DynPeak : An algorithm for pulse detection and frequency analysis in hormonal time series

The endocrine control of the reproductive function is often studied from the analysis of luteinizing hormone (LH) pulsatile secretion by the pituitary gland. Whereas measurements in the cavernous sinus cumulate anatomical and technical difficulties, LH levels can be easily assessed from jugular blood. However, plasma levels result from a convolution process due to clearance effects when LH enters the general circulation. Simultaneous measurements comparing LH levels in the cavernous sinus and jugular blood have revealed clear differences in the pulse shape, the amplitude and the baseline. Besides, experimental sampling occurs at a relatively low frequency (typically every 10 min) with respect to LH highest frequency release (one pulse per hour) and the resulting LH measurements are noised by both experimental and assay errors. As a result, the pattern of plasma LH may be not so clearly pulsatile. Yet, reliable information on the InterPulse Intervals (IPI) is a prerequisite to study precisely the steroid feedback exerted on the pituitary level. Hence, there is a real need for robust IPI detection algorithms. In this article, we present an algorithm for the monitoring of LH pulse frequency, basing ourselves both on the available endocrinological knowledge on LH pulse (shape and duration with respect to the frequency regime) and synthetic LH data generated by a simple model. We make use of synthetic data to make clear some basic notions underlying our algorithmic choices. We focus on explaining how the process of sampling affects drastically the original pattern of secretion, and especially the amplitude of the detectable pulses. We then describe the algorithm in details and perform it on different sets of both synthetic and experimental LH time series. We further comment on how to diagnose possible outliers from the series of IPIs which is the main output of the algorithm.Comment: Nombre de pages : 35 ; Nombre de figures : 16 ; Nombre de tableaux :

Magnetic-field dependence of the critical currents in a periodic coplanar array of narrow superconducting strip

We calculate the magnetic-field dependence of the critical current due to both geometrical edge barriers and bulk pinning in a periodic coplanar array of narrow superconducting strips. We find that in zero or low applied magnetic fields the critical current can be considerably enhanced by the edge barriers, but in modest applied magnetic fields the critical current reduces to that due to bulk pinning alone.Comment: 23 pages, 7 figure

The 3rd World Conference on Kisspeptin, â Kisspeptin 2017: Brain and Beyondâ : Unresolved questions, challenges and future directions for the field

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144298/1/jne12600-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144298/2/jne12600-sup-0002-FigS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144298/3/jne12600_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144298/4/jne12600.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144298/5/jne12600-sup-0003-FigS3.pd

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators

Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation

Neurons that produce gonadotropin-releasing hormone (GnRH) are the final common pathway by which the brain regulates reproduction. GnRH neurons are regulated by an afferent network of kisspeptin-producing neurons. Kisspeptin binds to its cognate receptor on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion—thus gating down-stream events supporting reproduction. We have developed kisspeptin antagonists to facilitate the direct determination of the role of kisspeptin neurons in the neuroendocrine regulation of reproduction. In vitro and in vivo studies of analogues of kisspeptin-10 with amino substitutions have identified several potent and specific antagonists. A selected antagonist was shown to inhibit the firing of GnRH neurons in the brain of the mouse and to reduce pulsatile GnRH secretion in female pubertal monkeys; the later supporting a key role of kisspeptin in puberty onset. This analogue also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the post-castration rise in LH in sheep, rats and mice, suggesting that kisspeptin neurons mediate the negative feedback effect of sex steroids on gonadotropin secretion in mammals. The development of kisspeptin antagonists provides a valuable tool for investigating the physiological and pathophysiological roles of kisspeptin in the regulation of reproduction and could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer

The 3rd World Conference on Kisspeptin, "Kisspeptin 2017: Brain and Beyond": Unresolved questions, challenges and future directions for the field

The 3rd World Conference on Kisspeptin, “Kisspeptin 2017: Brain and Beyond” was held on 30-31 March at the Rosen Centre Hotel in Orlando, Florida, providing an international forum for multidisciplinary scientists to meet and share cutting-edge research on kisspeptin biology and its relevance to human health and disease. The meeting built upon previous world conferences focused on the role of kisspeptin and associated peptides in the control of gonadotrophin-releasing hormone (GnRH) secretion and reproduction. Based on recent discoveries, the scope of this meeting was expanded to include functions of kisspeptin and related peptides in other physiological systems, including energy homeostasis, pregnancy, ovarian and uterine function, and thermoregulation. In addition, discussions addressed the translation of basic knowledge of kisspeptin biology to the treatment of disease, with the goal of seeking consensus about the best approaches to improve human health. The 2-day meeting featured a nontraditional structure, with each day starting with poster sessions followed by lunch discussions and facilitated large-group sessions with short presentations to maximise the exchange of new, unpublished data. Topics were identified by a survey prior to the meeting, and focused on major unresolved questions, important controversies and future directions in the field. Finally, career development activities provided mentoring for trainees and junior investigators, as well as networking opportunities for those individuals with established researchers in the field. Overall, the meeting was rated as a success by attendees and covered a wide range of lively and provocative discussion topics on the changing nature of the field of “kisspeptinology” and its future

An updated view of hypothalamic-vascular-pituitary unit function and plasticity

The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic–pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment

Androgen Receptor Antagonism and an Insulin Sensitizer Block the Advancement of Vaginal Opening by High-Fat Diet in Mice1

Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty. In high fat-fed rodents, the timing of vaginal opening (VO) is advanced, suggesting that puberty begins earlier. Because obesity can increase androgens, which interfere with normal steroid feedback in adult females, we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat-fed mice. Age at VO was examined in mice fed high-fat or low-fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle (controls). VO was advanced in high-fat vs. low-fat controls, and flutamide blocked this advancement. VO was also delayed in low fat-fed flutamide-treated females, suggesting involvement of androgens in the timing of normal puberty. We next investigated if high-fat diet-induced insulin resistance contributes to early VO, as elevated insulin can stimulate androgen production. VO was examined in mice on either diet treated with the insulin sensitizer metformin. Metformin blocked high-fat advancement of VO but did not alter the timing of VO in low fat-fed mice. Insulin was elevated in high fat-fed females that had undergone VO compared with age-matched low fat-fed or metformin-treated animals on either diet that had not undergone VO. Together, these data suggest a model in which metabolic changes induced by high-fat diet, including transient increased circulating insulin, act in part by increasing androgen action to influence the timing of puberty in females