SEARCH · Search bioRxiv

Results for “Physiology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,531 records · Page 85Linked to original sources

bioRxiv2020

The impact of dietary protein and carbohydrates on gene expression in a generalist insect herbivore

Nutrition fuels all of the physiological processes that animals rely on for survival and reproduction. Of all the nutrients that are required, dietary protein (p) and carbohydrates (c) have a primary role. Insect herbivores are capable of detecting amino acid and sugar concentrations in plant tissue via chemoreception and regulate their intake of these two macronutrients to reach an optimal protein:carbohydrate, or p:c, ratio, termed an intake target. A multitude of studies have shown that the two nutritional factors that have the strongest impact on insect survival and performance are dietary p:c ratio and total macronutrient content, which is the proportion of the diet made up by p and c and a proxy for energy content. Variations in these two dietary traits have strong unique and interactive effects on many insect life history traits, yet the mechanisms that mediate these effects are not well understood. While many studies have documented the effect of host plant usage on gene expression, differences in plant secondary compounds between plant species and tissue types have confounded efforts to understand nutritional contributions to transcriptional changes. This study is the first to document the transcriptional effects of dietary p:c ratio and total macronutrient content in a phytophagous insect, the polyphagous moth species Helicoverpa zea. Our results show that changes in dietary p:c ratio produced a rather limited transcriptional response, while total macronutrient content had more dramatic effects on gene expression. The invariable expression of many metabolic genes across diets also suggests that H. zea larvae employ a strategy of constitutive expression to deal with nutritional imbalances rather than diet-associated changes in expression. We also observed many similarities in the transcriptional response to diets that varied from the intake target diet in different ways (c-biased, p-biased, increased energy content). This indicates that similar mechanisms are used to deal with nutritional imbalances regardless of the direction of the imbalance, and further supports the importance of nutrient regulation. HIGHLIGHTSO_LIVariations in plant macronutrients can have strong impacts on herbivore fitness C_LIO_LIDespite a wealth of studies documenting the physiological effects of macronutrient nutrition, underlying mechanisms are still ambiguous C_LIO_LIDiet protein-to-carbohydrate ratio had an unexpectedly small impact on overall transcription, while total macronutrient content had a stronger effect C_LIO_LIThe transcriptional response to dietary variations away from an optimal diet was similar across diets that varied in different ways (carbohydrate-biased, protein-biased, more concentrated) C_LIO_LIMaintaining consistent consumption and constitutive expression of digestive enzymes across diets that varied in macronutrient profiles led to compensation for the most limiting dietary macronutrient C_LI

physiology↗

bioRxiv2020

Role of bradykinin type 2 receptors in human sweat secretion: translational evidence does not support a functional relationship

Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and non-human paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46-48{degrees}C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 M) and only the vehicle (lactated Ringers) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79{+/-}0.12 and vehicle = +0.64{+/-}0.10 mg/cm2/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/ml) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38{+/-}0.16 and vehicle = +0.32{+/-}0.12 mg/cm2/min); again no differences were observed with B2R antagonism. Lastly, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically-or pharmacologically-induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

physiology↗

bioRxiv2020

Feasibility and safety of a telemetric pulmonary artery pressure monitoring system in acute and chronic porcine models of pulmonary hypertension.

AimsPulmonary hypertension (PH) is associated with significant morbidity and mortality and leads to progressive right heart failure. In patients with PAH, haemodynamic parameters measured at catheterisation relate to clinical worsening events, in patients with heart failure proactive pulmonary artery pressure based therapeutic intervention reduces hospitalisation. We therefore investigated use of a novel implanted pulmonary artery (PA) pressure monitor to detect clinically relevant changes in pressure in large animal models of pulmonary hypertension (PH). Methods and ResultsPrototype pulmonary artery pressure sensors (Endotronix) were implanted using standard interventional techniques. Acute PH was induced by infusion of thromboxane A2 in domestic swine. Over a physiological range pressure monitors remained concordant to reference catheter (bias -0.43, 95%CI-5.3-4.4). Chronic PH was induced by i.p. injection of monocrotaline. Implanted pressure sensors demonstrated a gradual rise in PA pressure over 30 days (baseline: 20.7+/-0.4 vrs day-30: 31.74+/-1.4, p<0.01). Pressure sensor derived readings matched reference catheter at baseline and day-30. Pressure sensors remained stable and no adverse events were identified by clinical and histological examination. ConclusionsThe development of PA pressure monitors provide long-term haemodynamic data that identified clinically meaningful changes in pulmonary artery pressure. In addition to proactive heart failure management, such devices may be used to optimise or personalize patient therapy, investigate aspects of physiology and pathology essential to the understanding of disease and provide the opportunity to assess therapeutic interventions in clinical studies.

physiology↗

bioRxiv2021

Machine learning to extract muscle fascicle length changes from dynamic ultrasound images in real-time

Background and objectiveDynamic muscle fascicle length measurements through B-mode ultrasound have become popular for the non-invasive physiological insights they provide regarding musculoskeletal structure-function. However, current practices typically require time consuming post-processing to track muscle length changes from B-mode images. A real-time measurement tool would not only save processing time but would also help pave the way toward closed-loop applications based on feedback signals driven by in vivo muscle length change patterns. In this paper, we benchmark an approach that combines traditional machine learning (ML) models with B-mode ultrasound recordings to obtain muscle fascicle length changes in real-time. To gauge the utility of this framework for in-the-loop applications, we evaluate accuracy of the extracted muscle length change signals against time-series derived from a standard, post-hoc automated tracking algorithm. MethodsWe collected B-mode ultrasound data from the soleus muscle of six participants performing five defined ankle motion tasks: (a) seated, constrained ankle plantarflexion, (b) seated, free ankle dorsi/plantarflexion, (c) weight-bearing, calf raises (d) walking, and then a (e) mix. We trained machine learning (ML) models by pairing muscle fascicle lengths obtained from standardized automated tracking software (UltraTrack) with the respective B-mode ultrasound image input to the tracker, frame-by-frame. Then we conducted hyperparameter optimizations for five different ML models using a grid search to find the best performing parameters for a combination of high correlation and low RMSE between ML and UltraTrack processed muscle fascicle length trajectories. Finally, using the global best model/hyperparameter settings, we comprehensively evaluated training-testing outcomes within subject (i.e., train and test on same subject), cross subject (i.e., train on one subject, test on another) and within/direct cross task (i.e., train and test on same subject, but different task). ResultsSupport vector machine (SVM) was the best performing model with an average r = 0.70 {+/-}0.34 and average RMSE = 2.86 {+/-}2.55 mm across all direct training conditions and average r = 0.65 {+/-}0.35 and average RMSE = 3.28 {+/-}2.64 mm when optimized for all cross-participant conditions. Comparisons between ML vs. UltraTrack (i.e., ground truth) tracked muscle fascicle length versus time data indicated that ML tracked images reliably capture the salient qualitative features in ground truth length change data, even when correlation values are on the lower end. Furthermore, in the direct training, calf raises condition, which is most comparable to previous studies validating automated tracking performance during isolated contractions on a dynamometer, our ML approach yielded 0.90 average correlation, in line with other accepted tracking methods in the field. ConclusionsBy combining B-mode ultrasound and classical ML models, we demonstrate it is possible to achieve real-time tracking of human soleus muscle fascicles across a number of functionally relevant contractile conditions. This novel sensing modality paves the way for muscle physiology in-the-loop applications that could be used to modify gait via biofeedback or unlock novel wearable device control techniques that could enable restored or augmented locomotion performance.

physiology↗

bioRxiv2021

Larval nutrition impacts survival to adulthood, body size, and the allometric scaling of metabolic rate in adult honeybees

Resting metabolic rate (RMR) is a fundamental physiological measure linked to numerous aspects of organismal function, including lifespan. Although dietary restriction in insects during larval growth/development affects adult RMR, the impact of larval diet quality on adult RMR has not been studied. Using in vitro rearing to control larval diet quality, we determined the effect of dietary protein and carbohydrate on honeybee survival-to-adulthood, time-to-eclosion, body mass/size and adult RMR. High carbohydrate larval diets increased survival-to-adulthood and time-to-eclosion compared to both low carbohydrate and high protein diets. Upon emergence, bees reared on the high protein diet were smaller and lighter than those reared on other diets, whilst those raised on the high carbohydrate diet varied more in body mass. Newly emerged adult bees reared on the high carbohydrate diet showed a significantly steeper increase in allometric scaling of RMR compared to those reared on other diets. This suggests that diet quality influences survival-to-adulthood, time-to-eclosion, and the allometric scaling of RMR. Given that agricultural intensification and increasing urbanisation have led to a decrease in both forage availability and dietary diversity for bees, our results are critical to improving understanding of the impacts of poor developmental nutrition on bee growth/development and physiology. Summary statementWe show, for the first time, that the nutritional quality of insect larval diets affects the scaling of metabolic rate with body mass in newly emerged adult honeybees.

physiology↗

bioRxiv2021

Hot days are associated with short-term adrenocortical responses in a Southern African arid-zone passerine bird.

Non-invasive methods for investigating the biological effects of environmental variables are invaluable for understanding potential impacts of climate change on behavioural and physiological stress responses of free-ranging animals. Foraging efficiency, body mass maintenance and breeding success are compromised in Southern pied babblers Turdoides bicolor exposed to air temperatures between ~35{degrees}C and ~40{degrees}C. We tested the hypothesis that these very hot days are acute stressors for free-ranging babblers by quantifying the relationship between daily maximum air temperature (Tmax) and faecal glucocorticoid metabolite (fGCM) levels. We collected naturally-excreted droppings from free-ranging pied babblers and analysed fGCM levels. Levels of fGCMs in droppings collected after 3pm were independent of same-day Tmax < 38 {degrees}C and averaged 140.25 ng g-1 Dry Weight {+/-} 56.92 ng g-1 DW (mean {+/-} SD) over this range. Above an inflection Tmax = 38 {degrees}C, however, fGCM levels increased linearly with same-day Tmax and averaged 190.79 ng g-1 DW {+/-} 70.13 ng g-1 DW. There was no relationship between Tmax on the previous day and fGCM levels in droppings collected the following morning. Group size, breeding stage, sex and rank did not predict variation in fGCM levels. These results suggest that very high Tmax may be linked to acute, but not chronic, heat stress responses. The fGCM levels we measured are likely to represent a biologically meaningful response to an environmental stressor (high Tmax), suggesting a physiological mechanism underlying observed changes in behaviour and reproductive success at high temperatures in this species.

physiology↗

bioRxiv2021

Placental uptake and metabolism as determinants of pregnancy vitamin D status

Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.

physiology↗

bioRxiv2021

Salty surfaces deter feeding in a blood-sucking disease vector

Salts are essential nutrients required for many physiological processes, and deficient or excessive salt results in adverse health problems. Taste is the ultimate sensory modality involved in resource quality assessment, resulting in acceptance or rejection. Here, we show that detection of high-salt substrates by a salt-sensitive antennal gustatory receptor neuron, S1-GRN, results in feeding avoidance in the hematophagous bug Rhodnius prolixus. Knock-down of two antennal-expressed amiloride-sensitive pickpocket channel receptors (PPKs; RproPPK014276 and RproPPK28) using RNA interference, prevents avoidance of bugs to high-salt substrates. Tracing antennal GRNs to the central nervous system reveals the antennal lobes as a gustatory processing center. The identification of the gustatory basis of high-salt detection in a blood feeder provides novel targets to prevent biting and feeding, as well as to promote substrate avoidance in a relevant disease vector. Significance StatementDetection of aversive gustatory stimuli induces avoidance responses in animals. Avoidance acquires particular interest if it reduces the biting rates of blood-feeding insects of medical relevance. Here we describe the molecular and physiological basis of high-salt detection in the blood-sucking disease vector Rhodnius prolixus. We show that detection of high-salt substrates through two PPK receptors expressed in an antennal gustatory receptor neuron produces feeding avoidance. Understanding these gustatory-driven aversive responses allows the hitherto overlooked use of gustatory molecules as a complement to known olfactory repellents.

physiology↗

bioRxiv2021

Within- and transgenerational plasticity of a temperate salmonid in response to thermal acclimation and acute temperature stress

Environmental temperatures associated with climate change are rising too rapidly for many species to adapt, threatening the persistence of taxa with limited capacities for thermal acclimation. We investigated the capacity for within- and transgenerational responses to increasing environmental temperatures in brook trout (Salvelinus fontinalis), a cold-adapted salmonid. Adult fish were acclimated to temperatures within (10{square}) and above (21{square}) their thermal optimum for six months before spawning, then mated in a full factorial breeding design to produce offspring from cold- and warm-acclimated parents as well as bidirectional crosses between parents from both temperature treatments. Offspring families were subdivided and reared at two acclimation temperatures (15{square} and 19{square}) representing their current environment and a projected climate change scenario. Offspring thermal physiology was measured as the rate of oxygen consumption (MO2) during an acute change in temperature (+2{square} h-1) to observe their MO2-temperature relationship. We also recorded resting MO2, the highest achieved (peak) MO2, and critical thermal maximum (CTM) as performance metrics. Within-generation plasticity was greater than transgenerational plasticity, with offspring acclimation temperature having demonstrable effects on peak MO2 and CTM. Transgenerational plasticity was evident as an elevated resting MO2 and the MO2-temperature relationship in offspring from warm-acclimated parents. Both parents contributed to offspring thermal responses, although the paternal effect was stronger. Although brook trout exhibit both within- and transgenerational plasticity for thermal physiology, it is unlikely that these will be sufficient for coping with long-term changes to environmental temperatures resulting from climate change. SummaryBrook trout (Salvelinus fontinalis) exhibit within-generation and transgenerational plasticity for thermal performance, although neither response appears sufficient to cope with long-term climate change effects.

physiology↗

bioRxiv2021

Caloric restriction overcomes pre-diabetic and hypertension induced by high fat diet and renal artery stenosis

BackgroundCaloric restriction (CR) is a type of dietary intervention enjoyed as an essential tool in weight loss by modulating critical pathways of metabolic control, although it is not yet clear what repercussions this intervention model results when associated with renovascular hypertension. Here we demonstrate that CR can be beneficial in obese and hypertensive animals. MethodsRats were divided into groups: SHAM, and two groups underwent surgery to clip the left renal artery, to induce renovascular hypertension (OH and OHR). The SHAM diet was performed: 14 weeks normolipidic diet; OH: 2 weeks normolipidic diet + 12 weeks hyperlipidic diet, both ad libitum; OHR: 2 weeks normolipidic diet + 8 weeks ad libitum high fat diet + 4 weeks restricted 40% high fat diet. Resultsthe OHR group dissipated blood pressure, body weight and glucose homeostasis. Reductions in insulinemia, lipids, islets fibrotic areas in the OHR group were observed along with increased insulin sensitivity and normalization of the insulin-degrading enzyme. Nicotinamide phosphoribosyltransferase, insulin receptor, Sirtuin 1 and complex II protein were modulated in liver tissue in the OHR group. Strong correlations, direct or indirect, were evaluated by Spearmans model between SIRT1, AMPK, NAMPT, PGC-1 and NNMT with the reestablishment of blood pressure, weight loss, glycidic and lipid panel and mitochondrial adaptation. ConclusionCR provided short-term beneficial effects to recover physiological parameters induced by a high-fat diet and renal artery stenosis in obese and hypertensive animals. These benefits, even in the short term, can bring physiological benefits in the long run.

physiology↗

bioRxiv2021

Stress related network activity in the intact adrenal medulla.

The adrenal medulla has long been recognized as playing a critical role in mammalian homeostasis and the stress response. The adrenal medulla is populated by clustered chromaffin cells that secrete epinephrine or norepinephrine along with other peptides into the general bloodstream affecting multiple distant target organs. Although the sympatho-adrenal pathway has been heavily studied, detailed knowledge on the central control and in-situ spatiotemporal responsiveness remains poorly understood. For this work we implemented electrophysiological techniques originally developed to elucidate CNS circuitry to characterize the functional micro-architecture of the adrenal medulla. To achieve this, we continuously monitored the electrical activity inside the adrenal medulla in the living anesthetized rat under basal conditions and under physiological stress. Under basal conditions, chromaffin cells fired action potentials with frequencies between [~]0.2 and 4 Hz. Activity was exclusively driven by sympathetic inputs coming through the splanchnic nerve. Furthermore, chromaffin cells were organized into arrays of independent local networks in which cells fire in a specific order, with latencies from hundreds of microseconds to few milliseconds. Electrical stimulation of the splanchnic nerve evoked the exact same spatiotemporal firing patterns that occurred spontaneously. Induction of hypoglycemic stress by administration of insulin resulted in an increase in the activity of a subset of the chromaffin cell networks. In contrast, respiratory arrest induced by anesthesia overdose resulted in an increase in the activity of the entire adrenal medulla before cessation of all activity when the animal died. The results suggest the differential activation of specific networks inside the adrenal gland depending on the stressor. These results revealed a surprisingly complex electrical organization and circuitry of the adrenal medulla that likely reflects the dynamic nature of its neuroendocrine output during basal conditions and during different types of physiological stress. To our knowledge, these experiments are the first to use multi-electrode arrays in vivo to examine the electrical and functional architecture of any endocrine gland. Significance StatementStress from extrinsic (environmental, psychological) and intrinsic (biological) challenges plays a critical role in disturbing the homeostatic balance. While the bodys responses to stress are designed to ameliorate these imbalances, prolonged and dysregulated stress often drives adverse health consequences in many chronic illnesses. The better understanding of the sympatho-adrenal stress response, will potentially impact and improve the treatment of several stress related illnesses. This work focusses on the study of the functional architecture of the adrenal medulla, a key component in neuronal stress response.

physiology↗

bioRxiv2021

Group size influences individual metabolic traits in a social fish

O_LIGroup living is widespread among animal species and yields both costs and benefits. Presence of conspecifics can restrict or enhance the expression of individual behaviour, and the recent social environment is thought to affect behavioural responses in later contexts, even when individuals are alone. However, little is known about how social dynamics influence the expression of individual physiological traits, including metabolic rates. C_LIO_LIThere is some evidence that shoaling can reduce fish metabolic rates, but habitat conditions such as shelter availability may generate density-dependent influences on individual metabolic rates. C_LIO_LIWe investigated how social group size and availability of shelter influence Eurasian minnow Phoxinus phoxinus metabolic rates estimated by respirometry in the presence or absence of plant shelter. Respirometry trials were conducted before and after we housed fish for three weeks in a social treatment consisting in a specific group size (n= 4 or 8) and shelter availability (presence or absence of plant shelter in the holding tank). C_LIO_LIMinimum day-time and night-time metabolic rates estimated while in presence of plant shelter were lower than when estimated in absence of plant shelter, both before and after individuals were housed in their social group size and shelter availability treatment. Standard metabolic rate was higher for fish held in groups of four as compared to fish held in groups of eight while maximum metabolic rate showed no difference. Shelter availability during the social treatments did not influence standard or maximum metabolic rates. C_LIO_LIOur results suggest that group size may directly influence energy demands of individuals, highlighting the importance of understanding the role of social dynamics on variations in physiological traits associated with energy expenditure. C_LI

physiology↗

bioRxiv2021

Aldosterone, Dexamethasone and Triamcinolone Activate African Lungfish Mineralocorticoid Receptor: Increased Activation After Removal of the Amino-Terminal Domain

Aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding, hinge and steroid-binding domains, had a stronger response to corticosteroids and progesterone than full-length lungfish MR, indicating that the N-terminal domain represses steroid activation of lungfish MR, unlike human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.

physiology↗

bioRxiv2021

Salivary oxytocin co-varies with parturition and nursing behavior in domestic pigs (Sus scrofa domesticus)

Domestic pigs produce twice as many offspring as wild boars, but little is known about the effects of selection pressures for increased productivity on pig behavior and welfare. From an evolutionary perspective, producing larger litters is expected to increase parent-offspring conflict, which may help to explain why piglets from larger litters are more likely to die by starvation or infant-crushing. Our goals were to identify behavioral and physiological correlates of variation in maternal care that may be useful as selection criteria in breeding programs to improve pig welfare. We observed eleven sows regularly during their lactational period and recorded their hourly postural changes and the proportion of time that piglets had contact with teats (nursing contact) or any physical contact with the sow (social contact). As a potential physiological indicator of maternal care, we measured oxytocin concentrations in 119 saliva samples from sows following observations. Samples were extracted and measured in an Enzyme Immunoassay. As a biological validation, we measured changes in salivary oxytocin during parturition in an additional eleven sows. Laboratory validations confirmed that the assay is suitable for measuring salivary oxytocin in pigs, and oxytocin increased almost three-fold during parturition. Sows nursing contact was positively correlated with social contact and negatively correlated with postural changes. Sow oxytocin concentrations were predicted by their nursing contact, but not by their overall social contact with piglets. We compare our results with current evidence regarding best practice methods for salivary oxytocin measurements and discuss the potential to use indicators of maternal care as selection criteria to improve pig welfare.

physiology↗

bioRxiv2021

The dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after major surgery

Major surgery and critical illness produce a potentially life threatening systemic inflammatory response. The hypothalamic-pituitary-adrenal (HPA) axis is one of the key physiological systems that counterbalances this systemic inflammation through changes in adrenocorticotrophic hormone (ACTH) and cortisol. These hormones normally exhibit highly correlated ultradian pulsatility with an amplitude modulated by circadian processes. However, these dynamics are disrupted by major surgery and critical illness. In this work, we characterise the inflammatory, ACTH and cortisol responses of patients undergoing cardiac surgery and show that the HPA axis response can be classified into one of three phenotypes: single-pulse, two-pulses and multiple-pulses dynamics. We develop a mathematical model of cortisol secretion and metabolism that predicts the physiological mechanisms responsible for these different phenotypes. We show that the effects of inflammatory mediators are important only in the single-pulse pattern in which normal pulsatility is lost - suggesting that this phenotype could be indicative of the greatest inflammatory response. Investigating whether and how these phenotypes are correlated with clinical outcomes will be critical to patient prognosis and designing interventions to improve recovery.

physiology↗

bioRxiv2021

Serotonin regulates hepcidin expression via a gut-liver axis

Iron is essential to key biological processes of all living organisms. Proper iron levels must be maintained to meet biological needs and prevent toxicity. Given the central role played by the hormone hepcidin in systemic iron homeostasis, extensive research has sought to identify regulators of its expression. Diverse evidence shows the gut to be an essential sensor and regulator of iron homeostasis, independently of other known hepcidin regulators, including bone marrow signals. Here we identify gut-derived serotonin as a key physiological factor in hepcidin regulation. In response to hypoxia, serotonin synthesized and secreted by enterochromaffin cells can act beyond the gut to repress hepcidin expression in the liver, through a 5-HT2B receptor-dependent pathway. Bone marrow transplant experiments clearly indicate the gut is responsible for hepcidin repression. This regulatory system appears to be conserved in humans: a significant negative correlation exists between hepcidin and serotonin levels in the serum of healthy individuals. Our findings imply hepcidin regulation by serotonin is a physiological process, and modulation of the gut serotonergic system may have broad therapeutic implications.

physiology↗

bioRxiv2021

A mitochondrial electron transport chain with atypical subunit composition confers oxygen sensitivity to a mammalian chemoreceptor

The carotid body (CB) is the major chemoreceptor for blood oxygen in the control of ventilation in mammals, contributing to physiological adaptation to high altitude, pregnancy, and exercise, and its hyperactivity is linked to chronic conditions such as sleep-disorder breathing, hypertension, chronic heart failure, airway constriction, and metabolic syndrome (1-3). Upon acute hypoxia (PO2=100 mmHg to <80 mmHg), K+ channels on CB glomus cells are inhibited, causing membrane depolarization to trigger Ca+2 influx and neurotransmitter release that stimulates afferent nerves (1-3). A longstanding model proposes that the CB senses hypoxia through atypical mitochondrial electron transport chain (ETC) metabolism that is more sensitive to decreases in oxygen than other tissues. This model is supported by observations that ETC inhibition by pharmacology and gene knockout activates CB sensory activity and that smaller decreases in oxygen concentration inhibit ETC activity in CB cells compared to other cells (1-5). Determining the composition of atypical ETC subunits in the CB and their specific activities is essential to delineate molecular mechanisms underlying the mitochondrial hypothesis of oxygen sensing. Here, we identify HIGD1C, a novel hypoxia inducible gene domain factor isoform, as an ETC Complex IV (CIV) protein highly and selectively expressed in glomus cells that mediates acute oxygen sensing by the CB. We demonstrate that HIGD1C negatively regulates oxygen consumption by CIV and acts with the hypoxia-induced CIV subunit COX4I2 to enhance the sensitivity of CIV to hypoxia, constituting an important component of mitochondrial oxygen sensing in the CB. Determining how HIGD1C and other atypical CIV proteins expressed in the CB work together to confer exquisite oxygen sensing to the ETC will help us better understand how tissue- and condition-specific CIV subunits contribute to physiological function and disease (6) and allow us to potentially target these proteins to treat chronic diseases characterized by CB dysfunction (7).

physiology↗

bioRxiv2021

A multiscale model of the cardiovascular system that incorporates baroreflex control of chronotropism, cell-level contractility, and vascular tone

Multiscale models of the cardiovascular system can provide new insights into physiological and pathological processes. PyMyoVent is a computer model that bridges from molecular to organ-level function and which simulates a left ventricle pumping blood through the systemic circulation. Initial work with PyMyoVent focused on the End Systolic Pressure Volume Relationship and ranked potential therapeutic strategies by their impact on contractility. This manuscript extends the PyMyoVent framework by adding closed loop feedback control of arterial pressure. The control algorithm mimics important features of the physiological baroreflex and was developed as part of a long-term program that focuses on growth and biological remodeling. Inspired by the underlying biology, the reflex algorithm uses an afferent signal derived from arterial pressure to drive a kinetic model that mimics the net result of neural processing in the medulla and cell-level responses to autonomic drive. The kinetic model outputs control signals that are constrained between limits that represent maximum parasympathetic and maximum sympathetic drive and which modulate heart rate, intracellular Ca2+ dynamics, the molecular-level function of both the thick and the thin myofilaments, and vascular tone. Simulations show that the algorithm can regulate mean arterial pressure at user-defined set-points as well as maintaining arterial pressure when challenged by changes in blood volume and/or valve resistance. The reflex also regulates arterial pressure when cell-level contractility is modulated to mimic the idealized impact of myotropes. These capabilities will be important for future work that uses computer modeling to investigate clinical conditions and treatments.

physiology↗