Modulation hormonale du sentier protéolytique de l'ubiquitine

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

Accounting for end-user preferences in earthquake early warning systems

Earthquake early warning systems (EEWSs) that rapidly trigger risk-reduction actions after a potentially-damaging earthquake is detected are an attractive tool to reduce seismic losses. One brake on their implementation in practice is the difficulty in setting the threshold required to trigger pre-defined actions: set the level too high and the action is not triggered before potentially-damaging shaking occurs and set the level too low and the action is triggered too readily. Balancing these conflicting requirements of an EEWS requires a consideration of the preferences of its potential end users. In this article a framework to define these preferences, as part of a participatory decision making procedure, is presented. An aspect of this framework is illustrated for a hypothetical toll bridge in a seismically-active region, where the bridge owners wish to balance the risk to people crossing the bridge with the loss of toll revenue and additional travel costs in case of bridge closure. Multi-attribute utility theory (MAUT) is used to constrain the trigger threshold for four owners with different preferences. We find that MAUT is an appealing and transparent way of aiding the potentially controversial decision of what level of risk to accept in EEW

Lithologic Controls on Silicate Weathering Regimes of Temperate Planets

Weathering of silicate rocks at a planetary surface can draw down CO2 from the atmosphere for eventual burial and long-term storage in the planetary interior. This process is thought to provide essential negative feedback to the carbonate-silicate cycle (carbon cycle) to maintain clement climates on Earth and potentially similar temperate exoplanets. We implement thermodynamics to determine weathering rates as a function of surface lithology (rock type). These rates provide upper limits that allow the maximum rate of weathering in regulating climate to be estimated. This modeling shows that the weathering of mineral assemblages in a given rock, rather than individual minerals, is crucial to determine weathering rates at planetary surfaces. By implementing a fluid-transport-controlled approach, we further mimic chemical kinetics and thermodynamics to determine weathering rates for three types of rocks inspired by the lithologies of Earthʼs continental and oceanic crust, and its upper mantle. We find that thermodynamic weathering rates of a continental crust-like lithology are about one to two orders of magnitude lower than those of a lithology characteristic of the oceanic crust. We show that when the CO2 partial pressure decreases or surface temperature increases, thermodynamics rather than kinetics exerts a strong control on weathering. The kinetically and thermodynamically limited regimes of weathering depend on lithology, whereas the supply-limited weathering is independent of lithology. Our results imply that the temperature sensitivity of thermodynamically limited silicate weathering may instigate a positive feedback to the carbon cycle, in which the weathering rate decreases as the surface temperature increases

Nanodisc-cell fusion: Control of fusion pore nucleation and lifetimes by SNARE protein transmembrane domains

The initial, nanometer-sized connection between the plasma membrane and a hormone- or neurotransmitter-filled vesicle-the fusion pore- can flicker open and closed repeatedly before dilating or resealing irreversibly. Pore dynamics determine release and vesicle recycling kinetics, but pore properties are poorly known because biochemically defined single-pore assays are lacking. We isolated single flickering pores connecting v-SNARE-reconstituted nanodiscs to cells ectopically expressing cognate, "flipped" t-SNAREs. Conductance through single, voltage-clamped fusion pores directly reported sub-millisecond pore dynamics. Pore currents fluctuated, transiently returned to baseline multiple times, and disappeared ∼6 s after initial opening, as if the fusion pore fluctuated in size, flickered, and resealed. We found that interactions between v- and t-SNARE transmembrane domains (TMDs) promote, but are not essential for pore nucleation. Surprisingly, TMD modifications designed to disrupt v- and t-SNARE TMD zippering prolonged pore lifetimes dramatically. We propose that the post-fusion geometry of the proteins contribute to pore stability.Fil: Wu, Zhenyong. University of Yale; Estados Unidos. University of Yale. School of Medicine; Estados UnidosFil: Auclair, Sarah M.. University of Yale. School of Medicine; Estados Unidos. University of Yale; Estados UnidosFil: Bello, Oscar Daniel. University of Yale. School of Medicine; Estados Unidos. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Vennekate, Wensi. University of Yale. School of Medicine; Estados Unidos. University of Yale; Estados UnidosFil: Dudzinski, Natasha R.. University of Yale; Estados Unidos. University of Yale. School of Medicine; Estados UnidosFil: Krishnakumar, Shyam S.. University of Yale. School of Medicine; Estados Unidos. University of Yale; Estados UnidosFil: Karatekin, Erdem. University of Yale; Estados Unidos. University of Yale. School of Medicine; Estados Unidos. Universite Paris Descartes; Francia. Centre National de la Recherche Scientifique; Franci

Dilation of fusion pores by crowding of SNARE proteins

Hormones and neurotransmitters are released through fluctuating exocytotic fusion pores that can flicker open and shut multiple times. Cargo release and vesicle recycling depend on the fate of the pore, which may reseal or dilate irreversibly. Pore nucleation requires zippering between vesicle-associated v-SNAREs and target membrane t-SNAREs, but the mechanisms governing the subsequent pore dilation are not understood. Here, we probed the dilation of single fusion pores using v-SNARE-reconstituted ~23-nm-diameter discoidal nanolipoprotein particles (vNLPs) as fusion partners with cells ectopically expressing cognate, ’flipped’ t-SNAREs. Pore nucleation required a minimum of two v-SNAREs per NLP face, and further increases in v-SNARE copy numbers did not affect nucleation rate. By contrast, the probability of pore dilation increased with increasing v-SNARE copies and was far from saturating at 15 v-SNARE copies per face, the NLP capacity. Our experimental and computational results suggest that SNARE availability may be pivotal in determining whether neurotransmitters or hormones are released through a transient (’kiss and run’) or an irreversibly dilating pore (full fusion).Fil: Wu, Zhenyong. University of Yale; Estados Unidos. University of Yale. School of Medicine; Estados UnidosFil: Bello, Oscar Daniel. University of Yale. School of Medicine; Estados Unidos. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Thiyagarajan, Sathish. Columbia University; Estados UnidosFil: Auclair, Sarah Marie. University of Yale. School of Medicine; Estados Unidos. University of Yale; Estados UnidosFil: Vennekate, Wensi. University of Yale; Estados Unidos. University of Yale. School of Medicine; Estados UnidosFil: Krishnakumar, Shyam S. University of Yale; Estados Unidos. University of Yale. School of Medicine; Estados UnidosFil: O'Shaughnessy, Ben. Columbia University; Estados UnidosFil: Karatekin, Erdem. University of Yale; Estados Unidos. Universite Paris Descartes; Francia. University of Yale. School of Medicine; Estados Unido

The physiological burden of the 6-minute walk test compared with cardiopulmonary exercise stress test in patients with severe aortic atenosis

Background Management of aortic stenosis (AS) relies on symptoms. Exercise testing is recommended for asymptomatic patients with significant AS but is often experienced as forbidding and/or technically unrealistic for patients who are often frail, deconditioned, and intimidated by the exercise test. We compared the physiological burden assessed with gas exchange assessments to gauge and respiratory exchange ratio (RER) of a 6-minute walk test (6MWT) to a cardiopulmonary exercise stress test (CPET) in patients with severe AS. peak oxygen utilization Methods Adults with equivocal symptoms and severe AS (1-aortic valve area [AVA] ≤ 1.0 cm2 or AVA index ≤ 0.6 cm2/m2, 2-peak aortic jet velocity ≥ 4.0 m/sec, 3-mean transvalvular pressure gradient ≥ 40 mm Hg by rest or dobutamine stress echocardiography, or 4-aortic valve calcification ≥ 1200 in women or ≥ 2000 AU in men) were studied. All participants completed both a 6MWT and symptom-limited progressive bicycle exercise testing. Breath-by-breath gas analysis and 12-lead electrocardiography were completed during 6MWT and CPET. Results: Eleven patients were studied. Patients walked on average 330 ± 75 m during the 6MWT and achieved a maximal workload of 48 ± 14 watts during the CPET. During the 6MWT, peak maximal oxygen uptake (O2peak) was 12.8 ± 2.5 vs 10.8 ± 4.2 mL/kg/min during the CPET. Respiratory exchange ratio exceeded 1.1 in both the 6MWT and CPET indicating similarly high exertion. Compared with the CPET, a larger proportion of the 6MWT was performed at a high intensity level (78% ± 28% vs 33% ± 24% at > 85% V̇O2peak; P = 0.004). Conclusions The 6MWT with breath-by-breath gas analysis was well tolerated and able to achieve a physiological intense RER and O2peak that are similar to symptom-limited CPET in patients with severe AS.Introduction La prise en charge de la sténose aortique (SA) dépend des symptômes. L’épreuve d’effort est recommandée aux patients asymptomatiques qui ont une SA significative, mais elle est souvent perçue comme dangereuse et/ou théoriquement irréaliste chez ces patients qui sont souvent fragiles, en mauvaise forme et craintifs par l’épreuve d’effort. Nous avons comparé le fardeau physiologique calculé par la consommation maximale de l’oxygène (O2max) et le quotient respiratoire (QR) d’un test de marche de 6 minutes (TM6) et d'une épreuve d’effort maximal chez des patients avec une SA sévère. Méthodes Tous les patients présentaient une SA symptomatique et sévère (1-aire valvulaire aortique [AVA] ≤ 1,0 cm2 ouAVA ≤ 0,6 cm2/m2, 2-une vélocité maximale du flux aortique ≥ 4,0 m/sec, 3-un gradient de pression transvalvulaire moyen ≥ 40 mmHg au repos ou à l’échocardiographie à l’effort sous dobutamine ou 4-une calcification valvulaire aortique (AU) ≥ 1200 chez les femmes ou ≥ 2000 AU chez les hommes). Les participants ont effectué un TM6 et une ’épreuve d’effort maximal de type rampe sur vélo. L’analyse des échanges gazeux respiration par respiration et un électrocardiogramme à 12 dérivations ont été effectués durant le TM6 et l'épreuve d'effort maximal. Résultats Un total de 11 patients ont participé à l'étude. Les patients ont marché en moyenne 330 ± 75 m durant le TM6 et ont atteint une charge de travail maximale de 48 ± 14 watts durant l’épreuve d'effort maximal. Durant le TM6, le O2max était de 12,8 ± 2,5 vs 10,8 ± 4,2 ml/kg/min durant l’épreuve d'effort maximal. Le QR était supérieur à 1,1 au TM6 ainsi qu'à l’épreuve d'effort maximal. Comparativement à l’épreuve d'effort maximal, un pourcentage plus important au TM6 a été réalisée à une intensité élevée (78 % ± 28 % vs 33 % ± 24 % à > 85 % V̇O2max; P = 0,004). Conclusions Le TM6 avec mesure directe des échanges gazeux était bien toléré et susceptible d’atteindre des valeurs physiologiques d'intensité élevée pour le QR et le O2max. Les valeurs atteintes au TM6 étaient semblables à celles de l'épreuve d'effort maximal chez les patients avec une SA sévère

MAGE-A inhibit apoptosis and promote proliferation in multiple myeloma through regulation of BIM and p21Cip1.

The type I Melanoma Antigen Gene (MAGE) A3 is a functional target associated with survival and proliferation in multiple myeloma (MM). To investigate the mechanisms of these oncogenic functions, we performed gene expression profiling (GEP) of p53 wild-type human myeloma cell lines (HMCL) after MAGE-A knockdown, which identified a set of 201 differentially expressed genes (DEG) associated with apoptosis, DNA repair, and cell cycle regulation. MAGE knockdown increased protein levels of pro-apoptotic BIM and of the endogenous cyclin-dependent kinase (CDK) inhibitor p21Cip1. Depletion of MAGE-A in HMCL increased sensitivity to the alkylating agent melphalan but not to proteasome inhibition. High MAGEA3 was associated with the MYC and Cell Cycling clusters defined by a network model of GEP data from the CoMMpass database of newly diagnosed, untreated MM patients. Comparative analysis of CoMMpass subjects based on high or low MAGEA3 expression revealed a set of 6748 DEG that also had significant functional associations with cell cycle and DNA replication pathways, similar to that observed in HMCL. High MAGEA3 expression correlated with shorter overall survival after melphalan chemotherapy and autologous stem cell transplantation (ASCT). These results demonstrate that MAGE-A3 regulates Bim and p21Cip1 transcription and protein expression, inhibits apoptosis, and promotes proliferation

Probing the gravitational wave background from cosmic strings with LISA

Cosmic string networks offer one of the best prospects for detection of cosmological gravitational waves (GWs). The combined incoherent GW emission of a large number of string loops leads to a stochastic GW background (SGWB), which encodes the properties of the string network. In this paper we analyze the ability of the Laser Interferometer Space Antenna (LISA) to measure this background, considering leading models of the string networks. We find that LISA will be able to probe cosmic strings with tensions Gμ ≳ (10), improving by about 6 orders of magnitude current pulsar timing arrays (PTA) constraints, and potentially 3 orders of magnitude with respect to expected constraints from next generation PTA observatories. We include in our analysis possible modifications of the SGWB spectrum due to different hypotheses regarding cosmic history and the underlying physics of the string network. These include possible modifications in the SGWB spectrum due to changes in the number of relativistic degrees of freedom in the early Universe, the presence of a non-standard equation of state before the onset of radiation domination, or changes to the network dynamics due to a string inter-commutation probability less than unity. In the event of a detection, LISA's frequency band is well-positioned to probe such cosmic events. Our results constitute a thorough exploration of the cosmic string science that will be accessible to LISA