Activation of innate and specific immune responses in hemolytic uremic syndrome (HUS)- patients

La función primaria del sistema inmunológico es preservar al individuo sano frente a infinidad de agentes microbianos patógenos o injuriantes. Sin embargo, en determinadas circunstancias los mecanismos agresores normalmente montados contra un agente invasor, pueden tornarse altamente injuriantes para el propio individuo. Hay importantes evidencias tanto clínicas como experimentales, de que la reacción inflamatoria inducida por los distintos componentes de las bacterias Escherichia coli productoras de toxina Shiga (Stx) (STEC), fundamentalmente la Stx y los lipopolisacáridos (LPS), contribuye decisivamente en la evolución a la forma completa de SUH Así los pacientes al ser diagnosticados de SUH, presentan evidencias de haber sufrido un proceso de activación del sistema inmune innato, o reacción inflamatoria muy aguda y temprana en la evolución de la enfermedad. Algunas de estas evidencias pueden resumirse como: una neutrofilia marcada, leucocitos neutrófilos (PMN) circulantes que se encuentran “agotados o exhaustos”, los monocitos diferenciados hacia un fenotipo inflamatorio (menor expresión de CD14 y aumento de CD16), y se encuentra un significativo descenso en los leucocitos que presentan el receptor para la quimioquina Fractalquina (FKN, CX3CL1)) (CX3CR1): los. monocitos clásicos y células Natural Killer (NK). Estas células tienen un alto potencial citotóxico. La FKN se expresa en endotelio y epitelio renal y ha sido involucrada en los mecanismos patogénicos en distintas nefropatías. Llamativamente, encontramos una correlación significativa entre la severidad del cuadro renal y las alteraciones mencionadas. Por último se discute el papel protector que la respuesta inmune específica podría ejercer, fundamentalmente a través de la producción de anticuerpos neutralizantes de la Stx.The central role of the immune system is the preservation of the health against several pathogenic microbes and injury agents. However, on special conditions defensive mechanisms triggered towards the foreign agent can damage the host. Clinical and experimental evidence indicate that inflammatory reaction triggered by the main components of Shiga toxin (Stx)- producing Escherichia coli (STEC), participate in the evolution to the complete form of HUS. When children are diagnosed of HUS, they present evidence that have suffered a very strong and early inflammatory response. These features include: the presence of a marked neutrophilia, the polymorfonuclear leucocytes (PMN) are “deactivated or exhausted” and the monocytes are differentiated towards an inflammatory phenotype (CD14-reduced and CD16-enhanced membrane expression). In addition, HUS-patients show a marked reduction in the absolute and relative number of leucocytes carrying the receptor (CX3CR1) for the chemokine “Fractalkine” (FKN, CX3 CL1), which are the classic monocytes and Natural Killer cells (NK). All these cells express a high cytotoxic potencial. The chemokine FKN is expressed in endothelial and epithelial renal cells, and is involved in the pathogenic mechanism of different nephropathies. Noteworthy, we found a significant correlation between the severity of the renal damage (as days of anuria) and the alterations described above. Finally, the protective role of specific immune response, mainly through the antibody production with Stx-neutralizing capacity, is discussed.Fil: Palermo, Marina Sandra. Academia Nacional de Medicina de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernandez, Gabriela C.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Ramos, Maria Victoria. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Bentancor, Leticia. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Fernández Brando, Romina Jimena. Academia Nacional de Medicina de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dran, Graciela I.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Isturiz, Martín Amadeo. Academia Nacional de Medicina de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

The dark side of curvature

Geometrical tests such as the combination of the Hubble parameter H(z) and the angular diameter distance d_A(z) can, in principle, break the degeneracy between the dark energy equation of state parameter w(z), and the spatial curvature Omega_k in a direct, model-independent way. In practice, constraints on these quantities achievable from realistic experiments, such as those to be provided by Baryon Acoustic Oscillation (BAO) galaxy surveys in combination with CMB data, can resolve the cosmic confusion between the dark energy equation of state parameter and curvature only statistically and within a parameterized model for w(z). Combining measurements of both H(z) and d_A(z) up to sufficiently high redshifts around z = 2 and employing a parameterization of the redshift evolution of the dark energy equation of state are the keys to resolve the w(z)-Omega_k degeneracy.Comment: 18 pages, 9 figures. Minor changes, matches version accepted in JCA

Trigger efficiencies of a proposed beam monitoring detector (BeBe) for p+p collisions at NICA energies

The Multipurpose Detector (MPD) consists of a typical array of sub-detectors to study the nuclear matter originating from the collisions of beams provided by the Nuclotron-based Ion Collider fAcility (NICA). A beam monitoring detector~(BeBe) is proposed for stage 2 of MPD to increase the trigger capabilities. BeBe is constituted of two plastic scintillator disks segmented in 80 cells $\pm~2~m$ away from the interaction point of MPD. Laboratory measurements to obtain the energy resolution of an individual BeBe cell prototype are presented. It is shown that an energy resolution of $22\pm6\%$ can be obtained. Based on Monte Carlo simulations, the trigger efficiencies of the BeBe are presented for p+p collisions at 11~GeV considering a threshold in the energy loss of the charged particles reaching the detector

Shelves of the Iberian Peninsula and the Balearic Islands (I): Morphology and sediment types

Here we present a synthesis of bedforms and sediment types on the shelves surrounding the Iberian Peninsula and the Balearic Islands, after the integration several pieces of bathymetric, morphological and sedimentological datasets. The Iberian and Balearic shelves are divided into segments according to the largescale margin configuration, fluvial sediment supply and hydrodynamic regime. Their geological settings and large-scale sedimentation patterns place the investigated shelves into two broad categories: abrupt, steep and narrow sediment-starved shelves, illustrated by the Cantabrian shelf, and gentle, smooth and wide sediment- fed shelves, such as the shelves off some major flivial systems. An in-depth classification was subsequently attempted, based on morpho-sedimentary types. Under this approach, the Iberian and Balearic shelves can be classified as: (1) storm-dominated shelves, with erosional rocky floors, frequent abrasion surfaces and coarse-grained sediments; (2) current-dominated shelves, showing a good equilibriumbetween sediment fluxes and coastal and shallow ocean circulation, with laterally extensive muddy belts; (3) sediment supply-dominated shelves, where extensive subaqueous deltas develop off river mouths; and (4) wave-dominated shelves that occur off coastal stretches with minor and/or multiple fluvial sediment sources and enhanced littoral current

Boletín NUESTRA AMÉRICA XXI - Desafíos y alternativas, num.61, Noviembre 2021

Una excelente iniciativa del Grupo de Trabajo Crisis y economía mundial, coordinado por María Josefina Morales, Julio Gambina y Gabriela Roffinelli

Boletín NUESTRA AMÉRICA XXI - Desafíos y alternativas, num.71, Septiembre 2022

La ortodoxia en la política económica agrava las tendencias recesivas de la economía mundial, al tiempo que la inflación sostenida condiciona soluciones para satisfacer demandas sociales. En el simposio de política económica patrocinado por el Banco de la Reserva Federal de Kansas City, Jackson Hole, Wyoming, bajo el título: “Reevaluación de las restricciones en la economía y la política”, Jerome Powell, el titular de FED, no fue tan optimista como en la versión pasada de hace un año, señaló entonces, en 2021, que la inflación era un fenómeno pasajero y había capacidad de resolver la situación a corto plazo. La realidad fue muy distinta y no se cumplieron las previsiones. No es solo la guerra en Ucrania, sino limitaciones que presenta el capitalismo en general y en especial el estadounidense. Son problemas que viene de arrastre, del 2007-09, aunque también del 2001 estadounidense

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10<sup>−8</sup>, OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60×10<sup>−7</sup>, OR = 0.84, CI 95% = 0.78–0.90; rs10488631: P = 7.53×10<sup>−20</sup>, OR = 1.63, CI 95% = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10<sup>−22</sup>, OR = 1.75, CI 95% = 1.56–1.97) better explained the observed association (likelihood P-value = 1.48×10<sup>−4</sup>), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific

Brucella abortus–infected platelets modulate the activation of neutrophils

Brucellosis is a contagious disease caused by bacteria of the genus Brucella. Platelets (PLTs) have been widely involved in the modulation of the immune response. We have previously reported the modulation of Brucella abortus–mediated infection of monocytes. As a result, PLTs cooperate with monocytes and increase their inflammatory capacity, promoting the resolution of the infection. Extending these results, in this study we demonstrate that patients with brucellosis present slightly elevated levels of complexes between PLTs and both monocytes and neutrophils. We then assessed whether PLTs were capable of modulating functional aspects of neutrophils. The presence of PLTs throughout neutrophil infection increased the production of interleukin‐8, CD11b surface expression and reactive oxygen species formation, whereas it decreased the expression of CD62L, indicating an activated status of these cells. We next analyzed whether this modulation was mediated by released factors. To discriminate between these options, neutrophils were treated with supernatants collected from B. abortus–infected PLTs. Our results show that CD11b expression was induced by soluble factors of PLTs but direct contact between cell populations was needed to enhance the respiratory burst. Additionally, B. abortus–infected PLTs recruit polymorphonuclear (PMN) cells to the site of infection. Finally, the presence of PLTs did not modify the initial invasion of PMN cells by B. abortus but improved the control of the infection at extended times. Altogether, our results demonstrate that PLTs interact with neutrophils and promote a proinflammatory phenotype which could also contribute to the resolution of the infection.Fil: Trotta, Aldana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Milillo, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Serafino, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Castillo Montañez, Luis Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Birnberg Weiss, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Delpino, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Giambartolomei, Guillermo Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Fernández, Cecilia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Barrionuevo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Impact of the Reticular Stress and Unfolded Protein Response on the inflammatory response in endometrial stromal cells

During decidualization, endometrial stromal cells undergo reticular stress (RS) and unfolded protein response (UPR), allowing the endoplasmic reticulum-expansion and immunomodulators production. Physiological RS generates the activation of sensing proteins, inflammasome activation and mature-IL-1β secretion, associated with pro-implantatory effects. We focus on the impact of RS and UPR on decidualized cells and whether they induce a physiological sterile inflammatory response through IL-1β production. Human endometrial stromal cell line (HESC) after decidualization treatment with MPA + dibutyryl-cAMP (Dec) increased the expression of RS-sensors (ATF6, PERK and IRE1α) and UPR markers (sXBP1 and CHOP) in comparison with Non-dec cells. Then we found increased NLRP3 expression in Dec cells compared with Non-dec cells. In fact STF-083010 (an IRE1α inhibitor) prevented this increase. Downstream, increased levels of active caspase-1 on Dec cells were detected by FAM-Flica Caspase-1 associated with an increase in IL-1β production. Moreover, the treatment with STF-083010 decreased the invasion index observed in Dec cells, evaluated by an in vitro model of implantation. In endometrial biopsies from recurrent spontaneous abortion patients an increased expression of IRE1α was found in comparison with fertile women; while recurrent implantation failure samples showed a lower expression of sXBP1, TXNIP and NLRP3 than fertile women, suggesting that RS/UPR tenors might condition endometrial receptivity.Fil: Grasso, Esteban Nicolas. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Gori, María Soledad. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Soczewski, Elizabeth Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández, Laura del Carmen. Universidad de Buenos Aires; ArgentinaFil: Gallino, Lucila. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Vota, Daiana Marina. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Martínez, G.. Universidad de Buenos Aires; ArgentinaFil: Irigoyen, M.. Fertilidad San Isidro; ArgentinaFil: Ruhlmann, C.. Fertilidad San Isidro; ArgentinaFil: Lobo, T.F.. Department of Obstetrics, Universidade Federal de São Paulo, São Paulo, Brazil; BrasilFil: Salamone, Gabriela Veronica. Universidade Federal de Sao Paulo;Fil: Mattar, Rosana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Daher, S.. Universidade Federal de Sao Paulo; . Department of Obstetrics, Universidade Federal de São Paulo, São Paulo, Brazil; BrasilFil: Perez Leiros, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Ramhorst, Rosanna Elizabeth. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc