Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and a leading cause of neurological disability. The complex immunopathology and variable disease course of multiple sclerosis have limited effective treatment of all patients. Altering the metabolism of immune cells may be an attractive strategy to modify their function during autoimmunity. We examined the effect of inhibiting fatty acid metabolism in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Mice treated with an inhibitor of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme in the beta-oxidation of fatty acids, showed a reduction in disease severity as well as less inflammation and demyelination. Inhibition of CPT-1 in encephalitogenic T-cells resulted in increased apoptosis and reduced inflammatory cytokine production. These results suggest that disruption of fatty acid metabolism promotes downregulation of inflammation in the CNS and that this metabolic pathway is a potential therapeutic target for multiple sclerosis

Abandoned Dwellings in Beirut. Wars and Transformation of the Urban Space : 1860-2015

Dans un Beyrouth en pleine mutation, les habitats délaissés sont des lieux en suspens, condamnés à terme par la spéculation foncière. Notre recherche se propose d’examiner les transformations subies par ces architectures hors d’usage. Basé sur le terrain (près de 750 édifices répertoriés), les archives, témoignages et histoires orales, le travail réévalue également les pratiques artistiques et les regards qu’elles ont posé sur la ville. Cette imprégnation est d’autant plus importante que son déclencheur est un projet photographique entamé par l’auteur sur ce sujet. Trois chapitres sont consacrés aux interventions guerrières. Le premier, la bataille des hôtels aborde un espace disputé, le second explore la ligne de démarcation et le troisième s’intéresse aux baraquements, prisons et lieux de torture. Le quatrième chapitre réunit habitats informels, squats et autres réappropriations. Ces fonctionnalités qui s’enchevêtrent découlent de flux migratoires consécutifs à des violences. La guerre, plutôt les guerres, restent en toile de fond.In a rapidly changing Beirut, neglected dwellings are places in abeyance, condemned to disappear as a result of land speculation. Our research aims at examining the transformations that these obsolete architectures undergo. The study, carried on site (nearly 750 buildings have been identified), based on archives, testimonies and oral history, also re-examines artistic endeavours and the way artists have viewed the city, which is particularly important considering that its trigger has been a photographic project undertaken by the author. Three chapters are devoted to belligerent activities. The first, on the “Battle of the hotels”, addresses contested space; the second explores the demarcation line and the third examines the military barracks, prisons, and torture centres. The fourth covers informal dwellings, squatted buildings and other reappropriations. It observes the background of entangled features stemming from migration flows that were triggered by the violence of war, or rather wars

Metabolic Regulation of Caspase-2

<p>Apoptosis is a form of programmed cellular "suicide" which is activated in response to a variety of pro-death stimuli. Apoptotic cell death is orderly and energy-dependent, and cellular constituents are packaged into membrane-bound vesicles for consumption by phagocytes. Toxic intracellular signals are never exposed to neighboring cells or to the extracellular environment, and a host inflammatory response does not occur. Apoptosis is executed by the coordinated activation of caspase family proteins. Caspase-2 is an apical protease in this family, and promotes cell death after receipt of cues from intracellular stressor signals. Caspase-2 helps to initiate apoptosis by responding to cellular death stimuli and signaling for downstream cytochrome c release and executioner caspase activation.</p><p> Several years ago our lab determined that Xenopus laevis oocyte death is partly controlled by the activation of caspase-2. In the setting of oocyte or egg extract nutrient depletion, caspase-2 was observed to be activated upstream of mitochondrial cytochrome c. In fact, caspase-2 is suppressed in response to the nutrient status of the oocyte: nutrient-replete oocytes with healthy pentose phosphate pathway flux and abundant NADPH production are able to inhibit caspase-2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. Phosphorylation of caspase-2 at S135 is critical in preventing oocyte cell death, and a caspase-2 mutant unable to be phosphorylated loses its ability to respond to suppressive NADPH signals. </p><p> In this dissertation we examine the converse mechanism of metabolically-regulated caspase-2 activation in the Xenopus egg extract. We now show that caspase-2 phosphorylated at S135 binds the interactor 14-3-3 zeta, thus preventing caspase-2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1, which directly binds caspase-2. Although caspase-2 dephosphorylation is responsive to metabolism, neither PP1 activity nor binding is metabolically regulated. Rather, release of 14-3-3 zeta from caspase-2 is the point of metabolic control and allows for caspase-2 dephosphorylation. Accordingly, a caspase-2 mutant unable to bind 14-3-3 zeta is highly susceptible to activation. Although this mechanism was initially established in Xenopus, we now demonstrate similar control of murine caspase-2 by phosphorylation and 14-3-3 binding in mouse eggs. </p><p> In the second part of this dissertation we examine the paradigm of caspase-2 metabolic regulation in a mammalian somatic cell context. We observed that mammalian caspase-2 is a metabolically-regulated phosphoprotein in somatic cells, and that the site of regulation is caspase-2 S164. Phosphorylation at S164 appears to inhibit mammalian caspase-2 by preventing its induced proximity oligomerization, thus also preventing procaspase-2 autocatalytic processing. We further identify some of the molecular machinery involved in S164 phosphorylation and demonstrate conservation with the validated Xenopus regulators. Interestingly, we extend the findings of caspase-2 phosphorylation to a study of ovarian cancer, and show that caspase-2 S164 phosphorylation might be involved in determining cancer cell chemosensitivity. We further provide evidence that chemosensitivity can be modulated by the cellular metabolic status in a caspase-2-dependent manner. Thus, we have identified a novel phosphorylation site on mammalian caspase-2 in somatic cells, and are working further to understand the implications of caspase-2 signaling in the context of cancer cell responsiveness to chemotherapeutic treatments.</p>Dissertatio

Subscapular system free flaps for oromandibular reconstruction

The subscapular system can confer numerous flaps for the reconstruction of composite mandibular defects. This chapter aims to review the indications, advantages, and anatomy of subscapular system flaps in the reconstruction of the mandible. The subscapular system can serve as an alternative to the fibula free flap in the presence of significant atherosclerotic disease or other contraindications. The flexibility and abundance of its soft tissue components make this system particularly advantageous for complex composite defects. Avoiding a fibula free flap for osseous reconstruction of the mandible permits early patient mobilization and may prevent adverse postoperative complications. A long pedicle can be harvested with subscapular flaps, which may prove useful in the face of limited available recipient vessels. Critics of the subscapular system cite longer operative times due to the need for patient repositioning and concerns over the integrity of the bone stock. Positioning modifications may permit a two-team approach to subscapular reconstruction, thus limiting operative times. Subscapular harvest does incur shoulder morbidity; however, this does not appear to affect the quality of life significantly. The flap is reliable and can support endosseous implants if properly planned, though it may be more susceptible to bone resorption when compared to the fibula. Overall, the subscapular system remains a versatile donor that can achieve ideal reconstructive outcomes with minimal morbidity