2,3,7,8-Tetrachlorodibenzo-p-dioxin alters steroid secretion but does not affect cell viability and the incidence of apoptosis in porcine luteinised granulosa cells

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a by-product of human industrial activity, was found to affect ovarian steroidogenesis in animals, but the mechanism of its action is still unclear. The aims of the study were to examine the effect of TCDD on (1) progesterone (P4) and oestradiol (E2) production by granulosa cells isolated from medium (3–6 mm) and preovulatory (≥ 8 mm) porcine follicles, (2) the viability of the cells, and (3) the incidence of apoptosis. Porcine granulosa cells were cultured (48 h) with or without TCDD (100 pM, 100 nM). Steroid hormone concentrations in the medium were determined by radioimmunoassay. The viability of granulosa cells was tested spectrophotometrically (alamarBlue™ assay). Apoptosis was evaluated by flow cytometry using Annexin V and by TUNEL assay. The higher dose of TCDD (100 nM) significantly inhibited P4 and stimulated E2 production by luteinised granulosa cells isolated from medium follicles. The lower dose of TCDD (100 pM) significantly stimulated P4 and inhibited E2 secretion by the cells isolated from preovulatory follicles. None of the two TCDD doses affected cell viability or induced apoptosis in granulosa cells. In conclusion, TCDD directly affected steroid production by granulosa cells obtained from mature pigs, but the effect of TCDD was not due to its cytotoxicity

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

The Potential Role of Metalloproteinases in Neurogenesis in the Gerbil Hippocampus Following Global Forebrain Ischemia

BACKGROUND: Matrix metalloproteinases (MMPs) have recently been considered to be involved in the neurogenic response of adult neural stem/progenitor cells. However, there is a lack of information showing direct association between the activation of MMPs and the development of neuronal progenitor cells involving proliferation and/or further differentiation in vulnerable (Cornus Ammoni-CA1) and resistant (dentate gyrus-DG) to ischemic injury areas of the brain hippocampus. PRINCIPAL FINDINGS: We showed that dynamics of MMPs activation in the dentate gyrus correlated closely with the rate of proliferation and differentiation of progenitor cells into mature neurons. In contrast, in the damaged CA1 pyramidal cells layer, despite the fact that some proliferating cells exhibited antigen specific characteristic of newborn neuronal cells, these did not attain maturity. This coincides with the low, near control-level, activity of MMPs. The above results are supported by our in vitro study showing that MMP inhibitors interfered with both the proliferation and differentiation of the human neural stem cell line derived from umbilical cord blood (HUCB-NSCs) toward the neuronal lineage. CONCLUSION: Taken together, the spatial and temporal profiles of MMPs activity suggest that these proteinases could be an important component in neurogenesis-associated processes in post-ischemic brain hippocampus

Ante las seguridades evanescentes. Riesgo y subjetividades en la ciudad de Guadalajara

Este artículo presenta los hallazgos de una investigación etnográfica sobre las formas en que los riesgos propios de la modernidad configuran subjetividades en distintas posi - ciones sociales de la ciudad de Guadalajara. El análisis se enfoca en la relación de los sujetos con las instituciones Estado , trabajo y familia , en los significados y en las prácti - cas que surgen en torno a la cotidianidad urbana marcada por la expansión de lo siniestro, y en las concepciones de lo común en el contexto de inseguridad. El riesgo se revela como un dispositivo de control con un fuerte poder individualizador y fragmen - tador, capaz de debilitar la agencia social y de exacerbar la actual precariedad de lo común

In the face of the evanescent securities. Risk and subjectivities in the city of Guadalajara

This article presents the results of an ethnographic research\ua0into the ways in which the risks inherent to modernity\ua0shape subjectivities in the city of Guadalajara in different social\ua0positions. The analysis focuses on the subjects’ relationship\ua0with State institutions, work and family; on the meanings\ua0and practices that appear in the context of urban daily\ua0life marked by the expansion of the ominous; and on the\ua0conceptions of community in the context of risk. The risk is\ua0revealed as a control apparatus with a strong individualizing power, able to weaken the social agency and to exacerbate the precariousness of the common

Paisajes movedizos: riesgo y subjetividades en una modernidad en crisis

El continuado ascenso de riesgo, incertidumbre e inseguridad constituye uno de los fenómenos de mayor trascendencia en las sociedades contemporáneas; su incidencia en las subjetividades es tan diversa como los factores que lo desencadenan. Esta tesis doctoral es fruto de investigación sobre las formas en que los riesgos propios a la modernidad configuran subjetividades en la ciudad de Guadalajara, en distintas posiciones sociales. El análisis se enfoca en cuestiones que cobran centralidad a partir de las narrativas de los sujetos-protagonistas de la investigación: la relación de los sujetos con las instituciones del Estado, el trabajo y la familia; los significados y las prácticas que surgen en torno a la cotidianidad urbana marcada por la expansión de lo siniestro; las concepciones de lo común en el contexto de riesgo; las creencias y su poder orientador y protector ante las amenazas; las visiones del futuro. A lo largo del análisis el riesgo se revela como un dispositivo de control con un fuerte poder individualizador y fragmentador, capaz de debilitar la agencia social y exacerbar la actual precariedad de lo común. Al desenmascarar la peligrosidad latente en los procesos de respuesta individual frente a los riesgos que fragmentan y rompen el tejido social, la investigación constituye un punto de partida para la reflexión sobre las posibilidades de la apertura de nuevas formas (plurales e incluyentes) de vínculos, reciprocidades y solidaridades. The continuous rise of risk, uncertainty and insecurity is one of the most significant phenomena in contemporary societies; its impact on the subjectivities is as diverse as the factors that trigger it. This dissertation is the result of research into the ways in which the risks inherent to modernity shape subjectivities in the city of Guadalajara in different social positions. The analysis focuses on issues that turn out crucial in the narratives of the subjects that are protagonists of this research: subject’s relationship with state institutions, work and family; the meanings and practices that appear in the context of urban daily life marked by the expansion of the ominous; the conceptions of community in the context of risk; the beliefs and their importance as orientation and protection in the face of hazard; the visions of the future. During the analysis the risk is revealed as a control apparatus with a strong individualizing power, able to weaken the social agency and to exacerbate the precariousness of the common. By revealing the underlying dangers of the processes of individual response to risks that fragment and weaken the social fabric, this research can be understood as a starting point for reflection on the possibilities of opening up new forms of plural and inclusive links, reciprocity and solidarity

Architecture, City, People, and Structure

Architecture and structure are the basis for working, living, and resting for almost every human being [...

Composition of inflammatory infiltrate and its correlation with HBV/HCV antigen expression

AIM: To study the composition of liver inflammatory infiltrate in biopsy material from patients chronically infected with hepatotropic viruses and to evaluate the correlation of inflammatory infiltrate with hepatitis B virus (HBV) and hepatitis C virus (HCV) viral antigen expression in chronic B and C hepatitis