pinecone/core-2020-05-10-deduplication huggingface dataset:
Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.

International audienceTranscription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs
Kinetics and mechanics of two-dimensional interactions between T cell receptors and different activating ligands.

International audienceAdaptive immune responses are driven by interactions between T cell antigen receptors (TCRs) and complexes of peptide antigens (p) bound to Major Histocompatibility Complex proteins (MHC) on the surface of antigen-presenting cells. Many experiments support the hypothesis that T cell response is quantitatively and qualitatively dependent on the so-called strength of TCR/pMHC association. Most available data are correlations between binding parameters measured in solution (three-dimensional) and pMHC activation potency, suggesting that full lymphocyte activation required a minimal lifetime for TCR/pMHC interaction. However, recent reports suggest important discrepancies between the binding properties of ligand-receptor couples measured in solution (three-dimensional) and those measured using surface-bound molecules (two-dimensional). Other reports suggest that bond mechanical strength may be important in addition to kinetic parameters. Here, we used a laminar flow chamber to monitor at the single molecule level the two-dimensional interaction between a recombinant human TCR and eight pMHCs with variable potency. We found that 1), two-dimensional dissociation rates were comparable to three-dimensional parameters previously obtained with the same molecules; 2), no significant correlation was found between association rates and activating potency of pMHCs; 3), bond mechanical strength was partly independent of bond lifetime; and 4), a suitable combination of bond lifetime and bond strength displayed optimal correlation with activation efficiency. These results suggest possible refinements of contemporary models of signal generation by T cell receptors. In conclusion, we reported, for the first time to our knowledge, the two-dimensional binding properties of eight TCR/pMHC couples in a cell-free system with single bond resolution
Evaluation of the Defay-Prigogine model for the membrane interphase in relation to biological response in membrane-protein interactions

Surface water activity appears as a common factor when the interaction of several aqueous soluble and surface active proteins with lipid membranes of different composition is measured by the changes in surface pressure of a lipid monolayer. The perturbation of the lipid surface caused by aqueous soluble proteins depends on the composition of the hydrocarbon phases, either modified by unsaturated bonds in the acyl chains or by inclusion of cholesterol. The cut-off (critical) surface pressure in monolayers, at which no effect of the proteins is found, is related to the composition of the head group region. The perturbation of surface pressure is produced by proteins when the area per lipid is above just 4% larger than that corresponding to the hydration shell of the phospholipid head groups found in the cut -off. This area excess gives place to regions in which the chemical potential of water changes with respect to bulk water. According to the Defay-Prigogine relation this interfacial water activity is the reason of the surface pressure increase induced by aqueous soluble proteins injected in the subphase. As predicted by solution chemistry, the increase of surface pressure is independent of the protein nature but depends on the water surface state determined by the lipid composition.Fil: Disalvo, Edgardo Anibal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Santiago del Estero; Argentina;Fil: Hollmann, Axel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Microbiologia Molecular; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Santiago del Estero; Argentina;Fil: Semorile, Liliana Carmen. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Microbiología Molecular; Argentina;Fil: Martini, María Florencia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina
An Optimal Approach for Measuring the Integrated Sachs Wolfe Effect

International audienceContext. One of the main challenges of modern cosmology is to understand the nature of the mysterious dark energy that causes the cosmic acceleration. The integrated Sachs-Wolfe (ISW) effect is sensitive to dark energy, and if detected in a universe where modified gravity and curvature are excluded, presents an independent signature of dark energy. The ISW effect occurs on large scales where cosmic variance is high and where owing to the Galactic confusion we lack large amounts of data in the CMB as well as large-scale structure maps. Moreover, existing methods in the literature often make strong assumptions about the statistics of the underlying fields or estimators. Together these effects can severely limit signal extraction.Aims. We aim to define an optimal statistical method for detecting the ISW effect that can handle large areas of missing data and minimise the number of underlying assumptions made about the data and estimators.Methods. We first review current detections (and non-detections) of the ISW effect, comparing statistical subtleties between existing methods, and identifying several limitations. We propose a novel method to detect and measure the ISW signal. This method assumes only that the primordial CMB field is Gaussian. It is based on a sparse inpainting method to reconstruct missing data and uses a bootstrap technique to avoid assumptions about the statistics of the estimator. It is a complete method, which uses three complementary statistical methods.Results. We apply our method to Euclid-like simulations and show we can expect a  ~7σ model-independent detection of the ISW signal with WMAP7-like data, even when considering missing data. Other tests return  ~5σ detection levels for a Euclid-like survey. We find that detection levels are independent from whether the galaxy field is normally or lognormally distributed. We apply our method to the 2 Micron All Sky Survey (2MASS) and WMAP7 CMB data and find detections in the 1.0−1.2σ range, as expected from our simulations. As a by-product, we have also reconstructed the full-sky temperature ISW field from the 2MASS data.Conclusions. We present a novel technique based on sparse inpainting and bootstrapping, which accurately detects and reconstructs the ISW effect
Comparison between two multi objective optimization algorithms : PAES and MGDA. Testing MGDA on Kriging metamodels

Book dedicated to Professor P. Neittaanmaki on His 60th BithdayInternational audienceIn multi-objective optimization, the knowledge of the Pareto set provides valuable information on the reachable optimal performance. A number of evolutionary strategies (PAES [4], NSGA-II [3], etc), have been proposed in the literature and proved to be successful to identify the Pareto set. However, these derivative-free algorithms are very demanding in computational time. Today, in many areas of computational sciences, codes are developed that include the calculation of the gradient, cautiously validated and calibrated. Thus, an alternate method applicable when the gradients are known is introduced presently. Using a clever combination of the gradients, a descent direction common to all criteria is identified. As a natural outcome, the Multiple Gradient Descent Algorithm (MGDA) is defined as a generalization of the steepest-descent method and compared with PAES by numerical experiments. Using MGDA on a multi objective optimization problem requires the evaluation of a large number of points with regard to criteria, and their gradients. In the particular case of CFD problems, each point evaluation is very costly. Thus here we also propose to construct metamodels and to calculate approximate gradients by local finite differences
Ideal minimal residual-based proper generalized decomposition for non-symmetric multi-field models - Application to transient elastodynamics in space-time domain

International audienceIt is now well established that separated representations built with the help of Proper Generalized Decomposition (PGD) can drastically reduce computational costs associated with solution of a wide variety of problems. However, it is still an open question to know if separated representations can be efficiently used to approximate solutions of hyperbolic evolution problems in space-time domain. In this paper, we numerically address this issue and concentrate on transient elastodynamic models. For such models, the operator associated with the space-time problem is non-symmetric and low-rank approximations are classically computed by minimizing the space-time residual in a natural L2 sense, yet leading to non optimal approximations in usual solution norms. Therefore, a new algorithm has been recently introduced by one of the authors and allows to find a quasi-optimal low-rank approximation a priori with respect to a target norm. We presently extend this new algorithm to multi-field models. The proposed algorithm is applied to elastodynamics formulated over space-time domain with the time discontinuous Galerkin method in displacement and velocity. Numerical examples demonstrate convergence of the proposed algorithm and comparisons are made with classical a posteriori and a priori approaches
Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation\ud
with outcomes.

OBJECTIVES: \ud
\ud
The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure.\ud
\ud
BACKGROUND: \ud
\ud
Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage.\ud
\ud
METHODS: \ud
\ud
The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies.\ud
\ud
RESULTS: \ud
\ud
Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion.\ud
\ud
CONCLUSIONS: \ud
\ud
Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission
Study of hadronic event-shape variables in multijet final states in pp collisions at sqrt(s) = 7 TeV

We study twist operators in higher dimensional CFT’s. In particular, we express their conformal dimension in terms of the energy density for the CFT in a particular thermal ensemble. We construct an expansion of the conformal dimension in power series around n=1, with n being replica parameter. We show that the coefficients in this expansion are determined by higher point correlations of the energy-momentum tensor. In particular, the first and second terms, i.e. the first and second derivatives of the scaling dimension, have a simple universal form. We test these results using holography and free field theory computations, finding agreement in both cases. We also consider the ‘operator product expansion’ of spherical twist operators and finally, we examine the behaviour of correlators of twist operators with other operators in the limit n → 1
The miR-17-92 microRNA cluster regulates multiple components of the TGF-β pathway in neuroblastoma.

Abstract
The miR-17-92 microRNA cluster is often activated in cancer cells, but the identity of its targets remains elusive. Using SILAC and quantitative mass spectrometry, we examined the effects of activation of the miR-17-92 cluster on global protein expression in neuroblastoma (NB) cells. Our results reveal cooperation between individual miR-17-92 miRNAs and implicate miR-17-92 in multiple hallmarks of cancer, including proliferation and cell adhesion. Most importantly, we show that miR-17-92 is a potent inhibitor of TGF-β signaling. By functioning both upstream and downstream of pSMAD2, miR-17-92 activation triggers downregulation of multiple key effectors along the TGF-β signaling cascade as well as direct inhibition of TGF-β-responsive genes
Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives : in vitro evaluation, cell cycle analysis and QSAR studies

Hepatocellular carcinoma (HCC) is a highly complex cancer, resistant to commonly used treatments and new therapeutic agents are urgently needed. A total of thirty-two thieno[3,2-b]pyridine derivatives of two series: methyl 3-amino-6-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates (1a-1t) and methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates (2a-2n), previously prepared by some of us, were evaluated as new potential anti-HCC agents by studying their in vitro cell growth inhibition on human HepG2 cells and hepatotoxicity using a porcine liver primary cell culture (PLP1). The presence of amino groups linked to a benzene moiety emerges as the key element for the anti-HCC activity. The methyl 3-amino-6-[(3-aminophenyl)ethynyl]thieno[3,2-b]pyridine-2-carboxylate (2f) is the most potent compound presenting GI50 values on HepG2 cells of 1.2 μM compared to 2.9 μM of the positive control ellipticine, with no observed hepatotoxicity (PLP1 GI50>125 μM against 3.3 μM of ellipticine). Moreover this compound changes the cell cycle profile of the HepG2 cells, causing a decrease in the % of cells in the S phase and a cell cycle arrest in the G2/M phase. QSAR studies were also performed and the correlations obtained using molecular and 1D descriptors revealed the importance of the presence of amino groups and hydrogen bond donors for anti-HCC activity, and hydrogen bond acceptors for hepatotoxicity. The best correlations were obtained with 3D descriptors belonging to different subcategories for anti-HCC activity and hepatotoxicity, respectively. These results point to different molecular mechanisms of action of the compounds in anti-HCC activity and hepatotoxicity. This work presents some promising thieno[3,2-b]pyridine derivatives for potential use in the therapy of HCC. These compounds can also be used as scaffolds for further synthesis of more potent analogues.FCT, FEDER/COMPETE/QREN/E
Comparison of the Gottfried and Adler sum rules within the large-Nc expansion.

The Adler sum rule for deep inelastic neutrino scattering measures the isospin of the nucleon and is hence exact. By contrast, the corresponding Gottfried sum rule for charged lepton scattering was based merely on a valence picture and is modified both by perturbative and by non-perturbative effects. Noting that the known perturbative corrections to two-loop order are suppressed by a factor 1/Nc2, relative to those for higher moments, we propose that this suppression persists at higher orders and also applies to higher-twist effects. Moreover, we propose that the differences between the corresponding radiative corrections to higher non-singlet moments in charged-lepton and neutrino deep inelastic scattering are suppressed by 1/Nc2, in all orders of perturbation theory. For the first moment, in the Gottfried sum rule, the substantial discrepancy between the measured value and the valence-model expectation may be attributed to an intrinsic isospin asymmetry in the nucleon sea, as is indeed the case in a chiral-soliton model, where the discrepancy persists in the limit Nc→∞. \u
Searches for supersymmetry with the ATLAS detector using final states with two leptons and missing transverse momentum in root s=7 TeV proton-proton collisions

Results of three searches are presented for the production of supersymmetric particles decaying into final states with missing transverse momentum and exactly two isolated leptons, e or mu. The analysis uses a data sample collected during the first half of 2011 that corresponds to a total integrated luminosity of 1 fb(-1) of root s = 7 TeV proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider. Opposite-sign and same-sign dilepton events are separately studied, with no deviations from the Standard Model expectation observed. Additionally, in opposite-sign events, a search is made for an excess of same-flavour over different-flavour lepton pairs. Effective production cross sections in excess of 9.9 fb for opposite-sign events containing supersymmetric particles with missing transverse momentum greater than 250 GeV are excluded at 95% CL For same-sign events containing supersymmetric particles with missing transverse momentum greater than 100 GeV, effective production cross sections in excess of 14.8 fb are excluded at 95% CL The latter limit is interpreted in a simplified electroweak gaugino production model excluding chargino masses up to 200 GeV, under the assumption that slepton decay is dominant
Search for dark matter produced in association with a hadronically
  decaying vector boson in pp collisions at $\sqrt{s}$=13 TeV with the ATLAS
  detector

A search is presented for dark matter produced in association with a
hadronically decaying W or Z boson using 3.2 /fb of pp collisions at
$\sqrt{s}$=13 TeV recorded by the ATLAS detector at the Large Hadron Collider.
Events with a hadronic jet compatible with a W or Z boson and with large
missing transverse momentum are analysed. The data are consistent with the
Standard Model predictions and are interpreted in terms of both an effective
field theory and a simplified model containing dark matter.Comment: 13 pages plus author list (30 pages total), 5 figures, 2 tables,
  final version published in PLB, All figures including auxiliary figures are
  available at
  http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/EXOT-2015-08
A-Ward_p\b{eta}: Effective hierarchical clustering using the Minkowski
  metric and a fast k -means initialisation

In this paper we make two novel contributions to hierarchical clustering.
First, we introduce an anomalous pattern initialisation method for hierarchical
clustering algorithms, called A-Ward, capable of substantially reducing the
time they take to converge. This method generates an initial partition with a
sufficiently large number of clusters. This allows the cluster merging process
to start from this partition rather than from a trivial partition composed
solely of singletons. Our second contribution is an extension of the Ward and
Ward p algorithms to the situation where the feature weight exponent can differ
from the exponent of the Minkowski distance. This new method, called A-Ward
p\b{eta} , is able to generate a much wider variety of clustering solutions. We
also demonstrate that its parameters can be estimated reasonably well by using
a cluster validity index. We perform numerous experiments using data sets with
two types of noise, insertion of noise features and blurring within-cluster
values of some features. These experiments allow us to conclude: (i) our
anomalous pattern initialisation method does indeed reduce the time a
hierarchical clustering algorithm takes to complete, without negatively
impacting its cluster recovery ability; (ii) A-Ward p\b{eta} provides better
cluster recovery than both Ward and Ward p
High-$E_{\rm T}$ isolated-photon plus jets production in $pp$ collisions
  at $\sqrt s=$ 8 TeV with the ATLAS detector

The dynamics of isolated-photon plus one-, two- and three-jet production in
$pp$ collisions at a centre-of-mass energy of 8 TeV are studied with the ATLAS
detector at the LHC using a data set with an integrated luminosity of 20.2
fb$^{-1}$. Measurements of isolated-photon plus jets cross sections are
presented as functions of the photon and jet transverse momenta. The cross
sections as functions of the azimuthal angle between the photon and the jets,
the azimuthal angle between the jets, the photon-jet invariant mass and the
scattering angle in the photon-jet centre-of-mass system are presented. The
pattern of QCD radiation around the photon and the leading jet is investigated
by measuring jet production in an annular region centred on each object;
enhancements are observed around the leading jet with respect to the photon in
the directions towards the beams. The experimental measurements are compared to
several different theoretical calculations, and overall a good description of
the data is found.Comment: 59 pages in total, author list starting page 43, 16 figures, 5
  tables, submitted to Nuclear Physics B, All figures including auxiliary
  figures are available at
  http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2015-11