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in category physiology
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8,658 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.
6,950 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.
4,017 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.
3,398 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.
2,650 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.
2,451 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.
1,914 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.
1,833 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.
1,681 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.
1,559 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.
1,539 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.
1,347 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.
1,220 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.
1,215 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.
1,195 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. 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.
1,173 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.
1,131 downloads physiology
We respond to claims by Dong et al. that human lifespan is limited below 125 years. Using the log-linear increase in mortality rates with age to predict the upper limits of human survival we find, in contrast to Dong et al., that the limit to human lifespan is historically flexible and increasing. This discrepancy can be explained by Dong et al.'s use of data with variable sample sizes, age-biased rounding errors, and log(0) instead of log(1) values in linear regressions. Addressing these issues eliminates the proposed 125-year upper limit to human lifespan.
1,088 downloads physiology
This paper concerns the fully automatic direct in vivo measurement of active and passive dynamic skeletal muscle states using ultrasound imaging. Despite the long standing medical need (myopathies, neuropathies, pain, injury, ageing), currently technology (electromyography, dynamometry, shear wave imaging) provides no general, non-invasive method for online estimation of skeletal intramuscular states. Ultrasound provides a technology in which static and dynamic muscle states can be observed non-invasively, yet current computational image understanding approaches are inadequate. We propose a new approach in which deep learning methods are used for understanding the content of ultrasound images of muscle in terms of its measured state. Ultrasound data synchronized with electromyography of the calf muscles, with measures of joint torque/angle were recorded from 19 healthy participants (6 female, ages: 30 +- 7.7). A segmentation algorithm previously developed by our group was applied to extract a region of interest of the medial gastrocnemius. Then a deep convolutional neural network was trained to predict the measured states (joint angle/torque, electromyography) directly from the segmented images. Results revealed for the first time that active and passive muscle states can be measured directly from standard b-mode ultrasound images, accurately predicting for a held out test participant changes in the joint angle, electromyography, and torque with as little error as 0.022(degrees), 0.0001V, 0.256Nm (root mean square error) respectively.
1,021 downloads physiology
Ion channels are ubiquitous in living systems. Through interactions with membrane potential, ion channels both control metabolic events and mediate cell communication. Consequentially, membrane bioelectricity bears on fields ranging from cancer etiology to computational neuroscience. Conductance models have proven successful in quantitatively capturing these dynamics but are often considered difficult, with interpretation relegated to specialists. To facilitate research in membrane dynamics, especially in fields where roles for ion channels are just beginning to be quantified, we must make these models easy to understand. Here, we show that the membrane differential equation central to conductance models can be understood using simple circular geometry. The membrane state diagrams we construct are compact, faithful representations of conductance model state, designed to look like circular "cells" with currents flowing in and out. Every feature of a membrane state diagram corresponds to a physiological variable, so that insight taken from a diagram can be translated back to the underlying model. The construction is elementary: we convert conductances to angles subtended on the circle and potentials to radii; currents are then areas of the enclosed annular sectors. Our method clarifies a powerful but prohibitive modeling approach and has the potential for widespread use in both electrophysiological research and pedagogy. We illustrate how membrane state diagrams can augment traditional methods in the stability analysis of voltage equilibria and in depicting the Hodgkin-Huxley action potential, and we use the diagrams to infer the possibility of nontrivial fixed-voltage channel population dynamics by visual inspection rather than linear algebra.
992 downloads physiology
Objective: To examine possible bias of the doubly labeled water (DLW) method for measuring energy expenditure (EEDLW) in humans consuming a low-carbohydrate diet. Methods: EEDLW was measured during the final two weeks of a month-long baseline diet (BD; 50% carbohydrate, 35% fat, 15% protein) as well as a subsequent isocaloric ketogenic diet (KD; 5% carbohydrate, 80% fat, 15% protein) in 17 men with BMI between 25-35 kg/m2. Physical activity was measured by accelerometers. Subjects resided two days per week in respiratory chambers to measure energy expenditure (EEchamber). Body composition and energy intake measurements were used to calculate expenditure by energy balance (EEbal). Results: Neither EEchamber nor EEbal were significantly different during the KD versus the BD phase (ΔEEchamber=24±30 kcal/d; p=0.43 and ΔEEbal=-141±118 kcal/d; p=0.25). Similarly, physical activity (-5.1±4.8%; p=0.3) and the exercise efficiency (-1.6±2.4%; p=0.52) were unchanged. However, EEDLW was 209±83 kcal/d higher during the KD versus the BD (p=0.023). Conclusions: The increased EEDLW during the KD was incommensurate with the respiratory chamber, energy intake and body composition measurements and could not be explained by objective measures of physical activity or exercise efficiency. Our data raise the possibility of systematic bias of the DLW method for low-carbohydrate diets.
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