Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 94,912 bioRxiv papers from 404,161 authors.
Most downloaded bioRxiv papers, all time
in category physiology
1,298 results found. For more information, click each entry to expand.
25,618 downloads physiology
Objectives: This study explored the effects of gender-affirming treatment, which includes inhibition of endogenous sex hormones and replacement with cross-sex hormones, on muscle function, size and composition in 11 transwomen (TW) and 12 transmen (TM). Methods: Isokinetic knee extensor and flexor muscle strength was assessed at baseline (T00), 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement (T0), and 3 (T3) and 11 (T12) months after hormone replacement. In addition, at T00 and T12, we assessed lower-limb muscle volume using MRI, and cross-sectional area (CSA) and radiological density using CT. Results: Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps CSA (15%) and radiological density (6%). In TW, the corresponding parameters decreased by -5% (muscle volume) and -4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained or slightly increased in strength. Baseline muscle volume correlated highly with strength (R>0.75), yet the relative change in muscle volume and strength correlated only moderately (R=0.65 in TW and R=0.32 in TM). The absolute levels of muscle volume and knee extension strength after the intervention still favored the TW. Conclusion: Cross-sex hormone treatment markedly affects muscle strength, size and composition in transgender individuals. Despite the robust increases in muscle mass and strength in TM, the TW were still stronger and had more muscle mass following 12 months of treatment. These findings add new knowledge that could be relevant when evaluating transwomen's eligibility to compete in the women's category of athletic competitions.
22,222 downloads physiology
The prediction of future child's sex is a question of keen public interest. The probability of having a child of either sex is close to 50%, although multiple factors may slightly change this value. Some demographic studies suggested that sex determination can be influenced by previous pregnancies, although this hypothesis was not commonly accepted. This paper explores the correlations between siblings' sexes using data from the Demographic and Health Survey program. In the sample of about 2,214,601 women (7,985,855 children), the frequencies of sibships with multiple siblings of the same sex were significantly higher than can be expected by chance. A formal modelling demonstrated that sexes of the children were dependent on three kinds of sex ratio variation: a variation between families (Lexian), a variation within a family (Poisson) and a variation contingent upon the sex of preceding sibling (Markovian). There was a positive correlation between the sexes of successive siblings (coefficient = 0.067, p < 0.001), i.e. a child was more likely to be of the same sex as its preceding sibling. This correlation could be caused by secondary sex ratio adjustment in utero since the effect was decreasing with the length of birth-to-birth interval, and the birth-to-birth interval was longer for siblings with unlike sex.
5,461 downloads physiology
Information from many large data bases and published studies was integrated to estimate the age-specific spontaneous abortion rate in an economically-developed human population. Accuracy was tested with published data from a diverse array of studies. Spontaneous abortion was found to be: i) the predominant outcome of fertilization and ii) a natural and inevitable part of human reproduction at all ages. The decision to reproduce is inextricably coupled with the production of spontaneous abortions with high probability, and the decision to have a large family leads to many spontaneous abortions with virtual certainty. The lifetime number of spontaneous abortions was estimated for a canonical woman (constrained to have average age at marriage, first birth, inter-birth intervals, and family size) in two populations: one with and the other without effective birth control (including free access to elective abortions). Birth control was found to reduce lifetime abortions more than 6-fold.
3,541 downloads physiology
Objective: To quantify the homeostatic feedback control of energy intake in response to long-term covert manipulation of energy balance in free-living humans. Methods: We used a validated mathematical method to calculate energy intake changes during a 52 week placebo-controlled trial in 153 patients treated with canagliflozin, a sodium glucose co-transporter inhibitor that increases urinary glucose excretion thereby resulting in weight loss without patients being directly aware of the energy deficit. We analyzed the relationship between the body weight time course and the calculated energy intake changes using principles from engineering control theory. Results: We discovered that weight loss leads to a proportional homeostatic drive to increase energy intake above baseline by ~100 kcal/day per kg of lost weight - an amount more than 3-fold larger than the corresponding energy expenditure adaptations. Conclusions: While energy expenditure adaptations are often thought to be the main reason for slowing of weight loss and subsequent regain, feedback control of energy intake plays an even larger role and helps explain why long-term maintenance of a reduced body weight is so difficult.
3,019 downloads physiology
Background: Advances in research relating to menstruation and associated disorders (such as endometriosis and pre-menstrual syndrome) have been hindered by the lack of an appropriate animal model. Thus, many aspects of this phenomenon remain poorly understood limiting the development of efficacious treatment for women. Menstruating species account for only 1.5% of mammals, and less than 0.09% of these are non-primates. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents. Objective: Here we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus). Study Design: Virgin female spiny mice (n=14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles in our in-house colony at Monash Medical Centre, Clayton, Australia. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and ELISA assay of progesterone (n=5 / stage of the menstrual cycle). Normally distributed data are reported as the mean ± standard error and significant differences calculated using a one-way ANOVA. Non-normal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test. Results: Mean cycle length was 8.7 ± 0.4 days with red blood cells observed in the lavages over 3.0 ± 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase, when plasma progesterone peaked at ~102.1 ng/mL and the optical density for prolactin immunoreactivity was strongest. The spiny mouse undergoes spontaneous decidualisation, demonstrating for the first time menstruation in a rodent. Conclusion: The spiny mouse is the first rodent species known to menstruate and provides an unprecedented natural non-primate model to study the mechanisms of menstrual shedding and repair, and may be useful in furthering our understanding of human specific menstrual and pregnancy associated diseases.
2,945 downloads physiology
The most read article of 2018 published in The BMJ (https://doi.org/10.1136/bmj.k4583) claimed that restricting dietary carbohydrates offers a metabolic advantage to burn more calories and thereby help patients maintain lost weight. However, analyzing the data according to the original pre-registered statistical plan resulted in no statistically significant effects of diet composition on energy expenditure. The large reported diet effects on energy expenditure calculated using the revised analysis plan depended on data from subjects with excessive amounts of unaccounted energy. Adjusting the data to be commensurate with energy conservation resulted in a diet effect that was less than half the value reported in The BMJ paper. Furthermore, the measured daily average CO2 production rates were not significantly different between the diets and the reported expenditure differences were due to inaccurate calculations based on false assumptions about diet adherence.
2,635 downloads physiology
Lilia Espada, Alexander Dakhovnik, Prerana Chaudhari, Asya Martirosyan, Laura Miek, Tetiana Poliezhaieva, Yvonne Schaub, Ashish Nair, Nadia Döring, Norman Rahnis, Oliver Werz, Andreas Koeberle, Joanna Kirkpatrick, Alessandro Ori, Maria A. Ermolaeva
The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented.
2,471 downloads physiology
In elite sport, the Athlete Biological Passport (ABP) was invented to tackle cheaters by monitoring closely changes in biological parameters, flagging atypical variations. The haematological module of the ABP was indeed adopted in 2011 by the International Association of Athletics Federations (IAAF). This study estimates the prevalence of blood doping based on haematological parameters in a large cohort of track & field athletes measured at two international major events (2011 & 2013 IAAF World Championships) with a hypothesized decrease in prevalence due to the ABP introduction. A total of 3683 blood samples were collected and analysed from all participating athletes originating from 209 countries. The estimate of doping prevalence was obtained by using a Bayesian network with seven variables, as well as doping as a variable mimicking doping with low-doses of recombinant human erythropoietin (rhEPO), to generate reference cumulative distribution functions (CDFs) for the Abnormal Blood Profile Score (ABPS) from the ABP. Our results from robust haematological parameters indicate an estimation of an overall blood doping prevalence of 18% in average in endurance athletes (95% Confidence Interval (C.I.) 14-22%). A higher prevalence was observed in female athletes (22%, C.I. 16-28%) than in male athletes (15%, C.I. 9-20%). In conclusion, this study presents the first comparison of blood doping prevalence in elite athletes based on biological measurements from major international events that may help scientists and experts to use the ABP in a more efficient and deterrent way.
2,218 downloads physiology
Human adipose tissue depots perform numerous diverse physiological functions, and are differentially linked to metabolic disease risk, yet only two major human adipocyte subtypes have been described, white and brown/brite/beige. The diversity and lineages of adipocyte classes have been studied in mice using genetic methods that cannot be applied in humans. Here we circumvent this problem by studying the fate of single mesenchymal progenitor cells obtained from human adipose tissue. We report that a minimum of four human adipocyte subtypes can be distinguished by transcriptomic analysis, specialized for functionally distinct processes such as adipokine secretion and thermogenesis. Evidence for the presence of these adipocytes subtypes in adult humans is evidenced by differential expression of key adipokines leptin and adiponectin in isolated mature adipocytes. The human adipocytes most similar to the mouse brite/beige adipocytes are enriched in mechanisms that promote iron accumulation and protect from oxidative stress, and are derived from progenitors that express high levels of cytokines such as IL1B, IL8, IL11 and the IL6 family cytokine LIF, and low levels of the transcriptional repressors ID1 and ID3. Our finding of this adipocyte repertoire and its developmental mechanisms provides a high-resolution framework to analyze human adipose tissue architecture and its role in systemic metabolism and metabolic disease.
2,077 downloads physiology
Spring-like tissues attached to the swinging legs of animals are thought to improve running economy by simply reducing the effort of leg swing. Here we show that a spring, or 'exotendon,' connecting the legs of a human runner improves economy instead through a more complex mechanism that produces savings during both swing and stance. The spring increases the energy optimal stride frequency; when runners adopt this new gait pattern, savings occur in both phases of gait. Remarkably, the simple device improves running economy by 6.4 ± 2.8%, comparable to savings achieved by motorized assistive robotics that directly target the costlier stance phase of gait. Our results highlight the importance of considering both the dynamics of the body and the adaptive strategies of the user when designing systems that couple human and machine.
1,943 downloads physiology
Inbred C57BL/6J mice have been used to study diet-induced obesity and the detrimental physiological effects associated with it. Little is understood about predictive factors that predispose an animal to weight gain. To address this, mice were fed a high fat diet, control diet or normal chow diet. Several measurements including pre-diet serum hormone levels and pre-diet body weight were analyzed, but these had limited predictive value regarding weight gain. However, baseline measurements of weight loss in response to food deprivation showed a strong negative correlation with high fat diet-induced weight gain. These data suggest that fasting-induced weight loss in adolescent mice is a useful predictor of diet-induced weight gain.
1,930 downloads physiology
For nearly 100 years, Growth Hormone (GH) has been known to impact insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extra-hepatic, adipose tissue-dependent mechanism.
1,890 downloads physiology
The Atlantic Canary (Serinus canaria) is the most common caged bird with extensive carotenoid plumage coloration. Domestic strains of canaries have been bred for a range of colors and patterns, making them a valuable model for studies of the genetic bases for feather pigmentation. However, no detailed account has been published on the feather pigments of the various strains of this species, particularly in relation to dietary pigments available during molt. Moreover, in the twentieth century, aviculturists created a red canary by crossing Atlantic Canaries with Red Siskins (Carduelis cucullata). This red-factor canary is reputed to metabolically transform yellow dietary pigments into red ketocarotenoids, but such metabolic capacity has yet to be documented in controlled experiments. We fed molting yellow and red-factor canaries seed diets supplemented with either B-carotene, lutein/zeaxanthin, or B-cryptoxanthin/B-carotene and measured the coloration and carotenoid content of newly grown feathers. On all diets, yellow canaries grew yellow feathers and red canaries grew red feathers. Yellow canaries deposited dietary pigments and metabolically derived canary xanthophylls into feathers. Red-factor canaries deposited the same plumage carotenoids as yellow canaries, but also deposited red ketocarotenoids. Red-factor canaries deposited higher total amounts of carotenoids than yellow canaries, but otherwise there was little effect of diet treatment on feather hue or chroma. These observations indicate that canaries can use a variety of dietary precursors to produce plumage coloration and that red canaries can metabolically convert yellow dietary carotenoids into red ketocarotenoids.
1,601 downloads physiology
Kent Miner, Katja Labitzke, Benxian Liu, Paul Wang, Kathryn Henckels, Kevin Gaida, Robin Elliott, Jian Jeffrey Chen, Longbin Liu, Anh Leith, Esther Trueblood, Kelly Hensley, Xing-Zhong Xia, Oliver Homann, Brian Bennett, Mike Fiorino, John Whoriskey, Gang Yu, Sabine Escobar, Min Wong, Teresa L. Born, Alison Budelsky, Mike Comeau, Dirk Smith, Jonathan Phillips, James A. Johnston, Joe McGivern, Kerstin Weikl, David Powers, Karl Kunzelmann, Deanna Mohn, Andreas Hochheimer, John K. Sullivan
There is an unmet need in severe asthma where approximately 40% of patients exhibit poor beta-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated-Cl- channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ~580,000 compounds. The anthelmintics niclosamide, nitazoxanide and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting beta-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully (>92%) bronchodilated airways, while the beta-agonist isoproterenol showed only partial (26-43%) effects. TMEM16A antagonists and repositioning of niclosamide or nitazoxanide could represent an important additional treatment for uncontrolled severe disease.
1,584 downloads physiology
Ilia A. Droujinine, Dan Wang, Yanhui Hu, Namrata D Udeshi, Luye Mu, Tanya Svinkina, Rebecca Zeng, Tess Branon, Areya Tabatabai, Justin A Bosch, John M Asara, Alice Y Ting, Steven A. Carr, Norbert Perrimon
Secreted interorgan communication factors encode key regulators of homeostasis. However, long-standing questions surround their origins/destinations, mechanisms of interactions, and the number of proteins involved. Progress has been hindered by the lack of methodologies for these factors' large-scale identification and characterization, as conventional approaches cannot identify low-abundance factors and the origins and destinations of secreted proteins. We established an in vivo platform to investigate secreted protein trafficking between organs proteome-wide, whereby engineered promiscuous biotin ligase BirA*G3 (a relative of TurboID) biotinylates all proteins in a subcellular compartment of one tissue, and biotinylated proteins are affinity-enriched and identified from distal organs using quantitative mass spectrometry. Using this platform, we identified 51 putative muscle-secreted proteins from heads and 269 fat body-secreted proteins from legs/muscles, of which 60-70% have human orthologs. We demonstrate, in particular, that conserved fat body-derived novel interorgan communication factors CG31326, CG2145, and CG4332 promote muscle activity. Our results indicate that the communication network of secreted proteins is vast, and we identified systemic functions for a number of these factors. This approach is widely applicable to studies in interorgan, local and intracellular protein trafficking networks, non-conventional secretion, and to mammalian systems, under healthy or diseased states. ### Competing Interest Statement The authors have declared no competing interest.
1,514 downloads physiology
Fiona C Lewis-McDougall, Prashant J Ruchaya, Eva Domenjo-Vila, Tze Shin Teoh, Larissa Prata, Beverley J Cottle, James E Clark, Prakash P Punjabi, Wael Awad, Daniele Torella, Tamara Tchkonia, James L Kirkland, Georgina M Ellison-Hughes
Rationale: Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Objective: To determine the impact of ageing and senescence on human cardiac stem/progenitor cell (CPC) biology and regenerative potential, and investigate whether elimination of senescent cells in aged mice enhances CPC activation and cardiomyocyte proliferation. Methods and Results: CPCs were isolated from the right atrial appendage (~200mg) of human subjects with cardiovascular disease (n=119), aged 32-86 years, and assessed for expression of senescence-associated markers (p16INK4A, SAbetagal, DNA damage yH2AX, telomere length), Senescence-Associated Secretory Phenotype (SASP), cell growth, differentiation, and regenerative potential following transplantation into the infarcted mouse heart. Senescent cells were eliminated in aged mice (22 to 32 months) in vivo either genetically, using INK-ATTAC mice, which results in inducible elimination of p16Ink4a-expressing senescent cells upon the administration of the drug AP20187, or pharmacologically using intermittent oral administration of combined senolytics, Dasatinib (D) and Quercetin (Q). In aged subjects (>74 years old) over half of CPCs are senescent, unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. Aged-senescent CPCs secrete SASP factors, which renders otherwise healthy, cycling-competent CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q) in vivo activates resident CPCs (0.23±0.06% vs. 0.01±0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25±0.07% vs. 0.03±0.03% vehicle; p<0.05). Conclusions: Human CPCs become senescent with age, negatively impacting their regenerative capacity. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.
1,425 downloads physiology
The recent emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic have posed a public health crisis. Higher morbidity and mortality of men with COVID-19 may be explained by androgen-driven mechanisms. One such proposed mechanism is androgen regulation of pulmonary TMPRSS2, the host co-receptor for SARS-CoV-2. We find no evidence for increased TMPRSS2 mRNA expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide does not decrease pulmonary TMPRSS2 expression. Nevertheless, regardless of sex, smoking significantly increases the expression of TMPRSS2, which reverts back to never-smoker levels in former smokers. Finally, we show that in mouse models, despite equivalent AR transcript levels, males express markedly higher amounts of AR protein. If a similar sex-specific regulation of AR protein occurs in human lung, androgens could play important roles in clinical outcome of COVID-19 through mechanisms other than TMPRSS2 regulation. ### Competing Interest Statement The authors have declared no competing interest.
1,418 downloads physiology
Measures of erythrocytes volume and surface are helpful in several physiological studies, both for zoologists and veterinarians. Whilst diameter and volume are assessed with ease from observations of blood smears and complete blood count, respectively, thickness and surface area, instead, are much more difficult to be obtained. The accurate description of the erythrocyte geometry is given by the equation of the oval of Cassini, but the formulas deriving from it are very complex, comprising elliptic integrals. In this article three solids are proposed as models approximating the erythrocyte: sphere, cylinder and a spheroid with concave caps. Volumes and Surface Areas obtained with these models are compared to those effectively measured.
1,365 downloads physiology
The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs were scored longitudinally until death and machine learning was employed to develop two clocks. A random forest regression was trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model was trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of novel longevity genes and aging interventions.
1,346 downloads physiology
Mark A Aminzadeh, Russell G Rogers, Kenneth Gouin, Mario Fournier, Rachel E Tobin, Xuan Guan, Martin K Childers, Allen M Andres, David J Taylor, Ahmed Ibrahim, Xiangming Ding, Angelo Torrente, Joshua M. Goldhaber, Ronald A Victor, Roberta A Gottlieb, Michael Lewis, Eduardo Marbán
Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy, affecting the heart as well as skeletal muscle. Here we report that cardiosphere-derived cells (CDCs), which are being tested clinically for the treatment of Duchenne cardiomyopathy, improve cardiac and skeletal myopathy in the mdx mouse model of DMD and in human Duchenne cardiomyocytes. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human Duchenne cardiomyocytes. The findings further motivate the testing of CDCs in Duchenne patients, while identifying exosomes as next-generation therapeutic candidates.
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