Displacement of plasma protein and conduction velocity in rats under action of acceleration forces and hypokinesia

The permeability of capillary vessels was investigated in order to determine if acceleration alone or following prolonged hypokinesia would induce changes in the vascular wall leading to the penetration by l-albumins and/or proteins with larger molecules. In rats undergoing action of +5 Gz accelerations, no increase in vascular permeability, as tested with the use of (Cr-5k)-globulin, was demostrated. In rats immobilized for 4 weeks before centrifugation, rather weak migration of (Cr-51)-globulin from the vessels was observed. Immobilization resulted also in lowering of conduction velocity in the sciatic nerve

Residual subsidence analysis after the end of coalmine work. Example from Lorraine colliery, France

International audienceThis paper describes the residual movements associated with the deep coalmines. The studied case relates to works located into Lorraine coal basin. The paper is divided into two sections. The first one describes subsidence phenomena, especially the residual phase in terms of amplitude, duration and localization. The second one focus on Morsbach case: the total and residual subsidence measurements will be analyzed and compared to the state of the art as well as the currant knowledge. The results of the analysis show that the duration of residual movements does not exceed 24 months and their amplitude is about 5 % of total subsidence. We analyze also the declarations of the mining damage during and after the mining period. Damages occur, after this period are probably due to late observations.Cet article décrit les mouvements résiduels associés à l'exploitation des mines de charbon à grande profondeur. Le cas traité concerne le secteur de Morsbach, influencé par une exploitation de charbon en Lorraine. L'article se décompose en deux parties : la première partie décrit le phénomène d'affaissement, et particulièrement la phase résiduelle de l'affaissement (amplitude, durée, localisation), la deuxième partie est consacrée au cas de Morsbach, pour lequel nous analyserons les mesures d'affaissement (totales et résiduelles) par rapport à l'état de la connaissance. Les résultats de l'analyse montrent que la durée de l'affaissement résiduel ne dépasse pas 24 mois et que son amplitude est de l'ordre de 5 % de l'affaissement total. Nous avons également analysé les déclarations des dommages et des dégâts miniers pendant et après l'exploitation. Les dommages observés après l'arrêt des travaux sont probablement dus à des observations tardives

Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy

Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Here, we show that cytoplasmic lipid droplet (LD) accumulation, indicative of a lipogenic phenotype, is a cellular adaption to extracellular acidity. LD marker PLIN2 is strongly associated with poor overall survival in breast cancer patients. Acid-induced LD accumulation is triggered by activation of the acid-sensing G-protein-coupled receptor (GPCR) OGR1, which is expressed highly in breast tumors. OGR1 depletion inhibits acid-induced lipid accumulation, while activation by a synthetic agonist triggers LD formation. Inhibition of OGR1 downstream signaling abrogates the lipogenic phenotype, which can be rescued with OGR1 ectopic expression. OGR1-depleted cells show growth inhibition under acidic growth conditions in vitro and tumor formation in vivo. Isotope tracing shows that the source of lipid precursors is primarily autophagy-derived ketogenic amino acids. OGR1-depleted cells are defective in endoplasmic reticulum stress response and autophagy and hence fail to accumulate LDs affecting survival under acidic stress

Transforming bonds: ritualising post-mortem relationships in the Netherlands

People continue relationships with their dead in a variety of ways. Since the 1990s, the idea of ‘continuing bonds’ has provided a framework for exploring and understanding post-mortem relationships. However, the dynamics of the bonds between the living and the dead have received little attention. By looking at the intersection of things, practices and spaces, this paper demonstrates that expressions of continuing bonds do not always point to continuity, and indeed can signify discontinuity. It explores the ‘transforming bonds’ between the recently bereaved and their deceased in the Netherlands, illustrating how post-mortem relationships change and how such changes affect the social location of the deceased and the bereaved. By attending to the ritual dynamics of separation, transition and integration, two aspects of the social and material relationships between the living and the dead are highlighted. First, attention is given to the ways wherein the bereaved relocate their deceased through material objects within and outside of their homes, enabling them to renegotiate the absence–presence of the deceased. Second, the paper illustrates that personalised incorporation practices are inevitably linked to negotiations and contestations in the social sphere, and the norms and values of the social environment

Abortive Autophagy Induces Endoplasmic Reticulum Stress and Cell Death in Cancer Cells

Autophagic cell death or abortive autophagy has been proposed to eliminate damaged as well as cancer cells, but there remains a critical gap in our knowledge in how this process is regulated. The goal of this study was to identify modulators of the autophagic cell death pathway and elucidate their effects on cellular signaling and function. The result of our siRNA library screenings show that an intact coatomer complex I (COPI) is obligatory for productive autophagy. Depletion of COPI complex members decreased cell survival and impaired productive autophagy which preceded endoplasmic reticulum stress. Further, abortive autophagy provoked by COPI depletion significantly altered growth factor signaling in multiple cancer cell lines. Finally, we show that COPI complex members are overexpressed in an array of cancer cell lines and several types of cancer tissues as compared to normal cell lines or tissues. In cancer tissues, overexpression of COPI members is associated with poor prognosis. Our results demonstrate that the coatomer complex is essential for productive autophagy and cellular survival, and thus inhibition of COPI members may promote cell death of cancer cells when apoptosis is compromised

The Chaperone ClpX Stimulates Expression of Staphylococcus aureus Protein A by Rot Dependent and Independent Pathways

The Clp ATPases (Hsp100) constitute a family of closely related proteins that have protein reactivating and remodelling activities typical of molecular chaperones. In Staphylococcus aureus the ClpX chaperone is essential for virulence and for transcription of spa encoding Protein A. The present study was undertaken to elucidate the mechanism by which ClpX stimulates expression of Protein A. For this purpose, we prepared antibodies directed against Rot, an activator of spa transcription, and demonstrated that cells devoid of ClpX contain three-fold less Rot than wild-type cells. By varying Rot expression from an inducible promoter we showed that expression of Protein A requires a threshold level of Rot. In the absence of ClpX the Rot content is reduced below this threshold level, hence, explaining the substantially reduced Protein A expression in the clpX mutant. Experiments addressed at pinpointing the role of ClpX in Rot synthesis revealed that ClpX is required for translation of Rot. Interestingly, translation of the spa mRNA was, like the rot mRNA, enhanced by ClpX. These data demonstrate that ClpX performs dual roles in regulating Protein A expression, as ClpX stimulates transcription of spa by enhancing translation of Rot, and that ClpX additionally is required for full translation of the spa mRNA. The current findings emphasize that ClpX has a central role in fine-tuning virulence regulation in S. aureus

Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples