157 research outputs found
Mechanism of reactant and product dissociation from the anthrax edema factor: a locally enhanced sampling and steered molecular dynamics study
The anthrax edema factor is a toxin overproducing damaging levels of cyclic adenosine mono-phosphate (cAMP) and pyrophosphate (PPi) from ATP. Here, mechanisms of dissociation of ATP and products (cAMP, PPi) from the active site are studied using locally enhanced sampling (LES) and steered molecular dynamics simulations. Various substrate conformations and ionic binding modes found in crystallographic structures are considered. LES simulations show that PPi and cAMP dissociate through different solvent accessible channels, while ATP dissociation requires significant active site exposure to solvent. The ionic content of the active site directly affects the dissociation of ATP and products. Only one ion dissociates along with ATP in the two-Mg2+ binding site, suggesting that the other ion binds EF prior to ATP association. Dissociation of reaction products cAMP and PPi is impaired by direct electrostatic interactions between products and Mg2+ ions. This provides an explanation for the inhibitory effect of high Mg2+ concentrations on EF enzymatic activity. Breaking of electrostatic interactions is dependent on a competitive binding of water molecules to the ions, and thus on the solvent accessibility of the active site. Consequently, product dissociation seems to be a two-step process. First, ligands are progressively solvated while preserving the most important electrostatic interactions, in a process that is dependent on the flexibility of the active site. Second, breakage of the electrostatic bonds follows, and ligands diffuse into solvent. In agreement with this mecanism, product protonation facilitates dissociation
RÎle des lymphocytes T CD4+ régulateurs dans la suppression des réponses immunitaires anti-tumorales
La gĂ©nĂ©ration et/ou le recrutement de cellules immuno-suppressives fait partie des mĂ©canismes majeurs utilisĂ©s par les tumeurs afin d Ă©chapper aux rĂ©ponses anti-tumorales du systĂšme immunitaire. Parmi les cellules capables d inhiber les rĂ©ponses anti-tumorales, les lymphocytes T CD4+ rĂ©gulateurs et les macrophages de type II tiennent un rĂŽle de premier ordre dans le contexte tumoral. Au cours de ma thĂšse, j ai pu Ă©tudier l impact de ces deux populations dans la suppression des rĂ©ponses immunitaires anti-tumorales dans le modĂšle MT/ret de mĂ©lanome spontanĂ© mĂ©tastatique. L ensemble de nos rĂ©sultats met en avant plusieurs niveaux d immuno-suppression dans le modĂšle MT/ret. D une part, les lymphocytes T CD4+ rĂ©gulateurs, de par leur localisation dans les ganglions drainants et dans la peau, semblent impliquĂ©s dans la suppression des rĂ©ponses anti-tumorales aux localisations et aux moments oĂč les tumeurs nĂ©cessitent une forte inhibition des effecteurs anti-tumoraux. D un autre cĂŽtĂ©, les macrophages de type II prĂ©sentent, en plus de leurs capacitĂ©s immuno-suppressives, des fonctions importantes pour la croissance et la dissĂ©mination tumorale justifiant leur localisation dans le microenvironnement tumoral. Dans un second temps, nos donnĂ©es suggĂšrent pour la premiĂšre fois un rĂŽle des monocytes Ly-6Cfort dans le contrĂŽle tumoral via la lyse de ces derniĂšres ou encore le maintien de la dormance des cellules tumorales dissĂ©minĂ©es. En consĂ©quence, nous proposons de les ajouter Ă la liste des acteurs immunitaires directement impliquĂ©s lors des phases d Ă©limination et d Ă©quilibre de la thĂ©orie de l immuno-Ă©diting. De plus, nous mettons en Ă©vidence leur inhibition par les lymphocytes T CD4+ rĂ©gulateurs, ce qui n avait pas non plus Ă©tĂ© dĂ©crit prĂ©cĂ©demment. Ceci nous pousse Ă suggĂ©rer de prendre plus en compte l impact des lymphocytes T CD4+ rĂ©gulateurs sur d autres populations immunitaires que les lymphocytes T dans le contexte tumoralPas de rĂ©sumĂ© en anglaisPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF
API design for machine learning software: experiences from the scikit-learn project
Scikit-learn is an increasingly popular machine learning li- brary. Written
in Python, it is designed to be simple and efficient, accessible to
non-experts, and reusable in various contexts. In this paper, we present and
discuss our design choices for the application programming interface (API) of
the project. In particular, we describe the simple and elegant interface shared
by all learning and processing units in the library and then discuss its
advantages in terms of composition and reusability. The paper also comments on
implementation details specific to the Python ecosystem and analyzes obstacles
faced by users and developers of the library
Imaging massâwasting sliding surfaces within complex glacial deposits along coastal cliffs using geophysics
This study presents a multidisciplinary survey combining geological fieldwork and geophysical data to better constrain the parameters influencing the morphology and behaviour of a retreating coastal cliff. Erosion rates are spatially highly variable and hard to predict because of the manifold parameters acting on them. Among these parameters, rock resistance exerts a paramount influence on cliff retreat. Characterizing the rock resistance distribution along a coastal region requires the mapping of several key subsurface properties including the bulk lithology, faulting, fracturing, or weathering. This is a difficult and expensive task because of the high spatial variability of these factors linked to the spatial complexity of the geology. Geophysical methods can be used to tackle this challenge by quickly providing the 3D visualization and distribution of these parameters within the subsurface. A fast-eroding portion of the Norfolk coast (UK) at West Runton is investigated using a multidisciplinary approach, combining ground-penetrating radar, electrical resistivity tomography (ERT), cone penetration tests, and outcrop studies. The results allowed us to build a 3D geological and geophysical model of a highly complex area of glacial geology. It forms part of a relict glaciotectonic thrust-tip moraine and sand basin sequence. The surfaces interpreted on radar data are associated with strong resistivity contrasts on the ERT data. These contrasts have been attributed to petrophysical variations between the lithological units. The base of the sand basin is marked by a low-permeability clay bed. Its low shear strength is likely to be more susceptible to failure, hereby accelerating the erosion rate of an already fast-eroding sand basin. The resulting model can be used as input for locally constraining the ground parameters in coastal recession and erosion models
Exploring the mobility of mobile phone users
Mobile phone datasets allow for the analysis of human behavior on an
unprecedented scale. The social network, temporal dynamics and mobile behavior
of mobile phone users have often been analyzed independently from each other
using mobile phone datasets. In this article, we explore the connections
between various features of human behavior extracted from a large mobile phone
dataset. Our observations are based on the analysis of communication data of
100000 anonymized and randomly chosen individuals in a dataset of
communications in Portugal. We show that clustering and principal component
analysis allow for a significant dimension reduction with limited loss of
information. The most important features are related to geographical location.
In particular, we observe that most people spend most of their time at only a
few locations. With the help of clustering methods, we then robustly identify
home and office locations and compare the results with official census data.
Finally, we analyze the geographic spread of users' frequent locations and show
that commuting distances can be reasonably well explained by a gravity model.Comment: 16 pages, 12 figure
T Cells Contribute to Tumor Progression by Favoring Pro-Tumoral Properties of Intra-Tumoral Myeloid Cells in a Mouse Model for Spontaneous Melanoma
Tumors affect myelopoeisis and induce the expansion of myeloid cells with immunosuppressive activity. In the MT/ret model of spontaneous metastatic melanoma, myeloid cells are the most abundant tumor infiltrating hematopoietic population and their proportion is highest in the most aggressive cutaneous metastasis. Our data suggest that the tumor microenvironment favors polarization of myeloid cells into type 2 cells characterized by F4/80 expression, a weak capacity to secrete IL-12 and a high production of arginase. Myeloid cells from tumor and spleen of MT/ret mice inhibit T cell proliferation and IFNÎł secretion. Interestingly, T cells play a role in type 2 polarization of myeloid cells. Indeed, intra-tumoral myeloid cells from MT/ret mice lacking T cells are not only less suppressive towards T cells than corresponding cells from wild-type MT/ret mice, but they also inhibit more efficiently melanoma cell proliferation. Thus, our data support the existence of a vicious circle, in which T cells may favor cancer development by establishing an environment that is likely to skew myeloid cell immunity toward a tumor promoting response that, in turn, suppresses immune effector cell functions
COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study
Background:
The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms.
Methods:
International, prospective observational study of 60â109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms.
Results:
âTypicalâ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (â€â18 years: 69, 48, 23; 85%), older adults (â„â70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each Pâ<â0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country.
Interpretation:
This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men
Les fondements d'une philosophie de l'homme sans Dieu dans l'oeuvre d'Albert Camus
L'oeuvre camusienne jette les fondements d'une philosophie de l'homme sans Dieu selon une triple perspective : une maniĂšre de concevoir le monde ("l'absurde"); une maniĂšre d'exister ("la rĂ©volte"); une maniĂšre de se comporter ("l'amour"). L'absurde inaugure la prise de conscience du dĂ©robement sans fin de tout fondement transcendant dans un monde restĂ© Ă©trange Ă l'homme. Faisant face lucidement Ă l'absurde en congĂ©diant tout espoir, l'ĂȘtre humain se dĂ©couvre "rĂ©voltĂ©". EnvisagĂ©e dans sa dimension individuelle et sociale, la rĂ©volte rĂ©vĂšle un nouveau "cogito" : "je me rĂ©volte, donc nous sommes". Principe fondateur de la "nature humaine", il justifie la solidaritĂ©. Principe rĂ©gulateur de la rĂ©volte, il empĂȘche celle-ci de sombrer dans le nihilisme ou dans le ressentiment. Or la rĂ©volte, pour perdurer comme valeur, doit trouver un point d'appui "originaire" en deçà d'elle-mĂȘme et de l'absurde. Elle le trouve dans "l'amour", dans ce consentement originaire Ă la vie et Ă l'homme de chair.PARIS1-BU Pierre MendĂšs-France (751132102) / SudocSudocFranceF
Effect of multiple symmetries on the association of R67 DHFR subunits bearing interfacial complementing mutations
It was shown previously that complementation could be a powerful mean to probe proteinâprotein interactions in the normally tetrameric R67 DHFR. Indeed, mixing complementing inactive dimeric mutants produced active heterotetramers. This approach turned a homo-oligomer into a hetero-oligomer and thus allowed the use of combinatorial assays, a subtle analysis of the association forces, and a precise determination of the equilibrium dissociation constants (KD) by titrimetry. However, for some of the complementing pairs, the experimental data implied multiple equilibria involving heterodimers, although no monomers could be detected. Thus, the reactions involved had to be identified to elaborate a suitable model to determine the KD of those pairs correctly. That model suggested that homodimers associated rapidly before the protomers could be redistributed in a multiple equilibrium system. Kinetic data confirmed that view. The association data at equilibrium were analyzed by multiple curve fitting with all plausible combinations of parameters. This gave a confidence interval for KD that is safer than the usual 67% or 90% confidence interval. Finally, the KD of one specific reaction, the dissociation of a heterotetramer with the relevant symmetry into two homodimers could be determined with the relevant model for each complementing pair, although multiple equilibria were present. These KD can thus be used as a set of references data to test and improve theoretical methods such as association free energy calculations
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