1,720,956 research outputs found
Are peptidomimetics the compounds of choice for developing new modulators of the JAK-STAT pathway?
No full textProtein-protein interactions (PPIs) play critical roles in a wide range of biological processes including the dysregulation of cellular pathways leading to the loss of cell function, which in turn leads to diseases. The dysfunction of several signaling pathways is linked to the insurgence of pathological processes such as inflammation, cancer development and neurodegeneration. Thus, there is an urgent need for novel chemical modulators of dysregulated PPIs to drive progress in targeted therapies. Several PPIs have been targeted by bioactive compounds, and, often, to properly cover interacting protein regions and improve the biological activities of modulators, a particular focus concerns the employment of macrocycles as proteomimetics. Indeed, for their physicochemical properties, they occupy an intermediate space between small organic molecules and macromolecular proteins and are prominent in the drug discovery process. Peptide macrocycles can modulate fundamental biological mechanisms and here we will focus on peptidomimetics active on the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways
Iatrogenic ejaculation disorders and their prevention
No full textEjaculation is mediated by sympathetic fibers originating from the D10-L2 medullar center. These nerves rise from the lumbar ganglia of the paravertebral sympathetic trunk and travel posteriorly to the vena cava and then to the interaortocaval space, on the right side, and laterally to the aorta, on the left side. They are the principal constituents of the superior hypogastric plexus. Many surgical operations can cause an ejaculation disorder, but the most important is retroperitoneal lymphadenectomy (RL) for testis cancer, because it involves young patients and it has been the subject of important researches in order to perform lymph node dissection without ejaculation loss (unilateral lymphadenectomy and nerve sparing lymphadenectomy). Our experience concerns 41 patients who underwent RL for testis cancer from 1983 to 1998. Survival rate was 95.2% (mean follow up 64 months). RL was performed bilaterally in 14 patients. Two of them died of metastases within 2 years after the operation. Ejaculation was maintained in only 4 of the 12 surviving patients (33%). All the 17 patients (100%) underwent right monolateral RL and 7 of the 10 (70%) underwent left monolateral RL preserved ejaculation. The anatomosurgical concepts of the RL sparing the ejaculation can be adopted in other retroperitoneal surgical operations that can produce ejaculation disorders, such as wide lymphadenectomy for renal cell carcinoma or tumors of the upper urinary tract, exeresis of pre- aortic tumors, exeresis or disjunction of horseshoe kidney and aorto-iliac revascularization. Surgical therapy of benign prostatic hyperplasia (BPH) (open surgery or transurethral prostatic resection) is associated with retrograde ejaculation in nearly 100% of cases. The mechanism of the dysfunction is clear, if following the procedure the bladder neck remains opened. Loss of ejaculation is reported in variable percentage after the newer endoscopic techniques for the treatment of BPH. Transurethral needle ablation (TUNA) seems to have the lower risk of retrograde ejaculation. Retrograde ejaculation can also be related to a traumatic injury of the posterior urethra, because of the trauma itself or the therapy. Finally, the ejaculation disorder can be produced by several drugs that block, as a main or secondary effect, the alpha-adrenoreceptors or act at the central level. This side effect has to be kept in mind when these drugs are used in young or sexually active patients
Iatrogenic ejaculation disorders and their prevention
No full textEjaculation is mediated by sympathetic fibers originating from the D10-L2 medullar center. These nerves rise from the lumbar ganglia of the paravertebral sympathetic trunk and travel posteriorly to the vena cava and then to the interaortocaval space, on the right side, and laterally to the aorta, on the left side. They are the principal constituents of the superior hypogastric plexus. Many surgical operations can cause an ejaculation disorder, but the most important is retroperitoneal lymphadenectomy (RL) for testis cancer, because it involves young patients and it has been the subject of important researches in order to perform lymph node dissection without ejaculation loss (unilateral lymphadenectomy and nerve sparing lymphadenectomy). Our experience concerns 41 patients who underwent RL for testis cancer from 1983 to 1998. Survival rate was 95.2% (mean follow up 64 months). RL was performed bilaterally in 14 patients. Two of them died of metastases within 2 years after the operation. Ejaculation was maintained in only 4 of the 12 surviving patients (33%). All the 17 patients (100%) underwent right monolateral RL and 7 of the 10 (70%) underwent left monolateral RL preserved ejaculation. The anatomosurgical concepts of the RL sparing the ejaculation can be adopted in other retroperitoneal surgical operations that can produce ejaculation disorders, such as wide lymphadenectomy for renal cell carcinoma or tumors of the upper urinary tract, exeresis of pre- aortic tumors, exeresis or disjunction of horseshoe kidney and aorto-iliac revascularization. Surgical therapy of benign prostatic hyperplasia (BPH) (open surgery or transurethral prostatic resection) is associated with retrograde ejaculation in nearly 100% of cases. The mechanism of the dysfunction is clear, if following the procedure the bladder neck remains opened. Loss of ejaculation is reported in variable percentage after the newer endoscopic techniques for the treatment of BPH. Transurethral needle ablation (TUNA) seems to have the lower risk of retrograde ejaculation. Retrograde ejaculation can also be related to a traumatic injury of the posterior urethra, because of the trauma itself or the therapy. Finally, the ejaculation disorder can be produced by several drugs that block, as a main or secondary effect, the alpha-adrenoreceptors or act at the central level. This side effect has to be kept in mind when these drugs are used in young or sexually active patients
Design and functional studies of xylene-based cyclic mimetics of SOCS1 protein
No full textPeptidomimetics of Suppressors of cytokine signaling 1 (SOCS1) protein demonstrated valid therapeutic potentials as anti-inflammatory agents. Indeed, SOCS1 has a small kinase inhibitory region (KIR) primarily involved in the inhibition of the JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway Herein, on the basis of previous investigations on a potent mimetic of KIR-SOCS1, named PS5, we designed and evaluated the SAR (Structure Activity Relationship) features of two xylene-based macrocycles analogues of PS5. These novel compounds bear thiol-xylene linkages with mono- and bi-cyclic scaffolds: they were in vitro functionally investigated toward JAK2 catalytic domain, as ligands with microscale thermophoresis (MST) and as inhibitors through LC-MS analyses. To evaluate structural properties Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies were employed along with serum stability assays. Results indicated that a monocycle scaffold is well-tolerated by PS5 sequence enhancing the affinity toward the kinase with a KD in the low micromolar range and providing consistent inhibitory effects of the catalytic activity, which were evaluated for the first time in the case of SOCS1 mimetics. Conformationally, the presence of xylene scaffold affects the flexibility of the compounds and their stabilities to proteases degradation. This study contributes to the understanding of the factors necessary for accurately mimicking the inhibitory mechanism of SOCS1 protein towards JAK2 and to the translation of proteomimetics into drugs
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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