Conformational dynamics of alpha-synuclein:insights from mass spectrometry

The aggregation and deposition of alpha-synuclein in Lewy bodies is associated with the progression of Parkinson's disease. Here, Mass Spectrometry (MS) is used in combination with Ion Mobility (IM), chemical crosslinking and Electron Capture Dissociation (ECD) to probe transient structural elements of alpha-synuclein and its oligomers. Each of these reveals different aspects of the conformational heterogeneity of this 14 kDa protein. IM-MS analysis indicates that this protein is highly disordered, presenting in positive ionisation mode with a charge state range of 5 <= z <= 21 for the monomer, along with a collision cross section range of similar to 1600 angstrom(2)). Chemical crosslinking applied in conjunction with IM-MS captures solution phase conformational families enabling comparison with those exhibited in the gas phase. Crosslinking IM-MS identifies 3 distinct conformational families, Compact (similar to 1200 angstrom(2)), Extended (similar to 1500 angstrom(2)) and Unfolded (similar to 2350 angstrom(2)) which correlate with those observed in solution. ECD-Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry (ECD-FT-ICR MS) highlights the effect of pH on alpha-synuclein structure, identifying the conformational flexibility of the N and C termini as well as providing evidence for structure in the core and at times the C terminus. A hypothesis is proposed for the variability displayed in the structural rearrangement of alpha-synuclein following changes in solution pH. Following a 120 h aggregation time course, we observe an increase in the ratio of dimer to monomer, but no gross conformational changes in either, beyond the significant variations that are observed day-to-day from this conformationally dynamic protein

A combined fit to the Higgs branching ratios at the International Large Detector at ILC

International audienceThe Higgsstrahlung process as a Higgs boson production mechanism at a lepton colliderprovides access to a high-purity Higgs boson sample.The Higgs branching ratios can be measured simultaneouslyby analysing the data inclusively.For this purpose, we divide the sample into classes thatdistinguish reasonably well between the Higgs decay modes.These class counts are associated to the Higgs branching ratios through amodel-independent fit.The fit provides an estimate for each of the Higgs branching ratios withthe full matrix of statistical correlations between the channels.These are pure branching ratio measurements,independent of any Higgs production mode cross section measurement.We present a study on data simulated for the ILD conceptat the International Linear Collider (ILC) at 250 GeV center-of-mass energy

A combined fit to the Higgs branching ratios at the International Large Detector at ILC

International audienceThe Higgsstrahlung process as a Higgs boson production mechanism at a lepton collider providesaccess to a high-purity Higgs boson sample. The Higgs branching ratios can be measuredsimultaneously by analysing the data inclusively. For this purpose, we divide the sample intoclasses that distinguish reasonably well between the Higgs decay modes. These class countsare associated to the Higgs branching ratios through a model-independent fit. The fit providesan estimate for each of the Higgs branching ratios with the full matrix of statistical correlationsbetween the channels. These are pure branching ratio measurements, independent of any Higgsproduction mode cross section measurement.We present a study on data simulated for the ILD concept at the International Linear Collider(ILC) at 250 GeV center-of-mass energy

Mesure directe des rapports d’embranchement des bosons de Higgs dans les collisions électron-positon à 250 GeV

The couplings of standard model (SM) particles to the Higgs boson can be shifted if additional heavy particles exist. Many models of physics beyond the SM result in deviations of the order of 10% or less. This goes beyond the expected precision at HL-LHC that is limited by the systematic errors in proton-proton collisions. At an electron-positron collider with a center-of-mass energy of 250 GeV, referred to as a Higgs factory, most major Higgs couplings can be measured at the percent level or below.The main Higgs production channel is the associated production with a Z boson. If the momentum of the Z boson recoiling against the Higgs boson is properly reconstructed, the event can be selected independently of the Higgs decay. This reconstruction works best for Z bosons decaying to electrons or muons. During the proposed 250 GeV program of the ILC, more than 10.000 Higgs bosons are expected to be collected in high-purity model-independent samples. Each sample is partitioned into mutually exclusive regions with distinct Higgs decay and background compositions. Then the deviation of a Higgs branching ratio (BR) from the SM expectation leads to a characteristic pattern of excesses or deficits in the number of events per region. A simultaneous measurement of the Higgs BRs is obtained from a fit to the number of events per region. In contrast to the standard measurements of Higgs decays, it is not necessary to normalize these values by a production cross section. A large full simulation data set prepared for the ILD detector concept is used to validate this approach.The electromagnetic calorimeter in a particle flow detector like ILD must be able to resolve the individual tracks and showers within a jet. Therefore a high longitudinal and transversal granularity is essential. The SiW-ECAL is a sampling imaging calorimeter. A technological prototype featuring over 15.000 channels in 15 layers with 5 mm square cells was tested at DESY. This thesis presents improvements to the initial event reconstruction from individual hits.Les couplages des particules du modèle standard (SM) au boson de Higgs peuvent être modifiés si des particules lourdes supplémentaires existent. De nombreux modèles de physique au-delà du SM donnent lieu à des déviations de l’ordre de 10% ou moins. Cela est au-delà de la précision attendue au HL-LHC qui est limitée par les erreurs systématiques. Dans un collisionneur électron-positron avec une énergie au centre de la masse de 250 GeV, appelé une usine à Higgs, la plupart des principaux couplages de Higgs peuvent être mesurés au niveau du pourcent ou moins.Le canal principal de production de Higgs s’accompagne d’un boson Z. Si l’impulsion du boson Z reculant contre le boson de Higgs est correctement reconstruit, l’événement peut être sélectionné indépendamment de la désintégration du boson de Higgs. Cette reconstruction fonctionne mieux pour les bosons Z qui se désintègrent en electrons ou muons. Au cours du programme 250 GeV proposé pour le ILC, plus de 10.000 bosons de Higgs devraient être collectés dans des échantillons de haute pureté et indépendants du modèle de désintégration. Chaque échantillon est divisé en régions mutuellement exclusives avec des compositions distinctes par désintégration de Higgs et par bruit de fond. Ensuite, l’écart du rapport de branchement (BR) du boson de Higgs par rapport à l’attente du SM conduit à une structure caractéristique d’excès ou de déficit dans le nombre d’événements par région. Contrairement aux mesures standards des désintégrations du boson de Higgs, il n’est pas nécessaire de normaliser ces valeurs par la section efficace. Un grand ensemble de données de simulation complète préparé pour le concept de détecteur ILD est utilisé pour la validation de cette approche.Le calorimètre électromagnétique d’un détecteur flux de particules comme l’ILD doit pouvoir résoudre les différentes trajectoires et gerbes dans un jet. Une granularité longitudinale et transversale élevée est donc essentielle. Le calorimètre SiW-ECAL est un calorimètre d’imagerie par échantillonnage. Un prototype technologique de plus de 15.000 canaux en 15 couches avec des cellules carrées de 5 mm de coté a été testé en faisceau au DESY. Cette thèse présente les améliorations apportées à la reconstruction à la volée des événements à partir des cellules individuelles

Inclusive Higgsstrahlung cross section measurements with the new reference sample method

International audienceAn accurate determination of the Higgsstrahlung cross section is one of the main objectives at a future electron-positron collider. It allows for the only Higgs boson decay model independent measurement of the total Higgs width. Current results use the recoil mass shape method. That technique can be applied to Higgsstrahlung events with Z boson decays into muons, into electrons and, with reservations, into quarks. The samples built from Higgsstrahlung events with Z boson decays into taus and neutrinos are not used in previous analyses. We present here a new method, the reference sample method. It extends the recoil mass method to be usable with the tau and neutrino samples as well. The extension promises a model independent determination of the inclusive Higgsstrahlung cross section with a 2.1-2.2% uncertainty from each of the two ILC polarization scenarios at $\sqrt{s}$=250 GeV with an integrated luminosity of 250 $\mathrm{fb^{-1}}$. This represents an improvement of 20-30% on the accuracy from the application of the new approach without additional data collection

A combined fit to the Higgs Branching Ratios at ILD

International audienceHiggs decay branching ratios at future Higgs factories can be measured by directly exploiting class numeration. Given the clean environment at a lepton collider, it is possible to build an event sample highly enriched in Higgs bosons and essentially unbiased for any decay mode. The sample can be partitioned into categories using event properties linked to the expected Higgs decay modes. The counts per category are used to fit the Higgs branching ratios in a model independent way. The result of the fit is the set of branching ratios, independent from a Higgs production mode measurement. We present a simplified study on simulated data for the International Linear Detector (ILD) at the International Linear Collider (ILC) at 250 GeV center-of-mass energy

FOXA1 Gene Expression for Defining Molecular Subtypes of Muscle-Invasive Bladder Cancer after Radical Cystectomy

It remains unclear how to implement the recently revealed basal and luminal subtypes of muscle-invasive bladder cancer (MIBC) into daily clinical routine and whether molecular marker panels can be reduced. The mRNA expression of basal (KRT5) and luminal (FOXA1, GATA3, KRT20) markers was measured by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and correlated to clinicopathological features, recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS) in 80 patients with MIBC who underwent radical cystectomy. Additionally, the correlation of single markers with the basal and non-basal subtypes defined by a 36-gene panel was examined and then validated in the TCGA (The Cancer Genome Atlas) cohort. High expression of FOXA1 (p = 0.0048) and KRT20 (p = 0.0317) was associated with reduced RFS. In the multivariable analysis, only FOXA1 remained an independent prognostic marker for DFS (p = 0.0333) and RFS (p = 0.0310). FOXA1 expression (AUC = 0.79; p = 0.0007) was closest to the combined marker expression (AUC = 0.79; p = 0.0015) in resembling the non-basal subtype defined by the 36-gene panel. FOXA1 in combination with KRT5 may be used to distinguish the basal and non-basal subtypes of MIBC