Proyectos de Investigación

Buscador de proyectos en Publicaciones
  • Director: Bettaieb A, Vazquez Prieto MA, Rodriguez Lanzi C, Miatello RM, Haj FG, Fraga CG, Oteiza PI.


    We investigated the capacity of dietary (-)-epicatechin (EC) to mitigate insulin resistance through the modulation of redox-regulated mechanisms in a rat model of metabolic syndrome. Adolescent rats were fed a regular chow diet without or with high fructose (HFr; 10% w/v) in drinking water for 8 weeks, and a group of HFr-fed rats was supplemented with EC in the diet. HFr-fed rats developed insulin resistance, which was mitigated by EC supplementation. Accordingly, the activation of components of the insulin signaling cascade (insulin receptor, IRS1, Akt, and ERK1/2) was impaired, whereas negative regulators (PKC, IKK, JNK, and PTP1B) were upregulated in the liver and adipose tissue of HFr rats. These alterations were partially or totally prevented by EC supplementation. In addition, EC inhibited events that contribute to insulin resistance: HFr-associated increased expression and activity of NADPH oxidase, activation of redox-sensitive signals, expression of NF-κB-regulated proinflammatory cytokines and chemokines, and some sub-arms of endoplasmic reticulum stress signaling. Collectively, these findings indicate that EC supplementation can mitigate HFr-induced insulin resistance and are relevant for defining interventions that can prevent/mitigate MetS-associated insulin resistance.

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  • Director: Pelletan, LE, Suhaiman, L, Vaquer, CC, Bustos, MA, De Bias, GA, Vitale, N, Mayorga, LS, and Belmonte, SA


    Regulated secretion is a central issue for the specific function of many cells; for instance, mammalian sperm acrosomal exocytosis is essential for egg fertilization. ARF6 (ADP-ribosylation factor 6) is a small GTPase implicated in exocytosis, but its downstream effectors remain elusive in this process. We combined biochemical, functional, and microscopy-based methods to show that ARF6 is present in human sperm, localizes to the acrosomal region, and is required for calcium and diacylglycerol-induced exocytosis. Results from pulldown assays show that ARF6 exchanges GDP for GTP in sperm challenged with different exocytic stimuli. Myristoylated and guanosine 5'-3-O-(thio)triphosphate (GTPγS)-loaded ARF6 (active form) added to permeabilized sperm induces acrosome exocytosis even in the absence of extracellular calcium. We explore the ARF6 signaling cascade that promotes secretion. We demonstrate that ARF6 stimulates a sperm phospholipase D activity to produce phosphatidic acid and boosts the synthesis of phosphatidylinositol 4,5-bisphosphate. We present direct evidence showing that active ARF6 increases phospholipase C activity, causing phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate-dependent intra-acrosomal calcium release. We show that active ARF6 increases the exchange of GDP for GTP on Rab3A, a prerequisite for secretion. We propose that exocytic stimuli activate ARF6, which is required for acrosomal calcium efflux and the assembly of the membrane fusion machinery. This report highlights the physiological importance of ARF6 as a key factor for human sperm exocytosis and fertilization.

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  • Director: Saraví FD, Gonzalez Otarula KA, Carra GE, Ibañez JE


    The colonic epithelium is a classical aldos­terone target, but the effect of the hormone on the oxygen consumption rate (QO2 ) of this tissue is unknown. Acta Gastroenterológica Latinoamericana 2015;45(3):203-211 - ISSN 0300-9033

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  • Director: ELRodriguez Echandia y M Torrecilla

    En los últimos años, la sociedad se ha visto favorecida por numerosos adelantos tecnológicos desde la Medicina, estos avances se traducen en un aumento de la esperanza de vida para el ser humano y una gran disminución en la mortalidad infantil. En Neonatología, el progreso científico facilitó la posibilidad de diagnóstico y tratamiento precoz, poder identificar situaciones de riesgo y ofrecer tratamientos adecuados en el momento oportuno contribuyen a la disminución de la morbilidad y mortalidad infantil. Como resultado de estos progresos, los recién nacidos de alto riesgo tienen más posibilidades de sobreponerse favorablemente a las dificultades que les plantea nacer antes de término. Aun así, la prematurez continúa siendo uno de los principales problemas de salud pública; se ha descripto, entre las causas más frecuentemente relacionadas: factores sociales y biológicos, factores relacionados con una asistencia de salud inadecuada, problemas médicos anteriores al embarazo y complicaciones propias del embarazo en curso. (Ceriani Cernadas, 2008). Como plantea Ruiz (2004), los avances en el cuidado del prematuro han significado un progreso notable en Neonatología, sin embargo, se observan efectos no deseados, en especial en los padres. El trabajo con la familia de un recién nacido hospitalizado debe incluir primero y fundamentalmente a sus padres. En momentos posteriores se hace un trabajo extensivo al resto del grupo familiar (hermanos, abuelos), quienes ejercen la mayoría de las veces funciones de sostén hacia los padres del recién nacido hospitalizado. La llegada de un hijo prematuro o con otras dificultades requiere de una internación en el sector de Alto Riesgo que puede generar un fuerte impacto en los padres. Es fundamental, para que toda madre pueda desarrollar su capacidad materna, contar con un soporte socio-emocional adecuado, soporte familiar y del equipo de salud que asiste a su niño en la Unidad de Cuidados Intensivos Neonatales (UCIN).

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  • Director: Ratti, Silvia G.; Cioccale, Marcela; Carignano, Claudio; Alvarez, Edgardo O.


    Trace elements are well known in the geochemistry disciplines. However, its relationship to the biological and medical sciences is very recent. In spite that knowledge about the influence of environment in living processes is a traditional concept, until about the middle part of the 20 century, the possible influence on physiological functions of chemical elements present in waters and soil surrounding man habitat was not particularly investigated. Principal concern was concentrated to evaluate toxic actions of chemical elements on living systems. However, evidence showing that chemical elements are able to interact with enzymes, transcription factors and DNA in several living systems, put the inorganic elements into a new perspective. Higher concentrations of inorganic elements in the environment do not necessarily must be the only requirement for biological interactions in living systems. In the present paper historical aspects, some chemical properties of trace elements, an emphasized discussion about selenium and tellurium on functional processes in living systems are reviewed. In addition, hypothesis about the role of trace elements on epigenetic changes in the expression of gene action is also discussed. American Journal of Neuroprotection and Neuroregeneration 5(1): 17-24,2013.

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  • Director: Vazquez Prieto MA, Bettaieb A, Rodriguez Lanzi C, Soto VC, Perdicaro DJ, Galmarini CR, Haj FG, Miatello RM, Oteiza PI


    This study evaluated the capacity of dietary catechin (C), quercetin (Q), and the combination of both (CQ), to attenuate adipose inflammation triggered by high fructose (HFr) consumption in rats and by tumor necrosis factor alpha (TNF-α) in 3T3-L1 adipocytes.

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  • Director: Carvelli L, Bannoud N, Aguilera AC, Sartor T, Malossi E, Sosa MA


    One of the most striking features of the mammalian epididymis is the secretion of lysosomal enzymes (LE). These LE may play a role in sperm maturation. In the present study we investigated the activity and distribution of four LE (?-galactosidase (?-Gal), N-acetyl-?-D-glucosaminidase (?-NAG), ?-mannosidase (?-Man) and ?-glucuronidase (?-Glu)) in bull epididymis at two different ages (6 months and 4 years) to determine whether these enzymes vary with sexual maturity. In young, sexually immature (SI) bulls we found high LE activity in the epididymal tissue that accounts for a developed and active lysosomal apparatus. In contrast, low LE activity was measured in sexually mature (SM) bulls, and ?-NAG and ?-Gal were mostly secreted into the lumen. We also attempted to correlate LE distribution with the expression and functionality of mannose-6-phosphate receptors (MPRs), which are thought to be involved in proper delivery of LE to lysosomes. The cation-dependent MPR was highly expressed in SI bulls, with expression decreasing during adulthood, whereas the expression of the cation-independent MPR was higher in SM than SI bulls. In addition, the four enzymes recovered from the epididymal lumen interact with both MPRs at each age. We conclude that the activity and distribution of LE in bull epididymis varies with sexual maturity and that the distribution is regulated differently by the two types of MPR. These findings could provide some molecular basis for male infertility.

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  • Director: Losinno AD, Sorrivas V, Ezquer M, Ezquer F, López LA, Morales A.


    The wall of the seminiferous tubule in rodents consists of an inner layer of myoid cells covered by an outer layer of endothelial cells. Myoid cells are a type of smooth muscle cell containing α-actin filaments arranged in two independent layers that contract when stimulated by endothelin-1. The irregular surface relief of the tubular wall is often considered a hallmark of contraction induced by a variety of stimuli. We examine morphological changes of the rat seminiferous tubule wall during contraction by a combination of light, confocal, transmission and scanning electron microscopy. During ET-1-induced contraction, myoid cells changed from a flat to a conical shape, but their actin filaments remained in independent layers. As a consequence of myoid cell contraction, the basement membrane became wavy, orientation of collagen fibers in the extracellular matrix was altered and the endothelial cell layer became folded. To observe the basement of the myoid cell cone, the endothelial cell monolayer was removed by collagenase digestion prior to SEM study. In contracted tubules, it is possible to distinguish cell relief: myoid cells have large folds on the external surface oriented parallel to the tubular axis, whereas endothelial cells have numerous cytoplasmic projections facing the interstitium. The myoid cell cytoskeleton is unusual in that the actin filaments are arranged in two orthogonal layers, which adopt differing shapes during contraction with myoid cells becoming cone-shaped. This arrangement impacts on other components of the seminiferous tubule wall and affects the propulsion of the tubular contents to the rete testis

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  • Director: Bellera CL, Balcazar DE, Vanrell MC, Casassa AF, Palestro PH, Gavernet L, Labriola CA, Gálvez J, Bruno-Blanch LE, Romano PS, Carrillo C, Talevi A.


    In spite of remarkable advances in the knowledge on Trypanosoma cruzi biology, no medications to treat Chagas disease have been approved in the last 40 years and almost 8 million people remain infected. Since the public sector and non-profit organizations play a significant role in the research efforts on Chagas disease, it is important to implement research strategies that promote translation of basic research into the clinical practice. Recent international public-private initiatives address the potential of drug repositioning (i.e. finding second or further medical uses for known-medications) which can substantially improve the success at clinical trials and the innovation in the pharmaceutical field. In this work, we present the computer-aided identification of approved drugs clofazimine, benidipine and saquinavir as potential trypanocidal compounds and test their effects at biochemical as much as cellular level on different parasite stages. According to the obtained results, we discuss biopharmaceutical, toxicological and physiopathological criteria applied to decide to move clofazimine and benidipine into preclinical phase, in an acute model of infection. The article illustrates the potential of computer-guided drug repositioning to integrate and optimize drug discovery and preclinical development; it also proposes rational rules to select which among repositioned candidates should advance to investigational drug status and offers a new insight on clofazimine and benidipine as candidate treatments for Chagas disease. One Sentence Summary: We present the computer-guided drug repositioning of three approved drugs as potential new treatments for Chagas disease, integrating computer-aided drug screening and biochemical, cellular and preclinical tests.

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  • Director: Romina P. Salinas, Jesús S. Distel, Rodolfo M. Ortiz Flores, Milton O. Aguilera, María 1.Colombo and Walter Berón


    The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that process. 2015. PLoSONE, 10(12): e0145211.

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  • Director: Rivarola E, Innocenti A, Cippitelli M, Salomón S, Vargas Roig L.


    Cytokeratins (CK) are molecules of the cytoskeleton that contribute to the cellular differenciation. We studied the expression of CK1, CK13 and CK14 in thirty-three patients with OLP. The biopsied lesions were located in the dorsal surface of the tongue, the palatal keratinized mucosa and the nonkeratinized buccal mucosa.

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  • Director: Cargnelutti DE, Borremans CG, Tonelli RL, Carrizo LC, Salomón MC.


    American tegumentary leishmaniasis is the generic name for a variety of cutaneous and mucocutaneous presentations of parasitosis caused by several species of the genus Leishmania. This is a widespread infection in the American continent, from the South of the United States to the North of Argentina. We herein describe the management of a patient with American tegumentary leishmaniasis in Mendoza, Argentina, a nonendemic area of South America, whose diagnosis and treatment were significantly delayed, because the patient did not report a recent history of travel to any known endemic areas. This case stresses the need for training health-care professionals in the diagnosis and treatment of not only endemic parasitosis within their work zones but also nonendemic parasitosis. J Mícrobiollmmunollnfect. 2014 Dec 11. doi: 10.1016/j.jmii.2014.11.014.

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  • Director: Cynthia V Rivero, Patricia Silvia Romano


    Chagas disease is a life-threatening illness caused by the protozoan parasite Trypanosoma cruzi. One of the characteristics of chronic chagasic infection is the parasitic persistence in cardiac and smooth muscle tissues. For this reason etiologic treatment of Chagas disease in all phases of infection is highly recommended. Despite the high number of trypanocidal drugs that have been discovered in the last years, only two compounds, Benznidazole and Nifurtimox remain as the unique drugs approved for Chagas treatment. Far from ideal, these drugs display low sensitivity and specificity resulting in limited applications, mainly in the onset of the acute phase. Thus there is an urgent need to validate new anti- T. cruzi drugs that can be applied even in the cases of chronic patients, those who today have no safe and effective treatment available. This paper reviews the most important compounds that have been tested in clinical trials and the results obtained to date.

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  • Director: Carra GE, Matus O, Ibáñez JE, Saraví FD


    Aerobic metabolism is necessary for ion transport in many transporting epithelia, including the human colonic epithelium. We assessed the effects of the epithelial sodium channel blocker, amiloride, on oxygen consumption and short-circuit current of the human sigmoid epithelium to determine whether these effects were influenced by the age of the subject. Saudi Journal of Gastroenterology 2015; 21 (5): 290294. ISSN 1319-3767.

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  • Director: Renna NF, Diez EA, Miatello RM.


    In this study, we used vidagliptin(V) to examine the role of the DDP-IV, incretin system component, in the activation of different molecular inflammatory cytokines, NF-kB and VCAM-1 to generate a microenvironment that supports cardiovascular remodeling. 2014.

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  • Director: Rodriguez Lanzi C, de Rosas 1, Perdicaro DJ, Ponce MT, Martinez L, Miatello RM, Cavagnaro B, Vazquez Prieto MA.


    We evaluated the effects of Syrah red wine treated with salicylic acid (RW SA) and its control red wine (RW) on metabolic parameters, systolic blood pressure and adipose tissue insulin signaling in high-fructose (F) fed rats. Grape treated with SA increased the anthocyanin (ANTs) levels in RW. F induced increased systolic blood pressure, dislipidemia and insulin resistance (HOMA:IR). F rats treated with RW significantly prevented these alterations while RW SA partially attenuated triglycerides levels and HOMA:IR without modifications in HDL cholesterol levels. F impaired the adipose tissue response to insulin. Supplementation with RW and RW SA partially attenuated these alterations. Rats supplemented with RW SA had lesser beneficial effects on metabolic alterations than control RW, while both RW and RW SA attenuated altered adipose response to insulin. More studies are necessary to deeply evaluate the effect on SA-induced RW rich in ANTs levels on metabolic alterations associated to MetS.

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  • Director: tro GN, Cayado-Gutiérrez N, Zoppino FC, Fanelli MA, Cuello-Carrión FD, Sottile M, Nadin SB, Ciocca DR


    We previously reported the association of HSPA1A and HSPB1 with high-grade astrocytomas, suggesting that these proteins might be involved in disease outcome and response to treatment. With the aim to better understand the resistance/susceptibility processes associated to temozolomide (TMZ) treatment, the current study was performed in three human malignant glioma cell lines by focusing on several levels: (a) apoptotic index and senescence, (b) DNA damage, and (c) interaction of HSPB1 with players of the DNA damage response. Three human glioma cell lines, Gli36, U87, and DBTRG, were treated with TMZ evaluating cell viability and survival, apoptosis, senescence, and comets (comet assay). The expression of HSPA (HSPA1A and HSPA8), HSPB1, O6-methylguanine-DNA methyltransferase (MGMT), MLH1, and MSH2 was determined by immunocytochemistry, immunofluorescence, and Western blot. Immunoprecipitation was used to analyze protein interaction. The cell lines exhibited differences in viability, apoptosis, and senescence after TMZ administration. We then focused on Gli36 cells (relatively unstudied) which showed very low recovery capacity following TMZ treatment, and this was related to high DNA damage levels; however, the cells maintained their viability. In these cells, MGMT, MSH2, HSPA, and HSPB1 levels increased significantly after TMZ administration. In addition, MSH2 and HSPB1 proteins appeared co-localized by confocal microscopy. This co-localization increased after TMZ treatment, and in immunoprecipitation analysis, MSH2 and HSPB1 appeared interacting. In contrast, HSPB1 did not interact with MGMT. We show in glioma cells the biological effects of TMZ and how this drug affects the expression levels of heat shock proteins (HSPs), MGMT, MSH2, and MLH1. In Gli36 cells, the results suggest that interactions between HSPB1 and MSH2, including co-nuclear localization, may be important in determining cell sensitivity to TMZ.

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  • Director: María C Ruete, Ornella Lucchesi, Matías A Bustos and Claudia N Tomes


    Exocytosis of sperm’s single secretory granule or acrosome (acrosome reaction, AR) is a highly regulated event essential for fertilization. The AR begins with an influx of calcium from the extracellular milieu and continues with the synthesis of cAMP and the activation of its target Epac. The cascade bifurcates into a Rab3-GTP-driven limb that assembles the fusion machinery and a Rap-GTP-driven limb that mobilizes internal calcium.

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  • Director: Testasecca, E.; Testasecca, A.; Maneschi, E.; Fragapane, P.; Diumenjo, M. S.

    En la fisiopatología del síndrome coronario agudo (SCA) sin evidencia de lesión ateromatosa oclusiva, podría participar un estado de hipertrombogenicidad sanguínea, generado por factores trombogénicos sistémicos, como los factores de riesgo cardiovascular y los que intervienen en el balance coagulación-anticoagulación, fibrinolisis y formación de fibrina. Objetivo: Estudiar y comparar los factores trombogénicos sistémicos en pacientes con SCA y cinecoronariografía (CCG) normal y patológica.

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  • Director: Rodriguez Lanzi C, Perdicaro DJ, Antoniolli A, Fontana AR, Miatello RM, Bottini R, Vazquez Prieto MA.


    In this study the effect of diet supplementation with grape pomace (GP) and grape pomace extract (GPE) on insulin sensitive tissues (adipose, liver and muscle) was evaluated in an experimental model of metabolic syndrome (MetS). MetS was developed by giving a high-fat-fructose (HFF) diet to Wistar rats. Six weeks of HFF diet induced weight gain, which was partially attenuated by GP (1 g per kg per day) and GPE (300 mg per kg per day) supplementation. HFF diet increased systolic blood pressure, triglycerides, insulin resistance (HOMA:IR) and inflammation (c-reactive protein (CRP)). Supplementation with GP prevented SBP, triglycerides and CRP increased and partially attenuated insulin resistance. On the other hand, GPE partially reduced SBP and triglycerides and significantly prevented insulin resistance and inflammation. Also, HFF diet induced higher triglycerides content and enhanced NADPH oxidase activity in the liver. Also, HFF diet increased the epididymal adipose tissue weight, enlarged adipocyte size, and c-jun N-terminal kinase (JNK) activation, probably contributing to a pro-inflammatory cytokine pattern (higher resistin) and lower adiponectin protein expression. These alterations may result in an impairment of insulin signaling cascade observed in adipose, liver and muscle tissue (IRS1, Akt, and extracellular signal-regulated kinases (ERK1/2)) from HFF rats. Supplementation with GP and to a greater extent GPE attenuated liver triglyceride content and adiposity and restored adipose, liver and muscle response to insulin. These findings show that supplementation with GP and GPE to a greater extent can counteract adiposity, inflammation, liver damage and impaired insulin signaling associated to MetS, supporting the utilization of winemaking residues in food industry/human health due to their high amount of bioactive compounds.

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  • Director: Bustos, MA, Roggero, CM, De la Iglesia PX, Mayorga, LS, and Tomes CN


    Exocytosis of mammalian sperm dense-core secretory granule relies on the same fusion molecules as all other secretory cells; one such molecule is the small GTPase Rab3A. Here, we report an in-depth biochemical characterization of the role of Rab3A in secretion by scrutinizing the exocytotic response of streptolysin O-permeabilized human sperm to the acute application of a number of Rab3A-containing constructs and correlating the findings with those gathered with the endogenous protein. Full length, geranylgeranylated, and active Rab3A elicited human sperm exocytosis per se. With Rab3A/Rab22A chimeric proteins, we demonstrated that the carboxy-terminal domain of the Rab3A molecule was necessary and sufficient to promote exocytosis, whereas its amino-terminus prevented calcium-triggered secretion. Interestingly, full length Rab3A halted secretion when added after the docking of the acrosome to the plasma membrane. This effect depended on the inability of Rab3A to hydrolyze GTP. We combined modified immunofluorescence and acrosomal staining protocols to detect membrane fusion and the activation status of endogenous Rab3 simultaneously in individual cells, and found that GTP hydrolysis on endogenous Rab3 was mandatory for fusion pores to open. Our findings contribute to establishing that Rab3 modulates regulated exocytosis differently depending on the nucleotide bound and the exocytosis stage under study. 2014.

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  • Director: Bustos MA, Roggero CM, De la Iglesia PX, Mayorga LS, Tomes CN.


    Exocytosis of mammalian sperm dense-core secretory granule relies on the same fusion molecules as all other secretory cells; one such molecule is the small GTPase Rab3A. Here, we report an in-depth biochemical characterization of the role of Rab3A in secretion by scrutinizing the exocytotic response of streptolysin O-permeabilized human sperm to the acute application of a number of Rab3A-containing constructs and correlating the findings with those gathered with the endogenous protein. Full length, geranylgeranylated, and active Rab3A elicited human sperm exocytosis per se. With Rab3A/Rab22A chimeric proteins, we demonstrated that the carboxy-terminal domain of the Rab3A molecule was necessary and sufficient to promote exocytosis, whereas its amino-terminus prevented calcium-triggered secretion. Interestingly, full length Rab3A halted secretion when added after the docking of the acrosome to the plasma membrane. This effect depended on the inability of Rab3A to hydrolyze GTP. We combined modified immunofluorescence and acrosomal staining protocols to detect membrane fusion and the activation status of endogenous Rab3 simultaneously in individual cells, and found that GTP hydrolysis on endogenous Rab3 was mandatory for fusion pores to open. Our findings contribute to establishing that Rab3 modulates regulated exocytosis differently depending on the nucleotide bound and the exocytosis stage under study.

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  • Director: Diez ER, Altamirano LB, García 1M, Mazzei L, Prado NJ, Fornes MW, Carrión FD, Zumino Al, Ferder L, Manucha W.


    Cardiovascular disease is often associated with chronic kidney disease and vice versa; myocardial vitamin D receptors (VDRs) are among the probable links between the 2 disorders. The vitamin D receptor activator paricalcitol protects against some renal and cardiovascular complications. However, the structural and electrophysiological effects of myocardial vitamin D receptor modification and its impact on the response to ischemia-reperfusion are currently unknown. This work attempted to determine whether obstructive nephropathy induced myocardial changes (in rats) linked to vitamin D receptor deficiency and to ventricular arrhythmias in Langendorff-perfused hearts. Unilateral ureteral-obstructed and Sham-operated rats were treated with either paricalcitol (30 ng/kg/d intraperitoneal) or vehicle for 15 days. In 5 hearts from each group, we found that obstructed rats showed a reduction in VDRs and an increase in angiotensin II type 1 receptor expression (messenger RNA and protein), suffered fibrosis (determined by Masson trichrome stain) and myofibril reduction with an increase in mitochondrial size, and had dilated crests (determined by electron microscopy). These changes were reversed by paricalcitol. In 8 additional hearts per group, we found that obstructed rats showed a higher incidence of ventricular fibrillation during reperfusion (after 10 minutes of regional ischemia) than did those treated with paricalcitol. The action potential duration was prolonged throughout the experiment in paricalcitol-treated rats. We conclude that the reduction in myocardial vitamin D receptor expression in obstructed rats might be related to myocardial remodeling associated with an increase in arrhythmogenesis and that paricalcitol protects against these changes by restoring myocardial vitamin D receptor levels and prolonging action potentials. 2015.

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  • Director: Andrea F. Gil Lorenzo,Valeria V. Costantino, Martin López Appiolaza, Maria E. Benardon, Valeria Cacciamani, Victoria Bocanegra, Patricia G. Vallés


    Angiotensin II/Angiotensin II type 1 receptor (AT1R) effects are dependent on ROS production stimulated by NADPH oxidase activation. Hsp70 regulates a diverse set of signaling pathways through their interactions with proteins. CHIP is a E3 ubiquitin ligase that targets proteins for polyubiquitination and degradation.

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  • Director: Fader, C.M., Vergara A., Salassa, B., Moor, F. and Colombo, M.


    In eukaryotic cells, autophagy is considered a lysosomal catabolic process which participates in the degradation of intracellular components in a vacuolar structure termed autolysosome. This pathway plays a significant role in the erythropoiesis process, contributing to the clearance of some organelles (such as mitochondria) that are not necessary in the mature red blood cells. Nevertheless, the role of autophagy in erythrocyte maturation has not been fully established. Biol Cell. 2016 Jan 15

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  • Director: Cuello-Carrión FD, Shortrede JE, Alvarez-Olmedo D, Cayado-Gutiérrez N, Castro GN, Zoppino FC, Guerrero M, Martinis E, Wuilloud R, Gómez NN, Biaggio V,Orozco J, Gago FE, Ciocca LA, Fanelli MA, Ciocca DR.


    In human breast cancer, β-catenin localization has been related with disease prognosis. Since HER2-positive patients are an important subgroup, and that in breast cancer cells a direct interaction of β-catenin/HER2 has been reported, in the present study we have explored whether β-catenin location is related with the disease survival. The study was performed in a tumor bank from patients (n = 140) that did not receive specific anti-HER2 therapy. The proteins were detected by immunohistochemistry in serial sections, 47 (33.5%) patients were HER2-positive with a long follow-up. HER2-positive patients that displayed β-catenin at the plasma membrane (completely surrounding the tumour cells) showed a significant better disease-free survival and overall survival than the patients showing the protein on other locations. Then we explored the dynamics of the co-expression of β-catenin and HER2 in human MCF-7 and SKBR3 cells exposed to different stressful situations. In untreated conditions MCF-7 and SKBR3 cells showed very different β-catenin localization. In MCF-7 cells, cadmium administration caused a striking change in β-catenin localization driving it from plasma membrane to cytoplasmic and perinuclear areas and HER2 showed a similar localization patterns. The changes induced by cadmium were compared with heat shock, H2O2 and tamoxifen treatments. In conclusion, this study shows the dynamical associations of HER2 and β-catenin and their changes in subcellular localizations driven by stressful situations. In addition, we report for the first time the correlation between plasma membrane associated β-catenin in HER2-positive breast cancer and survival outcome, and the importance of the protein localization in breast cancer samples. 2015 Feb.

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  • Director: Bellera C, Sbaraglini M, Balcazar D, Fraccaroli l, Vanrell MC, Casassa AF, labriola CA I , Romano PS, Carrillo C, Talevi A.


    Despite affecting around 8 million people worldwide and representing an economic burden above $7 billion/ year, currently approved medications to treat Chagas disease are still limited to two drugs, nifurtimox and benznidazole, which were developed more than 40 years ago and present important efficacy and safety limitations. Drug repositioning (i.e. finding second or further therapeutic indications for known drugs) has raised considerable interest within the international drug development community. There are many explanations to the current interest on drug repositioning including the possibility to partially circumvent clinical trials and the consequent saving in time and resources. It has been suggested as a particular attractive approach for the development of novel therapeutics for neglected diseases, which are usually driven by public or non-profit organizations. Here we review current computer-guided approaches to drug repositioning and reports on drug repositioning stories oriented to Chagas disease, with a focus on computer-guided drug repositioning campaigns.

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  • Director: Persia FA, Mariani ML, Fogal TH, Penissi AB


    The aim of this study was to determine whether hydroxytyrosol and oleuropein, the major phenols found in olives and olive oil, inhibit mast cell activation induced by immune and non-immune pathways. Purified peritoneal mast cells were preincubated in the presence of test compounds (hydroxytyrosol or oleuropein), before incubation with concanavalin A, compound 48/80 or calcium ionophore A23187. Dose-response and time-dependence studies were carried out. Comparative studies with sodium cromoglycate, a classical mast cell stabilizer, were also made. After incubation the supernatants and pellets were used to determine the β-hexosaminidase content by colorimetric reaction. The percentage of β-hexosaminidase release in each tube was calculated and taken as a measure of mast cell activation. Other samples of cell pellets were used for cell viability studies by the trypan blue dye exclusion test, or fixed for light and electron microscopy. Biochemical and morphological findings of the present study showed for the first time that hydroxytyrosol and oleuropein inhibit mast cell degranulation induced by both immune and non-immune pathways. These results suggest that olive phenols, particularly hydroxytyrosol and oleuropein, may provide insights into the development of useful tools for the prevention and treatment of mast cell-mediated disorders.

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  • Director: Mayra L. Sottile, Antonella D. Losinno, F. Darío Cuello-Carrión, Mariel A. Fanelli, M. Magdalena Montt-Guevara, Laura M. VargasRoig, Silvina B. Nadin


    Hyperthermia is used in combination with conventional anticancer agents to potentiate their cytotoxicity. One of its key events is the synthesis of heat shock proteins (HSPs), which are able to associate with components from DNA repair mechanisms. However, little is known about their relationship with the mismatch repair system (MMR). Our aim was to study the effects of hyperthermia on cisplatin (cPt) sensitivity and to determine whether MLH1 and MSH2 associate with Hsp27 and Hsp72 in MMR-deficient(-)/-proficient(+) cells.

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  • Director: Rovetta, A.I., Peña, D., Hernández Del Pino, RE., Recalde, G., Pellegrini, J., Bigi, F., Musella, RM., Palmero, D. J., Colombo, M.I., and Garcia, V.E.


    Protective immunity against Mycobacterium tuberculosis (Mtb) requires IFNG. Besides, IFNG-mediated induction of autophagy suppresses survival of virulent Mtb in macrophage cell lines. We investigated the contribution of autophagy to the defense against Mtb antigen (Mtb-Ag) in cells from tuberculosis patients and healthy donors (HD). Patients were classified as high responders (HR) if their T cells produced significant IFNG against Mtb-Ag; and low responders (LR) when patients showed weak or no T cell responses to Mtb-Ag. The highest autophagy levels were detected in HD cells whereas the lowest quantities were observed in LR patients. Interestingly, upon Mtb-Ag stimulation, we detected a positive correlation between IFNG and MAP1LC3B-II/LC3-II levels. Actually, blockage of Mtb-Ag-induced IFNG markedly reduced autophagy in HR patients whereas addition of limited amounts of IFNG significantly increased autophagy in LR patients. Therefore, autophagy collaborates with human immune responses against Mtb in close association with specific IFNG secreted against the pathogen. Autophagy 2014 Dec 2; 10(12):2109-21.

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  • Director: Cueto JA, Rodriguez C, Vega IA, Castro-Vazquez A


    Hemocytes in the circulation and kidney islets, as well as their phagocytic responses to microorganisms and fluorescent beads, have been studied in Pomacea canaliculata, using flow cytometry, light microscopy (including confocal laser scanning microscopy) and transmission electron microscopy (TEM). Three circulating hemocyte types (hyalinocytes, agranulocytes and granulocytes) were distinguished by phase contrast microscopy of living cells and after light and electron microscopy of fixed material. Also, three different populations of circulating hemocytes were separated by flow cytometry, which corresponded to the three hemocyte types. Hyalinocytes showed a low nucleus/cytoplasm ratio, and no apparent granules in stained material, but showed granules of moderate electron density under TEM (L granules) and at least some L granules appear acidic when labeled with LysoTracker Red. Both phagocytic and non-phagocytic hyalinocytes lose most (if not all) L granules when exposed to microorganisms in vitro. The phagosomes formed differed whether hyalinocytes were exposed to yeasts or to Gram positive or Gram negative bacteria. Agranulocytes showed a large nucleus/cytoplasm ratio and few or no granules. Granulocytes showed a low nucleus/cytoplasm ratio and numerous eosinophilic granules after staining. These granules are electron dense and rod-shaped under TEM (R granules). Granulocytes may show merging of R granules into gigantic ones, particularly when exposed to microorganisms. Fluorescent bead exposure of sorted hemocytes showed phagocytic activity in hyalinocytes, agranulocytes and granulocytes, but the phagocytic index was significantly higher in hyalinocytes. Extensive hemocyte aggregates ('islets') occupy most renal hemocoelic spaces and hyalinocyte-like cells are the most frequent component in them. Presumptive glycogen deposits were observed in most hyalinocytes in renal islets (they also occur in the circulation but less frequently) and may mean that hyalinocytes participate in the storage and circulation of this compound. Injection of microorganisms in the foot results in phagocytosis by hemocytes in the islets, and the different phagosomes formed are similar to those in circulating hyalinocytes. Dispersed hemocytes were obtained after kidney collagenase digestion and cell sorting, and they were able to phagocytize fluorescent beads. A role for the kidney as an immune barrier is proposed for this snail. 2015.PLoS ONE 10(4): e0123964. doi:10.1371/journal.pone.0123964

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  • Director: Cueto JA, Rodriguez C, Vega lA & Castro-Vazquez A.


    Hemocytes in the circulation and kidney islets, as well as their phagocytic responses to microorganisms and fluorescent beads, have been studied in Pomacea canaliculata, using flow cytometry, light microscopy (including confocal laser scanning microscopy) and transmission electron microscopy (TEM). Three circulating hemocyte types (hyalinocytes, agranulocytes and granulocytes) were distinguished by phase contrast microscopy of living cells and after light and electron microscopy of fixed material. Also, three different populations of circulating hemocytes were separated by flow cytometry, which corresponded to the three hemocyte types. Hyalinocytes showed a low nucleus/cytoplasm ratio, and no apparent granules in stained material, but showed granules of moderate electron density under TEM (L granules) and at least some L granules appear acidic when labeled with LysoTracker Red. Both phagocytic and non-phagocytic hyalinocytes lose most (if not all) L granules when exposed to microorganisms in vitro. The phagosomes formed differed whether hyalinocytes were exposed to yeasts or to Gram positive or Gram negative bacteria. Agranulocytes showed a large nucleus/cytoplasm ratio and few or no granules. Granulocytes showed a low nucleus/cytoplasm ratio and numerous eosinophilic granules after staining. These granules are electron dense and rod-shaped under TEM (R granules). Granulocytes may show merging of R granules into gigantic ones, particularly when exposed to microorganisms. Fluorescent bead exposure of sorted hemocytes showed phagocytic activity in hyalinocytes, agranulocytes and granulocytes, but the phagocytic index was significantly higher in hyalinocytes. Extensive hemocyte aggregates ('islets') occupy most renal hemocoelic spaces and hyalinocyte-like cells are the most frequent component in them. Presumptive glycogen deposits were observed in most hyalinocytes in renal islets (they also occur in the circulation but less frequently) and may mean that hyalinocytes participate in the storage and circulation of this compound. Injection of microorganisms in the foot results in phagocytosis by hemocytes in the islets, and the different phagosomes formed are similar to those in circulating hyalinocytes. Dispersed hemocytes were obtained after kidney collagenase digestion and cell sorting, and they were able to phagocytize fluorescent beads. A role for the kidney as an immune barrier is proposed for this snail.

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  • Director: Cargnelutti DE, Salomón MC, Celedon V, García Bustos MF, Morea G, Cuello-Carrión FD, Scodeller EA.


    A proper adjuvant has a relevant role in vaccine formulations to generate an effective immune response. In this study, total Leishmania antigen (TLA) formulated with Montanide ISA 763 or R848 as adjuvants were evaluated as a first generation Leishmania vaccine in a murine model. J Microbiollmmunollnfect. 2016 Feb;49(1):24-32. doi: 10.1016/j.jmii.2014.01.006

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  • Director: Cargnelutti DE, Salomón MC, Celedon V, Cuello-Carrión FD, Gea S, Di Genaro MS, Scodeller EA


    Tumor necrosis factor (TNF) is involved in host resistance to several intracellular pathogens. Although the critical role of TNF receptor (TNFR)p55 in Leishmania (Leishmania) major infection has been demonstrated, the impact of TNFRp55 deficiency on L. (L.) amazonensis infection has not been explored. L. (L.) amazonensis-infected TNFRp55(-/-) mice failed to resolve lesions, whereas C57BL/6 wild-type mice completely healed. The susceptibility of the TNFRp55(-/-) mice was characterized by higher lesion size and histopathological damage in comparison with the wild-type mice. A marked increased of the splenic index was observed in the TNFRp55(-/-) mice after 15 weeks infection. These results show that in the absence of TNFRp55, L. (L.) amazonensis-infected knockout mice fail to resolve lesions, whereas wild-type mice completely heal. J Microbiollmmunollnfect. 2016 Apr;49(2):271-5. doi: 10.1016/j.jmii.2014.03.009

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  • Director: Martín Rodríguez, Jimena Cejas, Guillermo Esteves, Gabriel Minuchín, Juan M Rodríguez Vitoria, Montserrat Cruzado, Isabel Quesada, Claudia Castro.

    El estrés oxidativo y mediadores inflamatorios son considerados probables factores causales del aumento de la excreción urinaria de albúmina (EUA) en pacientes con diabetes mellitus tipo 1 (DM1). El ejercicio también aumenta transitoriamente la EUA en DM1 y en no diabéticos. Se desconocen los mecanismos del aumento de EUA en ejercicios intensos y no está claro si administrar antioxidantes tendría algún efecto. RevALAD 2015_5(1)38-47.

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  • Director: Gimenez MC, Rodríguez Aguirre JF, Colombo MI, Delgui LR


    Infectious bursal disease virus (IBDV) internalization is sparsely known in terms of molecular components of the pathway involved. To describe the cell biological features of IBDV endocytosis, we employed perturbants of endocytic pathways such as pharmacological inhibitors and overexpression of dominant-negative mutants. Internalization analysis was performed quantifying infected cells by immunofluorescence and Western blot detection of the viral protein VP3 at 12 h post-infection reinforced by the analysis of the capsid protein VP2 localization after virus uptake at 1 h post-infection. We compared IBDV infection to the internalization of well-established ligands with defined endocytic pathways: transferrin, cholera-toxin subunit B and dextran. To describe virus endocytosis at the morphological level, we performed ultrastructural studies of viral internalization kinetics in control and actin dynamics-blocked cells. Our results indicate that IBDV endocytic internalization was clathrin- and dynamin-independent, and that IBDV uses macropinocytosis as the primary entry mechanism. After uptake, virus traffics to early endosomes and requires exposure to the low endocytic pH as well as a functional endocytic pathway to complete its replication cycle. Moreover, our results indicate that the GTPase Rab5 is crucial for IBDV entry supporting the participation of the early endosomal pathway in IBDV internalization and infection of susceptible cells. 2015 Jan 7. doi: 10.1111 /cmi.12415.

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  • Director: Hayes KA, Burks RL., Castro-Vazquez A., Darby P.C., Heras H., Martín P.R, Qiu J-W., Thiengo S.C., Wada T., Yusa Y, Burela S., Cadierno M.P., Cueto JA, Dellagnola F.A., Dreon M.S., Frassa MV, Giraud-Billoud M., Godoy M.S., Ituarte S., Koch E., Matsukura K.


    Apple snails (Ampullariidae) are among the largest and most ecologically important freshwater snails. The introduction of multiple species has reinvigorated the field and spurred a burgeoning body of research since the early 1990s, particularly regarding two species introduced to Asian wetlands and elsewhere, where they have become serious agricultural pests. This review places these recent advances in the context of previous work, across diverse fields ranging from phylogenetics and biogeography through ecology and developmental biology, and the more applied areas of environmental health and human disease. The review does not deal with the role of ampullariids as pests, nor their control and management, as this has been substantially reviewed elsewhere. Despite this large and diverse body of research, significant gaps in knowledge of these important snails remain, particularly in a comparative framework. The great majority of the work to date concerns a single species, Pomacea canaliculata, which we see as having the potential to become a model organism in a wide range of fields. However, additional comparative data are essential for understanding this diverse and potentially informative group. With the rapid advances in genomic technologies, many questions, seemingly intractable two decades ago, can be addressed, and ampullariids will provide valuable insights to our understanding across diverse fields in integrative biology.

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  • Director: Sosa, CM, Pavarotti, MA, Zanetti, MN, Zoppino, FCM, De Bias, GA, and Mayorga, LS


    The acrosome reaction is a unique event in the lifespan of sperm characterized by the exocytosis of the acrosomal content and the release of hybrid vesicles formed by patches of the outer acrosomal membrane and the plasma membrane. This unique regulated exocytosis is mediated by essentially the same membrane fusion machinery present in neuroendocrine cells. However, whereas secretion in neuroendocrine cells occurs in less than a second, the acrosome reaction is normally assessed after several minutes of incubation with inducers. In this report, we measured the kinetics of human sperm exocytosis triggered by two stimuli (calcium ionophore and progesterone) by using electron microscopy and three different approaches based on the incorporation of fluorescent Pisum sativum agglutinin into the acrosome upon opening of fusion pores connecting the extracellular medium with the acrosomal lumen. The results with the different methods are consistent with a slow kinetics (t½ = 14 min). We also manipulated the system to measure different steps of the process. We observed that cytosolic calcium increased with a relatively fast kinetics (t½ = 0.1 min). In contrast, the swelling of the acrosomal granule that precedes exocytosis was a slow process (t½ = 13 min). When swelling was completed, the fusion pore opening was fast (t½ = 0.2 min). The results indicate that acrosomal swelling is the slowest step and it determines the kinetics of the acrosome reaction. After the swelling is completed, the efflux of calcium from intracellular stores triggers fusion pores opening and the release of hybrid vesicles in seconds.

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  • Director: Juan A. Cueto, María C. Vanrell, Sébastien Nola, Thierry Galli, María 1.Colombo, y Patricia Silvia Romano


    The protozoan parasite Trypanosoma cruzi has a complex bi-ological cycle that involves vertebrate and invertebrate hosts. In mammals, the infective trypomastigote form of this parasite can invade several cell types by exploiting phagocytic-like or non-phagocytic mechanisms depending on the class of cell involved. Morphological studies showed that when trypomastigotes contact macrophages, they induce the formation of plasma membrane protrusions that differ from the canonical phagocytosis that occurs in the case of noninfective epimastigotes. In contrast, when trypomastigotes infect epithelial or muscle cells, the cell surface is minimally modified, suggesting the induction of a different class of process. Lysosomal-dependent or -independent T. cruzi invasion of host cells are two different models that describe the molecular and cellular events activated during parasite entry into nonphagocytic cells. In this context, we have previously shown that induction of autophagy in host cells before infection favors T. cruzi invasion. Furthermore, we demonstrate that autophagosomes and the autophagosomal protein LC3 are recruited to the T. cruzi entry sites and that the newly formed T. cruzi parasitophorous vacuole has characteristics of an autophagolysosome. This review summarizes the current knowledge of the molecular and cellular mechanisms of T. cruzi invasion in nonphagocytic cells. Based on our findings, we propose a new model in which T. cruzi takes advantage of the up-regulation of autophagy during starvation to increase its successful colonization of host cells. 2016

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  • Director: Abrego, Valeria Andrea; Ratti, Silvia Gabriela; Alvarez Toro, Edgardo Orozimbo


    Lateralization of the brain in mammals has made animals more competitive during interaction with the environment in evolution. This property, first described in the 19th century in man, refers to the differentially modulation and control of some neuronal circuits of brain hemispheres on determined behavioural functions. In spite that lateralization has been described in several different animal species, still there are aspects not fully understood related to behavioural functions or identification of specific brain circuits involved. In the rat, coping behaviour is quite important for successful surviving; proper behavioural responses and careful analysis of spatial clues of the environment are needed. However, if lateralization mechanisms in the brain participate in these processes is still not known. In this work, exploratory lateralized responses and the possible role of the hippocampus as a probable lateralized structure were investigated. Intact and rats implanted with microinjection guide cannulae into the hippocampus were tested in three lateralized devices, the T labyrinth (TL), the multiple compartment labyrinth (MCL), and the double lateral hole-board labyrinth (DHBL). Decisions making to select left or right responses for seeking shelter (the TL), passing through left or right doors in a compartments in series (the MCL), and exploring left or right walls in a corridor (the DHBL) were investigated in these two groups of rats. Results show that intact rats presented lateralized exploratory behaviour with a left-bias in the DHBL but random responses in the other devices. This left preference observed in the DHBL was manifested in spending more time exploring the left wall of the DHBL than the right one. Hippocampus implanted rats retained the left-bias exploration in this device. Blocking the neural activity of left, right or both hippocampi with lidocaine in the implanted rats, the spontaneous left-bias exploration was nullified only when lidocaine was microinjected into the left hippocampus. Results suggest that the hippocampal structure is functionally lateralized for modulating exploration in novel environments emphasizing the hippocampus role on coping behaviour in the rat.

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  • Director: Sbar aglini Ml, Vanrell MC, Bellera Cl, Benaim GJ Carrillo C, Talevi A, Romano PS.


    Neglected tropical diseases represent a major sanitary problem and a huge economic burden to endemic countries, and are currently expanding to non-endemic countries owing to migration currents. Though long abandoned in the past, recent research on novel therapeutics has already started to show results. Drug repositioning is one of the prominent, more successful strategies to approach the development of new treatments for these diseases. Here we present an overview on the limitations of the current available medications to treat African trypanosomiasis, Chagas disease and Leishmaniasis, along with a review on drug candidates presently undergoing clinical trials and drug candidates identified through drug repositioning initiatives.

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  • Director: María Cristina Vanrell, Juan A. Cueto, Jeremías J. Barclay, Carolina Carrillo, María Isabel Colombo, Roberta A. Gottlieb, y Patricia S. Romano


    Autophagy is a cell process that in normal conditions serves to recycle cytoplasmic components and aged or damaged organelles. The autophagic pathway has been implicated in many physiological and pathological situations, even during the course of infection by intracellular pathogens. Many compounds are currently used to positively or negatively modulate the autophagic response. Recently it was demonstrated that the polyamine spermidine is a physiological inducer of autophagy in eukaryotic cells. We have previously shown that the etiological agent of Chagas disease, the protozoan parasite Trypanosoma cruzi, interacts with autophagic compartments during host cell invasion and that preactivation of autophagy significantly increases host cell colonization by this parasite. In the present report we have analyzed the effect of polyamine depletion on the autophagic response of the host cell and on T. cruzi infectivity. Our data showed that depleting intracellular polyamines by inhibiting the biosynthetic enzyme ornithine decarboxylase with difluoromethylornithine (DFMO) suppressed the induction of autophagy in response to starvation or rapamycin treatment in two cell lines. This effect was associated with a decrease in the levels of LC3 and ATG5, two proteins required for autophagosome formation. As a consequence of inhibiting host cell autophagy, DFMO impaired T. cruzi colonization, indicating that polyamines and autophagy facilitate parasite infection. Thus, our results point to DFMO as a novel autophagy inhibitor. While other autophagy inhibitors such as wortmannin and 3-methyladenine are nonspecific and potentially toxic, DFMO is an FDA-approved drug that may have value in limiting autophagy and the spread of the infection in Chagas disease and possibly other pathological settings. 2013.

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  • Director: López Vernengo Andrea Beatriz, Branzello Emanuel Eduardo, Mampel Alejandra, Persia Silvia Isabel, Baroni Albano Enrique, Pizarra Marcela Amalia, Rüttler María Elena

    La selección de aspirantes para el ingreso a la carrera de Medicina y otras carreras de las Ciencias de la Salud es un tema de constante actualidad tanto en el ámbito nacional como internacional. La Facultad de Ciencias Médicas de la Universidad Nacional de Cuyo tiene un sistema selectivo a través de exámenes de contenidos del nivel de educación secundaria y ofrece un curso de nivelación de un semestre de duración. Se observa que un alto porcentaje de aspirantes no logran compensar la diferencia existente entre los conocimientos que poseen y los que demandan las carreras ofrecidas, únicamente mediante la preparación individual y la preparación que brinda la Facultad. El propósito de este estudio fue el de caracterizar a los aspirantes a las carreras de la Facultad de Ciencias Médicas, de acuerdo a los establecimientos de educación secundaria de procedencia, realizando un estudio retrospectivo de cinco años, sobre la base de datos de aspirantes a las tres carreras de la Facultad, clasificándolos según dicha procedencia y relacionando esa característica con su rendimiento en los exámenes de admisión. La mayoría de los aspirantes a las carreras de la Facultad de Ciencias Médicas proviene de establecimientos oficiales, seguido por establecimientos privados y en tercer lugar por establecimientos dependientes de la Universidad Nacional de Cuyo. El rendimiento en los exámenes de los aspirantes a Enfermería y Tecnicaturas fue independiente a la modalidad de la escuela secundaria. Para ingresar a la carrera de Medicina la modalidad Ciencias Naturales favorece el rendimiento en los exámenes. Del mismo modo, provenir de un colegio de la Universidad o de una escuela privada otorga mayores posibilidades de éxito. La Facultad de Ciencias Médicas realiza esfuerzos constantes, a través de la información sobre los requisitos de admisión y de su oferta de cursos de nivelación para lograr que los aspirantes lleguen con mejor preparación a las instancias de evaluación. Sin embargo, las características relacionadas con la formación previa de los aspirantes deben ser consideradas como factores vinculantes con sus posibilidades de ingresar.

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  • Director: Sanchez A, Shortrede J, Vargas Roig L and Flamini M


    Breast cancer is the most common malignancy in women, with metastases being the cause of death in 98%. In previous works we have demonstrated that retinoic acid (RA), the main retinoic acid receptor (RAR) ligand, is involved in the metastatic process by inhibiting migration through a reduced expression of the specific migration-related proteins Moesin, c-Src, and FAK. At present, our hypothesis is that RA also acts for short periods in a non-genomic action to cooperate with motility reduction and morphology of breast cancer cells. Here we identify that the administration of 10(-6) M RA (10-20 min) induces the activation of the migration-related proteins Moesin, FAK, and Paxillin in T-47D breast cancer cells. The phosphorylation exerted by the selective agonists for RARα and RARβ, on Moesin, FAK, and Paxillin was comparable to the activation exerted by RA. The RARγ agonist only led to a weak activation, suggesting the involvement of RARα and RARβ in this pathway. We then treated the cells with different inhibitors that are involved in cell signaling to regulate the mechanisms of cell motility. RA failed to activate Moesin, FAK, and Paxillin in cells treated with Src inhibitor (PP2) and PI3K inhibitor (WM), suggesting the participation of Src-PI3K in this pathway. Treatment with 10(-6) M RA for 20 min significantly decreased cell adhesion. However, when cells were treated with 10(-6) M RA and FAK inhibitor, the RA did not significantly inhibit adhesion, suggesting a role of FAK in the adhesion inhibited by RA. By immunofluorescence and immunoblotting analysis we demonstrated that RA induced nuclear FAK translocation leading to a reduced cellular adhesion. These findings provide new information on the actions of RA for short periods. RA participates in cell adhesion and subsequent migration, modulating the relocation and activation of proteins involved in cell migration. 2016.

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  • Director: Flamini Marina Inés, Gauna Gisel Valeria, Sottile Mayra Lis, Nadin Silvina Beatriz, Sanchez Angel Matias and Vargas Roig Laura Maria


    Breast cancer is the most common malignancy in women and the appearance of distant metastases produces the death in 98% of cases. The retinoic acid receptor β (RARβ) is not expressed in 50% of invasive breast carcinoma compared with normal tissue and it has been associated with lymph node metastasis. Our hypothesis is that RARβ protein participates in the metastatic process. T47D and MCF7 breast cancer cell lines were used to perform viability assay, immunobloting, migration assays, RNA interference and immunofluorescence. Administration of retinoic acid (RA) in breast cancer cells induced RARβ gene expression that was greatest after 72 hrs with a concentration 1 μM. High concentrations of RA increased the expression of RARβ causing an inhibition of the 60% in cell migration and significantly decreased the expression of migration-related proteins [moesin, c-Src and focal adhesion kinase (FAK)]. The treatment with RARα and RARγ agonists did not affect the cell migration. On the contrary, the addition of the selective retinoid RARβ-agonist (BMS453) significantly reduced cell migration comparable to RA inhibition. When RARβ gene silencing was performed, the RA failed to significantly inhibit migration and resulted ineffective to reduce moesin, c-Src and FAK expressions. RARβ is necessary to inhibit migration induced by RA in breast cancer cells modulating the expression of proteins involved in cell migration. 2014.

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  • Director: Quintero AC, Gambarte Tudela J, Damiani MT.


    Pathogens have evolved highly specialized mechanisms to infect hosts. Several microorganisms modulate the eukaryotic cell surface to facilitate their engulfment. Once internalized, they hijack the molecular machinery of the infected cell for their own benefit. At different stages of phagocytosis, particularly during invasion, certain pathogens manipulate pathways governed by small GTPases. In this review, we focus on the role of Rho proteins on curable, sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum. Despite the high, worldwide frequencies of these sexually-transmitted diseases, very little is known about the strategies developed by these microorganisms to usurp key eukaryotic proteins that control intracellular signaling and actin dynamics. Improved knowledge of these molecular mechanisms will contribute to the elucidation of how these clinically important pathogens manipulate intracellular processes and parasitize their hosts. 2015

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  • Director: Quesada 1M, Lucero A, Amaya C, Meijles DN, Cifuentes ME, Pagano PJ and Castro C.


    A variety of NADPH oxidase (Nox) isoforms including Noxs 1, 2, 4 and 5 catalyze the formation of reactive oxygen species (ROS) in the vascular wall. The Nox2 isoform complex has arguably received the greatest attention in the progression of atherogenesis in animal models. Thus, in the current study we postulated that specific Nox2 oxidase inhibition could reverse or attenuate atherosclerosis in mice fed a high-fat diet. Atherosclerosis 2015, October242 (2): 469-475.

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  • Director: Cherkesova TS, Hargrove TY, Vanrell MC, Ges 1, Usanov SA, Romano PS, lepesheva GI.


    CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.

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  • Director: Peixoto, E., Atorrasagasti, C., Aquino,J., Militello, R, Bayo, J., Fiore, E., Piccioni, F., Salvatierra, E., Alaniz, L., Garcia, M., Bataller, R, Corrales, F., Gidekel, M., Podhajcer, O., Colombo, M. and Mazzolini, G.


    Secreted protein, acidic and rich in cysteine (SPARC) is involved in many biological process including liver fibrogenesis, but its role in acute liver damage is unknown. To examine the role of SPARC in acute liver injury, we used SPARC knock-out (SPARC(-/-)) mice. Two models of acute liver damage were used: concanavalin A (Con A) and the agonistic anti-CD95 antibody Jo2. SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis (AH). SPARC expression is increased on acute-on-chronic AH patients. Knockdown of SPARC decreased hepatic damage in the two models of liver injury. SPARC(-/-) mice showed a marked reduction in Con A-induced necroinflammation. Infiltration by CD4+ T cells, expression of tumor necrosis factor-α and interleukin-6 and apoptosis were attenuated in SPARC(-/-) mice. Sinusoidal endothelial cell monolayer was preserved and was less activated in Con A-treated SPARC(-/-) mice. SPARC knockdown reduced Con A-induced autophagy of cultured human microvascular endothelial cells (HMEC-1). Hepatic transcriptome analysis revealed several gene networks that may have a role in the attenuated liver damaged found in Con A-treated SPARC(-/-) mice. SPARC has a significant role in the development of Con A-induced severe liver injury. These results suggest that SPARC could represent a therapeutic target in acute liver injury. Gene Ther. 2015 Jan; 22(1):9-19.

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  • Director: Cannizzo B, Quesada 1, Militello R; Miatello R, Cruzado M and Castro C.


    Oxidative stress is an important factor in the generation of vascular injury in atherosclerosis. Chronic administration of fructose in rodents is able to facilitate oxidative damage. In the present study we evaluated the role of Tempol, a superoxide dismutase mimetic, on the effect of high fructose intake in apolipoprotein E-deficient (ApoE-KO) mice. Rodents were fed with fructose overload (FF, 10% w/v) for 8 weeks and treated with Tempol 1 mg/kg/day the latest 4 weeks. Tempol revert the pro-oxidant effects caused by FF, diminished lipid peroxidation and impaired vascular NADPH oxidase system through the downregulation of p47phox expression in the vascular wall. Tempol inhibited the expression of vascular adhesion molecule 1 (VCAM-1) in aorta and reduced the development of atheroma plaques. Our results indicate that tempol attenuates oxidative stress by interfering with the correct assembly of Nox2 oxidase complex in the vascular wall and is able to reduce atherosclerosis. Thus tempol represents a potential therapeutic target for preventing risk factors associated with metabolic syndrome. Free Radic Res. 2014 May;48(5):526-33.

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  • Director: Ratti, Silvia G.; Alvarez, Edgardo O.


    Trace elements are an omnipresent group of chemical elements that are present practically in all types of environments sustaining life. Since its principal characteristic is the very low concentration in ground and water, it was thought that its importance to metabolic processes to the living cell was minimal. However, in the past 15 years knowledge has been accumulated regarding that these chemical elements have important influences on the cell dynamic homeostatic mechanisms. Previous evidence from our laboratory has shown that chronic administration of ZnTe to pregnancy, delivery and subsequent juvenile stages in rats affected several of its behavioural parameters related to motivated, lateralized exploration, social and defensive behaviour. In the third part of this study, the possible effect of folic acid (FolA) on the Te-induced behavioural changes was studied. Three experimental groups were formed, Control, animals treated with tap water; ZnTe, animals treated with the trace elements, and ZnTe + FolA, animals treated with the combination of ZnTe and FolA, in the same way that of the previous experiments. Results show the folic acid treatment did not counteract the increase of motor activity observed in those animals treated with ZnTe. However, in the exploration induced by novelty measured in the Double Lateral Hole-board Labyrinth, the corridor behavioural activity displayed by animals under the combination of FolA and ZnTe was similar to control and significantly different from the ZnTe-treated group. The left exploration bias naturally present in control, and blocked in the ZnTe-treated animals, was restored to control values in the FolA + ZnTe treated animals. A similar observation was found with the percentage of animals with left-bias exploration, where those rats treated with the combination of FolA and ZnTe reached similar values to control and significantly greater than the ZnTe-treated rats which were statistically lower than control. Social behaviour, inhibited by ZnTe was restored to normal in the FolA treated animals. A similar observation was found in the defensive behaviour test. Results are compatible with the idea that FolA, which is known as a methyl donor reagent, can restore the behavioural effects of ZnTe, giving support to previous results suggesting that trace elements could act by molecular mechanisms involving epigenetical modulation of DNA. American Journal of Neuroprotection and Neuroregeneration 7(1): 1-9, 2015.

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  • Director: Ratti, Silvia G.; Alvarez, Edgardo O.


    Trace elements are an omnipresent group of chemical elements that are found practically in all types of environments sustaining life. Since its principal characteristic is the very low concentration in ground and water, it was thought that its importance to metabolic processes to the living cell was minimal. However, in the past 15 years knowledge has been accumulated regarding that these chemical elements have important influences on the cell dynamic homeostatic mechanisms. Previous evidence from our laboratory has shown that chronic administration of ZnTe to pregnancy, delivery and subsequent juvenile stages in rats affected several of its behavioural parameters related to motivated, lateralized exploration, and defensive behaviour. In the second part of this study, Zn and Te were examined to discern which of both elements could be responsible of the behavioural changes observed previously. ZnTe and ZnCl2 were used in chronic administration. All groups of rats were examined under 4 different experimental approaches: (1) general motor activity and motivated exploration; (2) lateralized exploratory activity; (3) defensive behaviour, and (4) social behaviour. Results shown that Te specifically increased motivated behaviour; blocked the spontaneous left-biased exploration, escape and social responses related to territorial challenges. On the other hand, Zn increased the ambulatory activity, rearing and focalized motivated behaviour, and modified differently some behavioural parameters associated to exploration. Present data are in agreement with previous results, and support the concept that trace elements can modulate behaviour by brain mechanisms that appear to be selective. American Journal of Neuroprotection and Neuroregeneration 6(1): 54-61,2014.

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  • Director: Carra GE, Ibañez JE, Saraví FD


    In isolated colonic mucosa, decreases in short-circuit current (ISC) and transepithelial resistivity (RTE) occur when hypoxia is either induced at both sides or only at the serosal side of the epithelium. We assessed in human colon biopsies the sensitivity to serosal-only hypoxia and mucosal-only hypoxia and whether Na, K-ATPase blockade with ouabain interacts with hypoxia. Digestive Diseases and Sciences, 58: 2499-25e6 -2013- 001-101007/ s10620-013-2711-0 [ISSN 0163-2116J.

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  • Director: Gambarte Tudela J, Capmany A, Romao M, Quintero e, Miserey-Lenkei S, Raposo G, Goud S, Damiani MT.


    Given their obligate intracellular lifestyle, Chlamydia trachomatis ensure that they have access to multiple host sources of essential lipids by interfering with vesicular transport. These bacteria hijack Rab6-, Rab11- and Rab14-controlled trafficking pathways to acquire sphingomyelin from the Golgi complex. Another important source of sphingolipids, phospholipids and cholesterol are multivesicular bodies (MVBs). Despite their participation in chlamydial inclusion development and bacterial replication, the molecular mechanisms mediating the interaction between MVBs and chlamydial inclusions remain unknown. In the present study, we demonstrate that Rab39a labels a subset of late endocytic vesicles - mainly MVBs - that move along microtubules. Moreover, Rab39a is actively recruited to chlamydial inclusions throughout the pathogen life cycle by a bacterial-driven process that depends on the Rab39a GTP- or GDP-binding state. Interestingly, Rab39a participates in the delivery of MVBs and host sphingolipids to maturing chlamydial inclusions, thereby promoting inclusion growth and bacterial development. Taken together, our findings indicate that Rab39a favours chlamydial replication and infectivity. This is the first report showing that a late endocytic Rab GTPase is involved in chlamydial infection development. 2015.

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  • Director: Tomes CN


    Exocytosis is a highly regulated process that consists of multiple functionally, kinetically and/or morphologically definable stages such as recruitment, targeting, tethering and docking of secretory vesicles with the plasma membrane, priming of the fusion machinery and calcium-triggered membrane fusion. After fusion, the membrane around the secretory vesicle is incorporated into the plasma membrane and the granule releases its contents. The proteins involved in these processes belong to several highly conserved families: Rab GTPases, SNAREs (soluble NSF-attachment protein receptors), α-SNAP (α-NSF attachment protein), NSF (N-ethylmaleimide-sensitive factor), Munc13 and -18, complexins and synaptotagmins. In the present article, the molecules of exocytosis are reviewed, using human sperm as a model system. Sperm exocytosis is driven by isoforms of the same proteinaceous fusion machinery mentioned above, with their functions orchestrated in a hierarchically organized and unidirectional signalling cascade. In addition to the universal exocytosis regulator calcium, this cascade includes other second messengers such as diacylglycerol, inositol 1,4,5-trisphosphate and cAMP, as well as the enzymes that synthesize them and their target proteins. Of special interest is the cAMP-binding protein Epac (exchange protein directly activated by cAMP) due in part to its enzymatic activity towards Rap. The activation of Epac and Rap leads to a highly localized calcium signal which, together with assembly of the SNARE complex, governs the final stages of exocytosis. The source of this releasable calcium is the secretory granule itself.

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  • Director: Lucchesi O, Ruete MC, Bustos MA, Quevedo MF, Tomes CN.


    Exocytosis of the sperm's single secretory granule, or acrosome, is a regulated exocytosis triggered by components of the egg's investments. In addition to external calcium, sperm exocytosis (termed the acrosome reaction) requires cAMP synthesized endogenously and calcium mobilized from the acrosome through IP3-sensitive channels. The relevant cAMP target is Epac. In the first part of this paper, we present a novel tool (the TAT-cAMP sponge) to investigate cAMP-related signaling pathways in response to progesterone as acrosome reaction trigger. The TAT-cAMP sponge consists of the cAMP-binding sites of protein kinase A regulatory subunit RIβ fused to the protein transduction domain TAT of the human immunodeficiency virus-1. The sponge permeated into sperm, sequestered endogenous cAMP, and blocked exocytosis. Progesterone increased the population of sperm with Rap1-GTP, Rab3-GTP, and Rab27-GTP in the acrosomal region; pretreatment with the TAT-cAMP sponge prevented the activation of all three GTPases. In the second part of this manuscript, we show that phospholipase Cε (PLCε) is required for the acrosome reaction downstream of Rap1 and upstream of intra-acrosomal calcium mobilization. Last, we present direct evidence that cAMP, Epac, Rap1, and PLCε are necessary for calcium mobilization from sperm's secretory granule. In summary, we describe here a pathway that connects cAMP to calcium mobilization from the acrosome during sperm exocytosis. Never before had direct evidence for each step of the cascade been put together in the same study.

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  • Director: Rivarola E, DI Fabio Amanda, Salomón S, Lanfranchi H.


    Oxidative stress is involved in oral lichen planus (OLP) pathogenesis; meanwhile anthocyanins are natural antioxidants present in grapes skin.

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  • Director: Carra GE, Galella, Flavia; Widenberg, Johan; Ibañez JE, Saraví


    Dietary sodium deprivation stimulates aldosterone secretion. In the rat colon, high aldosterone levels increases Na+ absorption but also switches the mechanism of Na+ absorption from electroneutral to electrogenic. Such electrogenic transport may be suppressed by either epithelial Na+ channel blockade at the apical membrane or Na, K-ATPase inhibition at the basolateral membrane. Electrogenic Na+ absorption is tightly coupled to aerobic metabolism, but it is not known whether epithelial Na+ channel blockade and Na, KATPase inhibition cause the same degree of reduction in epithelial oxygen consumption. Distal colon isolated mucosa preparations were obtained from rats fed with a low sodium diet for 10 days. Short-circuit current and oxygen consumption were simultaneously measured in baseline condition and after either blocking epithelial Na+ channels with amiloride (n=12) or the Na, KATPase with ouabain (n=12). Both treatments reduced short-circuit current to the same degree, but the reduction in oxygen consumption was larger with ouabain (p

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