Mycobacterium tuberculosis multi-drug-resistant strain M induces IL-17+ IFNγ- CD4+ T cell expansion through an IL-23 and TGF-β-dependent mechanism in patients with MDR-TB tuberculosis

We have previously reported that T cells from patients with multidrug-resistant tuberculosis (MDR-TB) express high levels of IL-17 in response to the MDR strain M(Haarlem family) of Mycobacterium tuberculosis (M.tuberculosis). Herein, we explore the pathways involved in the induction of h17 cells in MDR-TB patients and healthy tuberculin reactors (PPD+HD) by the M strain and the laboratory strain H37Rv. Our results show that IL-1β and IL-6 are crucial for the H37Rv and M-induced expansion of IL-17+IFNγ¯ and IL-17+IFNγ+ in CD4+ T cells from MDR-TB and PPD+HD. IL-23 plays an ambiguous role in Th1 and Th17 profiles: alone, IL-23 is responsible for M.tuberculosis induced IL-17 and IFNγ expression in CD4+ T cells from PPD+HD whereas, together with TGF-β, it promotes IL-17+IFNγ¯ expansion in MDR-TB. In fact, spontaneous and M.tuberculosis-induced TGF-β secretion is increased in cells from MDR-TB being theM strain the highest inducer. Interestingly, TLR-2 signaling mediates the expansion of IL-17+IFNγ¯ cells and the enhancement of latency-associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR-TB, which suggests that M strain promotes IL-17+IFNγ¯ T cells through a strong TLR-2-dependent TGF-β production by antigenpresenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR-TB patients infected with MDR Haarlem strains show higher IL-17+IFNγ¯ and lower IL-17+IFNγ+ levels than LAM-infected patients. The present findings deepen our understanding on the role of IL-17 in MDR-TB and highlight the influence of the genetic background of the infecting M.tuberculosis strain on the ex vivo Th17 response.Fil: Basile, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Kviatcovsky, Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Romero, María Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Monteserin, Johana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: Ritacco, Gloria Viviana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: López, Beatriz. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: Sabio y García, Carmen Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: García, A.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Vescovo, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Gonzalez Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Palmero, Domingo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: de la Barrera, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming

[EN] The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming holds great potential for modeling human diseases. However, the reprogramming process remains very inefficient and a better understanding of its basic biology is required. The mesenchymal-to-epithelial transition (MET) has been recognized as a crucial step for the successful reprogramming of fibroblasts into iPSCs. It has been reported that the p53 tumor suppressor gene acts as a barrier of this process, while its homolog p63 acts as an enabling factor. In this regard, the information concerning the role of the third homolog, p73, during cell reprogramming is limited. Here, we derive total Trp73 knockout mouse embryonic fibroblasts, with or without Trp53, and examine their reprogramming capacity. We show that p73 is required for effective reprogramming by the Yamanaka factors, even in the absence of p53. Lack of p73 affects the early stages of reprogramming, impairing the MET and resulting in altered maturation and stabilization phases. Accordingly, the obtained p73-deficient iPSCs have a defective epithelial phenotype and alterations in the expression of pluripotency markers. We demonstrate that p73 deficiency impairs the MET, at least in part, by hindering BMP pathway activation. We report that p73 is a positive modulator of the BMP circuit, enhancing its activation by DNp73 repression of the Smad6 promoter. Collectively, these findings provide mechanistic insight into the MET process, proposing p73 as an enhancer of MET during cellular reprogramming.S

Patients with Multidrug-Resistant Tuberculosis display impaired Th1 responses and enhanced regulatory T-Cell levels in response to an outbreak of Multidrug-Resistant Mycobacterium tuberculosis M and Ra Strains

Fil: Geffner, Laura. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Yokobori, Noemi. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Basile, Juan. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Schierloh, Pablo. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Balboa, Luciana. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Mercedes Romero, María. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Ritacco, Viviana. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Vescovo, Marisa. Hospital Muñiz. Instituto de Tisioneumonología; Argentina.Fil: Gonzalez Montaner, Pablo. Hospital Muñiz. Instituto de Tisioneumonología; Argentina.Fil: López, Beatriz. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Barrera, Lucía. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Alemán, Mercedes. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Sasiain, María C. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: de la Barrera, Silvia. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Abbate, Eduardo. Hospital Muñiz. Instituto de Tisioneumonología; Argentina.In Argentina, multidrug-resistant tuberculosis (MDR-TB) outbreaks emerged among hospitalized patients with AIDS in the early 1990s and thereafter disseminated to the immunocompetent community. Epidemiological, bacteriological, and genotyping data allowed the identification of certain MDR Mycobacterium tuberculosis outbreak strains, such as the so-called strain M of the Haarlem lineage and strain Ra of the Latin America and Mediterranean lineage. In the current study, we evaluated the immune responses induced by strains M and Ra in peripheral blood mononuclear cells from patients with active MDR-TB or fully drug-susceptible tuberculosis (S-TB) and in purified protein derivative-positive healthy controls (group N). Our results demonstrated that strain M was a weaker gamma interferon (IFN-gamma) inducer than H37Rv for group N. Strain M induced the highest interleukin-4 expression in CD4(+) and CD8(+) T cells from MDR-and S-TB patients, along with the lowest cytotoxic T-lymphocyte (CTL) activity in patients and controls. Hence, impairment of CTL activity is a hallmark of strain M and could be an evasion mechanism employed by this strain to avoid the killing of macrophages by M-specific CTL effectors. In addition, MDR-TB patients had an increased proportion of circulating regulatory T cells (Treg cells), and these cells were further expanded upon in vitro M. tuberculosis stimulation. Experimental Treg cell depletion increased IFN-gamma expression and CTL activity in TB patients, with M-and Ra-induced CTL responses remaining low in MDR-TB patients. Altogether, these results suggest that immunity to MDR strains might depend upon a balance between the individual host response and the ability of different M. tuberculosis genotypes to drive Th1 or Th2 profiles

Differential Expression of Immunogenic Proteins on Virulent Mycobacterium tuberculosis Clinical Isolates

Molecular epidemiology has revealed that Mycobacterium tuberculosis (Mtb), formerly regarded as highly conserved species, displays a considerable degree of genetic variability that can influence the outcome of the disease as well as the innate and adaptive immune response. Recent studies have demonstrated that Mtb families found worldwide today differ in pathology, transmissibility, virulence, and development of immune response. By proteomic approaches seven proteins that were differentially expressed between a local clinical isolate from Latin-American-Mediterranean (LAM) and from Haarlem (H) lineages were identified. In order to analyze the immunogenic ability, recombinant Rv2241, Rv0009, Rv0407, and Rv2624c proteins were produced for testing specific antibody responses. We found that these proteins induced humoral immune responses in patients with drug-sensitive and drug-resistant tuberculosis with substantial cross-reactivity among the four proteins. Moreover, such reactivity was also correlated with anti-Mtb-cell surface IgM, but not with anti-ManLAM, anti-PPD, or anti-Mtb-surface IgG antibodies. Therefore, the present results describe new Mtb antigens with potential application as biomarkers of TB

X-ray cross-complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients

Purpose: 5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. Methods and Materials: A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m2/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). Results: The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p =.003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p =.02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR-C677 and MTHFR-A1298 expression. Conclusions: XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil

Vitamin E dietary supplementation improves neurological symptoms and decreases c-Abl/p73 activation in niemann-pick C mice

Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. We have previously reported that oxidative stress is the main upstream stimulus activating the proapoptotic c-Abl/p73 pathway in NPC neurons. We have also observed accumulation of vitamin E in NPC lysosomes, which could lead to a potential decrease of its bioavailability. Our aim was to determine if dietary vitamin E supplementation could improve NPC disease in mice. NPC mice received an alpha-tocopherol (α-TOH) supplemented diet and neurological symptoms, survival, Purkinje cell loss, α-TOH and nitrotyrosine levels, astrogliosis, and the c-Abl/p73 pathway functions were evaluated. In addition, the effect of α-TOH on the c-Abl/p73 pathway was evaluated in an in vitro NPC neuron model. The α-TOH rich diet delayed loss of weight, improved coordination and locomotor function and increased the survival of NPC mice. We found increased Purkinje neurons and α-TOH levels and reduced astrogliosis, nitrotyrosine and phosphorylated p73 in cerebellum. A decrease of c-Abl/p73 activation was also observed in the in vitro NPC neurons treated with α-TOH. In conclusion, our results show that vitamin E can delay neurodegeneration in NPC mice and suggest that its supplementation in the diet could be useful for the treatment of NPC patients.This study was supported by grants from the Fondo Nacional de Desarrollo Científico y/nTecnológico (FONDECYT) (grant numbers 1120512 to A.R.A, and 1110310 to S.Z); Fondo de/nFomento al Desarrollo Científico y Tecnológico FONDEF D10I1077 (to A.R.A and S.Z.);/nFondo Nacional de Desarrollo de Areas Prioritarias, FONDAP, Project no. 15090007, Center for/nGenome Regulation (CGR) to S.Z.; Generalitat de Catalunya (SGR2009-1369) and La Marató de TV3/n(No. 100310

Resúmenes proyectos de investigación en Psicología con financiamiento del fondo nacional de desarrollo científico y tecnológico - FONDECYT, aprobados año 2011

During 2011 the Grants from FONDECYT for Regular Competitions 2012 and for Introduction to Research 2011 were resolved. For Introduction to Research, 525 projects was submitted and 262 projects were approved. Of these, 7 corresponded to Psychology (from a total of 12 projects nominated), with an amount of 322.630 million pesos, representing 2,3% of total awarded funding in this category. In Regular Competition, from 1164 projects submitted for funding and 605 were approved. Of these, 11 projects are from Psychology (out of 23 submitted), valued at 620.406 million, equivalent to 1.0% of the total amount allocated for this competition. In this special report, all summaries from projects approved in the area are presented. They began to run in November 2011 (Introduction) and will run until the period 2013-2014.Durante el año 2011 se resolvieron los concursos FONDECYT regular 2012 y de Iniciación a la investigación 2011. En el concurso de Iniciación a la Investigación, se presentaron 525 proyectos, de los cuales fueron aprobaron 262. De estos, 7 corresponden a Psicología (de un total de 12 proyectos postulados), por un valor de 322.630 millones de pesos, lo que constituye el 2,3% del total del financiamiento otorgado en esta categoría. En el concurso regular, de 1164 proyectos postulados, se aprobaron para financiamiento 605. De estos, 11 proyectos corresponden a Psicología (de un total de 23 presentados), por un valor de 620.406 millones, lo que equivale al 1,0% del monto total asignado a este concurso. Se presentan en este artículo especial, los resúmenes de la totalidad de proyectos aprobados para el área, los cuales comenzaron a ejecutarse en noviembre del 2011 (iniciación) y que estarán ejecutándose hasta el periodo 2013-2014

Inclusión de los alumnos con necesidades específicas de apoyo educativo. Una propuesta para el alumnado de la Facultad de Educación.

Depto. de Investigación y Psicología en EducaciónFac. de EducaciónFALSEsubmitte