28 research outputs found
The Role of ULK1 in the Pathophysiology of Osteoarthritis
L'arthrose est la maladie musculo-squelettique la plus commune dans le monde. Elle est l'une des principales causes de douleur et dāincapaciteĢ chez les adultes, et elle repreĢsente un fardeau consideĢrable sur le systeĢme de soins de santeĢ. L'arthrose est une maladie de lāarticulation entieĢre, impliquant non seulement le cartilage articulaire, mais aussi la synoviale, les ligaments et lāos sous-chondral. Lāarthrose est caracteĢriseĢe par la deĢgeĢneĢrescence progressive du cartilage articulaire, la formation dāosteĢophytes, le remodelage de l'os sous-chondral, la deĢteĢrioration des tendons et des ligaments et l'inflammation de la membrane synoviale. Les traitements actuels aident seulement aĢ soulager les symptoĢmes preĢcoces de la maladie, cāest pour cette raison que l'arthrose est caracteĢriseĢe par une progression presque ineĢvitable vers la phase terminale de la maladie.
La pathogeĢnie exacte de l'arthrose est encore inconnue, mais on sait que l'eĢveĢnement cleĢ est la deĢgradation du cartilage articulaire. Le cartilage articulaire est composeĢ uniquement des chondrocytes; les cellules responsables de la syntheĢse de la matrice extracellulaire et du maintien de l'homeĢostasie du cartilage articulaire. Les chondrocytes maintiennent la matrice du cartilage en remplacĢ§ant les macromoleĢcules deĢgradeĢes et en reĢpondant aux leĢsions du cartilage et aux deĢgeĢneĢrescences focales en augmentant l'activiteĢ de syntheĢse locale. Les chondrocytes ont un taux faible de renouvellement, cāest pour cette raison quāils utilisent des meĢcanismes endogeĢnes tels que l'autophagie (un processus de survie cellulaire et dāadaptation) pour enlever les organelles et les macromoleĢcules endommageĢs et pour maintenir l'homeĢostasie du cartilage articulaire.
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ļæ¼L'autophagie est une voie de deĢgradation lysosomale qui est essentielle pour la survie, la diffeĢrenciation, le deĢveloppement et lāhomeĢostasie. Elle reĢgule la maturation et favorise la survie des chondrocytes matures sous le stress et des conditions hypoxiques. Des eĢtudes effectueĢes par nous et d'autres ont montreĢ quāun deĢreĢglement de lāautophagie est associeĢ aĢ une diminution de la chondroprotection, aĢ l'augmentation de la mort cellulaire et aĢ la deĢgeĢneĢrescence du cartilage articulaire. Carames et al ont montreĢ que l'autophagie est constitutivement exprimeĢe dans le cartilage articulaire humain normal. Toutefois, l'expression des inducteurs principaux de l'autophagie est reĢduite dans le vieux cartilage.
Nos eĢtudes preĢceĢdentes ont eĢgalement identifieĢ des principaux geĢnes de lāautophagie qui sont exprimeĢs aĢ des niveaux plus faibles dans le cartilage humain atteint de l'arthrose. Les meĢmes reĢsultats ont eĢteĢ montreĢs dans le cartilage articulaire provenant des modeĢles de lāarthrose expeĢrimentaux chez la souris et le chien. Plus preĢciseĢment, nous avons remarqueĢ que l'expression dāUnc-51 like kinase-1 (ULK1) est faible dans cartilage humain atteint de l'arthrose et des modeĢles expeĢrimentaux de lāarthrose. ULK1 est la seĢrine / threĢonine proteĢine kinase et elle est lāinducteur principal de lāautophagie. La perte de lāexpression de ULK1 se traduit par un niveau dāautophagie faible. Etant donneĢ quāune signalisation adeĢquate de l'autophagie est neĢcessaire pour maintenir la chondroprotection ainsi que l'homeĢostasie du cartilage articulaire, nous avons proposeĢ lāhypotheĢse suivante : une expression adeĢquate de ULK1 est requise pour lāinduction de lāautophagie dans le cartilage articulaire et une perte de cette expression se traduira par une diminution de la chondroprotection, et une augmentation de la mort des chondrocytes ce qui conduit aĢ la deĢgeĢneĢrescence du cartilage articulaire. Le roĢle exact de ULK1 dans la pathogeĢnie de l'arthrose est inconnue, jāai alors creĢeĢ pour la premieĢre fois, des souris KO ULK1speĢcifiquement dans le cartilage en utilisant la technologie Cre-Lox et jāai ensuite soumis ces souris aĢ la deĢstabilisation du meĢnisque meĢdial (DMM), un modeĢle de l'arthrose de la souris pour eĢlucider le roĢle speĢcifique in vivo de ULK1 dans pathogeneĢse de l'arthrose. Mes reĢsultats montrent que ULK1 est essentielle pour le maintien de l'homeĢostasie du cartilage articulaire. Plus preĢciseĢment, je montre que la perte de ULK1 dans le cartilage articulaire a causeĢ un pheĢnotype de lāarthrose acceĢleĢreĢ, associeĢ aĢ la deĢgeĢneĢrescence acceĢleĢreĢe du cartilage, lāaugmentation de la mort cellulaire des chondrocytes, et lāaugmentation de l'expression des facteurs cataboliques. En utilisant des chondrocytes provenant des patients atteints de lāarthrose et qui ont eĢteĢ transfecteĢes avec le plasmide d'expression ULK1, je montre quāULK1 est capable de reĢduire lāexpression de la proteĢine mTOR (principal reĢgulateur neĢgatif de lāautophagie) et de diminuer lāexpression des facteurs cataboliques comme MMP-13 et ADAMTS-5 et COX-2. Mes reĢsultats jusqu'aĢ preĢsent indiquent que ULK1 est une cible theĢrapeutique potentielle pour maintenir l'homeĢostasie du cartilage articulaire.Osteoarthritis (OA) is the most common musculoskeletal disease worldwide. It is one of the leading causes of pain and disability among adults, and represents a considerable burden on the healthcare system. OA is a disease of the entire joint, involving not only the articular cartilage but also the synovium, ligaments and subchondral bone. It is characterized by the progressive degeneration of the articular cartilage, osteophyte formation, remodelling of the subchondral bone, deterioration of tendons and ligaments and various degrees of inflammation of the synovium. While current therapies and management strategies can help alleviate symptoms early in the disease process, OA is characterized by almost inevitable progression towards end-stage disease.
The exact pathogenesis of OA is largely unknown but the key event in OA is the degradation of the articular cartilage. The articular cartilage is only composed of chondrocytes; cells responsible for the synthesis of the extracellular matrix (ECM) and maintenance of articular cartilage homeostasis. Chondrocytes maintain the articular cartilage matrix by replacing degraded macromolecules and respond to focal cartilage injury or degeneration by increasing local synthesis activity. Since chondrocytes exhibit low levels of turnover, they rely on endogenous mechanisms such as autophagy (a cell survival and adaptation process) to remove damaged organelles and macromolecules in order to maintain articular cartilage homeostasis.
Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development and homeostasis. It regulates maturation and promotes survival of terminally differentiated chondrocytes under stress and hypoxic conditions. Studies by us and others have shown that compromised autophagy is associated with decreased chondroprotection, increased cell death and articular cartilage degeneration. Carames et al showed that autophagy is constitutively expressed in normal human articular cartilage. However, expression of key autophagy inducers is reduced in ageing cartilage. Our previous studies have also identified a panel of key autophagy genes that are expressed in low levels in human OA cartilage as well as in the articular cartilage from mouse and dog models of experimental OA. Specifically, we identified that expression of unc-51 like kinase-1 (ULK1) is suppressed in human OA cartilage and experimental OA models. ULK1 is a serine/threonine protein kinase and is the most upstream autophagy inducer. Loss of ULK1 results in disruption of autophagy induction. Since adequate autophagy signaling is required for maintaining chondroprotection as well as articular cartilage homeostasis, we hypothesized that ULK1 is required for autophagy induction in the articular cartilage and loss of it will result in decreased chondroprotection and enhanced chondrocyte death leading to the degeneration of articular cartilage. Since the exact role of ULK1 in pathogenesis of OA is unknown, I created for the first time, an inducible cartilage- specific ULK1 knockout (KO) mice using Cre-Lox technology and subjected these mice to the destabilization of the medial meniscus (DMM) mouse OA model to specifically elucidate the specific in vivo role of ULK1 in OA pathogenesis. My results show that ULK1 is essential for maintaining articular cartilage homeostasis. Specifically I show that loss of ULK1 in the articular cartilage results in an accelerated OA phenotype; which is associated with accelerated cartilage degeneration, enhanced chondrocyte cell death, increased expression of catabolic MMP-13. Using human OA chondrocytes transfected with ULK1 expression plasmid I show that ULK1 is able to reduce the expression of mTOR (major negative regulator of autophagy) and decrease the expression of OA catabolic factors including MMP-13, ADAMTS-5 and COX-2. My results so far suggest that ULK-1 is a potential therapeutic target to maintain articular cartilage homeostasis
AnĆ”lise do apgar no 1Āŗ e 5Āŗ minutos nos partos normais de posiĆ§Ć£o vertical e horizontal de recĆ©m-nascidos a termo na Maternidade do hospital UniversitĆ”rio (HU).
Trabalho de ConclusĆ£o de Curso - Universidade Federal de Santa Catarina, Centro de CiĆŖncias da SaĆŗde, Departamento de Tocoginecologia, Curso de Medicina, FlorianĆ³polis, 200
Multilevel algorithms for partitioning power-law graphs
Graph partitioning is an enabling technology for parallel processing as it allows for the effective decomposition of unstructured computations whose data dependencies correspond to a large sparse and irregular graph. Even though the problem of computing high-quality partitionings of graphs arising in scientific computations is to a large extent wellunderstood, this is far from being true for emerging HPC applications whose underlying computation involves graphs whose degree distribution follows a power-law curve. This paper presents new multilevel graph partitioning algorithms that are specifically designed for partitioning such graphs. It presents new clustering-based coarsening schemes that identify and collapse together groups of vertices that are highly connected. An experimental evaluation of these schemes on 10 different graphs show that the proposed algorithms consistently and significantl
Stent-assisted, balloon-induced intimal disruption and relamination of aortic dissection in patients with Marfan syndrome: Midterm outcomes and aortic remodeling.
International audienc
Spatial Frequency Selectivity Is Impaired in Dopamine D2 Receptor Knockout Mice
Dopamine is a neurotransmitter implicated in several brain functions, including vision. In the present study, we investigated the impacts of the lack of D2 dopamine receptors on the structure and function of the primary visual cortex (V1) of D2-KO mice using optical imaging of intrinsic signals. Retinotopic maps were generated in order to measure anatomo-functional parameters such as V1 shape, cortical magnification factor, scatter, and ocular dominance. Contrast sensitivity and spatial frequency selectivity (SF) functions were computed from responses to drifting gratings. When compared to control mice, none of the parameters of the retinotopic maps were affected by D2 receptor loss of function. While the contrast sensitivity function of D2-KO mice did not differ from their wild-type counterparts, SF selectivity function was significantly affected as the optimal SF and the high cut-off frequency (p < 0.01) were higher in D2-KO than in WT mice. These findings show that the lack of function of D2 dopamine receptors had no influence on cortical structure whereas it had a significant impact on the spatial frequency selectivity and high cut-off. Taken together, our results suggest that D2 receptors play a specific role on the processing of spatial features in early visual cortex while they do not seem to participate in its development
Mid-term Outcomes of Stent Assisted Balloon Induced Intimal Disruption and Relamination in Aortic Dissection Repair (STABILISE) in Acute Type B Aortic Dissection
International audienceObjectives: This article reports mid-term results of 41 patients treated by the stent assisted balloon induced intimal disruption and relamination (STABILISE) technique for acute type B aortic dissection.Methods: Between November 2011 and November 2017, 41 patients (10 male; median age 50 years) underwent proximal descending aortic stent grafting plus stent assisted balloon induced intimal disruption of the thoraco-abdominal aorta for acute type B aortic dissection. Serial computed tomography angiography was used to assess aortic remodelling.Results: There were no intra-procedural complications. Fifteen branch arteries supplied by the false lumen were stented (9% of the visceral branch arteries). The thirty day incidence of death, stroke, and paralysis/visceral ischaemia was 2% (n = 1), 0%, 5% (n = 2), and 2% (n = 1) respectively. During a median follow up of 12 months (range 1ā168) eight patients (20%) required re-intervention. Primary visceral stent patency was 93% (n = 14). No aortic related deaths occurred. On the most recent computed tomography angiogram, complete false lumen obliteration and aortic remodelling was obtained in all patients at the thoraco-abdominal level, and in 39% (n = 16) at the unstented infrarenal aorto-iliac level. The maximum aortic diameter increased in only two patients (5%) at the unstented infrarenal level.Conclusion: To obtain immediate and durable thoraco-abdominal aortic remodelling in acute type B dissections, the STABILISE technique is safe and reproducible while not compromising the patency of collateral branches