302 research outputs found
Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland
We have developed a mouse model of diet-induced obesity that shows numerous abnormalities relating to mammary gland function. Animals ate 40% more calories when offered a high-fat diet and gained weight at three times the rate of controls. They exhibited reduced conception rates, increased peripartum pup mortality, and impaired lactogenesis. The impairment of lactogenesis involved lipid accumulation in the secretory epithelial cells indicative of an absence of copius milk secretion. Expression of mRNAs for -casein, whey acid protein, and -lactalbumin were all decreased immediately postpartum but recovered as lactation was established over 2â3 days. Expression of acetyl-CoA carboxylase (ACC)- mRNA was also decreased at parturition as was the total enzyme activity, although there was a compensatory increase in the proportion in the active state. By day 10 of lactation, the proportion of ACC in the active state was also decreased in obese animals, indicative of suppression of de novo fatty acid synthesis resulting from the supply of preformed fatty acids in the diet. Although obese animals consumed more calories in the nonpregnant and early pregnant states, they showed a marked depression in fat intake around day 9 of pregnancy before food intake recovered in later pregnancy. Food intake increased dramatically in both lean and obese animals during lactation although total calories consumed were identical in both groups. Thus, despite access to high-energy diets, the obese animals mobilized even more adipose tissue during lactation than their lean counterparts. Obese animals also exhibited marked abnormalities in alveolar development of the mammary gland, which may partially explain the delay in differentiation evident during lactogenesis
Optimisation de tournées de service en temps réel
RĂSUMĂ : Les tournĂ©es de service concernent l'organisation de dĂ©placement de personnels vers des clients afin d'effectuer diffĂ©rentes activitĂ©s techniques ou commerciales. Ces tournĂ©es peuvent devoir rĂ©pondre Ă des objectifs et faire face Ă des contraintes nombreuses et complexes. Lors de la planification et de l'exĂ©cution de tournĂ©es de service mono-pĂ©riode, les entreprises sont confrontĂ©es aux alĂ©as des temps de service et de parcours. C'est pourquoi, dans cette thĂšse, nous nous intĂ©ressons Ă une variante du problĂšme de tournĂ©es de service, dans laquelle les temps de parcours et de service sont stochastiques. Il s'agit du problĂšme de tournĂ©es de service multi-dĂ©pĂŽt, incluant fenĂȘtres de temps, temps de service et de parcours stochastiques avec prioritĂ© entre les clients (distinction clients obligatoires / clients optionnels). Afin de rĂ©soudre cette problĂ©matique, nous proposons trois mĂ©thodes diffĂ©rentes. Dans la premiĂšre mĂ©thode, nous construisons d'abord des routes contenant uniquement des clients obligatoires puis nous procĂ©dons Ă l'insertion des clients optionnels. La deuxiĂšme mĂ©thode est une mĂ©thode approchĂ©e basĂ©e sur la gĂ©nĂ©ration de colonnes consistant Ă gĂ©nĂ©rer un ensemble de routes de bonne qualitĂ© pour chaque vĂ©hicule puis Ă en sĂ©lectionner une par vĂ©hicule. La derniĂšre mĂ©thode est un algorithme de branch and price basĂ© sur la deuxiĂšme mĂ©thode. Le sous-problĂšme consiste Ă gĂ©nĂ©rer des routes rĂ©alisables pour un vĂ©hicule donnĂ©, tandis que le problĂšme maĂźtre permet de sĂ©lectionner des routes en s'assurant que la prioritĂ© des clients est respectĂ©e. AprĂšs chacune de ces mĂ©thodes, afin d'Ă©valuer la qualitĂ© de ces solutions face aux alĂ©as, nous utilisons un algorithme de programmation dynamique et procĂ©dons Ă un ensemble de simulations du dĂ©roulement des tournĂ©es en temps rĂ©el. Nous avons testĂ© ces mĂ©thodes sur des problĂšmes dont les donnĂ©es sont issues du milieu industriel.Mots-clĂ©s : TournĂ©es de vĂ©hicules, multi-dĂ©pĂŽt, fenĂȘtres de temps, temps de service stochastiques, temps de parcours stochastiques, prioritĂ© entre les clients.----------ABSTRACT : The field service routing problem consists in assigning the visits of technicians to clients in order to satisfy their requests for service activities such as maintenance. When planning service routes, companies have to face hazardous travel and service times. Therefore, in this thesis, we deal with a variant of the single-period field service routing problem in which travel and service times are stochastic. It is the field service routing problem with multiple depots, time windows, stochastic travel and service times and priority within customers (distinguishing mandatory and optional customers). To solve this problem, we propose three different methods. In the first one, we first build routes containing only mandatory customers and then, we insert optional customers in these routes. The second one is a heuristic method based on column generation consisting in generating a set of valuable routes for each vehicle and then in selecting one route per vehicle. The last method is a branch and price algorithm, based on the second method, in which the subproblem consists in finding feasible routes for a given vehicle, whereas the master problem consists in selecting routes while ensuring that customer's priority is respected. After each of these methods, in order to evaluate the quality of these solutions regarding stochasticity, we use a dynamic programming algorithm and we proceed to a set of simulations of the real-time execution of the service activities over the period. All our experimentations have been made on problems coming from realistic data. Keywords : Vehicle routing, multi-depot, time windows, stochastic service times, stochastic travel times, priority within customers
The tyrosine kinase inhibitor sunitinib affects ovulation but not ovarian reserve in mouse: A preclinical study
The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-weekold female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti MĂŒllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women
Effects of deletion of the prolactin receptor on ovarian gene expression
Prolactin (PRL) exerts pleiotropic physiological effects in various cells and tissues, and is mainly considered as a regulator of reproduction and cell growth. Null mutation of the PRL receptor (R) gene leads to female sterility due to a complete failure of embryo implantation. Pre-implantatory egg development, implantation and decidualization in the mouse appear to be dependent on ovarian rather than uterine PRLR expression, since progesterone replacement permits the rescue of normal implantation and early pregnancy. To better understand PRL receptor deficiency, we analyzed in detail ovarian and corpora lutea development of PRLR-/- females. The present study demonstrates that the ovulation rate is not different between PRLR+/+ and PRLR-/- mice. The corpus luteum is formed but an elevated level of apoptosis and extensive inhibition of angiogenesis occur during the luteal transition in the absence of prolactin signaling. These modifications lead to the decrease of LH receptor expression and consequently to a loss of the enzymatic cascades necessary to produce adequate levels of progesterone which are required for the maintenance of pregnancy
Interaction of glucocorticosteroid receptor and wild-type or mutated 90-kDa heat shock protein coexpressed in baculovirus-infected Sf9 cells.
Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration
Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists
Prolactin induces apoptosis of lactotropes in female rodents
Anterior pituitary cell turnover occurring during female sexual cycle is a poorly understood process that involves complex regulation of cell proliferation and apoptosis by multiple hormones. In rats, the prolactin (PRL) surge that occurs at proestrus coincides with the highest apoptotic rate. Since anterior pituitary cells express the prolactin receptor (PRLR), we aimed to address the actual role of PRL in the regulation of pituitary cell turnover in cycling females. We showed that acute hyperprolactinemia induced in ovariectomized rats using PRL injection or dopamine antagonist treatment rapidly increased apoptosis and decreased proliferation specifically of PRL producing cells (lactotropes), suggesting a direct regulation of these cell responses by PRL. To demonstrate that apoptosis naturally occurring at proestrus was regulated by transient elevation of endogenous PRL levels, we used PRLR-deficient female mice (PRLRKO) in which PRL signaling is totally abolished. According to our hypothesis, no increase in lactotrope apoptotic rate was observed at proestrus, which likely contributes to pituitary tumorigenesis observed in these animals. To decipher the molecular mechanisms underlying PRL effects, we explored the isoform-specific pattern of PRLR expression in cycling wild type females. This analysis revealed dramatic changes of long versus short PRLR ratio during the estrous cycle, which is particularly relevant since these isoforms exhibit distinct signaling properties. This pattern was markedly altered in a model of chronic PRLR signaling blockade involving transgenic mice expressing a pure PRLR antagonist (TGÎ1â9-G129R-hPRL), providing evidence that PRL regulates the expression of its own receptor in an isoform-specific manner. Taken together, these results demonstrate that i) the PRL surge occurring during proestrus is a major proapoptotic signal for lactotropes, and ii) partial or total deficiencies in PRLR signaling in the anterior pituitary may result in pituitary hyperplasia and eventual prolactinoma development, as observed in TGÎ1â9-G129R-hPRL and PRLRKO mice, respectively.Fil: Ferraris, Maria Jimena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones BiomĂ©dicas; Argentina; Argentina. Universidad de Buenos Aires; ArgentinaFil: Zarate, Sandra Cristina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones BiomĂ©dicas; Argentina; Argentina. Universidad de Buenos Aires; ArgentinaFil: Jaita, Gabriela Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones BiomĂ©dicas; Argentina; Argentina. Universidad de Buenos Aires; ArgentinaFil: Boutillon, Florencia. Universite Paris Sud; FranciaFil: Bernadet, Marie. Universite Paris Descartes; FranciaFil: Auffret, Julien. Universite Paris Sud; FranciaFil: Seilicovich, Adriana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones BiomĂ©dicas; Argentina; Argentina. Universidad de Buenos Aires; ArgentinaFil: Binart, Nadine. Universite Paris Sud; FranciaFil: Goffin, Vincent. Universite Paris Descartes; FranciaFil: Pisera, Daniel Alberto. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones BiomĂ©dicas; Argentina; Argentina. Universidad de Buenos Aires; Argentin
Prolactin Controls Mammary Gland Development via Direct and Indirect Mechanisms
AbstractThe inactivation of the prolactin receptor gene by homologous recombination has made it possible to investigate the role of prolactin signaling in mammary gland development without resort to ablative surgery of the endocrine glands. In knockout mice lacking the prolactin receptor, mammary development is normal up to puberty. Subsequently, the ducts branch less frequently than those of wild-type animals. While terminal end buds differentiate to alveolar buds in wild-type females by the end of puberty, in knockout females terminal end bud-like structures persist at the ductal ends. To distinguish between the developmental defects that are intrinsic to the epithelium and those that result from systemic endocrine alterations in prolactin receptor knockout mice, mammary epithelium from prolactin receptor knockouts was transplanted into mammary fat pads of wild-type mice. In virgin mice, the knockout epithelial transplants developed normally at puberty, indicating an indirect effect of prolactin on ductal development. Prolactin receptor knockout females are infertile due to multiple reproductive defects, but epithelial transplants allowed us to assess the extent to which the absence of prolactin receptor is limiting, under systemic conditions that allow full mammary gland development. During pregnancy, the prolactin receptor knockout transplants showed normal side branching and the formation of alveolar buds, but no lobuloalveolar development. Thus, prolactin affects mammary morphogenesis in two different ways: it controls ductal side branching and terminal end bud regression in virgin animals via indirect mechanisms, but acts directly on the mammary epithelium to produce lobuloalveolar development during pregnancy
The Functional Relevance of the Heteromeric Structure of Corticosteroid Receptors a
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73195/1/j.1749-6632.1994.tb39213.x.pd
Hypothalamic-pituitary-ovarian Axis Reactivation by Kisspeptin-10 in Hyperprolactinemic Women with Chronic Amenorrhea
CONTEXT : Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major
cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In
hyperprolactinemic mice, we previously demonstrated that hypothalamic kisspeptin (Kp) expression
was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin
secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in
hPRL-HA.
OBJECTIVE : To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA.
PATIENTS : Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and
98 and 112 ng/mL, respectively) caused by cabergoline-resistant microprolactinomas.
INTERVENTIONS : Cabergoline was discontinued 6 months before inclusion. Blood samples were taken
every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB)
levels were also measured. Vehicle or Kp-10 (1.5 mg/kg/h) was infused intravenously for 12 hours.
RESULTS : Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and
IB serum levels were also significantly increased.
CONCLUSIONS : In this exploratory study, we demonstrated that administration of Kp-10 reactivated
gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that,
as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp
secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to
restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in
whom pituitary surgery is not possible.https://academic.oup.com/jesam2018ImmunologyPhysiolog
- âŠ