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The Darwinian fitness of mammals living in a rhythmic environment depends on endogenous daily (circadian) rhythms in behavior and physiology. Here, we discuss the mechanisms underlying the circadian regulation of physiology and behavior in mammals. We also review recent efforts to understand circadian flexibility, such as how the phase of activity and rest is altered depending on the encountered environment. We explain why shifting activity to the day is an adaptive strategy to cope with energetic challenges and show how this can reduce thermoregulatory costs. A framework is provided to make predictions about the optimal timing of activity and rest of non-model species for a wide range of habitats. This Review illustrates how the timing of daily rhythms is reciprocally linked to energy homeostasis, and it highlights the importance of this link in understanding daily rhythms in physiology and behavior.

The Darwinian fitness of mammals living in a rhythmic environment depends on endogenous daily (circadian) rhythms in behavior and physiology. Here, we discuss the mechanisms underlying the circadian regulation of physiology and behavior in mammals. We also review recent efforts to understand circadian flexibility, such as how the phase of activity and rest is altered depending on the encountered environment. We explain why shifting activity to the day is an adaptive strategy to cope with energetic challenges and show how this can reduce thermoregulatory costs. A framework is provided to make predictions about the optimal timing of activity and rest of non-model species for a wide range of habitats. This Review illustrates how the timing of daily rhythms is reciprocally linked to energy homeostasis, and it highlights the importance of this link in understanding daily rhythms in physiology and behavior.

AimThis review article is a collaborative report based upon the Authors' presentations and Group discussion on the role of testosterone (T) in the male and female lower urinary tract (LUT) which took place at the 6th International Consultation on Incontinence Research Society's (ICI-RS) annual meeting, in Bristol, UK (September 8-10, 2015).MethodsIt comprises overviews and opinions on both the current state of knowledge of the role of T in LUT function and dysfunction in both sexes.ResultsResults from animal studies suggest that T treatment may be beneficial for disorders of the LUT in women including urinary incontinence and pelvic organ prolapse. The need for clinical studies to evaluate the effect of T treatment in peri- and post-menopausal women, taking into account the type of applied androgen, the application form, timing and dosage, is especially emphasized. In males, findings on the impact of T on the male external urethral sphincter underscores that there is still much to learn about its role in male LUT physiology. The important topic of the use of T therapy in the treatment of enuresis in the young, both sexes, is also discussed. The importance of understanding the steroidogenic pathways linking T with estradiol is discussed as being of paramount importance in researching the unique actions of T in the LUT.ConclusionThe overall conclusion is that further research into the role of T in LUT function and dysfunction across genders and age groups (young to old) is extremely important. Neurourol. Urodynam. 36:859-862, 2017. (c) 2017 Wiley Periodicals, Inc.

Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking and drug addiction. Orexin-A treatment was also shown to reduce tumor development in xenografted nude mice and is thus a potential treatment for carcinogenesis. The aim of this work was to explore in healthy mice the consequences on energy expenditure components of an orexin-A treatment at a dose previously shown to be efficient to reduce tumor development. Physiological approaches were used to evaluate the effect of orexin-A on food intake pattern, energy metabolism body weight and body adiposity. Modulation of the expression of brain neuropeptides and receptors including NPY, POMC, AgRP, cocaine-and amphetamine related transcript (CART), corticotropin-releasing hormone (CRH) and prepro-orexin (HCRT), and Y-2 and Y-5 neuropeptide Y, MC4 (melanocortin), OX1 and OX2 orexin receptors (Y2R, Y5R, MC4R, OX1R and OX2R, respectively) was also explored. Our results show that orexin-A treatment does not significantly affect the components of energy expenditure, and glucose metabolism but reduces intraperitoneal fat deposit, adiposity and the expression of several brain neuropeptide receptors suggesting that peripheral orexin-A was able to reach the central nervous system. These findings establish that orexin-A treatment which is known for its activity as an inducer of tumor cell death, do have minor parallel consequence on energy homeostasis control.

Regulatory T (Treg) cells facilitate maternal immune tolerance of the semiallogeneic conceptus in early pregnancy, but the origin and regulation of these cells at embryo implantation is unclear. During the preimplantation period, factors in the seminal fluid delivered at coitus cause expansion of a CD4(+)CD25(+) putative Treg cell population in the para-aortic lymph nodes draining the uterus. Using flow cytometry, immunohistochemistry, and real-time quantitative PCR (qPCR) for the signature Treg cell transcription factor FOXP3, we confirmed the identity of the expanded lymph node population as FOXP3(+) Treg cells and showed that this is accompanied by a comparable increase in the uterus of FOXP3(+) Treg cells and expression of Foxp3 mRNA by Day 3.5 postcoitum. Seminal plasma was necessary for uterine Treg cell accumulation, as mating with seminal vesicle-deficient males failed to elicit an increase in uterine Treg cells. Furthermore seminal fluid induced expression of mRNA encoding the Treg chemokine CCL19 (MIP3beta), which acts through the CCR7 receptor to regulate Treg cell recruitment and retention in peripheral tissues. Glandular and luminal epithelial cells were identified as the major cellular origins of uterine CCL19, and exposure to both seminal plasma and sperm was required for maximum expression. Together, these results indicate that Treg cells accumulate in the uterus prior to embryo implantation and that seminal fluid is a key regulator of the uterine Treg cell population, operating by both increasing the pool of available Treg cells and promoting their CCL19-mediated recruitment from the circulation into the implantation site.

The human lung T cell compartment contains many CD8(+) T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8(+) T cells expressing CD 103 (alpha E integrin) resides. Here, we determined the specificity and function of CD103(+)CD8(+) T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103(+)CD8(+) T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8(+) T cells specific for influenza but not in those specific for EBV or CMV.CD103(+) and influenza-reactive cells preferentially expressed NKG2A, an inhibitor of CD8(+) T cell cytotoxic function. In contrast to CD103(-)CD8(+) T cells, most CD103(+)CD8(+) cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type IIFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier.

Many aspects of physiology and behavior in organisms from bacteria to man are subjected to circadian regulation. Indeed, the major function of the circadian clock consists in the adaptation of physiology to daily environmental change and the accompanying stresses such as exposition to UV-light and food-contained toxic compounds. In this way, most aspects of xenobiotic detoxification are subjected to circadian regulation. These phenomena are now considered as the molecular basis for the time-dependence of drug toxicities and efficacy. However, there is now evidences that these toxic compounds can, in turn, regulate circadian gene expression and thus influence circadian rhythms. As food seems to be the major regulator of peripheral clock, the possibility that food-contained toxic compounds participate in the entrainment of the clock will be discussed. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Many aspects of physiology and behavior in organisms from bacteria to man are subjected to circadian regulation. Indeed, the major function of the circadian clock consists in the adaptation of physiology to daily environmental change and the accompanying stresses such as exposition to UV-light and food-contained toxic compounds. In this way, most aspects of xenobiotic detoxification are subjected to circadian regulation. These phenomena are now considered as the molecular basis for the time-dependence of drug toxicities and efficacy. However, there is now evidences that these toxic compounds can, in turn, regulate circadian gene expression and thus influence circadian rhythms. As food seems to be the major regulator of peripheral clock, the possibility that food-contained toxic compounds participate in the entrainment of the clock will be discussed. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

The daily recurrence of activity and rest are so common as to seem trivial. However, they reflect a ubiquitous temporal programme called the circadian clock. In the absence of either anatomical clock structures or clock genes, the timing of sleep and wakefulness is disrupted. The complex nature of circadian behaviour is evident in the fact that phasing of the cycle during the day varies widely for individuals, resulting in extremes colloquially called 'larks' and 'owls'. These behavioural oscillations are mirrored in the levels of physiology and gene expression. Deciphering the underlying mechanisms will provide important insights into how the circadian clock affects health and disease.

The daily recurrence of activity and rest are so common as to seem trivial. However, they reflect a ubiquitous temporal programme called the circadian clock. In the absence of either anatomical clock structures or clock genes, the timing of sleep and wakefulness is disrupted. The complex nature of circadian behaviour is evident in the fact that phasing of the cycle during the day varies widely for individuals, resulting in extremes colloquially called 'larks' and 'owls'. These behavioural oscillations are mirrored in the levels of physiology and gene expression. Deciphering the underlying mechanisms will provide important insights into how the circadian clock affects health and disease.

Previous reports suggested the expression of four or live different Ins(1,4,5)P-3 receptor [Ins(1,4,5)P(3)R] isoforms in mouse cells [Ross, Danoff, Schell, Snyder and Ullrich (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 4265-4269; De Smedt, Missiaen, Parys, Bootman, Mertens, Van Den Bosch and Casteels (1994) J. Biol. Chem. 269, 21691-21698]. To explore this diversity further, we have isolated and sequenced partial clones of two Ins(1,4,5)P(3)R mRNAs from the mouse embryonic C(3)H10T1/2 cell line. These clones showed between 94.2 and 94.9% sequence identity with the corresponding rat Ins(1,4,5)P(3)R-II and Ins(1,4,5)P(3)R-III isoforms. Based on these newly obtained sequences we have determined the relative expression of the different Ins(1,4,5)P(3)R mRNAs in cultured cells and in animal tissues of mouse origin by a ratio reverse transcriptase polymerase chain reaction (RT-PCR). Ins(1,4,5)P(3)R-I was very prominent in brain and cerebellum and Ins(1,4,5)P(3)R-II in epithelia such as kidney as well as in both cardiac and skeletal muscle. Ins(1,4,5)P(3)R-III was highly expressed in all cultured cell types and in tissues with high cell turnover, e.g. testis. The prominent expression of Ins(1,4,5)P(3)R-I and Ins(1,4,5)P(3)R-III in A7r5 and C(3)H10T1/2 cells respectively was confirmed by immunoblot analysis and was compatible with a lower threshold for Ins(1,4,5)P-3-induced Ca2+ release in the former cell type. Screening of a large number of mouse cell lines and tissues revealed the presence of Ins(1,4,5)P(3)R-I as well as of the Ins(1,4,5)P(3)R-II and Ins(1,4,5)P(3)R-III isoforms which were identified in the present study, but in contrast with previous reports there was no evidence for more isoform diversity.

Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling(1,2). However, mechanisms that logically explain the coordination of nuclear hormone receptors and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in cryptochrome-deficient livers. These results reveal a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.

Regulatory T (Treg) cells facilitate maternal immune tolerance of the semiallogeneic conceptus in early pregnancy, but the origin and regulation of these cells at embryo implantation is unclear. During the preimplantation period, factors in the seminal fluid delivered at coitus cause expansion of a CD4(+)CD25(+) putative Treg cell population in the para-aortic lymph nodes draining the uterus. Using flow cytometry, immunohistochemistry, and real-time quantitative PCR (qPCR) for the signature Treg cell transcription factor FOXP3, we confirmed the identity of the expanded lymph node population as FOXP3(+) Treg cells and showed that this is accompanied by a comparable increase in the uterus of FOXP3(+) Treg cells and expression of Foxp3 mRNA by Day 3.5 postcoitum. Seminal plasma was necessary for uterine Treg cell accumulation, as mating with seminal vesicle-deficient males failed to elicit an increase in uterine Treg cells. Furthermore seminal fluid induced expression of mRNA encoding the Treg chemokine CCL19 (MIP3beta), which acts through the CCR7 receptor to regulate Treg cell recruitment and retention in peripheral tissues. Glandular and luminal epithelial cells were identified as the major cellular origins of uterine CCL19, and exposure to both seminal plasma and sperm was required for maximum expression. Together, these results indicate that Treg cells accumulate in the uterus prior to embryo implantation and that seminal fluid is a key regulator of the uterine Treg cell population, operating by both increasing the pool of available Treg cells and promoting their CCL19-mediated recruitment from the circulation into the implantation site.

Background— Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T-cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor ( ldlr ) knockout mice. Methods and Results— CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7 −/− T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild-type T cells but not ccr7 −/− -derived T cells primed with oxidized low-density lipoprotein–pulsed dendritic cells resulted in a reconstitution of atherogenesis in ccr7 −/− / ldlr −/− mice. Conclusion— These results demonstrate that both CCR7-dependent T-cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue are crucially involved in atherosclerotic plaque development.

Periodic environments like we experience on the surface of planet earth lead living organisms to evolve molecular anticipation devices known a circadian clocks. The word circadian refers to the period of these oscillations which last about (circa) one day (dies). A frequently felt manifestation of this oscillator is experienced by travelers crossing timezones, when the local external cues are suddenly set out of phase with respect to our internal timing, resulting in a discomfort called jetlag. Although we might be less conscious about them, the circadian pacemaker also regulates a number of our basic daily physiological functions such as hourly changes in our body temperature or heart beat rate. Such clocks are found throughout the tree of life, in bacteria, plants, insects, funghi, vertebrates and mammals. Since the 1970s1, genetics and molecular biology has begun to disentangle the molecular circuitries by which cell-autonomous oscillations can be maintained, and how external light or temperature entrainment cues are relayed to this pacemaker. The three defining characteristics of these oscillators is that (i) rhythms persists in constant conditions (after external cues have been removed); (ii) phases can be reset by light, temperature or hormone pulses; (iii) the period of oscillation is temperature compensated in a physiological range. A commonality across the many species whose oscillators were studied is the recurrence of negative feedback circuits among the core clock genes2. Several species including Arabidopsis Thaliana, Drosophila melanogaster and mouse, use interlocked feedback loops, with up to three loops in Arabidopsis.3,4 The resulting redundancy is thought to provide not only robustness,5 but also the necessary flexibility to allow accurate timekeeping despite seasonal changes in photoperiod duration 3 or temperature variations.

The aim of the present study was to investigate the presence and the distribution of cells containing orexin A and orexin type 2 receptor in the horse stomach and gut, by means of immunohistochemical techniques. Orexin A was identified in the stomach fundic and pyloric regions and in the duodenum. In the same stomach regions, a large subset of orexin A-positive cells also showed orexin type 2 receptor-like immunoreactivity. Moreover, in the duodenum, many of them, seemed to store serotonin. Characteristically, enteric neurons or ganglia also displayed orexin A and, sometimes, orexin type 2 receptor immunoreaction. Orexin A and orexin type 2 receptor immunoreactivity was also found in the nerve fibers in the enteric submucosal layer. Our results, together with data present in the literature, could contribute to the understanding of complex mechanisms regulating the horse gut functionality that are depending very likely on the consequence of the co-operation of both a central and a peripheral control.

Previous reports suggested the expression of four or live different Ins(1,4,5)P-3 receptor [Ins(1,4,5)P(3)R] isoforms in mouse cells [Ross, Danoff, Schell, Snyder and Ullrich (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 4265-4269; De Smedt, Missiaen, Parys, Bootman, Mertens, Van Den Bosch and Casteels (1994) J. Biol. Chem. 269, 21691-21698]. To explore this diversity further, we have isolated and sequenced partial clones of two Ins(1,4,5)P(3)R mRNAs from the mouse embryonic C(3)H10T1/2 cell line. These clones showed between 94.2 and 94.9% sequence identity with the corresponding rat Ins(1,4,5)P(3)R-II and Ins(1,4,5)P(3)R-III isoforms. Based on these newly obtained sequences we have determined the relative expression of the different Ins(1,4,5)P(3)R mRNAs in cultured cells and in animal tissues of mouse origin by a ratio reverse transcriptase polymerase chain reaction (RT-PCR). Ins(1,4,5)P(3)R-I was very prominent in brain and cerebellum and Ins(1,4,5)P(3)R-II in epithelia such as kidney as well as in both cardiac and skeletal muscle. Ins(1,4,5)P(3)R-III was highly expressed in all cultured cell types and in tissues with high cell turnover, e.g. testis. The prominent expression of Ins(1,4,5)P(3)R-I and Ins(1,4,5)P(3)R-III in A7r5 and C(3)H10T1/2 cells respectively was confirmed by immunoblot analysis and was compatible with a lower threshold for Ins(1,4,5)P-3-induced Ca2+ release in the former cell type. Screening of a large number of mouse cell lines and tissues revealed the presence of Ins(1,4,5)P(3)R-I as well as of the Ins(1,4,5)P(3)R-II and Ins(1,4,5)P(3)R-III isoforms which were identified in the present study, but in contrast with previous reports there was no evidence for more isoform diversity.