2,129 research outputs found
Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the luteinizing hormone beta-subunit gene
No full textG protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH beta-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH2-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH beta-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH2-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH beta-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression
Writing a History of Women's Writing from 700 to 1500
No full textHow can a history of British women’s writing be written? Such a project must necessarily be collaborative if it is to attempt to be comprehensive, but even then any claim to comprehensiveness has to be qualified: paradoxically the more expansive the history, the more partial it will be. The challenges of writing such a history are perhaps even greater for scholars working in the early periods because we are forced to confront and to rethink many deeply ingrained assumptions about women’s writing. This introductory essay focuses on a period of literary history that is often marginalized in accounts of women’s writing in English: the Middle Ages. It is a widely accepted view that there are only two women writers in English in the period before 1500, and therefore there is little to be said for an age (or ages) when women writers were so much an exception. Furthermore, the two medieval English women writers whose names are widely known, Julian of Norwich (1342/3-after 1416) and Margery Kempe (c.1373-after 1439), did not think of themselves as writers or authors. Nor were they responsible for literature as it is thought of today—they did not compose poetry, or romances, or fiction of any sort. Even these two ‘named’ women writers do not comfortably fit established evolutionary models of women’s literary history over the longue durée, with their emphases on the spread of literacy, the bias towards print culture, and the emergence of the woman poet, and ultimately of the professional author of drama or fiction. Yet the difficulty of locating how the medieval period fits in to literary history is not unique to women’s writing: medieval understandings of authorship, literature, and national identity, and the contexts and processes of writing and textual circulation were quite distinct from later periods and therefore deemed problematic more generally. This essay explores some of these issues and reflects on the difficulties we face writing a history of early women's writing
Writing a History of Women's Writing from 700 to 1500
No full textHow can a history of British women’s writing be written? Such a project must necessarily be collaborative if it is to attempt to be comprehensive, but even then any claim to comprehensiveness has to be qualified: paradoxically the more expansive the history, the more partial it will be. The challenges of writing such a history are perhaps even greater for scholars working in the early periods because we are forced to confront and to rethink many deeply ingrained assumptions about women’s writing. This introductory essay focuses on a period of literary history that is often marginalized in accounts of women’s writing in English: the Middle Ages. It is a widely accepted view that there are only two women writers in English in the period before 1500, and therefore there is little to be said for an age (or ages) when women writers were so much an exception. Furthermore, the two medieval English women writers whose names are widely known, Julian of Norwich (1342/3-after 1416) and Margery Kempe (c.1373-after 1439), did not think of themselves as writers or authors. Nor were they responsible for literature as it is thought of today—they did not compose poetry, or romances, or fiction of any sort. Even these two ‘named’ women writers do not comfortably fit established evolutionary models of women’s literary history over the longue durée, with their emphases on the spread of literacy, the bias towards print culture, and the emergence of the woman poet, and ultimately of the professional author of drama or fiction. Yet the difficulty of locating how the medieval period fits in to literary history is not unique to women’s writing: medieval understandings of authorship, literature, and national identity, and the contexts and processes of writing and textual circulation were quite distinct from later periods and therefore deemed problematic more generally. This essay explores some of these issues and reflects on the difficulties we face writing a history of early women's writing
Blowout of non-premixed turbulent jet flames with coflow under microgravity condition
No full textThe blowout behavior of non-premixed turbulent coflow jet flames under microgravity environment was studied experimentally by utilizing a 3.6 s drop tower. Variations of flames leading to liftoff as well as blowout were examined by varying the coflow velocity and compared with those obtained under the normal gravity condition. A modeling work was conducted to incorporate the effects of the gravity (buoyancy) and coflow velocity on blowout behavior. Major findings include: (1) the flame length in microgravity was longer than that in normal gravity and decreased with increasing coflow velocity. The flame in microgravity showed more intense yellow luminosity with larger sooting zone; (2) the flame liftoff height increased with increasing coflow velocity in both gravity levels. The flame base was closer to the burner in microgravity as compared with that in normal gravity; (3) the blowout velocity in microgravity was appreciably larger than that obtained in normal gravity; and (4) a physical model based on Damkohler number was developed by using similarity solutions to characterize the differences in the blowout limits considering both the coflow and gravity (buoyancy) effects. The proposed model can successfully predict the experimental data. This work provided new data and basic scaling analysis for blowout limit of non-premixed turbulent jet flames considering both the coflow and gravity (buoyancy) effects. (C) 2019 The Combustion Institute. Published by Elsevier Inc. All rights reserved
Charles Berlitz, Author of "Doomsday," Takes Predictions
No full textCharles Berlitz, author of "Doomsday," makes predictions that life will cease after 2000 A.D
IMMUNOCYTOLOGICAL EVIDENCE OF LH-RF IN HYPOTHALAMUS AND MEDIAN EMINENCE : A REVIEW
No full textInternational audienceThe author reviews reports about the immunocytological demonstration of LH-RF in the hypothalamus and describes the materials and methods used by different groups of workers. The different authors are in agreement about the localization of LH-RF axons and axonal endings. The hypothalamo-infundibular pathway, which is the principal LH-RF neurosecretory pathway, and the accessory extra-hypophyseal pathways in guinea-pig, dog, cat and primates, and the distribution of LH-RF in the median eminence of ram, birds (cock, duck) and amphibians (toad, xenopus, triton) are described
Deletion of arcuate nucleus-specific Kiss1 disrupts estrous cyclicity and LH pulsatility in female mice
No full textKisspeptin (encoded by Kiss1), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two discrete hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). Current data indicates that AVPV Kiss1 is important for the pre-ovulatory luteinizing hormone (LH) surge unique to females as well as estrogen-induced positive feedback control of GnRH and LH. In contrast, ARC Kiss1 neurons, which largely co-express the neuropeptides NKB and dynorphin (collectively known as KNDy neurons), are thought to be the major regulators of pulsatile release of GnRH and LH, and mediate estrogen- induced negative feedback control of both GnRH and LH. Previous studies have not definitively separated the specific roles of Kiss1 in the AVPV versus KNDy-ARC neurons in the downstream control of GnRH and LH release. Therefore, we generated a Pdyn-Cre/Kiss1fl/fl (KO) mouse model to target Kiss1 in KNDy neurons to differentiate KNDy neuron-specific function from AVPV Kiss1 function in the maturation and maintenance of the reproductive axis. qRT-PCR data documented the loss of Kiss1 expression in the mediobasal hypothalamus (containing ARC) compared to controls, whereas Kiss1 in the preoptic area (containing AVPV) was similar in both KO and controls. Immunofluorescent staining for kisspeptin confirmed the loss of Kiss1 specifically in the ARC of KO mice. Although no changes in pubertal body weight gain or pubertal onset were observed in KO animals, KO females exhibited disrupted estrous cyclicity in adulthood. Interestingly, KO female mice had disrupted estrous cycles presenting with persistent diestrus and a small vaginal opening. We tested the hypothesis that ARC KNDy neurons are necessary for generating and maintaining episodic LH pulsatile release by serial collection of whole blood and measuring LH. KO female mice exhibited significantly fewer LH pulses in a 3-hour timespan compared to controls, suggesting that KNDy neurons were functionally compromised. These observations indicate the central role of KNDy neurons in the regulation of GnRH/LH pulsatility and estrous cyclicity. The functional effects of disrupted estrous cyclicity and slowed LH pulsatility observed in KO females result in arrested folliculogenesis and infertility. Future experiments will determine whether ARC Kiss1 deletion disrupts the KNDy- driven negative feedback response of LH to gonadectomy, as well as address potential sex differences in ARC Kiss1-mediated negative feedback control of LH release.M.S.Includes bibliographical reference
LH-power coupling in advanced tokamak plasmas in JET
No full textLower Hybrid Current Drive (LHCD) is the most efficient tool to generate non-inductive current in tokamak plasmas. In JET, significant modifications of the current profile have been recently achieved in coupling up to 3MW of LH power in optimised shear discharges. However, the improved particle confinement during optimised shear plasmas results in a sharp decrease of the electron density in front the launcher close or below the cut-off density (ne=1.7.10"1"7 m"-"3 for f_L_H=37GHz) and makes difficult the coupling of the LH power. Deuterium gas near the launcher can help to improve the coupling, but has also the effect of increasing the ELM activity leading to the erosion of the internal transport barrier (ITB). Future development of lower hybrid launcher should include the constraints imposed by scenario such as the optimised shear. (author)Available from British Library Document Supply Centre-DSC:4672.2625(99/09) / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo
A central role for cAMP/EPAC/RAP/PI3K/AKT/CREB signaling in LH-induced follicular Pgr expression at medaka ovulation
No full textNuclear progestin receptor (PGR) is a ligand-activated transcription factor that has been identified as a pivotal mediator of many processes associated with ovarian and uterine function, and aberrant control of PGR activity causes infertility and disease including cancer. The essential role of PGR in vertebrate ovulation is well recognized, but the mechanisms by which PGR is rapidly and transiently induced in preovulatory follicles after the ovulatory LH surge are not known in lower vertebrates. To address this issue, we utilized the small freshwater teleost medaka Oryzias latipes, which serves as a good model system for studying vertebrate ovulation. In the in vitro ovulation system using preovulatory follicles dissected from the fish ovaries, we found that inhibitors of EPAC (brefeldin A), RAP (GGTI298), PI3K (Wortmannin), AKT (AKT inhibitor IV), and CREB (KG-501) inhibited LH-induced follicle ovulation, while the PKA inhibitor H-89 had no effect on follicle ovulation. The inhibitors capable of inhibiting follicle ovulation also inhibited follicular expression of Pgr and matrix metalloproteinase-15 (Mmp15), the latter of which was previously shown to not only be a downstream effector of Pgr but also a proteolytic enzyme indispensable for follicle rupture in medaka ovulation. Further detailed analysis revealed for the first time that the cAMP/EPAC/RAP/PI3K/AKT/CREB signaling pathway mediates the LH signal to induce Pgr expression in preovulatory follicles. Our data also showed that phosphorylated Creb1 is a transcription factor essential for pgr expression and that Creb1 phosphorylated by Akt1, rather than PKA, may be preferably used to induce pgr expression. Summary sentence EPAC/RAP/PI3K/AKT/CREB signaling mediates LH-induced cAMP signaling to induce medaka Pgr expression in ovulating follicles
INTERACTION OF GONADAL STEROIDS AND ENDOGENOUS OPIOIDS IN THE INHIBITION OF LH RELEASE (NALOXONE, ENDORPHINS)
No full textOpioid-mediated inhibition of luteinizing hormone (LH) was investigated in sheep and cattle. Naloxone (NAL) injection abruptly stimulated LH release (i.e. disinhibited the opioid-mediated suppression) in intact ewes with corpora lutea or those receiving progesterone (P4). In ovariectomized (OVEX) ewes, P4 suppressed serum LH and NAL injection in these ewes disinhibited the release of LH. After treatment with P4 for 30 days, serum LH was no longer suppressed and NAL injection no longer disinhibited the release of LH. A single injection of estradiol-17B (E2) in these ewes reinstated the suppression of LH secretion and the ability of NAL to disinhibit LH release. In other OVEX ewes, continuous administration of E2 or E2 and P4 suppressed LH release, but NAL failed to disinhibit consistently the release of LH in these ewes. Procedures were developed and validated for the in vitro quantification of specific binding of (\u273)H-NAL to homogenates of brain tissue of sheep and cattle. In steroid-treated OVEX ewes, brain tissue was removed for assay of (\u273)H-NAL binding several hours after the serum LH response to exogenous NAL had been determined. Administration of E2 appeared to antagonize the opioid-mediated suppression of LH, and ewes were divided retrospectively into NAL-sensitive or insensitive groups based upon their in vivo LH response to NAL. Binding of (\u273)H-NAL to homogenates of POA or HYP did not differ between the two groups of ewes, but the NAL-sensitive ewes had a higher concentration of binding sites in the ventral SEP area when compared with the NAL-insensitive ewes. Brain tissue was obtained from suckled beef cows at several stages of the postpartum period. Specific binding of (\u273)H-NAL was demonstrated in homogenates of HYP, POA, and ventral SEP with the highest concentration of binding sites in the ventral SEP as also observed in sheep. The escape of cows from the inhibitory effects of suckling and the occurrence of estrous cycles were associated with a decrease in the concentration of binding sites for (\u273)H-NAL in homogenates of POA and ventral SEP. (Abstract shortened with permission of author.
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