274 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
Discussion required for correct interpretation
No full textThank you for the opportunity to comment on the editorial
by Romero and colleagues [1], which raises a number of
important and interesting questions. Such discussion is
mandatory if results of scientific techniques such as gene
array are to be correctly interpreted and used as the basis for future improvements in patient care
A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance
No full textabstract: In eutherians, the placenta acts as a barrier and conduit at the maternal-fetal interface. Syncytiotrophoblasts, the multinucleated cells that cover the placental villous tree surfaces of the human placenta, are directly bathed in maternal blood and are formed by the fusion of progenitor cytotrophoblasts that underlie them. Despite their crucial role in fetal protection, many of the events that govern trophoblast fusion and protection from microbial infection are unknown. We describe a three-dimensional (3D)–based culture model using human JEG-3 trophoblast cells that develop syncytiotrophoblast phenotypes when cocultured with human microvascular endothelial cells. JEG-3 cells cultured in this system exhibit enhanced fusogenic activity and morphological and secretory activities strikingly similar to those of primary human syncytiotrophoblasts. RNASeq analyses extend the observed functional similarities to the transcriptome, where we observed significant overlap between syncytiotrophoblast-specific genes and 3D JEG-3 cultures. Furthermore, JEG-3 cells cultured in 3D are resistant to infection by viruses and Toxoplasma gondii, which mimics the high resistance of syncytiotrophoblasts to microbial infections in vivo. Given that this system is genetically manipulatable, it provides a new platform to dissect the mechanisms involved in syncytiotrophoblast development and microbial resistance
"If the age aspires to the abyss, it is better to get behind it" – the biblical text in the novel by B.A. Sadovsky "The Sixth Hour"
No full textThe article’s materials complement the topic “Christianity and Russian literature” based on the example of B.A.Sadovsky’s novel “The Sixth Hour”. B.A.Sadovskaya (1881-1952) is known as the author of historical novels devoted to the study of the causes of the fall of the monarchical system in Russia in the twentieth century. He examines the history of Russia from the time of Peter I to Nicholas II from the point of view of Orthodox historiosophy. The author of the article describes the role and significance of the biblical text in creating an apocalyptic artistic picture of the world in B.A.Sadovsky’s novel “The Sixth Hour”. The biblical text was introduced by the writer into the titles (the title complex), represented by quotations from the New Testament, and is present at the level of associative symbolism in the images (names) of the characters. The novelty of the research is determined not only by the insufficient study of the writer’s literary heritage and the lack of full-fledged works on his novel work, but also by the attempt to present the novel “The Sixth Hour” by B.A.Sadovsky as a warning novel that Russia must return to monarchy and Orthodoxy as the only sources of its civilizational existence.
The author concludes that the biblical text in B.A.Sadovsky’s novel “The Sixth Hour” defines its stylistic unity and forms an idea of the author’s historiosophical concept, in which pre-revolutionary and pre-war Russia is depicted as a place of battle between good and evil, emphasizing the inevitability of its sacrificial path as a condition for its future revival
Technológia elektronického podpisu
No full textAn electronic signature uses a hash of message and an asymetrical algorithm of encryption for its generation. During verification of message on receiver side the hash of original message must be identical with the hash of received message. Electronic message is secured autentization of author and integrity of transmission date. By electronic signature it is possible to sign everything what is in digital form
Enriched Environment Affects Positively a Progression of Neurodegeneration: Elastic Maps-Based Analysis
No full text
Diagnosis and Treatment of Erectile Dysfunction for Reduction of Cardiovascular Risk
No full textPURPOSE: Here, we 1) establish erectile dysfunction (ED) as an often neglected but valuable marker of cardiovascular risk, particularly in younger and diabetic men; and 2) review evidence that lifestyle change, combined with informed prescribing of pharmacotherapies used to mitigate cardiovascular risk, can improve overall vascular health and sexual functioning in men with ED. MATERIALS AND METHODS: A PubMed search for articles and guidelines pertinent to relationships between ED and cardiovascular disease (CVD), cardiovascular and all-cause mortality, and pharmacotherapies for dyslipidemia and hypertension was performed. The clinical guidance presented incorporates the current literature and the expertise of the multi-specialty author group. RESULTS: Numerous cardiovascular risk assessment tools exist, but risk stratification remains challenging, particularly for those patients at low or intermediate short-term risk. ED has a predictive value for cardiovascular events that is comparable to or better than traditional risk factors. Interventional studies support lifestyle changes as means of improving overall vascular health as well as sexual functioning. Statins, diuretics, beta blockers, and renin-angiotensin system modifiers may positively or negatively affect erectile function. Furthermore, phosphodiesterase type 5 (PDE5) inhibitors used to treat ED may have systemic vascular benefits. CONCLUSIONS: Treatment of ED should be considered secondary to cardiovascular risk reduction, but informed prescribing may prevent worsening of sexual function in men receiving pharmacotherapy for dyslipidemia and hypertension. As the first point of medical contact for men with ED symptoms, the primary care physician or urologist has a unique opportunity to identify patients who require early intervention to prevent cardiovascular disease
TRANSPORT-ENTROPY FORMS OF DIRECT AND CONVERSEBLASCHKE-SANTALÓ INEQUALITIES
No full textWe explore alternative functional or transport-entropy formulations of the Blaschke-Santaló inequality and of its conjectured counterpart due to Mahler. In particular, we obtain new direct and reverse Blaschke-Santaló inequalities for s-concave functions. We also obtain new sharp symmetrized transport-entropy inequalities for a large class of spherically invariant probability measures, including the uniform measure on the unit Euclidean sphere and generalized Cauchy and Barenblatt distributions. Finally, we show that the Mahler’s conjecture is equivalent to some reinforced log-Sobolev type inequality on the sphere
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