Exosome-delivered microRNAs promote IFN-α secretion by human plasmacytoid DCs via TLR7

The excessive production of type I IFNs is a hallmark and a main pathogenic mechanism of many autoimmune diseases, including systemic lupus erythematosus (SLE). In these pathologies, the sustained secretion of type I IFNs is dependent on the improper activation of plasmacytoid DCs (pDCs) by self-nucleic acids. However, the nature and origin of pDC-activating self-nucleic acids is still incompletely characterized. Here, we report that exosomes isolated from the plasma of SLE patients can activate the secretion of IFN-α by human blood pDCs in vitro. This activation requires endosomal acidification and is recapitulated by microRNAs isolated from exosomes, suggesting that exosome-delivered microRNAs act as self-ligands of innate single-stranded endosomal RNA sensors. By using synthetic microRNAs, we identified an IFN induction motif that is responsible for the TLR7-dependent activation, maturation, and survival of human pDCs. These findings identify exosome-delivered microRNAs as potentially novel TLR7 endogenous ligands able to induce pDC activation in SLE patients. Therefore, microRNAs may represent novel pathogenic mediators in the onset of autoimmune reactions and potential therapeutic targets in the treatment of type I IFN-mediated diseases

c-Jun Proto-Oncoprotein Plays a Protective Role in Lung Epithelial Cells Exposed to Staphylococcal α-toxin

c-Jun is a member of the early mammalian transcriptional regulators belonging to the AP-1 family, which participates in a wide range of cellular processes such as proliferation, apoptosis, tumorigenesis, and differentiation. Despite its established role in cell survival upon stress, its participation in the stress response induced by bacterial infections has been poorly investigated. To study the potential role of c-Jun in this context we choose the widely studied α-toxin produced by Staphylococcus aureus, a pore-forming toxin that is a critical virulence factor in the pathogenesis of these bacteria. We analyzed the effect of α-toxin treatment in the activation, expression, and protein levels of c-Jun in A549 lung epithelial cells. Furthermore, we explored the role of c-Jun in the cellular fate after exposure to α-toxin. Our results show that staphylococcal α-toxin per se is able to activate c-Jun by inducing phosphorylation of its Serine 73 residue. Silencing of the JNK (c-Jun N-terminal Kinase) signaling pathway abrogated most of this activation. On the contrary, silencing of the ERK (Extracellular Signal-Regulated Kinase) pathway exacerbated this response. Intriguingly, while the exposure to α-toxin induced a marked increase in the levels of c-Jun transcripts, c-Jun protein levels noticeably decreased in the same time-frame as a consequence of active proteolytic degradation through the proteasome-dependent pathway. In addition, we established that c-Jun promoted cell survival when cells were challenged with α-toxin. Similarly, c-Jun phosphorylation was also induced in cells upon intoxication with the cytolysin produced by Vibrio cholerae in a JNK-dependent manner, suggesting that c-Jun-JNK axis would be a conserved responsive cellular pathway to pore-forming toxins. This study contributes to understanding the role of the multifaceted c-Jun proto-oncoprotein in cell response to bacterial pore-forming toxins, positioning it as a relevant component of the complex early machinery mounted to deal with staphylococcal infections.Fil: Moyano, Alejandro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Racca, Ana Cristina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Soria, Ramiro Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Saka, Hector Alex. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Andreoli, Veronica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Smania, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Sola, Claudia del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentin

A geospatial analysis of cardiometabolic diseases and their risk factors considering environmental features in a midsized city in Argentina

New approaches to the study of cardiometabolic disease (CMD) distribution include analysis of built environment (BE), with spatial tools as suitable instruments. We aimed to characterize the spatial dissemination of CMD and the associated risk factors considering the BE for people attending the Non-Invasive Cardiology Service of Hospital Nacional de Clinicas in Córdoba City, Argentina during the period 2015-2020. We carried out an observational, descriptive, cross-sectional study performing non-probabilistic convenience sampling. The final sample included 345 people of both sexes older than 35 years. The CMD data were collected from medical records and validated techniques and BE information was extracted from Landsat-8 satellite products. A geographic information system (GIS) was constructed to assess the distribution of CMD and its risk factors in the area. Out of the people sampled, 41% showed the full metabolic syndrome and 22.6% only type-2 diabetes mellitus (DM2), a cluster of which was evidenced in north-western Córdoba. The risk of DM2 showed an association with high values of the normalized difference vegetation index (NDVI) (OR= 0.81; 95% CI:-0.30 to 1.66; p=0.05) and low normalized difference built index (NDBI) values that reduced the probability of occurrence of DM2 (OR=-1.39; 95% CI:-2.62 to-0.17; p=0.03). Considering that the results were found to be linked to the environmental indexes, the study of BE should include investigation of physical space as a fundamental part of the context in which people develop medically within society. The novel collection of satellite-generated information on BE proved efficient.Fil: Campero, Micaela Natalia. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Scavuzzo, Carlos Matias. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Actividades Espaciales. Instituto de Altos Estudios Espaciales "Mario Gulich"; ArgentinaFil: Andreoli, Veronica. Comision Nacional de Actividades Espaciales. Instituto de Altos Estudios Espaciales "Mario Gulich"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Mileo, María Sol. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Franzois, Micaela Belén. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Oberto, María Georgina. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Gonzalez Rodriguez, Carla. Comision Nacional de Actividades Espaciales. Instituto de Altos Estudios Espaciales "Mario Gulich"; ArgentinaFil: Defagó, María Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentin

The efficacy of adding short-term psychodynamic psychotherapy to antidepressants in the treatment of depression:A systematic review and meta-analysis of individual participant data

Contains fulltext : 220185.pdf (Publisher’s version ) (Closed access)Purpose: We examined the efficacy of adding short-term psychodynamic psychotherapy (STPP) to antidepressants in the treatment of depression by means of a systematic review and meta-analysis of individual participant data, which is currently considered the most reliable method for evidence synthesis. Results: A thorough systematic literature search resulted in 7 studies comparing combined treatment of antidepressants and STPP versus antidepressant mono-therapy (n = 3) or versus antidepressants and brief supportive psychotherapy (n = 4). Individual participant data were obtained for all these studies and totaled 482 participants. Across the total sample of studies, combined treatment of antidepressants and STPP was found significantly more efficacious in terms of depressive symptom levels at both post-treatment (Cohen's d = 0.26, SE = 0.10, p = .01) and follow-up (d = 0.50, SE = 0.10, p < .001). This effect was most apparent at follow-up and in studies examining STPP's specific treatment efficacy. Effects were still apparent in analyses that controlled for risk of bias and STPP quality in the primary studies. Conclusions: These findings support the evidence-base of adding STPP to antidepressants in the treatment of depression. However, further studies are needed, particularly assessing outcome measures other than depression and cost-effectiveness, as well as examining the relative merits of STPP versus other psychotherapies as added to antidepressants.10 p

Monitoreo del virus del síndrome de la mancha blanca (WSSV) en muestras de langostino (Pleoticus muelleri) durante los años 2010 a 2014 en la Argentina

Argentine red shrimp (Pleoticus muelleri) fishery, one of the most important in the Argentine Sea, exceeded in 2016 50% of the total value of fishing exports. The implementation and development of health controls are requirements of international trade. Among the pathogens that affect crustaceans is the White spot syndrome virus (WSSV) and, according to the World Organisation for Animal Health (OIE), it is a mandatory reportable disease. Due to the need to count on scientific information to establish the sanitary state of the resource with respect to WSSV, the aim of this work was to continuously monitor the viral infection in wild red shrimp. Samples caught in areas close to Rawson port and San Jorge Gulf during 2010-2014 were studied. The total of 506 specimens analized with the nested PCR technique using the IQ2000TM WSSV Commercial Kit, a method validated by the OIE, were virus negative. It is concluded that during the five years of continuous monitoring there was no evidence of WSSV in Argentine red shrimp. In this study a scientific data base that would help to guarantee the sanitary quality and international trade for said fishery of commercial interest in Argentina is offered. In addition, tools that would allow to protect the product against possible sanctions and unnecessary trade barriers are provided.La pesquería de langostino (Pleoticus muelleri), una de las más importantes del Mar Argentino, superó en 2016 el 50% del valor total de las exportaciones pesqueras. La implementación y desarrollo de controles sanitarios son requisitos del comercio internacional. Entre los patógenos que afectan a los crustáceos se encuentra el virus del síndrome de la mancha blanca (White spot syndrome virus: WSSV) y, según lo establecido por la Organización Mundial de Sanidad Animal (OIE), la enfermedad es de declaración obligatoria. Debido a la necesidad de contar con datos científicos para establecer el estado sanitario del recurso respecto del WSSV, el objetivo del presente trabajo fue relevar en forma continua la infección viral en langostinos salvajes. Se trabajó con muestras capturadas durante 2010-2014 en áreas cercanas a puerto Rawson y el Golfo San Jorge. El total de 506 ejemplares analizados con la técnica de PCR anidada utilizando el Kit Comercial IQ2000TM WSSV, método validado por la OIE, resultaron negativos al virus. Se concluye que en los cinco años de monitoreo continuo no se evidenció presencia de WSSV en langostino. Este estudio ofrece una base de datos científicos que ayudaría a garantizar la calidad sanitaria y el comercio internacional de esta pesquería de interés comercial en la Argentina. Además, proporciona herramientas que permitirán proteger el producto ante posibles sanciones y barreras comerciales innecesarias

Krüppel-like factor 6 interferes with cellular transformation induced by the H- ras oncogene

KLF6 is a member of the Krüppel-like factor family of transcription factors with diverse roles in the regulation of cell physiology including proliferation, signal transduction, and apoptosis. Mutations or downregulation of klf6 have been described in several human cancers. In this work, we found that KLF6 knockdown resulted in the formation of transformed foci and allowed the spontaneous conversion of NIH3T3 cells to a tumorigenic state. We further assessed the role of KLF6 in the context of oncogenic Ras expression. KLF6 expression was up-regulated in cells expressing H-RasG12V in a Jun N-terminal Kinase-dependent manner, correlated with enhanced klf6 promoter activity. We also demonstrate that ectopic KLF6 expression induced a G1-phase cell cycle arrest, thereby decreasing cell proliferation rate. Additionally, constitutive KLF6 expression impaired H-RasG12V-mediated loss of density-dependent growth inhibition and anchorage-independent growth. Moreover, stably KLF6 expression reduced tumor growth in mice challenged with cells expressing H-RasG12V. KLF6 expression correlated with up-regulation of p21, whereas neither p53 induction nor apoptotic cell death was detected. Further, p21 knockdown impaired KLF6-induced G1 cell cycle arrest. These findings provide novel evidence highlighting KLF6 function in response to malignant transformation, suggesting a relevant activity of KLF6 in controlling cell proliferation and hindering tumorigenesis.Fil: Trucco, Lucas Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Andreoli, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Nuñez, Nicolás Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Exosome-delivered microRNAs promote IFN-α secretion by human plasmacytoid DCs via TLR7

The excessive production of type I IFNs is a hallmark and a main pathogenic mechanism of many autoimmune diseases, including systemic lupus erythematosus (SLE). In these pathologies, the sustained secretion of type I IFNs is dependent on the improper activation of plasmacytoid DCs (pDCs) by self-nucleic acids. However, the nature and origin of pDC-activating self-nucleic acids is still incompletely characterized. Here, we report that exosomes isolated from the plasma of SLE patients can activate the secretion of IFN-α by human blood pDCs in vitro. This activation requires endosomal acidification and is recapitulated by microRNAs isolated from exosomes, suggesting that exosome-delivered microRNAs act as self-ligands of innate single-stranded endosomal RNA sensors. By using synthetic microRNAs, we identified an IFN induction motif that is responsible for the TLR7-dependent activation, maturation, and survival of human pDCs. These findings identify exosome-delivered microRNAs as potentially novel TLR7 endogenous ligands able to induce pDC activation in SLE patients. Therefore, microRNAs may represent novel pathogenic mediators in the onset of autoimmune reactions and potential therapeutic targets in the treatment of type I IFN-mediated diseases

Perinatal exposure to bisphenol A (BPA) impairs neuroendocrine mechanisms regulating food intake and kisspetin system in adult male rats. Evidences of metabolic disruptor hypothesis

Bisphenol A (BPA) is a compound used in the polymerization of plastic polycarbonates. It is an endocrine disruptor and it has been postulated to be an obesogen. Our objective was to determine the influence of perinatal exposure to BPA on body weight, hormone levels, metabolic parameters and hypothalamic signals that regulate food intake and kisspeptin system in adult male rats. Male rats were exposed to 50 µg/kg/day of BPA or vehicle from day 9 of gestation to weaning in the drinking water. Since weaning, they were fed with control or high fat diet for 20 weeks. Perinatal exposure to BPA impaired glucose homeostasis, induced obesity and increased food intake in adult male rats altering hypothalamic signals, partially mimicking and/or producing an exacerbation of the effects of feeding fat diet. We also observed an increase in kisspeptin expression by BPA exposure. Evidences shown in this work support the metabolic disruptor hypothesis for BPAFil: Stoker, Cora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Andreoli, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Kass, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Bosquiazzo, Veronica Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Rossetti, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Canesini, Guillermina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Luque, Enrique Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; ArgentinaFil: Ramos, Jorge Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentin

Early onset of posterior reversible encephalopathy syndrome (PRES) during Cyclosporine-A infusion

[No abstract available

The Pathogenicity of Anti-β2GP1-IgG Autoantibodies Depends on Fc Glycosylation

To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity