 women and 1,233 men) aged 5-85 years. Participants were assigned to different groups based on their sex, age, and BMI. The LLC was measured using a Flexicurve. Normal LLC values were established for different sexes, age, and BMI groups. Overall, normal LLC ranges from 10.2° to 74.9° with a mean of 42.34°±13° (male, 38.57°±11.44°; female, 46°±13.38°). LLC was generally higher by 7.5° in women than in men. A significant three-way interaction of sex, age, and BMI with LLC was found. The association of age and BMI with LLC was also significant. Our results can be used as a reference by physicians, healthcare, etc., when the LLC values in different ages and sexes are measured noninvasively. In other words, this information can be used as reference when determining whether the obtained LLC is within the normal range.

Dynamics of the main parameters of carbohydrate metabolism and possible causes of its disorders in the autumn and winter periods in modern residents of the North

To assess the reserve capacity of the body from a physiological point of view, it is important to study the specific “northern” hormone metabolic profile of the body during critical (autumn and winter) periods in apparently healthy individuals born and living in the North.The aim of the work. To study the main parameters of carbohydrate metabolism, as well as possible causes of its disorders in the dynamics of autumn and winter periods in men living in the North.Materials and methods. The autumn (October) and winter (December) stages of the study included 45 men (mean age 40.0 ± 0.8 years) permanently residing in the Magadan Region. We used chemiluminescent immunoassay, enzymatic method and immunochromatographic assay.Results of the study. It was found that the average values of carbohydrate metabolism parameters in the examined male northern residents are comparable with the standard ranges with a shift towards higher values relative to the established limits and do not meet the main criteria of the “polar metabolic type”. “Polar metabolic type” is characterized by hypoglycemia and hypoinsulinemia against the background of elevated serum cortisol values. It is shown that during the critical period of the year from October to December (temperature transition through zero) against the background of relative “hypercortisolism”, activation of the insular apparatus of the pancreas is observed, accompanied by an increase in the insulin level, as well as the development of insulin resistance in the absence of compensatory secretion of β-cells of the pancreas. At the same time, the presence of signs of insulin resistance in northern male residents in the winter period may be determined by an imbalance towards greater dominance of the sympathetic nervous system, formed as a response to the critical period of the year.Conclusion. The obtained results indicate the formation of a transformed “northern” hormone metabolic profile of the body of a modern resident of the North, which should be considered as a certain adaptive response to the modern modification of the socio-economic lifestyle of northern residents (hypodynamia, overeating, etc.).

Exogenous application of melatonin and chitosan mitigate simulated microgravity stress in the Rocket (Eruca sativa L.) plant

Starting life in space and implementing spaceflight missions requires raising of plants in special conditions, where various stresses, including microgravity, are applied to plant. The use of stimulants is known as a promising effective approach that enhances plant resistance encountered a variety of abiotic stresses. In this study, the impact of two stimulants, melatonin and chitosan, in reducing negative effects of clinorotation on Rocket (Eruca sativa L.) seedlings was investigated from a physiological and biochemical point of view. For this purpose, a completely randomized experiment was designed where the treatments included control (without stimulants and normal gravity), melatonin (100 μM), chitosan (230 M), microgravity, microgravity + melatonin, and microgravity + chitosan. The results disclosed that the microgravity significantly impaired the plant growth and morphology, while exogenous application of melatonin and chitosan improved the plant growth parameters under stress conditions. Under microgravity, there was a reduction of 46.15% in shoot length (4.9 mm) and 41.44% in root length (4.7 mm) compared with the control (9.1 mm; 8.03 mm), respectively. Clinorotation led to a marked increment in the enzymes activity, wherein the POD, SOD and CAT activities increased by 75.13%, 72.67%, and 53.42%, respectively, compared with the control seedlings. In addition, supply of these two stimulants strengthened the scavenging of radial oxygen species and helped the plant to tolerate stress conditions, by activated the enzymatic and non-enzymatic systems. These results can pave the road for more studies and broad application of biological stimuli to overcome the space harsh environmental conditions by plants.

Analgesia and peripheral c-fiber modulation by selective Nav1.8 inhibition in rhesus.

Voltage-gated sodium (Nav) channels present untapped therapeutic value for better and safer pain medications. The Nav1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. In addition, the relevance of rodent pain assays to the human condition is under increasing scrutiny as a number of mechanisms (or at the very least molecules) that are active in rodents have not translated to humans, and direct impact on pain fibers has not been confirmed in vivo. In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Nav1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Nav1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Nav1.8 inhibition broadly.

Cellular Profile of Subfornical Organ Insulin Receptors in Mice.

Brain insulin receptor signaling is strongly implicated in cardiovascular and metabolic physiological regulation. In particular, we recently demonstrated that insulin receptors within the subfornical organ (SFO) play a tonic role in cardiovascular and metabolic regulation in mice. The SFO is a forebrain sensory circumventricular organ that regulates cardiometabolic homeostasis due to its direct exposure to the circulation and thus its ability to sense circulating factors, such as insulin. Previous work has demonstrated broad distribution of insulin receptor-expressing cells throughout the entire SFO, indirectly indicating insulin receptor expression in multiple cell types. Based on this, we sought to determine the cellular phenotypes that express insulin receptors within the SFO by combining immunohistochemistry with genetically modified reporter mouse models. Interestingly, SFO neurons, including both excitatory and inhibitory types, were the dominant cell site for insulin receptor expression, although a weak degree of insulin receptor expression was also detected in astrocytes. Moreover, SFO angiotensin type 1a receptor neurons also expressed insulin receptors. Collectively, these anatomical findings indicate the existence of potentially complex cellular networks within the SFO through which insulin signaling can influence physiology and further point to the SFO as a possible brain site for crosstalk between angiotensin-II and insulin.

The value of objective methods for assessing nasal breathing function in the diagnostic algorithm for allergic rhinitis

The visual analogue score (VAS) is recommended to assess the severity of symptoms of allergic rhinitis (AR), but despite its advantages, it is a tool for subjective assessment of symptoms and often does not correlate with the true state of nasal patency. Anterior active rhinomanometry (AAR) is the method to objectify obstructive changes in the nasal cavity in patients with AR and is the most accurate method to assess nasal breathing function from a physiological and aerodynamic point of view. In addition, AAR with a decongestant test allows a differential diagnosis of the causes of nasal obstruction. Our study showed that there was no correlation between VAS and AAR scores. In addition, we found the importance of performing AAR with a decongestant test and subsequent assessment of unilateral flow and resistance parameters, which allowed us to suspect the presence of structural changes in the nasal cavity in patients with AR, as recorded as a result of anterior rhinoscopy and/or endoscopic examination. Thus, in addition to the use of VAS, it is necessary to include AAR in the diagnostic algorithm for AR, which allows not only to confirm the presence or absence of nasal breathing impairment, but also to differentiate the causes of its occurrence for the subsequent selection of the optimal management of patients with AR.

Eje hipotálamo-hipofisario. Regulación neurohormonal, implicaciones patológicas, pruebas funcionales hipofisarias, indicaciones e interpretación

The hypothalamic-pituitary axis is a crucial system for maintaining homeostasis by integrating hormonal and neuronal inputs and outputs. Almost all bodily functions are regulated directly or indirectly by this axis. The hypothalamus, a small but vital brain region, monitors various inputs and maintains physiological set points through hormonal secretion, coordinating with the pituitary gland. This regulation involves multiple feedback mechanisms and interactions with other brain areas.The hypothalamus is anatomically divided into several regions and nuclei, each with specific functions. It produces a variety of hormones, including growth hormone-releasing hormone, corticotropin-releasing hormone, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. These hormones regulate the secretion of corresponding hormones from the anterior pituitary gland, which control several physiological processes, including growth, metabolism, reproduction, and stress response.Pathological implications of hypothalamic-pituitary axis dysfunctions include endocrine disorders such as hyperprolactinemia, growth hormone deficiency, and hypogonadism. In addition, hypothalamic damage can lead to neurological and behavioral problems such as sleep disturbances and thermoregulation.

Linking physiology, epidemiology, and demography: Understanding how lianas outcompete trees in a changing world

Extending and safeguarding tropical forest ecosystems is critical for combating climate change and biodiversity loss. One of its constituents, lianas, is spreading and increasing in abundance on a global scale. This is particularly concerning as lianas negatively impact forests' carbon fluxes, dynamics, and overall resilience, potentially exacerbating both crises. While possibly linked to climate-change-induced atmospheric CO2 elevation and drought intensification, the reasons behind their increasing abundance remain elusive. Prior research shows distinct physiological differences between lianas and trees, but it is unclear whether these differences confer a demographic advantage to lianas with climate change. Guided by extensive datasets collected in Panamanian tropical forests, we developed a tractable model integrating physiology, demography, and epidemiology. Our findings suggest that CO2 fertilization, a climate change factor promoting forest productivity, gives lianas a demographic advantage. Conversely, factors such as extreme drought generally cause a decrease in liana prevalence. Such a decline in liana prevalence is expected from a physiological point of view because lianas have drought-sensitive traits. However, our analysis underscores the importance of not exclusively relying on physiological processes, as interactions with demographic mechanisms (i.e., the forest structure) can contrast these expectations, causing an increase in lianas with drought. Similarly, our results emphasize that identical physiological responses between lianas and trees still lead to liana increase. Even if lianas exhibit collinear but weaker responses in their performance compared to trees, a temporary liana prevalence increase might manifest driven by the faster response time of lianas imposed by their distinct life-history strategies than trees.

Isolation of Aerobic Bacterial Species Associated with Palpable Udder Defects in Non-Dairy Ewes.

The objectives of these studies were to identify associations between udder half defects (hard or lump) and bacteria isolated from milk or mammary tissue swabs, to compare with samples from normal udder halves at different physiological time points and to compare bacterial species isolated via milk and swabs of mammary tissue from within the same udder halves. A total of 1054 samples were aseptically collected from each udder half of 199 non-dairy breed (Romney) ewes from three different studies (Study A, n = 77; Study B, n = 74; and Study C, n = 48). Conventional bacterial culture and MALDI-ToF mass spectrometry were used for bacterial identification. Of the 225 samples from which bacteria were isolated, Mannheimia haemolytica and Streptococcus uberis were the dominantly identified species from defective udder halves, whereas coagulase-negative staphylococcus (CNS) species, mostly Staphylococcus simulans and Staphylococcus chromogenes, were more frequently isolated from normal udder halves. The ongoing presence of bacterial species over time was variable, although less frequently identified species showed less stability over time. A very high agreement (91.5%) of bacterial species identified was observed between the mammary tissue swab and udder half milk samples during post-weaning. In summary, palpable udder half defects were associated with bacterial positivity, and the ongoing presence of the bacteria over time was dependent on the species involved. Hence, culling ewes with palpable udder half defects that had more stable bacterial species could contribute to reducing the recurrence of palpable defects or mastitis.

The influence of pre‐exposure to marine heatwaves on the critical thermal maxima (CTmax) of marine foundation species

Abstract Marine foundation species underpin some of the world's most diverse ecosystems but they are increasingly threatened by intensification of marine heatwaves (MHWs). Where MHWs exceed critical thermal maxima (CTmax), increased mortality and population declines can occur. CTmax is increasingly used to assess MHW population vulnerability but studies estimating CTmax across species, range edges and thermal histories in a comparable manner remain lacking. We determined the impact of MHWs on subsequent CTmax estimates of matched cool/warm affinity pairs of marine foundation species (kelp, seagrass and bivalves) in the Western English Channel. Following a 4‐week MHW simulation, individuals were subjected to a CTmax trial, where temperatures were raised by 2°C day−1 until physiological end points were reached. We found no positive effect of MHWs on CTmax but clear negative impacts were observed for some groups of foundation species. Increased MHW intensity had a stepwise negative impact on the physiology of both warm (Laminaria ochroleuca) and cool water (L. digitata) kelp species that manifested in significant reductions in CTmax. Surprisingly, this was most marked in the warm water species, which runs opposite to the assumed safety of leading‐edge populations. The physiology of warm (Zostera noltii) and cool (Z. marina) seagrasses was negatively impacted by increasing MHW intensity but no significant decrease in CTmax was observed. Both bivalve species (Mytilus edulis and Magallana gigas) showed marked resistance to exposure to MHWs, which was unexpected given the observed vulnerability of these species to stressful summertime conditions. Our results show pre‐exposure to realistic MHWs can influence CTmax values but generalities are difficult to make across groups or based on assumed thermal safety margins. We show CTmax is a labile trait and exposure to MHWs, can erode the resilience of an individual or population to subsequent thermal challenges. This leaves uncertainty within frameworks built to understand where and when MHWs will be most impactful. Further experimentation across a wider range of species and thermal challenges is needed to better understand the dynamic nature of CTmax and field validation is needed to determine the responses of individuals and populations within complex natural systems. Read the free Plain Language Summary for this article on the Journal blog.

An accurate tidal peak localization method in radial arterial pulse signals based on hybrid neural networks

Background: cardiovascular diseases (CVDs) have become the leading causes of death worldwide. Arterial stiffness and elasticity are important indicators of cardiovascular health. Pulse wave analysis (PWA) is essential for analyzing arterial stiffness and elasticity, which are highly dependent on the tidal peak (P 2). P 2 is one of the four key physiological points, which also include percussion peaks (P 1), diastolic notches (P 3), and diastolic peaks (P 4). P 1, P 3, and P 4 are often local maxima or minima, facilitating their identification via the second derivatives method, a classic localization method for key physiological points. Classic methods such as the second derivative method, Empirical Mode Decomposition (EMD), and Wavelet Transform (WT), have been employed for the extraction and analysis of the P 2. Due to individual variation and arterial stiffness, locating the P 2 using classic methods is particularly challenging. Methods: we propose a hybrid neural network based on Residual Networks (ResNet) and bidirectional Long Short-Term Memory Networks (Bi-LSTM), successfully achieving high-precision localization of the P 2 in radial artery pulse signals. Meanwhile, we compared our method with the second derivative method, EMD, WT, Convolutional Neural Networks (CNN) and the hybrid model with ResNet and LSTM. Results: the results indicate that our proposed model exhibits significantly higher accuracy compared to other algorithms. Overall, MAEs and RMSEs for our proposed method are 62.60% and 58.84% on average less than those for other algorithms. The average R Adj 2 is 29.20% higher. The outcomes of the efficiency evaluation suggest that the hybrid model performs more balancedly without any significant shortcomings, which indicates that the Bi-LSTM structure upgrades the performances of LSTM. Significance: our hybrid model can provide the medical field with improved diagnostic tools and promote the development of clinical practice and research.

The Envelope of Function: Revisiting the Theory With New Concepts-A Narrative Review.

Musculoskeletal injuries are a complex multifactorial phenomenon, and several factors can contribute to their occurrence. This review aimed to discuss some relevant and often unexpected elements involved in musculoskeletal injuries and rehabilitation. One of the main factors discussed is the role of physiological adaptation to training in musculoskeletal injury susceptibility. This is probably the most modifiable factor in preventing and treating musculoskeletal injuries. Other factors discussed are the role of genetics in injury susceptibility; the effect of stressors and environmental factors and the way we deal with setbacks; anabolic steroid use as aesthetic and performance-enhancement drugs; nutrition, sleeping, and the imbalance between rest, energy intake, and training; anatomic and biomechanical factors; and the role of systemic disease. Moreover, the topic of unknown factors keeps an open door for future discoveries. This review highlights the importance of understanding the various factors contributing to musculoskeletal injuries and the need for an individualized approach to injury prevention and rehabilitation, from both a historical and a physiological point of view.

Physical parametric study of bacterial biofilm disruption and removal by jet impingement: A CFD investigation

Bacterial biofilm formation is one of the most critical challenges in industrial and health systems. It is the leading cause of nearly 80 % of clinical infections. Biofilms are usually evaluated from the physiological point of view as microbial cells enclosed in an extracellular polymer and represent a complex, dynamic bacterial community. Cohesive mechanical forces hold the bacteria within the biofilm together. These forces contribute to the biofilm's mechanical and structural stability, resulting in its viscoelastic properties. Studying the biofilm's mechanical properties as a viscoelastic matter can provide a better understanding of the biofilm's characteristics and the survival strategies of bacteria in the biofilm state of life. In the present study, a 2D-axisymmetric RANS-CFD simulation model using the Volume Of Fluid (VOF) method was developed to track changes in biofilm surface and ripple formation across six biofilm thicknesses ranging from 15 μm to 115 μm, two substrate geometries including flat and curved, and two substrate roughnesses of 0.4 μm and 0.9 μm height. A modified Herschel-Bulkley model was employed to capture the biofilm's non-Newtonian shear-thinning behavior under high-velocity gas jet impingement. The results revealed the importance of biofilm thickness, substrate geometries, and properties like roughness in biofilm's mechanical behavior. Higher thickness of biofilm resulted in smaller jet-impingement region and more significant ripples formation. Biofilm on curved substrates decreased in thickness more rapidly than those on flat substrates. The substrate's geometry impacted biofilm folding patterns, removal, and mechanical behavior. Selected substrate roughnesses did not create any resistance against the mechanical removal of biofilms. Here, we successfully captured biofilms' non-Newtonian and shear-thinning behavior with numerical simulations consistent with previously reported experimental results. This could benefit industrial and health systems by tackling biofilm-related challenges and developing more accurate and detailed models of biofilms to optimize tools for drug testing or screening and enhance the models for in-vitro and in-vivo analysis.

Математическое моделирование мягкого экзоскелета из магнитно-реологических модулей с интеллектуальным управлением

The article considers a fundamentally new generation of soft exoskeletons based on magnetic rheological modules. A model of an exoskeleton link with adjustable rigidity is proposed, for which a system of differential equations of motion is compiled. A model of an exoskeleton for human lower extremities, composed of modules with magnetic rheological fluid, has been developed. The problems of kinematics and dynamics that arise when controlling the movement of an exoskeleton are presented. A block diagram of an algorithm for controlling the movement of an exoskeleton has been developed, solving control problems taking into account neural network methods. A qualitative study by analytical methods of the proposed mathematical model of an exoskeleton with links with adjustable stiffness is carried out. The use of regulation of the rigidity of the links of the exoskeleton modules in the necessary way will make it possible to create devices that are comfortable for the user, both from the physiological and psychological points of view. Soft exoskeletons will be in demand in many industries and medicine. The use of electromagnetic actuators, which, as a rule, have smaller dimensions and energy consumption, an almost instantaneous response speed in comparison with pneumatic drives, hydraulic drives and electric drives, is promising and technically, energetically, environmentally, economically more acceptable. Under the action of electric or magnetic fields, the stiffness of electroelastic and magneto-rheological materials can change by more than an order of magnitude. This makes it possible to create exoskeleton links with adjustable stiffness. Regulation of the rigidity of the elements of the exoskeleton modules in real time is a complex control task. Therefore, exoskeleton motion control requires the development of adaptive type algorithms based on a neuro-fuzzy approach, using information received from feedback. Neural network algorithms for self-learning in the process of functioning are a logically expedient part of a soft bionic exoskeleton. Also, as a necessary component of the exoskeleton, along with the actuator part, a sensor system is needed with sensitive sensors for the user’s neuromuscular impulses and various sensors for position, speed, acceleration, force, moment of force of the exoskeleton. A comprehensive study of scientific and technical problems of the functioning of the model of the magnetic-rheological medium, exoskeleton modules and their compilation into a single multi-link structure, its movement using the technology of modern mathematical modeling was carried out. The construction of neuro-fuzzy control systems for soft exoskeletons is described as part of the development of new mathematical methods for modeling complex technical objects using modern mechatronics and cyborgics.

Kinetic Behavior of Glutathione Transferases: Understanding Cellular Protection from Reactive Intermediates.

Glutathione transferases (GSTs) are the primary catalysts protecting from reactive electrophile attack. In this review, the quantitative levels and distribution of glutathione transferases in relation to physiological function are discussed. The catalytic properties (random sequential) tell us that these enzymes have evolved to intercept reactive intermediates. High concentrations of enzymes (up to several hundred micromolar) ensure efficient protection. Individual enzyme molecules, however, turn over only rarely (estimated as low as once daily). The protection of intracellular protein and DNA targets is linearly proportional to enzyme levels. Any lowering of enzyme concentration, or inhibition, would thus result in diminished protection. It is well established that GSTs also function as binding proteins, potentially resulting in enzyme inhibition. Here the relevance of ligand inhibition and catalytic mechanisms, such as negative co-operativity, is discussed. There is a lack of knowledge pertaining to relevant ligand levels in vivo, be they exogenous or endogenous (e.g., bile acids and bilirubin). The stoichiometry of active sites in GSTs is well established, cytosolic enzyme dimers have two sites. It is puzzling that a third of the site's reactivity is observed in trimeric microsomal glutathione transferases (MGSTs). From a physiological point of view, such sub-stoichiometric behavior would appear to be wasteful. Over the years, a substantial amount of detailed knowledge on the structure, distribution, and mechanism of purified GSTs has been gathered. We still lack knowledge on exact cell type distribution and levels in vivo however, especially in relation to ligand levels, which need to be determined. Such knowledge must be gathered in order to allow mathematical modeling to be employed in the future, to generate a holistic understanding of reactive intermediate protection.

An early Prussian study on the composition of milk from 1871

Connections between the 2 scientific fields of physiology and dairy science have existed for a very long time-since the 19th century. One possible explanation for this circumstance could have been the necessity for financial support, which might have played a significant role for many theoretical physiologists to conduct studies on dairy products. This study discusses a correspondence written by the physiologist R. Gscheidlen to J. A. Winter, the main editor of the German (previously Saxon) journal "Schmidt's Yearbooks on the Entire Field of Domestic and Foreign Medicine" ("Schmids Jahrbücher der in-und ausländischen gesammten Medicin"). Gscheidlen submitted a review manuscript on the composition of milk to Winter's journal. In that work, which was published later as the first issue's very first article of the first volume (of in total 4 quarterly volumes) in 1871, Gscheidlen mainly refers to Eduard Kemmerich, who later became a pioneer of cattle breeding in Argentine. Therefore, studies on dairy products and on dairy science, although regularly not very significant from a theoretical and physiological point of view, obviously had concrete implications for practical purposes. Furthermore, other parts of Winter's journal, volume 1871, indicate that Gscheidlen tried to connect these studies with his early theoretical works on physiological metabolism. These theoretical studies included experiments that already explored basic principles of the urea cycle from today's point of view. Of course, these works, which were partly carried out on animals, must have been extravagant and expensive. For that reason, it is possible to assume that early dairy science and other scientific fields in Germany around 1870, which were linked to the developing food industry, had a very significant influence on the advances in theoretical metabolism physiology.

Bile Acids and Bilirubin Role in Oxidative Stress and Inflammation in Cardiovascular Diseases.

Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs/bilirubin and CVD were examined in depth to better interpret the possible link between them.