2,226 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

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    G 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

    Noninvasive Evaluation of Cardiac Function in Non Hypertensive and Asymptomatic Diabetic Patients

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    Background & Objectives: Type 2 diabetes is a major cardiovascular risk factor such as HTN, HLP and smoking. A primary diabetic cardiomyopathy represents a high risk factor for heart failure in the absence of ischemic, valvular and hypertensive heart disease in the diabetic population. CAD is more common in diabetic patients and it is almost asymptomatic. Unquestionably, an early detection of LV damage and CAD is a major goal for the prevention of cardiac disease in the diabetic population. Methods: This study was done as Cross-Sectional method. The study sample consisted of 40 patients with type 2 diabetes mellitus without hypertension and cardiac symptoms (mean age 47 years) who recourse to diabetes clinic of Ardabil Emam Khomeini Hospital during 2009-2010. Left ventricular (LV) function was studied by echocardiography and exercise test using Bruce protocol. Data from the patients were collected and analyzed using SPSS 17 software. Results: All studied cases had a normal systolic function. 22 cases (55%) had diastolic dysfunction and 8 people (20%) had a positive stress test, which all had diastolic dysfunction too. Conclusion: This study showed that an impairment of left ventricular diastolic function occurs early in the natural history of diabetes mellitus and CAD is more common in diabetic patients with diastolic dysfunction

    Writing a History of Women's Writing from 700 to 1500

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    How 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

    Signalling pathways involved in TNFα-induced cytoprotection : role of reactive oxygen species

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    Includes bibliographical references (leaves 73-89).Tumour necrosis factor alpha (TNFa) is a pleiotropic cytokine which has both beneficial and deleterious effects. It has previously been shown in our laboratory that TNFa can mimic ischemic preconditioning (IPC). However, the signalling pathways involved in this protection remain incompletely understood. One potential protective pathway involves the generation of reactive oxygen species (ROS), which are known to be activated by TNFa. It was therefore hypothesized that TNFa-induced cytoprotection requires the generation of ROS. In addition, it was postulated that this ROS generation originates in the mitochondria

    Writing a History of Women's Writing from 700 to 1500

    No full text
    How 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

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    The 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

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    Charles Berlitz, author of "Doomsday," makes predictions that life will cease after 2000 A.D
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