A Flexible Double-Sided Curvature Sensor Array for Use in Soft Robotics.

This paper describes the design, fabrication, integration, characterization, and demonstration of a novel flexible double-sided curvature sensor array for use in soft robotics. The paper explores the performance and potential applications of a piezoresistive sensor array consisting of four gold strain gauges on a flexible polyimide (PI) substrate arranged in a Wheatstone bridge configuration. Multiple sensor strips were arranged like the fingers of a hand. Integrating Shape Memory Alloy (SMA) foils alongside the fingers was explored to mimic a human hand-gripping motion controlled with temperature, while curvature sensor array strips measure the resulting finger shapes. Moreover, object sensing in a flexible granular material gripper was demonstrated. The sensors were embedded within Polydimethylsiloxane (PDMS) to enhance their tactile feel and adhesive properties. The findings of this study are promising for future applications, particularly in robotics and prosthetics, as the ability to accurately mimic human hand movements and reconstruct sensor surfaces paves the way for robotic hand functionality.

Sex-specific heterothermy patterns in wintering captive Microcebus murinus do not translate into differences in energy balance.

The physiological mechanisms of responses to stressors are at the core of ecophysiological studies that examine the limits of an organism's flexibility. Interindividual variability in these physiological responses can be particularly important and lead to differences in the stress response among population groups, which can affect population dynamics. Some observations of intersexual differences in heterothermy raise the question of whether there is a difference in energy management between the sexes. In this study, we assessed male and female differences in mouse lemurs (Microcebus murinus), a highly seasonal malagasy primate, by measuring their physiological flexibility in response to caloric restriction and examining the subsequent impact on reproductive success. Using complementary methods aiming to describe large-scale and daily variations in body temperature throughout a 6-month winter-like short-day (SD) period, we monitored 12 males and 12 females, applying chronic 40% caloric restriction (CR) to 6 individuals in each group. We found variations in Tb modulation throughout the SD period and in response to caloric treatment that depended on sex, as females, regardless of food restriction, and CR males, only, entered deep torpor. The use of deeper torpor, however, did not translate into a lower loss of body mass in females and did not affect reproductive success. Captive conditions may have buffered the depth of torpor and minimised the positive effects of torpor on energy savings. However, the significant sex differences in heterothermy we observed may point to physiological benefits other than preservation of energy reserves.

An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome.

Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

Molecular Liver Fingerprint Reflects the Seasonal Physiology of the Grey Mouse Lemur (Microcebus murinus) during Winter.

Grey mouse lemurs (Microcebus murinus) are primates that respond to environmental energetic constraints through strong physiological seasonality. They notably fatten during early winter (EW), and mobilize their lipid reserves while developing glucose intolerance during late winter (LW), when food availability is low. To decipher how the hepatic mechanisms may support such metabolic flexibility, we analyzed the liver proteome of adult captive male mouse lemurs, whose seasonal regulations are comparable to their wild counterparts. We highlight profound hepatic changes that reflect fat accretion in EW at the whole-body level, without triggering an ectopic storage of fat in the liver, however. Moreover, molecular regulations are consistent with the decrease in liver glucose utilization in LW, and therefore with reduced tolerance to glucose. However, no major regulation was seen in insulin signaling/resistance pathways. Fat mobilization in LW appeared possibly linked to the reactivation of the reproductive system while enhanced liver detoxification may reflect an anticipation to return to summer levels of food intake. Overall, these results show that the physiology of mouse lemurs during winter relies on solid molecular foundations in liver processes to adapt fuel partitioning while opposing the development of a pathological state despite large lipid fluxes.

Flexibility Is Costly: Hidden Physiological Damage From Seasonal Phenotypic Transitions in Heterothermic Species.

Heterothermy allows organisms to cope with fluctuating environmental conditions. The use of regulated hypometabolism allows seasonal heterothermic species to cope with annual resource shortages and thus to maximize survival during the unfavorable season. This comes with deep physiological remodeling at each seasonal transition to allow the organism to adjust to the changing environment. In the wild, this adaptation is highly beneficial and largely overcomes potential costs. However, researchers recently proposed that it might also generate both ecological and physiological costs for the organism. Here, we propose new perspectives to be considered when analyzing adaptation to seasonality, in particular considering these costs. We propose a list of putative costs, including DNA damage, inflammatory response to fat load, brain and cognitive defects, digestive malfunction and immunodeficiency, that should receive more attention in future research on physiological seasonality. These costs may only be marginal at each transition event but accumulate over time and therefore emerge with age. In this context, studies in captivity, where we have access to aging individuals with limited extrinsic mortality (e.g., predation), could be highly valuable to experimentally assess the costs of physiological flexibility. Finally, we offer new perspectives, which should be included in demographic models, on how the adaptive value of physiological flexibility could be altered in the future in the context of global warming.

Sex-Specific Response to Caloric Restriction After Reproductive Investment in Microcebus murinus: An Integrative Approach.

In seasonal environments, males and females usually maintain high metabolic activity during the whole summer season, exhausting their energy reserves. In the global warming context, unpredictability of food availability during summer could dramatically challenge the energy budget of individuals. Therefore, one can predict that resilience to environmental stress would be dramatically endangered during summer. Here, we hypothesized that females could have greater capacity to survive harsh conditions than males, considering the temporal shift in their respective reproductive energy investment, which can challenge them differently, as well as enhanced flexibility in females' physiological regulation. We tackled this question on the gray mouse lemur (Microcebus murinus), focusing on the late summer period, after the reproductive effort. We monitored six males and six females before and after a 2-weeks 60% caloric restriction (CR), measuring different physiological and cellular parameters in an integrative and comparative multiscale approach. Before CR, females were heavier than males and mostly characterized by high levels of energy expenditure, a more energetic mitochondrial profile and a downregulation of blood antioxidants. We observed a similar energy balance between sexes due to CR, with a decrease in metabolic activity over time only in males. Oxidative damage to DNA was also reduced by different pathways between sexes, which may reflect variability in their physiological status and life-history traits at the end of summer. Finally, females' mitochondria seemed to exhibit greater flexibility and greater metabolic potential than males in response to CR. Our results showed strong differences between males and females in response to food shortage during late summer, underlining the necessity to consider sex as a factor for population dynamics in climate change models.

Mini-review: Aging of the neuroendocrine system: Insights from nonhuman primate models.

The neuroendocrine system (NES) plays a crucial role in synchronizing the physiology and behavior of the whole organism in response to environmental constraints. The NES consists of a hypothalamic-pituitary-target organ axis that acts in coordination to regulate growth, reproduction, stress and basal metabolism. The growth (or somatotropic), hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes are therefore finely tuned by the hypothalamus through the successive release of hypothalamic and pituitary hormones to control the downstream physiological functions. These functions rely on a complex set of mechanisms requiring tight synchronization between peripheral organs and the hypothalamic-pituitary complex, whose functionality can be altered during aging. Here, we review the results of research on the effects of aging on the NES of nonhuman primate (NHP) species in wild and captive conditions. A focus on the age-related dysregulation of the master circadian pacemaker, which, in turn, alters the synchronization of the NES with the organism environment, is proposed. Finally, practical and ethical considerations of using NHP models to test the effects of nutrition-based or hormonal treatments to combat the deterioration of the NES are discussed.

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms†.

Torpor and hibernation are powerful strategies enabling animals to survive periods of low resource availability. The state of torpor results from an active and drastic reduction of an individual's metabolic rate (MR) associated with a relatively pronounced decrease in body temperature. To date, several forms of torpor have been described in all three mammalian subclasses, i.e., monotremes, marsupials, and placentals, as well as in a few avian orders. This review highlights some of the characteristics, from the whole organism down to cellular and molecular aspects, associated with the torpor phenotype. The first part of this review focuses on the specific metabolic adaptations of torpor, as it is used by many species from temperate zones. This notably includes the endocrine changes involved in fat- and food-storing hibernating species, explaining biomedical implications of MR depression. We further compare adaptive mechanisms occurring in opportunistic vs. seasonal heterotherms, such as tropical and sub-tropical species. Such comparisons bring new insights into the metabolic origins of hibernation among tropical species, including resistance mechanisms to oxidative stress. The second section of this review emphasizes the mechanisms enabling heterotherms to protect their key organs against potential threats, such as reactive oxygen species, associated with the torpid state. We notably address the mechanisms of cellular rehabilitation and protection during torpor and hibernation, with an emphasis on the brain, a central organ requiring protection during torpor and recovery. Also, a special focus is given to the role of an ubiquitous and readily-diffusing molecule, hydrogen sulfide (H2S), in protecting against ischemia-reperfusion damage in various organs over the torpor-arousal cycle and during the torpid state. We conclude that (i) the flexibility of torpor use as an adaptive strategy enables different heterothermic species to substantially suppress their energy needs during periods of severely reduced food availability, (ii) the torpor phenotype implies marked metabolic adaptations from the whole organism down to cellular and molecular levels, and (iii) the torpid state is associated with highly efficient rehabilitation and protective mechanisms ensuring the continuity of proper bodily functions. Comparison of mechanisms in monotremes and marsupials is warranted for understanding the origin and evolution of mammalian torpor.

Reduced central and peripheral inflammatory responses and increased mitochondrial activity contribute to diet-induced obesity resistance in WSB/EiJ mice.

Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial dysfunctions. This hypothesis was tested by comparing the wild-derived diet-induced obesity- (DIO-) resistant mouse strain WSB/EiJ to the obesity-prone C57BL/6J strain. We analysed circulating and hypothalamic markers of inflammatory status and hypothalamic mitochondrial activity in both strains exposed to high-fat diet (HFD). We further analysed the regulations of hypothalamic genes involved in inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei. HFD induced increased body weight gain, circulating levels of leptin, cholesterol, HDL and LDL in C57BL/6J whereas WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. The gene expression data analysis allowed identifying strain-specific hypothalamic metabolic pathways involved in the respective responses to HFD. Our results point to the involvement of hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.

Promoting healthspan and lifespan with caloric restriction in primates.

Recent data confirmed the efficiency of caloric restriction for promoting both healthspan and lifespan in primates, but also revealed potential adverse effects at the central level. This paper proposes perspectives and future directions to counterbalance potential adverse effects. Efforts should be made in combining nutrition-based clinical protocols with therapeutic and/or behavioral interventions to aim for synergetic effects, and therefore delay the onset of age-related diseases without adverse effects.

Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates.

The health benefits of chronic caloric restriction resulting in lifespan extension are well established in many short-lived species, but the effects in humans and other primates remain controversial. Here we report the most advanced survival data and the associated follow-up to our knowledge of age-related alterations in a cohort of grey mouse lemurs (Microcebus murinus, lemurid primate) exposed to a chronic moderate (30%) caloric restriction. Compared to control animals, caloric restriction extended lifespan by 50% (from 6.4 to 9.6 years, median survival), reduced aging-associated diseases and preserved loss of brain white matter in several brain regions. However, caloric restriction accelerated loss of grey matter throughout much of the cerebrum. Cognitive and behavioural performances were, however, not modulated by caloric restriction. Thus chronic moderate caloric restriction can extend lifespan and enhance health of a primate, but it affects brain grey matter integrity without affecting cognitive performances.

Temporal Control of Metabolic Amplitude by Nocturnin.

The timing of food intake and nutrient utilization is critical to health and regulated partly by the circadian clock. Increased amplitude of circadian oscillations and metabolic output has been found to improve health in diabetic and obesity mouse models. Here, we report a function for the circadian deadenylase Nocturnin as a regulator of metabolic amplitude across the day/night cycle and in response to nutrient challenge. We show that mice lacking Nocturnin (Noct-/-) display significantly increased amplitudes of mRNA expression of hepatic genes encoding key metabolic enzymes regulating lipid and cholesterol synthesis, both over the daily circadian cycle and in response to fasting and refeeding. Noct-/- mice have increased plasma triglyceride throughout the night and increased amplitude of hepatic cholesterol levels. Therefore, posttranscriptional control by Nocturnin regulates the amplitude of these critical metabolic pathways, and loss of this activity results in increased metabolic flux and reduced obesity.

A comparative study of the neural stem cell niche in the adult hypothalamus of human, mouse, rat and gray mouse lemur (Microcebus murinus).

The adult brain contains niches of neural stem cells that continuously add new neurons to selected circuits throughout life. Two niches have been extensively studied in various mammalian species including humans, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus. Recently, studies conducted mainly in rodents have identified a third neurogenic niche in the adult hypothalamus. In order to evaluate whether a neural stem cell niche also exists in the adult hypothalamus in humans, we performed multiple immunofluorescence labeling to assess the expression of a panel of neural stem/progenitor cell (NPC) markers (Sox2, nestin, vimentin, GLAST, GFAP) in the human hypothalamus and compared them with the mouse, rat and a non-human primate species, the gray mouse lemur (Microcebus murinus). Our results show that the adult human hypothalamus contains four distinct populations of cells that express the five NPC markers: (a) a ribbon of small stellate cells that lines the third ventricular wall behind a hypocellular gap, similar to that found along the lateral ventricles, (b) ependymal cells, (c) tanycytes, which line the floor of the third ventricle in the tuberal region, and (d) a population of small stellate cells in the suprachiasmatic nucleus. In the mouse, rat and mouse lemur hypothalamus, co-expression of NPC markers is primarily restricted to tanycytes, and these species lack a ventricular ribbon. Our work thus identifies four cell populations with the antigenic profile of NPCs in the adult human hypothalamus, of which three appear specific to humans.

Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates.

Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus, spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (rs=0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (rs=0.56) and hippocampus (rs=-0.62) or septum (rs=-0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes.

The Icelandic 16-electrode electrohysterogram database.

External recordings of the electrohysterogram (EHG) can provide new knowledge on uterine electrical activity associated with contractions. Better understanding of the mechanisms underlying labor can contribute to preventing preterm birth which is the main cause of mortality and morbidity in newborns. Promising results using the EHG for labor prediction and other uses in obstetric care are the drivers of this work. This paper presents a database of 122 4-by-4 electrode EHG recordings performed on 45 pregnant women using a standardized recording protocol and a placement guide system. The recordings were performed in Iceland between 2008 and 2010. Of the 45 participants, 32 were measured repeatedly during the same pregnancy and participated in two to seven recordings. Recordings were performed in the third trimester (112 recordings) and during labor (10 recordings). The database includes simultaneously recorded tocographs, annotations of events and obstetric information on participants. The publication of this database enables independent and novel analysis of multi-electrode EHG by the researchers in the field and hopefully development towards new life-saving technology.

Postural- and respiratory-related activities of abdominal muscles during post-exercise hyperventilation.

The present study focuses on the role of superficial abdominal muscles revealed by electromyographic recordings during the maintenance of a bipedal stance perturbed by post-exercise hyperventilation. Twelve healthy subjects performed six 30-s postural tests: one pre-exercise test while breathing quietly, then one test every minute for the 5 min immediately following a maximum-intensity, incremental cycling exercise test. Displacement of the centre of pressure in the sagittal plane was monitored over time. Myoelectric activities of the obliquus externus (OE), obliquus internus (OI) and rectus abdominis (RA) muscles were recorded by surface electromyography (EMG). Metabolic parameters were measured with a portable telemetric device. The change in ventilatory drive induced by exercise was accompanied by a significant increase in both postural sway parameters and EMG activities. For OE and OI, the increased EMG activities were prominent during expiration, whereas OI was silent during inspiration. OE and RA were activated during both expiration and inspiration. It is concluded that the compensation of respiratory disturbances of the erect posture appears to be less effective when minute ventilation increases. The patterns of muscle activity suggest that abdominal muscles are controlled differentially and that their functional coordination is dependent on the respiratory demand.

Bivariate piecewise stationary segmentation; improved pre-treatment for synchronization measures used on non-stationary biological signals.

Analysis of synchronization between biological signals can be helpful in characterization of biological functions. Many commonly used measures of synchronicity assume that the signal is stationary. Biomedical signals are however often strongly non stationary. We propose to use a bivariate piecewise stationary pre-segmentation (bPSP) of the signals of interest, before the computation of synchronization measures on biomedical signals to improve the performance of standard synchronization measures. In prior work we have shown how this can be achieved by using the auto-spectrum of either one of the signals under investigation. In this work we show how major improvements of the performance of synchronization measures can be achieved using the cross-spectrum of the signals to detect stationary changes which occur independently in either signal. We show on synthetic as well as on real biological signals (epileptic EEG and uterine EMG) that the proposed bPSP approach increases the accuracy of the measures by making a good tradeoff between the stationarity assumption and the length of the analyzed segments, when compared to the classical windowing method.

Better pregnancy monitoring using nonlinear correlation analysis of external uterine electromyography.

The objective of this paper is to evaluate the novel method for analyzing the nonlinear correlation of the uterine electromyography (EMG). The application of this method may improve monitoring in pregnancy, labor detection, and preterm labor detection. Uterine EMG signals recorded from a 4 × 4 matrix of electrodes on the subjects' abdomen are used here. The propagation was analyzed using the nonlinear correlation coefficient h(2). Signals from 49 women (36 during pregnancy and 13 in labor) at different gestational age were used. ROC curves were computed to evaluate the potential of three methods to differentiate between 174 contractions recorded during pregnancy and 115 contractions recorded during labor. The results indicate considerably better performance of the nonlinear correlation analysis (area under curve = 0.85) when compared to classical frequency parameters (area under curve = 0.76 and 0.66) in distinguishing labor contractions from normal pregnancy contractions. We conclude that the analysis of the propagation of the uterine electrical activity using the nonlinear correlation coefficient h(2) is a promising way of improving the usefulness of uterine EMG signals for clinical purposes, such as monitoring in pregnancy, labor detection, and prediction of preterm labor.

Nocturnin: at the crossroads of clocks and metabolism.

Many aspects of metabolism exhibit daily rhythmicity under the control of endogenous circadian clocks, and disruptions in circadian timing result in dysfunctions associated with the metabolic syndrome. Nocturnin (Noc) is a robustly rhythmic gene that encodes a deadenylase thought to be involved in the removal of polyA tails from mRNAs. Mice lacking the Noc gene display resistance to diet-induced obesity and hepatic steatosis, due in part to reduced lipid trafficking in the small intestine. In addition, Noc appears to play important roles in other tissues and has been implicated in lipid metabolism, adipogenesis, glucose homeostasis, inflammation and osteogenesis. Therefore, Noc is a potential key post-transcriptional mediator in the circadian control of many metabolic processes.

Postural control and ventilatory drive during voluntary hyperventilation and carbon dioxide rebreathing.

The present study sought to establish links between hyperventilation and postural stability. Eight university students were asked to stand upright under two hyperventilation conditions applied randomly: (1) a metabolic hyperventilation induced by 5 min of hypercapnic-hyperoxic rebreathing (CO(2)-R); and, (2) a voluntary hyperventilation (VH) of 3 min imposed by a metronome set at 25 cycles per min. Recordings were obtained with eyes open, with the subjects standing on a force plate over 20-s periods. Ventilatory response, displacements in the centre of pressure in both the frontal and sagittal planes and fluctuations in the three planes of the ground reaction force were monitored in the time and frequency domains. Postural changes related to respiratory variations were quantified by coherence analysis. Myoelectric activities of the calf muscles were recorded using surface electromyography. Force plate measurements revealed a reduction in postural stability during both CO(2)-R and VH conditions, mainly in the sagittal plane. Coherence analysis provided evidence of a ventilatory origin in the vertical ground reaction force fluctuations during VH. Electromyographic analyses showed different leg muscles strategies, assuming the existence of links between the control of respiration and the control of posture. Our results suggest that the greater disturbing effects caused by voluntary hyperventilation on body balance are more compensated when respiration is under automatic control. These findings may have implications for understanding the organisation of postural and respiratory activities and suggest that stability of the body may be compromised in situations in which respiratory demand increases and requires voluntary control.