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1
Marcenaro, Giuseppe. « Alphonse Bernoud et les photographes ambulants sur la côte ligure : 1839-1870 ». Le Monde alpin et rhodanien. Revue régionale d’ethnologie 23, no 2 (1995) : 161–74. http://dx.doi.org/10.3406/mar.1995.1566.
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Mariotti Lippi, Marta, Mariangela Guido, Bruna I. Menozzi, Cristina Bellini et Carlo Montanari. « The Massaciuccoli Holocene pollen sequence and the vegetation history of the coastal plains by the Mar Ligure (Tuscany and Liguria, Italy) ». Vegetation History and Archaeobotany 16, no 4 (11 janvier 2007) : 267–77. http://dx.doi.org/10.1007/s00334-006-0090-6.
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Hetch, Hans H., et John H. McClement. « Un caso de "Mal de montaña crónico" en los Estados Unidos ». Anales de la Facultad de Medicina 41, no 4 (18 octobre 2014) : 666. http://dx.doi.org/10.15381/anales.v41i4.8965.
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1.- Se decribe un caso de Mal de Montaña crónico en un residente de las Montañas Rocallosas de Colorado. Se han hecho estudios clínicos, electrocardiográficos y de fisiología cardio-pulmonar. Los síntomas, signos y anormalidades electrocardiográficas desaparecieron al descender el paciente al nivel del mar. Sin embargo, se ha podido poner en evidencia una enfermedad pulmonar ligera, intensamente persistente, después de residencia a nivel del mar por más de dos años. 2.- Puede suponerse que algunos casos del Mal de Montaña crónico son el resultado de perturbaciones en el cambio respiratorio de gases y de alteraciones de los índices de ventilación perfusión basados de una enfermedad pulmonar intrínseca, sumamente ligera para ocasionar signos o síntomas al nivel del mar.
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Gonzales R., Alberto, Doris Rafael M., Haydee Zuñiga C. et Elizabeth Carranza A. « Actividad específica de la Glucosa-6-fostato deshidrogenasa (EC 1.1.1.49) en tejido adiposo y hepático durante la exposición a la altura ». Ciencia e Investigación 2, no 2 (31 décembre 1999) : 88–96. http://dx.doi.org/10.15381/ci.v2i2.5220.
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Se determinó la actividad especifica de la enzima Glucosa-6-fosfato deshidrogenasa (E.C. 1.1.1.49) en tejidos adiposo y hepático de 67 ratas Holtzman, machos, nacidas y criadas a nivel del mar. De ellas, 48 fueron transportadas en automóvil (3 horas de viaje) hacia 4 540 m sobre el nivel del mar, y sacrificadas a 0,1,2,3,5,15 Y 30 días después de su arribo. Las restantes se separaron en dos grupos, un grupo que no viajó, y otro que viajó tres horas a nivel del mar, tras lo cual fueron sacrificadas.El tejido adiposo de los animales llevados a la altura, presentó una menor actividad específica de la enzima que el de los del nivel del mar. Se observó una disminución acentuada durante los primeros dos dias, luego se recuperó lentamente sin volver al valor inicial de arribo.En cuanto al tejido hepático, la actividad específica de la enzima de los animales llevados a la altura, se elevó ya durante el viaje y se mantuvo por encima de los valores del nivel del mar, sin experimentar cambios durante 15 días en la altura, mostrando un ligero aumento en el día 30 con respecto a su arribo.
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Muhammad Irfan Zia, Sajid Malik, Sana Anum, Fatima Tu Zahara et Zirwa Anum. « Comparison of outcomes of LigaSure system and conventional electrocautery in patients undergoing modified radical mastectomy for breast cancer. » Professional Medical Journal 30, no 01 (1 janvier 2023) : 107–12. http://dx.doi.org/10.29309/tpmj/2023.30.01.7236.
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Objective: To compare LigaSure system and conventional electrocautery in patients undergoing modified radical mastectomy for breast cancer in terms of mean wound drainage. Study Design: Randomized Controlled Trial. Setting: Department of Surgery, of Allama Iqbal Medical College, Jinnah Hospital Lahore. Period: April 2019 to Mar 2020. Material & Methods: Total of 162 patients were selected. Patients divided in two group A & B for Ligasure and electrocautery group respectively. Two drains placed, one in each flap and axilla after surgery. The drains were removed when the output was less than 30ml/ 24 hours. All patients were discharged after the drain removal. Results: The mean age in Ligasure group was 56.16 ± 7.87 years and in Electrocautery group was 55.00 ± 8.38 years. The mean wound drainage output in Ligasure group was 652.67 ± 93.05 ml and in Electrocautery group was 973.91 ± 87.84 ml. The mean drainage output was statistically lower in Ligasure group as compared to Electrocautery group, p-value < 0.001. Conclusion: Through the findings of current study it is concluded that LigaSure system leads less mean wound drainage than conventional electrocautery in patients undergoing modified radical mastectomy for breast cancer. So, in future therapeutic efficacy of LigaSure system can be opted to minimized the risk related wound drainage in patients undergoing modified radical mastectomy for breast cancer in terms of mean wound drainage.
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Toso, Fiorenzo. « Contatto linguistico e percezione. Per una valutazione delle voci d’origine sarda in tabarchino* ». Linguistica 40, no 2 (1 décembre 2000) : 291–326. http://dx.doi.org/10.4312/linguistica.40.2.291-326.
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Questo saggio intende approfondire il tema del contatto linguistico e dei meccanismi percettivi connessi, esaminando criticamente il problema dell 'interferenza sarda nella parlata ligure-tabarchina di Carloforte e Calasetta. Malgrado l'esistenza di studi specifici su questa varietà, una valutazione complessiva della componente lessicale sarda nelle sue motivazioni storico-linguistiche e sociolinguistiche non è mai stata avanzata; nondimeno, essa assume particolare interesse per quanto attiene non solo ai meccanismi di assunzione dei prestiti, ma anche alia percezione dei fenomeni di contatto da parte dei parlanti.
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Urteaga, Oscar. « Sobre la hematología y particularmente la excresión de la bilirrubina en la enfermedad de Monge (Soroche Crónico) ». Anales de la Facultad de Medicina 25, no 1 (18 octobre 2014) : 67. http://dx.doi.org/10.15381/anales.v25i1.9709.
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El autor ha estudiado cuatro casos de la enfermedad de Monge (Mal de Montaña Crónico), desde el punto de vista, sobre todo la excreción de bilirrubina hematológica. Se ha confirmado conclusiones respecto a Hurtado de algunos aspectos de la sangre a gran altura. Hay hipervolemia policitémico. La policitemia es macrocítica e hipocroma. La macrocitosis se debe principalmente a un aumento en el diámetro con una ligera disminución del índice esférico. Es por tanto, un eritrocito plano. La capacidad de la excreción de la bilirrubina, se retarda en los casos más severos, y en particular en aquellos casos complicados con neumoconiosis. En los casos en promedio, se cree que hay un nivel especial de bilirrubina en la sangre, a mayor nivel del mar. Después de 80 días de estar en el nivel del mar, se encontró una remisión casi completa de todos los síntomas hematológicas y clínicos, así como una mejora en la función.
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Zhang, Zubin, Jiefei Tong, Xiaowen Tang, Jiaxiang Juan, Biyin Cao, Rose Hurren, Guodong Chen et al. « The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice ». Blood 127, no 13 (31 mars 2016) : 1676–86. http://dx.doi.org/10.1182/blood-2015-07-658203.
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Morel, Thomas. « La Ligue des droits de l'Homme en mai 68 ». Matériaux pour l histoire de notre temps N° 127-128, no 1 (2018) : 90. http://dx.doi.org/10.3917/mate.127.0090.
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Merino-Serrais, P., P. Casado-Amezúa, Ó. Ocaña, J. Templado et A. Machordom. « Leve diferenciación genética entre los límites occidental y oriental de distribución de Astroides calycularis (Pallas, 1776) (Anthozoa, Scleractinia, Dendrophylliidae), inferida a partir de secuencias de COI e ITS ». Graellsia 68, no 1 (30 juin 2012) : 207. http://dx.doi.org/10.3989/graellsia.2012.v68.057.
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El estudio de la estructura de las poblaciones y su diferenciación a nivel genético es de gran utilidad para la elaboración de planes de manejo y conservación de especies amenazadas. En este estudio, utilizamos marcadores nucleares y mitocondriales (espaciadores internos de genes ribosomales -ITS y citocromo oxidasa, subunidad I -COI) y métodos de análisis filogenéticos y de clados anidados (NCA), para realizar la primera valoración de la estructura genética del coral naranja Astroides calycularis (Pallas, 1766), una especie amenazada del Mediterráneo, a partir de muestras de 12 localidades a lo largo de su área de distribución. En las localidades situadas en la región más occidental del Mediterráneo se encontró cierta homogeneidad genética, mientras que al comparar estas localidades con las de las cuencas argelina y del mar Tirreno se observó una ligera diferenciación.
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Ishii, Takenobu, Montserrat Ruiz-Torruella, Kenta Yamamoto, Tsuguno Yamaguchi, Alireza Heidari, Roodelyne Pierrelus, Elizabeth Leon et al. « Locally Secreted Semaphorin 4D Is Engaged in Both Pathogenic Bone Resorption and Retarded Bone Regeneration in a Ligature-Induced Mouse Model of Periodontitis ». International Journal of Molecular Sciences 23, no 10 (18 mai 2022) : 5630. http://dx.doi.org/10.3390/ijms23105630.
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It is well known that Semaphorin 4D (Sema4D) inhibits IGF-1-mediated osteogenesis by binding with PlexinB1 expressed on osteoblasts. However, its elevated level in the gingival crevice fluid of periodontitis patients and the broader scope of its activities in the context of potential upregulation of osteoclast-mediated periodontal bone-resorption suggest the need for further investigation of this multifaceted molecule. In short, the pathophysiological role of Sema4D in periodontitis requires further study. Accordingly, attachment of the ligature to the maxillary molar of mice for 7 days induced alveolar bone-resorption accompanied by locally elevated, soluble Sema4D (sSema4D), TNF-α and RANKL. Removal of the ligature induced spontaneous bone regeneration during the following 14 days, which was significantly promoted by anti-Sema4D-mAb administration. Anti-Sema4D-mAb was also suppressed in vitro osteoclastogenesis and pit formation by RANKL-stimulated BMMCs. While anti-Sema4D-mAb downmodulated the bone-resorption induced in mouse periodontitis, it neither affected local production of TNF-α and RANKL nor systemic skeletal bone remodeling. RANKL-induced osteoclastogenesis and resorptive activity were also suppressed by blocking of CD72, but not Plexin B2, suggesting that sSema4D released by osteoclasts promotes osteoclastogenesis via ligation to CD72 receptor. Overall, our data indicated that ssSema4D released by osteoclasts may play a dual function by decreasing bone formation, while upregulating bone-resorption.
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Li, Lei, Guang Gao, Jay Shankar, Bharat Joshi, Leonard J. Foster et Ivan R. Nabi. « p38 MAP kinase–dependent phosphorylation of the Gp78 E3 ubiquitin ligase controls ER–mitochondria association and mitochondria motility ». Molecular Biology of the Cell 26, no 21 (novembre 2015) : 3828–40. http://dx.doi.org/10.1091/mbc.e15-02-0120.
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Gp78 is an ERAD-associated E3 ubiquitin ligase that induces degradation of the mitofusin mitochondrial fusion proteins and mitochondrial fission. Gp78 is localized throughout the ER; however, the anti-Gp78 3F3A monoclonal antibody (mAb) recognizes Gp78 selectively in mitochondria-associated ER domains. Epitope mapping localized the epitope of 3F3A and a commercial anti-Gp78 mAb to an 8–amino acid motif (533–541) in mouse Gp78 isoform 2 that forms part of a highly conserved 41–amino acid region containing 14-3-3– and WW-binding domains and a p38 MAP kinase (p38 MAPK) consensus site on Ser-538 (S538). 3F3A binds selectively to nonphosphorylated S538 Gp78. Using 3F3A as a reporter, we induced Gp78 S538 phosphorylation by serum starvation and showed it to be mediated by p38 MAPK. Mass spectroscopy analysis of Gp78 phosphopeptides confirmed S538 as a major p38 MAPK phosphorylation site on Gp78. Gp78 S538 phosphorylation limited its ability to induce mitochondrial fission and degrade MFN1 and MFN2 but did not affect in vitro Gp78 ubiquitin E3 ligase activity. Phosphomimetic Gp78 S538D mutation prevented Gp78 promotion of ER–mitochondria interaction, and SB203580 inhibition of p38 MAPK increased ER–mitochondria association. p38 MAPK phosphorylation of Gp78 S538 therefore regulates Gp78-dependent ER–mitochondria association and mitochondria motility.
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Stöckl, J., O. Majdic, P. Kohl, W. F. Pickl, J. E. Menzel et W. Knapp. « Leukosialin (CD43)-major histocompatibility class I molecule interactions involved in spontaneous T cell conjugate formation. » Journal of Experimental Medicine 184, no 5 (1 novembre 1996) : 1769–79. http://dx.doi.org/10.1084/jem.184.5.1769.
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Resting T cells spontaneously adhere in a selective manner to potent accessory cells, such as dendritic cells (DC) and lymphoblastoid B blasts (LCL). Here we demonstrate that leukosialin (CD43) and major histocompatibility complex class I molecules (MHC-I) might play a critical role in this process. T cell conjugate formation with monocyte-derived DC (md-DC) and LCL could be strongly inhibited by either preincubating T cells with Fab fragments of CD43 monoclonal antibody (mAb) 6F5 or by preincubating md-DC or LCL with MHC-I mAb W6/32. Intact CD43 mAb 6F5, in contrast to monovalent Fab fragments, enhanced T cell adhesiveness by transactivating CD2 binding to CD58 molecules. Interestingly, induction of this proadhesive signal via CD43 with intact 6F5 mAb was found to revert mAb W6/32-mediated inhibition of T cell conjugate formation. These observations indicated that CD43 cross-linkage mimics and monovalent mAb 6F5 inhibits interaction of T cell CD43 with a stimulatory ligand on opposing cells, presumably MHC-I. For the demonstration of direct physical interaction between CD43 on T cells and MHC-I-coated beads it was necessary, however, to ligate CD2 on T cells with a stimulatory pair of CD2 mAbs (VIT13 plus TS2/18). This suggests that CD2 ligation crosswise upregulates CD43 binding avidity for MHC-I and that both adhesion molecule pairs (CD43/MHC-I and CD2/CD58) act in concert to induce and mediate T cell conjugate formation with certain cell types.
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Debecque-Michel, Laurence. « Douglas Gordon au MAM de Paris ». Ligeia N° 133-136, no 2 (2014) : 109. http://dx.doi.org/10.3917/lige.133.0109.
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Durafour, Jean-Michel. « Man Ray : voir le cinéma en peinture ». Ligeia N° 97-100, no 1 (2010) : 62. http://dx.doi.org/10.3917/lige.097.0062.
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Recalt, Mario Adrián, et Francisco Ramallo. « Formas de evaluación de los aprendizajes en nivel superior : Notas a partir de una investigación narrativa en la Facultad de Psicología de la Universidad Nacional de Mar del Plata ». Espiral, Revista de Docencia e Investigación 8, no 1 (15 mars 2019) : 11–30. http://dx.doi.org/10.15332/erdi.v8i1.2115.
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Objetivo. Interpretar los relatos de profesores sobre la enseñanza y específicamente sobre la evaluación de los aprendizajes en la carrera de Psicología de la Universidad Nacional de Mar del Plata.Metodología. Se optó por un enfoque cualitativo desde una perspectiva narrativa concentrada en la comprensión de los significados que los participantes de la investigación otorgan a las prácticas evaluativas. Para recolección de datos se privilegió la técnica de entrevistas semiestructuradas combinadas con materiales, instrumentos y prácticas de evaluación de los aprendizajes elaborados y empleados por los profesores seleccionados. El diseño y la puesta en práctica de los sistemas de evaluación propuestos por cada uno de los docentes entrevistados tienden a ligarse a las valoraciones particulares que cada uno de ellos verbaliza sobre la evaluación de los aprendizajes.Resultados. Variables como la complejidad, la articulación y el trazado de las formas de evaluación son distintas en función de que las mismas sean consideradas de mayor o menor importancia dentro de las actividades pedagógico docentes. Reconocemos además una recurrencia similar donde evaluación, enseñanza y aprendizaje suceden casi en simultáneo y los cambios en las prácticas refieren a modificaciones más amplias desde el currículo y la didáctica.
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Payne, Michael C., Hai-Ying Zhang, Yuichi Shirasawa, Yasuhiko Koga, Mitsuo Ikebe, Joseph N. Benoit et Steven A. Fisher. « Dynamic changes in expression of myosin phosphatase in a model of portal hypertension ». American Journal of Physiology-Heart and Circulatory Physiology 286, no 5 (mai 2004) : H1801—H1810. http://dx.doi.org/10.1152/ajpheart.00696.2003.
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Myosin phosphatase is a target for signaling pathways that modulate calcium sensitivity of force production in smooth muscle. Myosin phosphatase targeting subunit 1 (MYPT1) isoforms are generated by cassette-type alternative splicing of exons in the central and 3′ portion of the transcript. Exclusion of the 3′ alternative exon, coding for the leucine zipper (LZ)-positive MYPT1 isoform, is associated with the ability to desensitize to calcium (relax) in response to NO/cGMP-dependent signaling. We examined expression of MYPT1 isoforms and smooth muscle phenotype in normal rat vessels and in a prehepatic model of portal hypertension characterized by arteriolar dilation. The large capacitance vessels, aorta, pulmonary artery, and inferior vena cava expressed predominantly the 3′ exon-out/LZ-positive MYPT1 isoform. The first-order mesenteric resistance artery (MA1) and portal vein (PV) expressed severalfold higher levels of MYPT1 with predominance of the 3′ exon-included/LZ-negative isoform. There was minor variation in the presence of the MYPT1 central alternative exons. Myosin heavy and light chain splice variants in part cosegregated with MYPT1 isoforms. In response to portal hypertension induced by PV ligature, abundance of MYPT1 in PV and MA1 was significantly reduced and switched to the LZ-positive isoform. These changes were evident within 1 day of PV ligature and were maintained for up to 10 days before reverting to control values at day 14. Alteration of MYPT1 expression was part of a complex change in protein expression that can be generalized as a modulation from a phasic (fast) to a tonic (slow) contractile phenotype. Implications of vascular smooth muscle phenotypic diversity and reversible phenotypic modulation in portal hypertension with regards to regulation of blood flow are discussed.
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Carrino, Annastella. « Fra nazioni e piccole patrie. "Padroni" e mercanti liguri sulle rotte tirreniche del secondo settecento ». SOCIETÀ E STORIA, no 131 (mai 2011) : 36–67. http://dx.doi.org/10.3280/ss2011-001002.
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Nell'immagine storiografica diffusa, l'economia settecentesca si presenta come una macchina che produce sviluppo e, al tempo stesso, dominazione e emarginazione. Ai suoi vertici si collocherebbero potenze superiori sotto il profilo della capacitÀ produttiva, mercantile e politico-militare; all'altra estremitÀ, residuerebbero spazi secondari, praticabili da soggetti privi di ambizioni, relegati dentro circuiti locali in grado di affacciarsi a quelli piů ampi solo in un nesso di subordinazione, o collocandosi sul crinale fra lecito e illecito. Accogliendo suggestioni presenti in studi recenti, l'a. prova a sfumare e complicare questa immagine, sottolineando come una parte significativa dell'espansione commerciale mediterranea settecentesca veda come protagonisti soggetti, luoghi e pratiche spesso privi di capitali rilevanti, saperi codificati e protezioni statali robuste. Il nuovo protagonismo dei "Genovesi" al centro di questo contributo non si pone in continuitÀ con la gloriosa storia del commercio e della finanza genovesi fra tardo medioevo e prima etÀ moderna. Essi sono in realtÀ micro-mercanti provenienti non dalla Dominante, ma da alcuni borghi costieri liguri. Non restano tuttavia figure marginali: riescono invece a fuoriuscire dall'andirivieni del piccolo cabotaggio e a diventare protagonisti di una parte significativa del commercio in grande, inventando modi di fare mercato, strumenti inediti per acquisire informazione e fiducia. Alla base della loro vitalitÀ vi č un anche rapporto forte e mai interrotto con i villaggi natali: minuscoli centri costieri, debolissimi sotto il profilo demografico, istituzionale, commerciale e finanziario, ma al tempo stesso custodi di un capitale relazionale importante, di funzioni mercantili decisive per il loro successo imprenditoriale. Tratteggiando biografie individuali e di gruppo, il saggio suggerisce l'immagine di un Mediterraneo settecentesco affollato di attori, pratiche e luoghi non sempre canonici. Ignorandoli e concentrandosi esclusivamente sulle grandi imprese mercantili, sulle grandi "nazioni" protette da mercantilismi prepotenti, si rischierebbe di non comprendere il funzionamento di questo mercato in una fase decisiva della sua trasformazione.
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Carroll, Elizabeth C., Shai Berlin, Joshua Levitz, Michael A. Kienzler, Zhe Yuan, Dorte Madsen, Delmar S. Larsen et Ehud Y. Isacoff. « Two-photon brightness of azobenzene photoswitches designed for glutamate receptor optogenetics ». Proceedings of the National Academy of Sciences 112, no 7 (4 février 2015) : E776—E785. http://dx.doi.org/10.1073/pnas.1416942112.
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Mammalian neurotransmitter-gated receptors can be conjugated to photoswitchable tethered ligands (PTLs) to enable photoactivation, or photoantagonism, while preserving normal function at neuronal synapses. “MAG” PTLs for ionotropic and metabotropic glutamate receptors (GluRs) are based on an azobenzene photoswitch that is optimally switched into the liganding state by blue or near-UV light, wavelengths that penetrate poorly into the brain. To facilitate deep-tissue photoactivation with near-infrared light, we measured the efficacy of two-photon (2P) excitation for two MAG molecules using nonlinear spectroscopy. Based on quantitative characterization, we find a recently designed second generation PTL, l-MAG0460, to have a favorable 2P absorbance peak at 850 nm, enabling efficient 2P activation of the GluK2 kainate receptor, LiGluR. We also achieve 2P photoactivation of a metabotropic receptor, LimGluR3, with a new mGluR-specific PTL, d-MAG0460. 2P photoswitching is efficiently achieved using digital holography to shape illumination over single somata of cultured neurons. Simultaneous Ca2+-imaging reports on 2P photoswitching in multiple cells with high temporal resolution. The combination of electrophysiology or Ca2+ imaging with 2P activation by optical wavefront shaping should make second generation PTL-controlled receptors suitable for studies of intact neural circuits.
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Gisiger, Joel. « Raspagens das Palhetas por Oboístas Brasileiros - Um Estudo dos ajustes nas palhetas de oboé sob ação de agentes climáticos externos ». Revista da Tulha 3, no 1 (30 octobre 2017) : 175–208. http://dx.doi.org/10.11606/issn.2447-7117.rt.2017.128895.
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A presente pesquisa visa observar e identificar os ajustes propostos por oboístas brasileiros em palhetas de oboé preparadas para a performance e que sofrem alterações devido a ação da umidade do ar, temperatura do ambiente e altitude relativa ao nível do mar. Também, investigou-se possíveis tendências nas preferências de sonoridade e flexibilidade dos oboístas entrevistados, procurando compreender se existe algum fator que ligue tais tendências com os tipos de ajustes propostos. Com a finalidade de direcionar a pesquisa a um foco de interesse comum aos entrevistados, resumiu-se as diferentes escolas de raspado em duas, Escola Alemã e Escola Americana, tendo em vista que estas escolas exercem grande influência nos mais diversos estilos de raspagem. Um fenômeno notório brasileiro também foi investigado, que é a convivência pacífica das diferentes escolas dentro das orquestras. Como parte dos procedimentos metodológicos, foi realizado um breve levantamento bibliográfico de autores discorrendo sobre raspagens de palhetas de oboé, com a finalidade de compreender o que se considera uma palheta pronta para performance e o que a caracteriza. Utilizou-se também a ferramenta de pesquisas on-line “survey mokey” para uma investigação com oboístas brasileiros, mediante a observação das tendências de sonoridade, flexibilidade e ajustes da palheta. Após a análise dos dados, houve uma listagem graduada de ajustes classificada pelos oboístas brasileiros dentro de suas escolas de raspagem. Concluiu-se haver características muito semelhantes nas preferências de sonoridade, flexibilidade e ajustes, apontando uma provável causa que aproxima as diferentes escolas de oboé em território nacional.
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Desbuissons, Frédérique. « Voir le mal en face : "L’Origine du monde" de Gustave Courbet ». Ligeia N°19-20, no 1 (1996) : 14. http://dx.doi.org/10.3917/lige.019.0014.
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Resche, Stéphane. « Un système d’audiodescription d’opéra pour public de mal- et non-voyants ». Ligeia N° 141-144, no 2 (2015) : 212. http://dx.doi.org/10.3917/lige.141.0212.
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Jacobs, Jana L., Jianzhong Zhu, Saumendra N. Sarkar et Carolyn B. Coyne. « Regulation of Mitochondrial Antiviral Signaling (MAVS) Expression and Signaling by the Mitochondria-associated Endoplasmic Reticulum Membrane (MAM) Protein Gp78 ». Journal of Biological Chemistry 289, no 3 (27 novembre 2013) : 1604–16. http://dx.doi.org/10.1074/jbc.m113.520254.
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In a previous study, we identified the E3 ubiquitin ligase Gp78 by RNAi high-throughput screening as a gene whose depletion restricted enterovirus infection. In the current study, we show that Gp78, which localizes to the ER-mitochondria interface, is a regulator of RIG-I-like receptor (RLR) antiviral signaling. We show that depletion of Gp78 results in a robust decrease of vesicular stomatitis virus (VSV) infection and a corresponding enhancement of type I interferon (IFN) signaling. Mechanistically, we show that Gp78 modulates type I IFN induction by altering both the expression and signaling of the mitochondria-localized RLR adaptor mitochondrial antiviral signaling (MAVS). Expression of mutants of Gp78 that abolish its E3 ubiquitin ligase and its participation in ER-associated degradation (ERAD) lost their ability to degrade MAVS, but surprisingly maintained their ability to repress RLR signaling. In contrast, Gp78 lacking its entire C terminus lost both its ability to degrade MAVS and repress RLR signaling. We show that Gp78 interacts with both the N- and C-terminal domains of MAVS via its C-terminal RING domain, and that this interaction is required to abrogate Gp78-mediated attenuation of MAVS signaling. Our data thus implicate two parallel pathways by which Gp78 regulates MAVS signaling; one pathway requires its E3 ubiquitin ligase and ERAD activity to directly degrade MAVS, whereas the other pathway occurs independently of these activities, but requires the Gp78 RING domain and occurs via a direct association between this region and MAVS.
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Oyola H., Luz, Haydée Zúñiga C., Delia Whu W., Edgar Florentini R., Elizabeth Carranza A. et Elizabeth Gonzáles L. « Actividad de ATP asa en corazón de cobayos de altura ». Ciencia e Investigación 7, no 2 (31 décembre 2004) : 9–12. http://dx.doi.org/10.15381/ci.v7i2.3345.
Texte intégralRésumé :
Se compara la actividad de ATPasa, la relación ADP:O (P:O) y el Control Respiratorio (RCR) en mitocondria de corazón entre cobayos de altura (Morococha, 4540 m.s.n.m.) (Alt) y cobayos del nivel del mar (Lima, 150 m,s.n.m.) (NM). El estudio se realizó en 60 cobayos machos, 30 en cada nivel de altitud, con un peso promedio de 400 a 450 gramos. Las mitocondrias de corazón fueron obtenidas por centrifugación diferencial a 4° C. La relación P:O y el RCR fueron medidos polarográficamente por el método de Tyler, y la hidrólisis del ATP se realizó por el método de Holton et al. Los valores medios obtenidos en mitocondrias de corazón al NM y en Alt, expresados en micromoles de oxígeno consumido / mg de proteína/hora, fueron: con Glutamato + Malato como sustratos, respectivamente: P:O 2.90, RCR 6.02 y P:O 2.93, RCR 6.0; y con Piruvato + Malato como sustratos, respectivamente: P:O 2.60, RCR 5.0 y P:O 2.70, RCR 4.80. La actividad ATPasa fue al NM y en Alt, respectivamente: 57.50 y 64.50 mmoles de P /mg proteína/hora. Los resultados sugieren que los cobayos de altura han desarrollado la habilidad de realizar la fosforilación oxidativa en forma más eficiente, y el ligero incremento observado en la actividad de ATPasa indica que tal vez se realizan pequeños ajustes para mantener el equilibrio dentro del medio ambiente mitocondrial.
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Taylor, Eric B., et Jared Rutter. « Mitochondrial quality control by the ubiquitin–proteasome system ». Biochemical Society Transactions 39, no 5 (21 septembre 2011) : 1509–13. http://dx.doi.org/10.1042/bst0391509.
Texte intégralRésumé :
Mitochondria perform multiple functions critical to the maintenance of cellular homoeostasis and their dysfunction leads to disease. Several lines of evidence suggest the presence of a MAD (mitochondria-associated degradation) pathway that regulates mitochondrial protein quality control. Internal mitochondrial proteins may be retrotranslocated to the OMM (outer mitochondrial membrane), multiple E3 ubiquitin ligases reside at the OMM and inhibition of the proteasome causes accumulation of ubiquitinated proteins at the OMM. Reminiscent of ERAD [ER (endoplasmic reticulum)-associated degradation], Cdc48 (cell division cycle 42)/p97 is recruited to stressed mitochondria, extracts ubiquitinated proteins from the OMM and presents ubiquitinated proteins to the proteasome for degradation. Recent research has provided mechanistic insights into the interaction of the UPS (ubiquitin–proteasome system) with the OMM. In yeast, Vms1 [VCP (valosin-containing protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1] protein recruits Cdc48/p97 to the OMM. In mammalian systems, the E3 ubiquitin ligase parkin regulates the recruitment of Cdc48/p97 to mitochondria, subsequent mitochondrial protein degradation and mitochondrial autophagy. Disruption of the Vms1 or parkin systems results in the hyper-accumulation of ubiquitinated proteins at mitochondria and subsequent mitochondrial dysfunction. The emerging MAD pathway is important for the maintenance of cellular and therefore organismal viability.
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Brenes-Rodriguez, Carlos Luis, Rosario Benavides-Morera, Juan Pablo Salazar Ceciliano et Luis Fernando Alvarado Gamboa. « Condiciones hidrográficas y climatológicas en el Caribe Sur de Costa Rica durante El Niño 2014-2016 ». Revista Ciencias Marinas y Costeras 9, no 2 (14 décembre 2017) : 101. http://dx.doi.org/10.15359/revmar.9-2.5.
Texte intégralRésumé :
En mayo, junio, septiembre y octubre del año 2014 y junio, agosto, septiembre y noviembre del año 2015, se realizaron campañas hidrográficas en el Caribe Sur de Costa Rica, con el objetivo de determinar la influencia del fenómeno de El Niño sobre esta región. Con un perfilador se determinó en 23 estaciones la temperatura, la salinidad y la clorofila a. La temperatura superficial se ubicó entre 26.6 y 30°C, las salinidades superficiales entre 29-33.5 UPS y la clorofila a superficial varió entre 1.1 mg m-3 y 0.1 mg m-3. Existe una capa de mezcla delgada (T ~ 29°C), la cual no sobrepasó los 20 m de profundidad en el 2014 y se extendió hasta los 40 m en septiembre y noviembre del año 2015. Los índices termohalinos del Agua Superficial del Caribe presentaron una disminución considerable en su salinidad por dilución debido a El Niño y un ligero aumento en su temperatura. El análisis entre una serie temporal de la temperatura superficial del mar en un punto situado 15 km frente a Cahuita y el Índice Oceánico de El Niño (ONI) determinaron que la zona estudiada presenta una señal de calentamiento con un desfase de 7 meses posterior a la presencia de El Niño en el Océano Pacífico Tropical. Durante El Niño 2014-2016 el área de estudio presentó en algunos meses un exceso en las precipitaciones que superó el valor de la norma climatológica en más de un 50%.
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Richet, Denis, et Marie-Claude Lapeyre. « Les barricades à Paris, le 12 mai 1588 ». Annales. Histoire, Sciences Sociales 45, no 2 (avril 1990) : 383–95. http://dx.doi.org/10.3406/ahess.1990.278841.
Texte intégralRésumé :
Ce texte est le dernier que nous ait donné Denis Richet, quelques mois avant sa mort, survenue brusquement en septembre dernier. Il témoigne du projet qui l'animait : comprendre les ruptures du tissu politique et social de la France moderne. Comme tel il témoigne d'une attitude, que Denis Richet a su enseigner : « Aimer l'histoire pour elle-même… ». Sa chaleur nous manque.Isoler le fait-barricades de l'histoire générale de Paris est une nécessité et une gageure. Les barricades ne sont pas comme un élément chimiquement pur ; elles supposent une convergence de données historiques qu'il serait fastidieux de rappeler. Je note seulement que la Commune de 1871 a joué un grand rôle dans l'intérêt porté au 12 mai 1588. Dans la Revue des Deux Mondes, dès septembre 1871, A. Maury publiait un article sur «La commune de Paris de 1588». Et Paul Robiquet, en écrivant de 1884 à 1904 ses trois volumes de l'Histoire municipale de Paris, qui demeure la meilleure synthèse accessible, ne manque pas de faire allusion, avec une certaine prudence, au printemps tragique de 1871. Il est, à mon sens, intéressant de constater que l'historiographie actuelle — disons : trentenaire — de la journée du 12 mai 1588 s'est enrichie grâce à des recherches menées par des historiens français et non français. En Union Soviétique, à Lvow plus précisément, en cette partie de la Biélorussie naguère polonaise, où le professeur Lozinsky a mené un travail d'autant plus exemplaire qu'il n'a jamais pu bénéficier du contact direct avec les archives parisiennes; en Israël, où Elie Barnavi, après un long séjour en France, a pu éclairer l'histoire de la Ligue ; aux États-Unis, grâce aux recherches des professeurs Salmon et Ascoli; en France même, les recherches de Robert Descimon ont largement déblayé le terrain.
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Mongini, P. K., M. A. Vilensky, P. F. Highet et J. K. Inman. « The affinity threshold for human B cell activation via the antigen receptor complex is reduced upon co-ligation of the antigen receptor with CD21 (CR2). » Journal of Immunology 159, no 8 (15 octobre 1997) : 3782–91. http://dx.doi.org/10.4049/jimmunol.159.8.3782.
Texte intégralRésumé :
Abstract The present studies have examined whether the potential of an Ag to co-ligate the complement (C3d)-binding CD21 receptor complex with the membrane IgM (mIgM) receptor complex can reduce the mIgM:Ag affinity threshold for triggering human B cell S phase entry. A series of Ab:dextran conjugates consisting of affinity-diverse anti-IgM mAb, with and without anti-CD21 mAb, were synthesized as polyclonally reactive, moderately multivalent ligands that mimic C3d-bearing and non-C3d-bearing Ag. Co-ligation of mIgM and CD21 significantly diminished both the ligand concentration threshold and the IgM:ligand affinity threshold for eliciting S phase entry in the presence of IL-4. Furthermore, such co-engagement ablated the triggering bonus associated with high mlgM:ligand affinity, suggesting that B cells with a high affinity for Ag are not preferentially activated over B cells of intermediate affinity upon encountering a multivalent Ag with bound C3d. The enhancing effects of mIgM:CD21 co-ligation were restricted to low concentrations of ligand; at high concentrations, a decrease in B cell DNA synthesis was often observed. The findings suggest that the ability a moderately multivalent Ag substrate to engage B cells through both mIgM and CD21 is critical for B cell activation at limiting Ag concentrations, and furthermore, that mIgM:CD21 co-engagement may be particularly important in eliciting an immune response to such Ags in unprimed individuals in whom the majority of specific B cells are of low affinity.
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Shahcheraghi, Seyed Hossein, Fateme Salemi, Niloufar Peirovi, Jamshid Ayatollahi, Waqas Alam, Haroon Khan et Luciano Saso. « Nrf2 Regulation by Curcumin : Molecular Aspects for Therapeutic Prospects ». Molecules 27, no 1 (28 décembre 2021) : 167. http://dx.doi.org/10.3390/molecules27010167.
Texte intégralRésumé :
Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc–curcumin Zn (II)–curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc–curcumin Zn (II)–curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.
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Zakharikhina, Lalita V., et Lyudmila S. Malyukova. « Génesis y Geoquímica de Suelos de Paisajes Urbanísticos en la Costa Rusa del Mar Negro ». Revista Ingeniería UC 28, no 1 (3 mai 2021) : 69–82. http://dx.doi.org/10.54139/revinguc.v28i1.1.
Texte intégralRésumé :
Comparados con los suelos naturales zonales (tierras parda y amarilla), los suelos de la ciudad de Sochi situada en la costa Rusa del Mar Negro tienen propiedades ácidas alcalinas transformadas; se ve un contenido adicional de humus en los suelos del tipo abrozemo. El pH del agua cambia de 5,8 a 7,5 (valores medios para los horizontes genéticos de suelos); la saturación con álcalis en los horizontes superior y metamórfico estructural BM (árgico) aumentó por casi treinta (de 72,9 a 97,7 %) y cincuenta (de 64,8 a 97,3 %) por ciento. Los abrazemos tienen un contenido del humus dos veces más bajo en comparación con los suelos de fondo. La evaluación del contenido en suelos de diferentes paisajes de Sochi de una amplia gama de elementos químicos (61) que son excesivos y deficientes en relación con el fondo ha demostrado lo siguiente: La contaminación del suelo se debe principalmente a su enriquecimiento con elementos de los horizontes medios del suelo y rocas madre subyacentes que pueden ingresar a los horizontes superiores durante los trabajos de excavación y el relleno de sitios de construcción y carreteras con suelo local. La excepción es el Ca que entra el suelo por medio del tecnogénesis urbano. En el transcurso del monitoreo de suelos urbanos hay que controlar el contenido de Ca, Cu, Ni, Mg, Mn, Cd, K y también el contenido de Cs, Ga, Be, Rb, V, Fe, Li, Al y de nueve elementos de tierras raras (ETR) (Dy, Tb, Sm, Ho, Eu, Gd, Sc, Y, Er) en paisajes urbanos subordinados. El índice total de contaminación de los suelos en la ciudad no es alto y tiene un valor admisible (Zc>16) en las pendientes, encaja en una categoría de peligro ligero (Zc=16−32) en la superficie plana adyacente a la pendiente y en una categoría de peligro alto (Zc<32) en la zona litoral del territorio de los sanatorios.
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Zhu, Chengbo, Jingrui Li, Chaonan Tian, Mengmeng Qin, Zhenni Wang, Bingjun Shi, Guanggang Qu, Chunyan Wu et Yuchen Nan. « Proteomic Analysis of ISGylation in Immortalized Porcine Alveolar Macrophage Cell Lines Induced by Type I Interferon ». Vaccines 9, no 2 (17 février 2021) : 164. http://dx.doi.org/10.3390/vaccines9020164.
Texte intégralRésumé :
Interferon-stimulated gene product 15 (ISG15), a ubiquitin-like molecule, can be conjugated to protein substrates through a reversible process known as ISGylation. ISG15 and ISGylation are both strongly upregulated by type I interferons and play putative key roles in host innate immunity against viral infection. However, the function of ISGylation and identities of ISGylation substrates are largely unknown. Here, a novel monoclonal antibody (Mab) that specifically recognizes porcine ISG15 (pISG15) was employed to capture ISG15-conjugated proteins from IFNs-stimulated porcine cell lysates. Next, Mab-captured conjugates were analyzed using proteomics-based tools to identify potential ISGylation protein targets in order to elucidate the roles of ISG15 and ISGylation in porcine cells. Subsequently, 190 putative ISGylation sites were detected within 98 identified ISGylation candidates; several candidates contained more than one ISGylation-modifiable lysine residue, including pISG15 itself. Motif enrichment analysis of confirmed ISGylation sites demonstrated a moderate bias towards certain sites with specific upstream amino acid residues. Meanwhile, results of Gene Ontology (GO)-based annotation and functional enrichment and protein-protein interaction (PPI) network analyses of porcine ISG15-conjugated substrate proteins indicated that these substrates were mainly associated with the host metabolism, especially nucleotide metabolic pathways that ultimately may participate in cellular antiviral defenses. Notably, several ISGs (MX1, IFIT1, OAS1, ISG15 and putative ISG15 E3 ligase Herc6) were also identified as putative ISGylation substrates within a regulatory loop involving ISGylation of ISGs themselves. Taken together, proteomics analysis of porcine ISGylation substrates revealed putative functional roles of ISG15 and novel host ISGylation targets that may ultimately be involved in cellular antiviral responses.
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Melchor-Marroquín, José Isidro, et Jorge Luis Chagoya-Fuentes. « Diagnóstico de la Erosión Hídrica en la cuenca del río Tuxpan, Veracruz, México ». Aqua-LAC 8, no 2 (30 septembre 2016) : 25–35. http://dx.doi.org/10.29104/phi-aqualac/2016-v8-2-03.
Texte intégralRésumé :
En la cuenca del río Tuxpan, las intensas lluvias que ocurren dentro de su área, generan gran cantidad de sedimentos que son transportados y depositados en la parte baja de su cauce que reducen su profundidad, lo cual provoca que sea dragado frecuentemente en los últimos 11 kilómetros antes de desembocar al mar, ya que es utilizado como canal de navegación para barcos de gran calado que arriban al puerto de Tuxpan, el cual es uno de los tres más importantes de Veracruz, México. Por lo anterior y como primer paso para entender el problema de erosión hídrica en la cuenca del río Tuxpan, se realizó el presente estudio cuyos objetivos fueron identificar las áreas con riesgo de erosión hídrica y estimar la pérdida de suelo, mediante la aplicación de la Ecuación Universal de Pérdida de Suelo (A=R*k*LS*C), con la técnica de algebra de mapas en ARCGIS 10.1. Los resultados indican que el riesgo promedio de erosión hídrica varía de 19.4 a 794.9 Mg ha-1 año-1, valores superiores a la clasificación de los grados de severidad establecidos por la FAO (1980). La erosión actual promedio de la cuenca es ligera en el 2.52 %, moderada en el 71.38 %, alta en el 9.42 % y muy alta en el 16.88 % de su área. Dos subcuencas abarcaron la mayor superficie y riesgo de erosión con 70.4 % y 89.2 %, respectivamente, cuyo grado de severidad fluctuó de 21.5 a 1,971.5 Mg ha-1 año-1. Las áreas más afectadas son las partes alta y media de la cuenca con mayor pendiente; las menos afectadas son las áreas con vegetación y las partes bajas, planas y zonas pantanosas
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Kalinichenko, Svetlana V., Keiji Itoh, Elena V. Korobko, Sergei Y. Sokol, Vladimir L. Buchman et Igor V. Korobko. « Identification of Nedd4 E3 Ubiquitin Ligase as a Binding Partner and Regulator of MAK-V Protein Kinase ». PLoS ONE 7, no 6 (20 juin 2012) : e39505. http://dx.doi.org/10.1371/journal.pone.0039505.
Texte intégral
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Vega Sequeda, Johanna Carolina, Sven Zea et Gladys Bernal. « EFECTOS DE EVENTOS OCEÁNICOS EXTREMOS EN FORMACIONES CORALINAS DE ISLAS DEL ROSARIO, CARIBE COLOMBIANO ». CICIMAR Oceánides 32, no 1 (30 juin 2017) : 25. http://dx.doi.org/10.37543/oceanides.v32i1.194.
Texte intégralRésumé :
El incremento en la frecuencia e intensidad de eventos oceánicos extremos limita la capacidad de recuperación de los ecosistemas, amenazando su subsistencia. Con el fin de entender la relación entre la estructura y salud arrecifal y los eventos extremos ambientales, se analizaron series de datos ambientales de las islas del Rosario (e.g., temperatura del mar, caudal y/o salinidad, turbidez), en comparación con cobertura coralina y signos de deterioro (e.g., blanqueamiento, enfermedades). En las series de tiempo de las variables ambientales se calcularon los eventos oceánicos que excedieron un umbral estadístico, estableciendo su intensidad, duración y frecuencia. Para los atributos de la comunidad, se evaluaron dos estaciones del Sistema Nacional de Monitoreo de Arrecifes Coralinos en Colombia (SIMAC), en dos ventanas temporales (largo plazo, 1998–2013 y corto plazo, 2013 - 2014). Los eventos extremos de temperatura superficial del mar, el caudal de descarga continental y la turbidez asociada fueron las principales variables relacionadas con la reducción de la cobertura coralina. El blanqueamiento masivo de 2005 y otros eventos posteriores dieron como resultado una reducción de la cobertura coralina entre 2004 y 2010. En el corto plazo no se registraron fuertes eventos extremos ni cambios en las formaciones coralinas, si bien el estrés térmico y las reducciones de salinidad en la época de lluvias estuvieron asociados con un ligero blanqueamiento en noviembre de 2014. Aunque los signos de deterioro sean bajos, es importante considerarlos, ya que la sinergia entre perturbaciones continuas puede conllevar a una pérdida de cobertura del coral. Effect of extreme oceanic events in the coral formations of Islas del Rosario, Colombian CaribbeanThe increase in frequency and intensity of extreme oceanic events limits the capacity of recovery of ecosystems, threatening their subsistence. Thus, in order to understand the relationship between coral health and extreme environmental events, data on sea temperature, runoff and / or salinity, turbidity were analyzed in the Islas del Rosario in comparison with coral cover, and coral signs of deterioration (e.g., bleaching, coral diseases). In the time series of environmental variables, oceanic events that exceeded a statistical threshold were calculated, establishing their intensity, duration and frequency. The attributes of the community were studied through observations in two stations of the National Coral Reef Monitoring System in Colombia (SIMAC), assessed in two time windows (long term, 1998-2013 and short term, 2013-2014). The extreme events of sea surface temperature, river discharge and associated turbidity, were the main variables related to the reduction of coral cover. The massive coral bleaching of 2005 and other subsequent events resulted in a reduction in coral coverage between 2004 and 2010. During the short-term observations there were no strong extreme events or changes in coral formations, although thermal stress and reductions in salinity in the rainy season were associated with a slight bleaching in November 2014. Although the signs of deterioration are low, it is important to consider them, since the synergy between continuous disturbances can lead to a loss of coral cover.
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Tasnuva Aziz Munalisa, Md. Shamsul Islam, Md. Abdul Hye Minar, Tahmina Islam, Kanta Deb et Iffath Farooqui. « Autopsy Analysis of Suicidal Hanging Cases in Sylhet ». Journal of Sylhet Women’s Medical College 11, Number 1 (1 janvier 2021) : 39–43. http://dx.doi.org/10.47648/jswmc2021v11-05.
Texte intégralRésumé :
Background:Suicide is one of the leading cause of unnatural death in the world. The frequency of suicidal hanging is dramatically increasing over the period of time in Bangladesh. Methods:Anautopsy reports based retrospective study carried out in the Department of Forensic Medicine of Sylhet MAG Osmani Medical College to analysis of suicidal hanging cases during the study period January 2017 to December 2018. After reviewing all postmortem reports, 230 cases of death were found due to suicidal hanging casesduring the study period. Results:The highest number of the victims 76(33.04%) were from the age group 10-19 years, followed by 61(26.52%) from 20-29 years and 126(54.78%) were female. Most of the dead bodies 38(16.52%) were brought from Gowainghat police station and majority victims 32(13.91%) locality were also in Gowainghat. The commonest autopsy findings were skin and subcutaneous tissue underneath the ligature mark found pale, white, hard, glistening 225(97.83%) and cyanosis 208(90.43%). The most common cause of deathin post mortem findings was asphyxia 213(92.61%). Conclusion: A well intended and inclusive programme is needed to reduce the frequency of suicidal hanging, which will ascertain the causative factor and helps incontrol and prevention.
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Kho, Liew Ching, Mohd Shareduwan Mohd Kasihmuddin, Mohd Asyraf Mansor et Saratha Sathasivam. « Logic mining in football matches ». Indonesian Journal of Electrical Engineering and Computer Science 17, no 2 (1 février 2020) : 1074. http://dx.doi.org/10.11591/ijeecs.v17.i2.pp1074-1083.
Texte intégralRésumé :
Sports results forecast has became increasingly popular among the fans nowadays. It made predicting the outcome of a sport’s match, a new and interesting challenge. This paper presented a logic mining technique to model the results (Win Draw / Lose) of the football matches played in English Premier League, Spanish La Liga and France Ligue 1. In this research, a method namely <em>k</em> satisfiability based reverse analysis method (<em>k</em>SATRA) hybridized with Ant Colony Optimization (ACO) was brought forward to obtain the logical relationship among the clubs in these leagues. The logical rule obtained from the football matches was used to categorize the results of future matches. ACO is a population-based and nature-inspired algorithm to decipher several combinatorial optimization problems. <em>k</em>SATRA made use of the advantages of Hopfield Neural Network and k Satisfiability representation. The data set used in this study included the data of 6 clubs from each league, which composed of all league matches from year 2014 to 2018. The effectiveness of <em>k</em>SATRA with ACO in obtaining logical rule in football matches was tested based on root mean square error (RMSE), mean absolute error (MAE), mean absolute percentage error (MAPE) and CPU time. Results acquired from the computer simulation showed the robustness of <em>k</em>SATRA in exhibiting the performance of the clubs.
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Zapata, Daniela, Joyce Wixsan, Katherine Hinostroza, Santiago Justo et Hugo Gonzales-Figueroa. « EFECTOS DEL EXTRACTO DE β -CARIOFILENO DE PIPER NIGRUM EN LA HIPERACTIVACIÓN ESPERMÁTICA Y EN LA CAPACIDAD FECUNDANTE DE TETRAPYGUS NIGER (MOLINA, 1782) ‘‘ERIZO NEGRO DE MAR’’ ». Biotempo 16, no 2 (18 décembre 2019) : 185–91. http://dx.doi.org/10.31381/biotempo.v16i2.2529.
Texte intégralRésumé :
En el presente trabajo se analizó la hiperactivación espermática y la capacidad fecundante del espermatozoide de Tetrapygus niger (Molina, 1782) “erizo negro de mar” en presencia de β-cariofileno. Se utilizó el sesquiterpeno β-cariofileno obtenido a partir de extracto de Piper nigrum L. “pimienta negra” y de β-cariofileno sintético donado por el Instituto de Biociencias de la Universidad de Sao Paulo (Sao Paulo, Brasil). Espermatozoides de Tetrapygus niger pretratados con los extractos de β-cariofileno sintético (β-cariofileno A) y β-cariofileno de pimienta negra (β-cariofileno B) fueron utilizados para la hiperactividad espermática (velocidad media y porcentajes de movimiento progresivo y continuo) y la capacidad fecundante (porcentaje de óvulos fecundados). Los valores promedios del área de la cabeza del espermatozoide en el control y en los tratamientos con β-cariofileno A y β-cariofileno B fueron de: 33,8; 32,33 y 33,59 um2, respectivamente, indicando la homogeneidad en la muestra y que esta no fue influenciada por el sesquiterpeno. En presencia de β-cariofileno A y B se observó la disminución de la velocidad promedio en aproximadamente 30 y 20 um/s, respectivamente, con respecto al control; existiendo diferencias significativas entre el control y los tratamientos con β-cariofileno A y B, pero no entre los dos tratamientos con β-cariofileno. El movimiento progresivo de los espermatozoides también fue afectado, mientras la totalidad de los espermatozoides del grupo control presentaron progresividad rápida, en el tratamiento con β-cariofileno B solo el 40 % presentaron esta característica y en el tratamiento con β-cariofileno A el 100 % fueron progresivos lento. Por otro lado, el β-cariofileno B produjo una ligera disminución de fecundación (96,76 % de óvulos fecundados) y en presencia de β-cariofileno A, esta se redujo a 79,50 % con respecto al grupo control. Un posible mecanismo para explicar los efectos observados en este estudio sería la capacidad del β-cariofileno para activar proteínas G inhibitorias, como ha sido reportado en otros estudios.
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Gadhoum, Zeineb, Marie-Pierre Leibovitch, Junyuan Qi, Dominique Dumenil, Laetitia Durand, Serge Leibovitch et Florence Smadja-Joffe. « CD44 : a new means to inhibit acute myeloid leukemia cell proliferation via p27Kip1 ». Blood 103, no 3 (1 février 2004) : 1059–68. http://dx.doi.org/10.1182/blood-2003-04-1218.
Texte intégralRésumé :
AbstractAcute myeloid leukemia (AML) is sustained by the extensive proliferation of leukemic stem and progenitor cells, which give rise to the population of leukemic blasts with defective differentiation and low proliferative capacity. We have recently shown that ligation of CD44, a cell surface molecule present on AML cells, with specific monoclonal antibodies (mAbs) inhibits their proliferation. However, its mechanism has not been investigated yet. Here, using the NB4 cell line as a model of proliferating human AML cells, and the A3D8 mAb to ligate CD44, we show for the first time that CD44 ligation stabilizes the cyclin-dependent kinase inhibitor p27Kip1 (p27) protein, resulting in increased association with cyclin E/Cdk2 complexes and inhibition of their kinase activity. Moreover, using a p27 antisense vector, we provide direct evidence that p27 is the main mediator of cell growth arrest by CD44. CD44 ligation also leads to p27 accumulation in THP-1, KG1a, and HL60 cell lines and in primary leukemic cells, suggesting that this process is general in AML. Taken together, our present results suggest that CD44 is a new and efficient means to increase the expression of p27 in AML cells. Considering that elevated expression of p27 is a factor of good prognosis in AML, these results provide a new basis for developing CD44-targeted therapy in AML. (Blood. 2004;103:1059-1068)
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Follit, Courtney A., Patricia A. R. Brunker et Willy A. Flegel. « SNP Genotyping and LD Testing in ERMAP : Revealing Scianna Blood Group Diversity in NIH Blood Donors ». Blood 118, no 21 (18 novembre 2011) : 2322. http://dx.doi.org/10.1182/blood.v118.21.2322.2322.
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Abstract Abstract 2322 Background: The Scianna blood group system has been implicated in cases of hemolytic disease of the fetus and newborn and the detection of antibodies to rare antigens in this system have impacted on transfusion management in some patients. Recently, it has been discovered that the Scianna blood group antigens are expressed by the erythrocyte membrane-associated protein (ERMAP), a 475 amino acid red cell adhesion protein consisting of 12 exons with the transcription region spanning exons 3–12. Rare variants in exons 4 and 12 have been reported in patients who have made antibodies to Scianna antigens or have a serological null phenotype for the Scianna system. ERMAP is a member of the butyrophilin-like family, featuring an extracellular immunoglobulin variable and intracellular B30.2 domains. Although one ERMAP variant is detected in one commercial molecular assay (Sc1/Sc2), most reported variants in this gene are rare, and therefore remain largely unrecognized during transfusion planning. ERMAP polymorphisms remain unreported on a large scale, contributing to the uncertainty concerning their clinical significance. To fill this void, we characterized seventeen single nucleotide polymorphisms (SNPs) in exons 3, 4, and 12 of ERMAP in 905 repeat blood donors. Methods: The DNA of consenting, repeat NIH blood donors were genotyped for seventeen variants in the ERMAP gene. DNA was isolated from whole blood using the Qiagen's MagAttract EZ1 kit. Following polymerase chain reaction amplification, the samples were genotyped by ligation detection reaction (LDR). LDR utilizes a thermostable ligase to generate single stranded DNA fragments of engineered length with allele-specific fluorescent labels, allowing for rapid, multiplexed genotyping. Ligated products were resolved by capillary electrophoresis (3730 DNA analyzer and GeneMapper software (Life Technologies)). Results: Eleven of the seventeen variants (G35S, R81Q, nt307Δ2, Q296Q, R332X, R392H, L399L, L409L, S442P, L452P, and L452L) were monomorphic in this cohort (N=905). Overall, the 54c>t and 76c>t transitions in exon 3 had minor allele frequencies (MAF) of 0.21 and 0.23, respectively, and appeared in all self-identified ethnic groups (except Native American donors (n=2)) with maxima observed in donors of self-identified Hispanic ethnicity (n=16; MAF=0.41 and 0.44, respectively). These SNPs showed significant linkage disequilibrium (r2=0.86 [95%CI 0.85–0.88]). African-American donors (n=57) had the highest frequency of variant 11c>t (MAF 0.07) and variant 755c>t (MAF 0.018), which was absent or extremely rare in other ethnic groups. The Caucasian donor population was the only group to display variations 788g>a and 1094g>a (MAF 0.003 and 0.0008 respectively). Conclusions: This is the largest sample of blood donors to be comprehensively genotyped for Scianna variants to date. We observed population-specific polymorphism of these rare variants according to the donor's self-identified ethnicity, which is under further study. Determining the diversity in the Scianna blood group system may help explain otherwise unclear transfusion reactions, particularly if these variants impact on Scianna antigen surface density (especially the predicted leader sequence variants in exon 3) or other ERMAP functions (via variants in the intracellular domain encoded by exon 12). High throughput donor genotyping will allow evaluation of the clinical importance in alloimmunization for variants like the 11c>t, 54c>t, and 76c>t SNPs that lie in the predicted leader sequence and polymorphisms 755c>t, 788g>a, and 1094g>a that lie within the intracellular B30.2 domain of the ERMAP protein. Awareness of the frequencies of these variations can therefore be a clinically useful aid in the investigation of donors implicated in transfusion reactions. Disclosures: No relevant conflicts of interest to declare.
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Dennig, D., et R. J. O'Reilly. « Dissection of the function of HLA class II and costimulation in B cell-mediated and toxic shock syndrome toxin-1-induced T cell proliferation. » Journal of Immunology 150, no 12 (15 juin 1993) : 5231–40. http://dx.doi.org/10.4049/jimmunol.150.12.5231.
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Abstract In this study we have demonstrated that costimulation for TSST-1-induced T cell proliferation is provided by HLA class II negative accessory B cells. In addition, TSST-1 binding to these HLA class II negative accessory B cells could not be detected by immunocytofluorescence, or in a system in which T cell proliferation depended on TSST-1 pretreated HLA class II negative B cells. These findings suggest that accessory signals can be supplied by B cells that are not involved in the activation of T cells via Ag-HLA/TCR-CD3 complex interaction: TCR ligation by a TSST-1/HLA complex and costimulation need not be delivered by the same cell. In the presence of HLA class II negative B cells, T cell proliferation in response to TSST-1 could be achieved despite addition of a mAb that can block HLA class II binding sites for TSST-1. These findings suggest the possibility that TSST-1 may directly ligate TCR. In the presence of anti-BB1-treated HLA class II negative accessory cells, TSST-1-induced T cell proliferation was inhibited by over 50% indicating the involvement of the BB1/CD28 pathway. The leukemic pre-B cell lines NALM-6, and BLIN-1, both of which express surface HLA class II Ag, but not the costimulatory B cell activation Ag BB1, were deficient in their accessory function for T cell proliferation in response to the superantigen TSST-1 and the mitogen Con A.
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Kamata, Tetsuji, Makoto Handa, Yasuo Ikeda et Sadakazu Aiso. « Dissecting the Structural Rearrangement and Activation of αIIbβ3 Integrin with a Disulfide Bridge. » Blood 104, no 11 (16 novembre 2004) : 328. http://dx.doi.org/10.1182/blood.v104.11.328.328.
Texte intégralRésumé :
Abstract Platelet αIIbβ3 integrin undergoes extensive structural rearrangement upon activation. Crystallographic and high-resolution electron microscopic observation revealed that integrins could assume multiple conformers under physiological conditions. However, functional assignment of each conformer has not been clearly determined. It is postulated that transition from the bent to the extended conformer (switchblade-like movement) and widening of the angle between the βA and the β hybrid domains (swing-out of the hybrid domain) that accompanies the extension is the critical event for integrin activation. To examine the authenticity of this hypothesis, we created and characterized mutant αIIbβ3 of which conformation was fixed in a specific conformer with an artificially introduced disulfide bridge. A double cysteine mutation βV332C/βS674C was designed to ligate βA and βTD, thus it is expected to fix integrin in a bent conformer by stabilizing the βA/βTD interface. Another mutation αD319C/βV359C was designed to ligate α β-propeller and the β hybrid domains. This mutation is expected to prevent the swing-out of the hybrid domain and the possible α/β headpiece dissociation. When expressed in CHO cells, both mutants were unable to bind fibrinogen, unless the disulfide bridge had been disrupted by DTT treatment. The LIBS epitope expression in βV332C/βS674C was significantly impaired and did not respond to induction by RGD peptide. The binding of ligand-mimetic mAb OP-G2 was also significantly impaired. By contrast, αD319C/βV359C showed comparable LIBS epitope expression and OP-G2 binding as wild-type αIIbβ3. The RGD peptide induced LIBS epitope expression, albeit slightly weaker than wild-type. Consistently, the βG327C/βV419C mutation that was designed to ligate βA and β hybrid domains, thus fix integrin headpiece in closed conformer by preventing the swing-out of the hybrid domain without affecting the α/β head interface, specifically blocked fibrinogen binding without affecting the binding of anti-LIBS or OP-G2. These results indicate that βV332C/βS674C is absolutely inactive and incapable of undergoing structural rearrangements associated with activation, while the αD319C/βV359C and βG327C/βV419C are capable of doing so upon binding to ligand-mimetic RGD peptide. Disruption of the βA/βTD interface by introducing a bulky amino acid residue in the interface or by deletion of the CD loop in the βTD did not induce integrin activation. However, introducing a bulky N-glycan at βV332 or at βS674 in the βA/βTD interface significantly potentiated ligand binding. Notably, the effects of the two N-glycans were synergistic. In summary, these results suggest, 1) that the bent conformer represents an inactive conformer, 2) that the contribution of the putative βA/βTD interface interaction in restraining integrin in the bent conformer is minimal, 3) that increasing the distance between the βA and the βTD, i.e. decreasing the angle of the bend, makes integrin highly susceptible to activation, 4) integrin with closed headpiece represents low affinity conformer, but it is capable of undergoing structural rearrangement upon ligand binding. Taken together, our results are consistent with the switchblade model. Conformational change other than the swing-out of the hybrid domain may trigger the structural rearrangement from bent to extended conformer upon ligand binding.
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Tzachanis, Dimitrios, Alla Berezovskaya, Esther M. Lafuente, Lequn Li, Gordon J. Freeman et Vassiliki A. Boussiotis. « The E3 Ubiquitin Ligase TRIM36, a Transcriptional Target of Tob, Is Expressed in Anergic T Cells and Mediates Unresponsiveness through Proteolysis of Signaling Proteins PLC- γ1 and PKC-𝛉. » Blood 104, no 11 (16 novembre 2004) : 113. http://dx.doi.org/10.1182/blood.v104.11.113.113.
Texte intégralRésumé :
Abstract Ligation of the T cell receptor (TCR) and costimulatory receptors leads to cytokine secretion and clonal expansion, whereas ligation of TCR alone leads to anergy. We have previously determined that anergic cells express Tob, a member of the novel APRO gene family, which inhibits T cell activation. The precise molecular mechanisms via which Tob mediates its effects in T cells are not fully understood. Tob functions as transcriptional coactivator and enhances DNA binding of Smads. Therefore, Tob may regulate de novo mRNA synthesis or gene transcription. To identify genes that are induced by Tob, Jurkat T cells that lack endogenous Tob, were transfected with Tob cDNA or empty vector and differential gene expression was determined by suppression subtractive hybridization. TRIM36 was one of the genes induced by Tob. TRIM36 is a RING finger E3 ubiquitin ligase. It belongs to a recently identified tripartite motif (TRIM) gene family which also includes Pyrin/Marenosrtin, MID1, MUL, PML, RFP and TIF1, proteins implicated in familial human diseases and cancer. E3 proteins confer substrate specificity to the ubiquitin system. Previous studies have shown that the trancriptional profile of anergic cells includes the E3 ubiquitin ligases Cbl-b, GRAIL and Itch. Therefore, the finding that Tob, a transcriptional regulator expressed in anergic cells, induces expression of TRIM36 E3 ubiquitin ligase is very intriguing. Northern blot analysis confirmed that TRIM36 mRNA was selectively upregulated in anergic T cells. To determine the role of TRIM36 on IL-2 gene transcription, Jurkat T cells were transfected with full-length TRIM36 cDNA along with the IL-2 promoter/enhancer cDNA (2kb) linked to the luciferase gene. TRIM36 inhibited CD3+CD28-mediated IL-2 transcription by 90%. Interestingly, when cells were stimulated with PMA+Ionomycin, which bypass the TCR proximal signals, IL-2 transcription was almost unaffected. These results prompted us to search for candidate ubiquitination substrates among signaling molecules that have a critical role on TCR-mediated T cell activation and IL-2 transcription. Previous studies have shown that among T cell signaling molecules, TCRζ, ZAP70, PLC-γ1 and PKC-𝛉 undergo ubiquitin-targeted degradation. For this reason, we investigated whether any of these proteins might be substrates for TRIM36-mediated ubiquitination. V5-tagged TRIM36 or empty vector was expressed in Jurkat T cells followed by stimulation with anti-CD3+anti-CD28 mAbs in the presence of ubiquitin aldehyde that prevents substrate deubiquitination. Immunoblot with antibodies specific for TCR ζ, ZAP70, PLC-γ1 and PKC-𝛉 showed that expression of PLC-γ1 and PKC-𝛉 was selectively reduced in the presence of TRIM36. Immunoprecipitation with V5 mAb followed by immunoblot with substrate-specific antibodies revealed that PLC- γ1 and PKC-𝛉 coprecipitated with TRIM36. Immunoblot with ubiquitin-specific antibody revealed that PLC-γ1 and PKC- 𝛉 were substrates for ubiquitination by TRIM36. Our results show that at least one molecular mechanism via which Tob mediates its inhibitory effect on T cell activation involves the induction of TRIM36 ubiquitin ligase, which mediates degradation of two key signaling proteins, PLC- γ1 and PKC-𝛉. Moreover, these results suggest that TRIM36 may represent a novel target of molecular intervention for induction of transplantation tolerance.
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Lucas, Carrie L., Thomas Fehr, Fabienne Haspot et Megan Sykes. « CD40L-specific mAb mediates its tolerogenic effects through engagement of FcgRIIB, not via depletion of activated T cells (141.17) ». Journal of Immunology 182, no 1_Supplement (1 avril 2009) : 141.17. http://dx.doi.org/10.4049/jimmunol.182.supp.141.17.
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Abstract Objective: To determine the mechanism by which a widely used anti-mouse CD40L mAb (clone MR1) given with allogeneic bone marrow cells (BMCs) tolerizes peripheral CD8 T cells. Methods: B6 mice received 3Gy total body irradiation one day prior to ip injection of 2mg a-CD40L & iv infusion of 25x106 MHC-mismatched B10.A BMCs. This regimen induces long-term mixed chimerism, as measured by durable presence of donor leukocytes, without depletion of recipient CD4 or CD8 T cells. Results: Although genetic deficiency of CD40L alone allowed graft acceptance in recipients depleted of CD8 cells, it did not prevent rejection in mice replete with CD8 T cells. Thus, Fc-dependent functions of a-CD40L were studied. A role for complement was excluded, as 4/5 C3 KO recipients became chimeric. CD8 T cell-intrinsic CD40L was dispensable (3/5 chimeras each in mice with WT or KO CD8 cells), indicating that a-CD40L need not act directly on CD8 cells. However, FcgRIIB KO recipients promptly rejected donor BM unless CD8 T cells were depleted (5/7, 0/5, 7/8, & 5/7 chimeras for WT, KO, WT + a-CD8, & KO + a-CD8 groups, respectively). Recipient B cells are the likely source of FcgRIIB, as DC-derived FcgRIIB was not essential (4/6 chimeras each in mice with WT or KO DC). Conclusions: A-CD40L with allogeneic BMCs generates immune complexes that ligate FcgRIIB, inducing as yet undefined downstream effects essential for CD8 T cell tolerance. Supported by NIH Grant RO1 49915 & NDSEG Fellowship.
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Tanigawa, S., C. H. Lee, C. S. Lin, C. C. Ku, H. Hasegawa, S. Qin, A. Kawahara et al. « Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis ». Cell Death & ; Disease 4, no 11 (novembre 2013) : e921-e921. http://dx.doi.org/10.1038/cddis.2013.448.
Texte intégralRésumé :
Abstract Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.
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Medford, Arielle J., Marko Velimirovic, Andrzej Niemierko, Whitney L. Hensing, Andrew A. Davis, Katherine K. Clifton, Jennifer C. Keenan et al. « Abstract P5-02-07 : Cell-free DNA detection of GATA3 mutations in metastatic hormone receptor positive breast cancer : a retrospective, observational multi-institutional analysis ». Cancer Research 83, no 5_Supplement (1 mars 2023) : P5–02–07—P5–02–07. http://dx.doi.org/10.1158/1538-7445.sabcs22-p5-02-07.
Texte intégralRésumé :
Abstract Background GATA3 mutations (GATA3mut) have been reported in 10-20% of hormone receptor positive (HR+) breast cancers. It has been shown that targeting GATA3mut HR+ breast cancer with MDM2 inhibitors invokes synthetic lethality. MDM2 is an E3 ubiquitin ligase that targets p53 for degradation, and research suggests that restoring p53 by blocking MDM2 may be effective in treating GATA3mut HR+ breast cancer. One potential mechanism of this efficacy has been shown to be through the PI3K-AKT pathway. We thus sought to characterize the GATA3mut landscape in a multi-institutional cell-free DNA (cfDNA) analysis and to determine the association between GATA3mut and TP53 mutations, as well as alterations in the PI3K-AKT pathway and the impact of GATA3 on survival. Methods We analyzed cfDNA data collected at the Massachusetts General Hospital and at Washington University in St Louis via Guardant360, a next generation sequencing assay that analyzed up to 74 genes during the study period. The association of GATA3mut and co-mutations as well as number of prior therapies was estimated using Pearson’s chi-squared test for categorical variables, two-sample Wilcoxon rank-sum test for continues variables, and multivariable logistic regression. The impact of GATA3mut and GATA3 wildtype (WT) on progression-free survival (PFS) and overall survival (OS) was analyzed using multivariable Cox regression analysis, adjusting for age, number of prior therapies, visceral metastases, and de novo metastases. PFS and OS were evaluated in the overall study population, as well as in subgroups of patients that received endocrine monotherapy and chemotherapy. Results Out of 647 patients with HR+ MBC, 10% (n = 68) had non-synonymous GATA3 mutations. Among these 68 GATA3mut patients, 37% (n = 25) were mutations in exon 5, all but two of which were in the second zinc finger, and 62% (n = 42) were in exon 6. 62% (n = 42) were frameshift mutations, 20% (n = 14) were indels, and 18% (n = 12) were point mutations. Median mutant allele fraction (MAF) of GATAmut was 0.95% (range 0.03 – 30.5%). There was no statistically significant association of GATA3mut with the number of prior therapies, PR status, or the presence of ESR1, TP53, or PI3K-AKT pathway mutations. In the GATA3mut population, TP53 co-mutations (n = 21) were found with a median MAF of 0.6%. PI3K-AKT pathway alterations occurred in 47% (n=32) of GATA3mut patients (PIK3CA n = 27; AKT n = 2; PTEN n = 3). In the combined cohort, there was no significant difference in PFS or OS after adjusting for visceral metastases, de novo disease, number of prior therapies, and age. In a cohort of 80 patients that received endocrine monotherapy (GATA3 WT n = 74, GATA3mut n = 6), GATA3mut were associated with borderline worse PFS (HR 2.6; p = 0.061) and worse OS (HR 4.5; p = 0.009). There was no statistically significant difference in PFS or OS in a subgroup that received chemotherapy. Conclusions GATA3 mutations can be identified via cfDNA in patients with HR+ MBC. Co-mutations in TP53 occurred at overall low MAF. Further research is needed to characterize the functional impact of these low level TP53 co-mutations and develop therapeutic strategies to target GATA3 mutant MBC. Citation Format: Arielle J. Medford, Marko Velimirovic, Andrzej Niemierko, Whitney L. Hensing, Andrew A. Davis, Katherine K. Clifton, Jennifer C. Keenan, Charles S. Dai, Lesli A. Kiedrowski, Ami N. Shah, Lorenzo Gerratana, Laura M. Spring, Leif Ellisen, Robert C. Doebele, Massimo Cristofanilli, Aditya Bardia. Cell-free DNA detection of GATA3 mutations in metastatic hormone receptor positive breast cancer: a retrospective, observational multi-institutional analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-07.
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Bugge, K. E. « The Genesis of a Poem ». Grundtvig-Studier 67, no 1 (4 janvier 2018) : 109–38. http://dx.doi.org/10.7146/grs.v67i1.96651.
Texte intégralRésumé :
Tilblivelsen af et digtI sit store digt I Kveld blev der banket paa Helvedes Port beskriver GrundtvigJesu nedfart til de dødes rige. Digtet, der for første gang blev trykt i1837, har i perioder været genstand for intensiv forskning. Det er fastslået,at både kirkefaderen Irenæus og den angelsaksiske digter Cædmon heltafgørende har inspireret tilblivelsen. Ikke desto mindre tilbagestår spørgsmåletom, hvornår og under hvilke nærmere omstændigheder digtet erskrevet.Grundtvig har kendt nedfartsmotivet i 1. Peters brev kap. 3 allerede frasin barndom og ungdom. I de tidlige år synes motivet dog ikke at havegjort særligt indtryk på ham. I 1815-17 stifter Grundtvig under sine tidligsteangelsaksiske studier bekendtskab med Cædmons bibelparafrase, somhan vurderer positivt, men med kritiske forbehold. Først i årene 1823-24udvikler han under påvirkning fra Irenæus en entydig positiv holdningover for dette led af den apostolske trosbekendelse.Under sine Englandsrejser i 1829-31 studerer Grundtvig bl.a. manuskripternetil Cædmons behandling af nedfarten. Atter hjemme i Danmarkbliver Grundtvig hurtigt optaget af arbejdet med Nordens mytologiog verdenshistorien. Endvidere engagerer han sig i den offentlige debat omforholdet mellem stat og kirke. Først i 1835 påbegyndes arbejdet med densalmeudgave, han for år tilbage havde lovet vennen Gunni Busck. Selv omde angelsaksiske studier kommer noget på afstand under disse mangfoldigetiltag, blev Grundtvig i årene 1831-35 gang på gang mindet om nedfartsmotivet.I den offentlige debat blev netop nedfarten ofte inddraget ide gudelige forsamlingers opposition mod statskirken og dens præster. Idenne debat spillede ugeskriftet Nordisk Kirke-Tidende en fremtrædenderolle. Tidsskriftet redigeredes af Grundtvigs medkæmper Jacob ChristianLindberg, og Grundtvig bidrog med digte og artikler. Lindbergs udførligstebidrag, der er en artikelserie på 80 spalter, omhandler netop nedfarten.Artiklen kom i 1835.I de første måneder af 1836 ligger arbejdet med salmerne stille. I januarer Grundtvig dybt deprimeret. I februar-marts melder en ny inspirationsig, og Grundtvig skriver sit første større højskoleskrift, Det Danske Fiir-Kløver. I den situation har han ikke tid til at digte salmer. Arbejdet med“Fiir-Kløveret” har imidlertid bibragt Grundtvig en optimisme, der i tidenefter påske inspirerer ham til at genoptage salmearbejdet i sidste halvdelaf april. Torsdag d. 12.5 1836 prædiker han på Kristi himmelfartsdag.I denne prædiken foretager han en udførlig kombination af Jesu nedfartog himmelfart. I Kveld er derfor sandsynligvis på denne baggrund digteti første halvdel af maj 1836. Det påvises, at andre tilblivelsesperioder i1836-37 ikke er sandsynlige.
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Gandhi, Anita K., Derek Mendy, Anastasia Parton, Lei Wu, Jolanta Kosek, Ling-Hua Zhang, Lori Capone, Antonia Lopez-Girona, Peter H. Schafer et Rajesh Chopra. « CC-122 Is a Novel Pleiotropic Pathway Modifier with Potent in Vitro Immunomodulatory and Anti-Angiogenic Properties and in Vivo Anti-Tumor Activity in Hematological Cancers. » Blood 120, no 21 (16 novembre 2012) : 2963. http://dx.doi.org/10.1182/blood.v120.21.2963.2963.
Texte intégralRésumé :
Abstract Abstract 2963 Background: The immunomodulatory agents thalidomide (THAL), lenalidomide (LEN), and pomalidomide (POM) have significant activity in a wide range of hematologic cancers. THAL is primarily a potent anti-angiogenic agent with minimal immunomodulatory activity. LEN and POM both demonstrate significant immunomodulatory activity. Additionally, POM displays anti-myeloma activity in patients with LEN-resistant multiple myeloma (MM). Recently, modulation of cereblon (CRBN)-bound E3 ubiquitin ligase complexes has been implicated in the mechanisms of action of THAL, LEN, and POM. This has enabled rational development of a next generation of compounds. CC-122 is a non-phthalimide analog of the immunomodulatory drugs and a first in class PPM™ pleiotropic pathway modulator that binds the CRBN-DDB1-Cul4-Roc1 E3 ubiquitin ligase complex. This study investigated the anti-proliferative, immunomodulatory, and anti-angiogenic activity of CC-122 in MM and lymphoma cells. Results: CC-122 inhibited proliferation of H929 MM cells in a CRBN-dependent and dose-dependent manner (IC50 = 43 nM). CC-122 induced cell cycle arrest at G0/G1 stage, which was associated with reduced retinoblastoma protein phosphorylation, and increased CDK inhibitor p27 protein expression. CC-122 also inhibited the growth of LEN-resistant H929 cells, although the proliferation IC50 for CC-122 was relatively higher in LEN-resistant cells vs H929 control cells (Table). CC-122 has significant anti-myeloma activity, and has greater activity in LEN-resistant H929 cells vs LEN and POM. Compared with LEN, CC-122 had a greater anti-proliferative effect in diffuse-large B-cell lymphoma (DLBCL). Furthermore, CC-122 had greater anti-proliferative effects in ABC- and PBML-subtypes compared with GCB subtype lines. In ABC-subtype U2932 and OCI-Ly10-DLBCL cell lines, 10 μM CC-122 treatment significantly inhibited DNA-binding of NF-κB p65 (P < .001), p50 subunits (P < .05), and IRF4 in a CRBN-dependent manner. In vivo anticancer activity of CC-122 was demonstrated in xenograft models of human lymphoma and MM. CC-122 exhibits potent immunomodulatory activity in whole blood, T, and natural killer (NK) cells. Additionally, CC-122 enhanced the anti-CD3 mAb-stimulated T-cell production of IL-5, IL-13, GM-CSF, IFN-γ, RANTES, and TNF-α. The immunomodulatory activity of CC-122 was 10-fold more potent vs LEN. We investigated the anti-angiogenic properties of CC-122. In a human umbilical artery sprout outgrowth assay, CC-122 inhibited new vessel growth as well as endothelial cell migration and invasion. It also inhibited endothelial cell sprout formation and migration in a growth factor-induced endothelial cell migration and invasion assay. CC-122 has significantly greater anti-angiogenic activity compared with the LEN and POM in human angiogenesis assays (Table). In contrast, it has less of an anti-platelet effect as measured by megakaryocyte proliferation vs LEN and POM. CRBN binding competition assays were conducted with THAL-binding beads. As demonstrated by the higher IC50 concentration, CC-122 has less potency with regard to CRBN binding compared with LEN or POM. Conclusion: Together, these data demonstrate that the first-in-class PPM™ CC-122 has anti-proliferative, immunomodulatory, and anti-angiogenic properties that may have clinical significance in the treatment of advanced refractory lymphoproliferative disorders and is currently in Phase I studies. Furthermore the data suggest that the potency of binding to CRBN per se does not explain the broad pleiotropic activity of CC-122. Disclosures: Gandhi: Celgene Corp: Employment, Equity Ownership. Mendy:Celgene Corp.: Employment, Equity Ownership. Parton:Celgene Corp: Employment, Equity Ownership. Wu:Celgene Corp: Employment, Equity Ownership. Kosek:Celgene Corp: Employment, Equity Ownership. Zhang:Celgene Corp: Employment, Equity Ownership. Capone:Celgene Corp: Employment, Equity Ownership. Lopez-Girona:Celgene Corp: Employment, Equity Ownership. Schafer:Celgene: Employment, Equity Ownership. Chopra:Celgene Corp: Employment, Equity Ownership.
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Badger-Brown, Karla M., Monica L. Bailey, Josef Penninger et Dwayne L. Barber. « Cbl-b Deficiency Enhances Motility and Impairs Leukemogenesis by Bcr-Abl. » Blood 110, no 11 (16 novembre 2007) : 1019. http://dx.doi.org/10.1182/blood.v110.11.1019.1019.
Texte intégralRésumé :
Abstract One of the prominent tyrosine phosphorylated substrates of BCR-ABL identified in cells from chronic-phase Chronic Myeloid Leukemia (CML) patients is the Cbl ubiquitin ligase and adaptor protein. Bone marrow transplantation studies have revealed that Cbl is dispensable for CML development, as animals receiving Cbl-deficient bone marrow cells expressing BCR-ABL develop a myeloproliferative disease (MPD) with a similar latency and phenotype as wild type bone marrow recipients (Dinulescu et al. 22: 8852–60, 2003). Cbl belongs to a family of E3 ubiquitin ligases that also contains Cbl-b and Cbl-3. In contrast to the equivalent Cbl protein expression displayed in hematopoietic cell lines expressing BCR-ABL, addition of the oncogene leads to a decreased expression of the related family member, Cbl-b. The objective of this study was to determine whether Cbl-b is a critical signaling intermediate downstream of BCR-ABL. To investigate this objective, we performed retroviral transduction of wild type- and Cbl-b- deficient bone marrow with BCR-ABL and utilized these cells for bone marrow transplantation of lethally irradiated mice. Recipients of wild type donor cells transduced with the p210 isoform of BCR-ABL, succumb to a rapidly fatal CML-like MPD, while the lack of Cbl-b produces a significant delay in morbidity (average latency of 32 days as compared with 18 days for recipients of wild-type marrow). Expansion of differentiated neutrophils, as visualized by histopathological analysis, is evident in the peripheral blood, bone marrow and spleen of all transplanted animals. However, circulating white blood cells are augmented in number (average wbc count for Cbl-b(+/+), 150 × 106 cells / mL; Cbl-b(−/−), 83 × 106 cells / mL) and enhanced spleen size is observed in Cbl-b(+/+) mice (35 mg / g of body mass) as compared to Cbl-b(−/−) (19 mg/g) animals. Liver masses were comparable between the two transplants. In depth flow cytometric studies of splenic cells reveals the characteristic decrease in B and T cells and enhanced myeloid lineages. Notably, an increased number of granulocytes (Gr-1+/Mac-1+ cells) is observed in the Cbl-b-knockout animals, suggesting enhanced migration but decreased survival of leukemic cells in the Cbl-b−/− spleen. In support of this hypothesis, fibroblasts deficient in Cbl-b display enhanced chemotactic migration toward Fetal Calf Serum. As migration is a key determinant of cellular retention in the bone marrow, the loss of Cbl-b could ultimately be affecting cell localization. Therefore, our data supports a continued study of Cbl-b as a motility regulator in BCR-ABL-dependent CML progression.
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Abraham, Shaji, Leonard C. Edelstein, Chad A. Shaw, Pierrette Andre, Xianguo Kong, Carol T. Dangelmaier, Alexander Tsygankov, Paul F. Bray, Satya P. Kunapuli et Steven E. McKenzie. « Platelet FcγRIIA Signaling Results in Ubiquitination and Cellular Translocation of Activated Syk ». Blood 124, no 21 (6 décembre 2014) : 2761. http://dx.doi.org/10.1182/blood.v124.21.2761.2761.
Texte intégralRésumé :
Abstract Platelet FcγRIIA is central to the pathophysiology of immune-mediated thrombocytopenia and thrombosis syndromes, such as heparin-induced thrombocytopenia (HIT). FcγRIIA is also the major transmembrane signaling adapter for αIIbβ3 outside-in signaling. In HIT, antibody to heparin/PF4 is necessary but not sufficient for disease to occur. Inter-individual variation in platelet activation via FcγRIIA contributes to HIT risk, but the molecular basis for the variation is incompletely understood. In our PRAX1 study of platelet reactivity and RNA expression (Edelstein, Nature Med 2013; Simon, Blood 2014), we identified differentially expressed mRNAs from healthy donors with different platelet reactivity to FcγRIIA stimulation. We observed significant differential expression of molecules involved in ubiquitination processes in relation to platelet reactivity to FcγRIIA stimulation. Syk is a protein tyrosine kinase and the major signaling node downstream of platelet receptors that use immunotyrosine activation motif (ITAM) signaling, such as FcγRIIA, GPVI and CLEC-2. We previously reported Syk ubiquitination following GPVI stimulation, and the role of c-cbl as the E3 ubiquitin ligase (Dangelmaier, Blood 2005). Ubiquitination is an important post-translational modification that modulates signal transduction by regulating the activity, subcellular localization or stability of proteins. We tested the hypothesis that ubiquitination participates in signaling, and examined ubiquitination of Syk downstream of platelet FcγRIIA activation. Using both washed human platelets and HEL cells, we observed ubiquitination of Syk upon FcγRIIA engagement by cross-linking IV.3 mAb (10 ug/ml) with goat anti-mouse Fab’2 (30 ug/ml). Both tyrosine phosphorylation and ubiquitination of Syk occurred within 15 sec, peaked by 1-3 min and decreased thereafter. The pattern of ubiquitination was consistent with 1 to 3 Ub molecules per Syk molecule. Ubiquitinated-Syk (Ub-Syk) was increased in the presence of PR-619, a deubiquitinating enzyme inhibitor, confirming ubiquitination of Syk. Ub-Syk associates with the cytoskeletal-rich platelet fraction, membrane skeleton fraction and with cytosolic fraction in detergent lysed platelets that were fractionated by lower g-forces (15,500 x g) and higher g-forces (100,000 x g). This suggests that Ub-Syk is translocated into all cellular compartments upon platelet activation. Ub-Syk was absent upon pre-treatment with Src-family kinase inhibitor PP2 (10 uM), but minimally affected in the presence of Syk inhibitor PRT318 (1 uM), in both platelets and HEL cells, as compared to DMSO treated control cells. Further, phosphorylation of c-cbl was inhibited strongly by PP2, but only slightly inhibited by PRT318, suggesting that ubiquitination of Syk depends on Src kinase activity. Of note, Ub-Syk was not degraded by the proteasome, since no accumulation of Ub-Syk was observed by pretreatment with proteasome inhibitors MG132 or Epoxomicin in either platelets or HEL cells, compared to control cells. In conclusion, Syk is ubiquitinated upon cross-linking platelet FcγRIIA and is translocated to all major subcellular compartments. Since ubiquitinated Syk is activation-dependent and not subject to proteasomal degradation, it likely serves as a novel adapter molecule for protein-protein interactions in mediating platelet activation via FcγRIIA. Disclosures No relevant conflicts of interest to declare.
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Brown, Julia, Nikolaos Patsoukis et Vassiliki A. Boussiotis. « PD-1 Signals Inhibit Cell Cycle Progression by Mediating Upregulation of Both KIP and INK Family of Cdk Inhibitors ». Blood 116, no 21 (19 novembre 2010) : 585. http://dx.doi.org/10.1182/blood.v116.21.585.585.
Texte intégralRésumé :
Abstract Abstract 585 The PD-1 pathway plays a critical role in the inhibition of T cell activation and the maintenance of T cell tolerance. PD-1 is expressed on activated T cells and limits T cell clonal expansion and effector function upon engagement with its ligands PD-L1 and PD-L2. PD-1 signals are vital for inhibition of autoimmunity whereas PD-1 ligation by PD-L1 and PD-L2 expressed on malignant cells has a detrimental effect on tumor-specific immunity. Furthermore, PD-1 signals result in T cell exhaustion in several chronic viral infections. The mechanism via which PD-1 signals mediate inhibition of T cell expansion is currently poorly understood. Here, we sought to determine the effects of PD-1 signals on mechanistic regulation of cell cycle progression mediated via TCR/CD3 and CD28 in primary human CD4+ T cells using anti-CD3/CD28 with or without agonist anti-PD-1 mAb conjugated to magnetic beads. Cell cycle analysis by ethynyl-deoxyuridine incorporation revealed that PD-1 induced blockade of cell cycle progression at the early G1 phase. To determine the molecular mechanisms underlying the blocked cell cycle progression we examined the expression and activation of cyclins and cdks and the regulation of cdk inhibitors that counterbalance the enzymatic activation of cyclin/cdk holoenzyme complexes. Our studies revealed that PD-1 mediated signals inhibited upregulation of Skp2, the SCF ubiquitin ligase that leads p27kip1 cdk inhibitor to ubiquitin-dependent degradation, and resulted in accumulation of p27kip1. Expression of cyclin E that is induced at the G1/S phase transition, and cyclin A that is synthesized during the S phase of the cell cycle, was dramatically reduced in the presence of PD-1 signaling. Strikingly, although expression of cdk4 and cdk2 was comparable between cells cultured in the presence or in the absence of PD-1, cdk2 enzymatic activation was significantly reduced in the presence of PD-1 signaling. Smad3 is a novel critical cdk substrate. Maximum cdk-mediated Smad3 phosphorylation occurs at the G1/S phase junction and requires activation of cdk2. Phosphorylation by cdk antagonizes TGF-β-induced transcriptional activity and antiproliferative function of Smad3 whereas impaired phosphorylation on the cdk-specific sites renders Smad3 more effective in executing its antiproliferative function. Based on those findings, we examined the effects of PD-1 signaling on Smad3 phosphorylation on cdk-specific and TGF-β-specific sites using site-specific phospho-Smad3 antibodies. Compared to anti-CD3/CD28 alone, culture in the presence of PD-1 induced impaired cdk2 activity, reduced levels of Smad3 phosphorylation on the cdk-specific sites and increased Smad3 phophorylation on the TGF-b-specific site. To determine whether the differential phosphorylation of Smad3 might differentially regulate Smad3 transcriptional activity in CD4+ T cells cultured in the presence versus the absence of PD-1, we examined expression of the INK family cdk4/6 inhibitor p15, a known downstream transcriptional target of Smad3. Expression of p15 was upregulated in CD4+ T cells cultured in the presence of PD-1 but not in cells cultured in the presence of CD3/CD28-coated beads alone. These results indicate that PD-1 signals inhibit cell cycle progression by mediating upregulation of both KIP and INK family of cdk inhibitors and Smad3 is a critical component of this mechanism, regulating blockade at the early G1 phase. Disclosures: No relevant conflicts of interest to declare.