2,187 research outputs found
The Expression and Localization of N-Myc Downstream-Regulated Gene 1 in Human Trophoblasts
No full textThe protein N-Myc downstream-regulated gene 1 (NDRG1) is implicated in the regulation of cell proliferation, differentiation, and cellular stress response. NDRG1 is expressed in primary human trophoblasts, where it promotes cell viability and resistance to hypoxic injury. The mechanism of action of NDRG1 remains unknown. To gain further insight into the intracellular action of NDRG1, we analyzed the expression pattern and cellular localization of endogenous NDRG1 and transfected Myc-tagged NDRG1 in human trophoblasts exposed to diverse injuries. In standard conditions, NDRG1 was diffusely expressed in the cytoplasm at a low level. Hypoxia or the hypoxia mimetic cobalt chloride, but not serum deprivation, ultraviolet (UV) light, or ionizing radiation, induced the expression of NDRG1 in human trophoblasts and the redistribution of NDRG1 into the nucleus and cytoplasmic membranes associated with the endoplasmic reticulum (ER) and microtubules. Mutation of the phosphopantetheine attachment site (PPAS) within NDRG1 abrogated this pattern of redistribution. Our results shed new light on the impact of cell injury on NDRG1 expression patterns, and suggest that the PPAS domain plays a key role in NDRG1's subcellular distribution. © 2013 Shi et al
Cancer and Sexual Problems
No full textIntroduction. There are many data on sexual problems subsequent to cancer and its treatment, although the likelihood of problems in specific individuals depends on multiple variables. Aims. To gain knowledge about the risks of sexual problems among persons with cancer and to provide recommendations concerning their prevention and optimal treatment. Methods. A committee of multidisciplinary specialists was formed as part of a larger International Consultation working with urologic and sexual medicine societies over a 2-year period to review the result of chronic illness management on sexual function and satisfaction. The aims, goals, data collection techniques, and report format were defined by a central committee. Main Outcomes Measures. Expert consensus was based on evidence-based medical and psychosocial literature review, extensive group discussion, and an open presentation with a substantial discussion period. Results. Cancer and cancer treatments have both direct and indirect effects on physiologic, psychological, and interpersonal factors that can all impact negatively on sexual function and satisfaction. Data on the likelihood of specific sexual problems occurring with cancer and its management vary depending on prediagnosis function, patient response, support from the treatment team, specific treatments used, proactive counseling, and efforts to mitigate potential problems. This summary details available literature concerning the pathophysiologic and psychological impacts of cancer diagnosis and treatment on sexual function, plus recommendations for their prevention and management. Conclusions. Cancer and its management have a significant negative impact on sexual function and satisfaction. These negative effects can be somewhat mitigated by understanding prediagnosis sexual functioning level, counseling, careful treatment choices, and, when indicated, therapy post-treatment using educational, psychological, pharmacologic, and mechanical modalities. Sadovsky R, Basson R, Krychman M, Morales AM, Schover L, Wang R, and Incrocci L. Cancer and sexual problems. J Sex Med 2010;7:349-373
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
Members of the ALICE collaboration greet the arrival of the experiment's first 500 lead tungstate crystals
No full textL. to r: Vladislav Manko (Kurchatov Institute, Moscow, PHOS project leader), Arne Klovning (University of Bergen, PHOS technical coordinator), Vyacheslav Demanov (VNIIEF, Sarov), Bjorn Pommeresche (University of Bergen), Hans de Groot (CERN, ALICE resource coordinator), Dimitri Alexandrov (Kurchatov Institute, Moscow), Mikhail Ippolitov (Kurchatov Institute, Moscow), Yuri Vinogradov (VNIIEF, Sarov), Chris Fabjan (CERN, ALICE technical coordinator), Yuri Sibiriak (Kurchatov Institute, Moscow), Sergei Sadovsky (IHEP, Protvino), Jurgen Schukraft (CERN, ALICE spokesperson)
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
International Society for Sexual Medicine`s Guidelines for the Diagnosis and Treatment of Premature Ejaculation
No full textIntroduction. Over the past 20 years our knowledge of premature ejaculation (PE) has significantly advanced. Specifically, we have witnessed substantial progress in understanding the physiology of ejaculation, clarifying the real prevalence of PE in population-based studies, reconceptualizing the definition and diagnostic criterion of the disorder, assessing the psychosocial impact on patients and partners, designing validated diagnostic and outcome measures, proposing new pharmacologic strategies and examining the efficacy, safety and satisfaction of these new and established therapies. Given the abundance of high level research it seemed like an opportune time for the International Society for Sexual Medicine (ISSM) to promulgate an evidenced-based, comprehensive and practical set of clinical guidelines for the diagnosis and treatment of PE. Aim. Develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. Method. Review of the literature. Results. This article contains the report of the ISSM PE Guidelines Committee. It affirms the ISSM definition of PE and suggests that the prevalence is considerably lower than previously thought. Evidence-based data regarding biological and psychological etiology of PE are presented, as is population-based statistics on normal ejaculatory latency. Brief assessment procedures are delineated and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients. Conclusion. Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. Therefore, it is strongly recommended that these guidelines be re-evaluated and updated by the ISSM every 4 years. Althof SE, Abdo CHN, Dean J, Hackett G, McCabe M, McMahon CG, Rosen RC, Sadovsky R, Waldinger M, Becher E, Broderick GA, Buvat J, Goldstein I, El-Meliegy AI, Giuliano F, Hellstrom WJG, Incrocci L, Jannini EA, Park K, Parish S, Porst H, Rowland D, Segraves R, Sharlip I, Simonelli C, and Tan HM. International Society for Sexual Medicine`s guidelines for the diagnosis and treatment of premature ejaculation. J Sex Med 2010;7:2947-2969
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
A Scheduling Algorithm Compatible with a Distributed Management of Arrivals in the National Airspace System
No full textThe current system used by the FAA to schedule arrivals is the Traffic Based Flow Manager (TBFM). It is a centralized system that gives an operator (airline) no influence over scheduled times of arrival assigned to its flights. Future systems for managing arrival scheduling are proposed as distributed systems. Such a system is called upon to give operators influence to schedule and negotiate resources for their flights, and to resolve other technical challenges, such as eliminating a single point of failure. A distributed system for managing diverse air traffic will need the capability of computing a schedule for the given arriving flights in a way that complies with the operational constraints. This paper contributes an algorithm that computes such a schedule. Although developed as part of an effort toward a distributed system, the algorithm itself is neither inherently distributed nor inherently centralized and can be used in either type of system
The pairwise distances between the centers of the clusters (<i>L</i>) and their radiuses (<i>R</i>) on the 16 × 16 elastic map in Figs 4–6.
No full textThe pairwise distances between the centers of the clusters (L) and their radiuses (R) on the 16 × 16 elastic map in Figs 4–6.</p
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
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