Regulation of vascular smooth muscle cell bioenergetic function by protein glutathiolation

AbstractProtein thiolation by glutathione is a reversible and regulated post-translational modification that is increased in response to oxidants and nitric oxide. Because many mitochondrial enzymes contain critical thiol residues, it has been hypothesized that thiolation reactions regulate cell metabolism and survival. However, it has been difficult to differentiate the biological effects due to protein thiolation from other oxidative protein modifications. In this study, we used diamide to titrate protein glutathiolation and examined its impact on glycolysis, mitochondrial function, and cell death in rat aortic smooth muscle cells. Treatment of cells with diamide increased protein glutathiolation in a concentration-dependent manner and had comparably little effect on protein–protein disulfide formation. Diamide increased mitochondrial proton leak and decreased ATP-linked mitochondrial oxygen consumption and cellular bioenergetic reserve capacity. Concentrations of diamide above 200 μM promoted acute bioenergetic failure and caused cell death, whereas lower concentrations of diamide led to a prolonged increase in glycolytic flux and were not associated with loss of cell viability. Depletion of glutathione using buthionine sulfoximine had no effect on basal protein thiolation or cellular bioenergetics but decreased diamide-induced protein glutathiolation and sensitized the cells to bioenergetic dysfunction and death. The effects of diamide on cell metabolism and viability were fully reversible upon addition of dithiothreitol. These data suggest that protein thiolation modulates key metabolic processes in both the mitochondria and cytosol

A vocação da Amazônia é florestal e a criação de novos estados pode levar ao aumento do desflorestamento na Amazônia brasileira

The state of Pará has a rich diversity of ecosystems. However, it is one of the states that the most contribute with the deforestation of Amazonian. Actually, 22% of the state was deforested. Currently, a new policy of occupation is being studied for the Amazonian, based on the creation of new states. The creation of new states can increase deforestation in the Amazonian, especially in regions where the agricultural frontier and minerals activities are intense such as the state of Para. This study compares the changes of the representativeness of protected areas and deforestation, considering the proposed of division of the Para in three new states. The creation of new states can lead to a reduction or elimination of the protected areas resulting in the increase of the deforestation. Another serious consequence of the creation of new states will be the extinction of the Ecological-Economic Zoning of Para, an important instrument of public policy. The creation of new states must be preceded by studies involving the evaluation of the environmental, social and economic variables. One of the most serious consequences if it is not taken into consideration is the creation of a legal vacuum that will be used to increase the pressure on natural resources of the Amazon.O Pará detém uma rica diversidade de ecossistemas. Contudo, é um dos Estados que mais contribuem para o desmatamento na Amazônia. Atualmente, 22% do Estado foram desflorestados. Uma nova política de ocupação está sendo estudada para a Amazônia, baseada na criação de novos Estados. A criação de novos Estados pode aumentar o desmatamento na Amazônia, especialmente em regiões onde a fronteira agropecuária e mineraria é intensa como no Pará. Este estudo compara as mudanças da representatividade das áreas protegidas e do desmatamento, considerando a proposta de divisão do Estado do Pará em três novos Estados. A criação dos novos Estados pode levar a uma diminuição ou mesmo eliminação de algumas unidades de conservação, o que terá como consequência direta o aumento do desmatamento. Outra consequência grave da criação de novos Estados será a extinção do Zoneamento Ecológico-Econômico do Pará, um importante instrumento de políticas públicas. A criação de novos Estados deve ser precedida de estudos que envolvam uma avaliação criteriosa dos impactos ambientais, sociais e econômicos. Umas das consequências mais graves se isso não for levado em consideração é a criação de um vácuo jurídico que será aproveitado para aumentar a pressão nos recursos naturais da Amazônia

Targeting the Ataxia Telangiectasia Mutated-null Phenotype in Chronic Lymphocytic Leukemia with Pro-oxidants

Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumours with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia

Using virtual reality in criminological research

Since the pioneering early studies of the 1990s hinted at its promise as a research method, virtual reality (VR) technology has increasingly been used by social scientists. Given recent developments that have greatly enhanced realism, reduced costs, and increased possibilities for application, VR seems well on its way to become an established research tool in the social sciences. However, as with other ethodological innovations, the field of criminology hasbeen slow to catch on. To address this gap, this article explores the potential of VR as a tool for crime research. It provides readers with a brief and non-technical description of VR and its main elements and reviews severalapplications of VR in social scientific research that are potentially relevant for criminologists. By way of illustration, we identify and discuss in more detail different areas in which we think the field of criminology can particularly benefit from VR and offer suggestions for research. Some of the equipment available on the consumer market is also reviewed.In conjunction, the different sections should equip readers interested in applying VR in their own research with a fundamental understanding of what it entails and how it can be applied

Benefiting From Misfortune: When Harmless Actions Are Judged to Be Morally Blameworthy

Dominant theories of moral blame require an individual to have caused or intended harm. However, the current four studies demonstrate cases where no harm is caused or intended, yet individuals are nonetheless deemed worthy of blame. Specifically, individuals are judged to be blameworthy when they engage in actions that enable them to benefit from another’s misfortune (e.g., betting that a company’s stock will decline or that a natural disaster will occur). Evidence is presented suggesting that perceptions of the actor’s wicked desires are responsible for this phenomenon. It is argued that these results are consistent with a growing literature demonstrating that moral judgments are often the product of evaluations of character in addition to evaluations of acts

A novel approach to measure mitochondrial respiration in frozen biological samples.

Respirometry is the gold standard measurement of mitochondrial oxidative function, as it reflects the activity of the electron transport chain complexes working together. However, the requirement for freshly isolated mitochondria hinders the feasibility of respirometry in multi-site clinical studies and retrospective studies. Here, we describe a novel respirometry approach suited for frozen samples by restoring electron transfer components lost during freeze/thaw and correcting for variable permeabilization of mitochondrial membranes. This approach preserves 90-95% of the maximal respiratory capacity in frozen samples and can be applied to isolated mitochondria, permeabilized cells, and tissue homogenates with high sensitivity. We find that primary changes in mitochondrial function, detected in fresh tissue, are preserved in frozen samples years after collection. This approach will enable analysis of the integrated function of mitochondrial Complexes I to IV in one measurement, collected at remote sites or retrospectively in samples residing in tissue biobanks

Cultural theory and the dynamics of organizational change: the response of housing associations in London to the Housing Act 1988

The aim of this article is to consider the most effective way of conceptualizing a sector that has undergone radical change: the UK voluntary housing sector. The article considers existing accounts of housing associations and classifies these into five analytically distinct groups: practitioners, historical accounts, managerialist approaches, network theorists and institutionalist accounts. The main contention is that each of these is limited in explanatory potential, primarily due to their neglect of culture. This article proposes a more detailed framework for developing an understanding of the substantial changes affecting housing associations since the 1980s; that offered by "grid-group cultural theory". The article provides longitudinal qualitative data obtained from London housing associations to support the contention that organizational change can most usefully be understood by reference to the cultural themes of hierarchy and individualism. The article contends that cultural theory offers the opportunity to develop a systematic analysis that accounts for institutional history and organizational differentiation