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排序方式: 共有756条查询结果,搜索用时 11 毫秒
1.
Adele Boccuto Filippo Dragoni Francesca Picarazzi Alessia Lai Carla Della Ventura Carla Veo Federica Giammarino Francesco Saladini Gianguglielmo Zehender Maurizio Zazzi Mattia Mori Ilaria Vicenti 《International journal of molecular sciences》2021,22(5)
The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC50) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC50 shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development. 相似文献
2.
3.
Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
4.
C. Manneschi R. C. Pereira G. Marinaro A. Bosca M. Francardi P. Decuzzi 《Microfluidics and nanofluidics》2016,20(8):113
The interface between the blood pool and the extravascular matrix is fundamental in regulating the transport of molecules, nanoparticles and cells under physiological and pathological conditions. In this work, a microfluidic chip is presented comprising two parallel microchannels connected laterally via an array of high aspect ratio micropillars, constituting the permeable vascular membrane. A double-step lithographic process combined with a replica molding approach is employed to realize 80 different arrays of micropillars exhibiting three cross-sectional geometries (rectangular, elliptical and curved); two orientations (normal and parallel) with respect to the flow; and a variety of width and gap sizes, respectively, ranging from 10 to 20 μm and 2 to 5 μm. As compared to conventional rectangular structures, the curved pillars provide higher bending stiffness, lower adhesive interactions, and smaller intra-channel separation distances. Specifically, 10-μm-wide curved pillars, laying parallel to the flow, offered the highest mechanical stability. To assess vascular permeability, the extravascular channel was filled with a hyaluronic acid hydrogel, while fluorescent Dextran molecules and calibrated polystyrene beads were injected in the vascular channel. Membrane permeability was observed to reduce with the molecular weight of Dextran and diameter of the beads, ranging from about 6 × 10?5 to 2 × 10?5 cm/s for 40 and 250 kDa Dextran and up to zero for 1.5 μm beads. The presented data demonstrate the potential of the proposed microfluidic chip for analyzing the vascular and extravascular mass transport, over multiple spatial and temporal scales, in a variety of diseases involving differential permeation across vascular walls. 相似文献
5.
Giulia RabottinoAuthor Vitae Federica CaselliAuthor Vitae 《Computer Standards & Interfaces》2011,33(2):128-135
At present, mammography is the most effective examination for an early diagnosis of breast cancer. Nevertheless, the detection of cancer signs in mammograms is a difficult procedure owing to the great number of non-pathological structures which are also present in the image. Recent statistics show that in current breast cancer screenings 10%-25% of the tumors are missed by the radiologists. For this reason, a lot of research is currently being done to develop systems for Computer Aided Detection (CADe). Probably, some causes of the false-negative screening examinations are that tumoral masses have varying dimension and irregular shape, their borders are often ill-defined and their contrast is very low, thus making difficult the discrimination from parenchymal structures. Therefore, in a CADe system a preliminary segmentation procedure has to be implemented in order to separate the mass from the background tissue. In this way, various characteristics of the segmented mass can be evaluated and used in a classification step to discriminate benign and malignant cases. In this paper, we describe an effective algorithm for massive lesions segmentation based on a region-growing technique and we provide full details the performance evaluation procedure used in this specific context. 相似文献
6.
Federica Cena 《Journal of Intelligent Information Systems》2011,36(2):131-166
Nowadays there is a great number of Web information systems that build a model of the user and adapt their services according
to the needs and preferences maintained by the user model (UM). One of the most challenging issues of this scenario is the
possibility to enable different systems to cooperate in order to exchange the available information about a user. Our aim
is to create rich (and scalable) communication protocols and infrastructures to enable consumers and providers of UM data
to interact. Our solution for dealing with such an issue is to exploit Web standards for interoperability (i.e. Semantic Web
and Web Services) for implementing simple atomic communication, and a dialogue model for implementing enhanced communication
capabilities. In particular, two systems can start a semantics-enhanced Dialogue Game as a form of negotiation to clarify
the meaning of the requested concepts when a shared knowledge model does not exist, and to approximate the response when the
exact one is not available. We propose a distributed semantic conversation framework based on the Sesame semantic environment
for the exchange of user model knowledge on the Web. Systems have to expose their user model data as a Web Service, and to
exploit a public dialogue knowledge base to start the dialogue. The main advantage of the approach is to allow systems to
deal with difficult situations by starting an appropriate dialogue game instead of stopping the communication as in the traditional
“all-or-nothing” Web Service approach. On the basis of a preliminary evaluation, the approach has shown an improvement of
the adaptation results provided by the systems we tested. 相似文献
7.
In this work we present Bio-PEPA, a process algebra for the modelling and the analysis of biochemical networks. It is a modification of PEPA, originally defined for the performance analysis of computer systems, in order to handle some features of biological models, such as stoichiometry and the use of general kinetic laws. Bio-PEPA may be seen as an intermediate, formal, compositional representation of biological systems, on which different kinds of analyses can be carried out. Bio-PEPA is enriched with some notions of equivalence. Specifically, the isomorphism and strong bisimulation for PEPA have been considered and extended to our language. Finally, we show the translation of a biological model into the new language and we report some analysis results. 相似文献
8.
Julia Andreeva Simone Campana Federica Fanzago Juha Herrala 《Journal of Grid Computing》2008,6(1):3-13
In this paper we present the experience of the ATLAS and CMS High-Energy Physics (HEP) experiments at the Large Hadron Collider
(LHC) with the LCG/EGEE Grid infrastructure. The activity developed around the following two main lines: large-scale physics
and detector simulations and end-user analysis. The LCG/EGEE Grid infrastructure offers a large amount of computing and storage
resources and is growing very rapidly. It provides the natural environment for large-scale physics and detector simulations.
Also, the analysis of these detector simulation data (and in the near future of the reconstructed data from physics collisions)
requires efficient end-users access to Grid resources. In this paper, the main findings and lessons learned in terms of performance,
robustness and scalability of the whole system are discussed in detail. 相似文献
9.
Laura Mannarino Lara Paracchini Federica Pezzuto Gheorghe Emilian Olteanu Laura Moracci Luca Vedovelli Irene De Simone Cristina Bosetti Monica Lupi Rosy Amodeo Alessia Inglesi Maurizio Callari Serena Penpa Roberta Libener Sara Delfanti Antonina De Angelis Alberto Muzio Paolo Andrea Zucali Paola Allavena Giovanni Luca Ceresoli Sergio Marchini Fiorella Calabrese Maurizio DIncalci Federica Grosso 《International journal of molecular sciences》2022,23(10)
10.
Gianmaria Salvio Alessandro Ciarloni Melissa Cutini Nicola delli Muti Federica Finocchi Michele Perrone Silvia Rossi Giancarlo Balercia 《International journal of molecular sciences》2022,23(10)
Metabolic syndrome (MetS) is a highly prevalent condition among adult males, affecting up to 41% of men in Europe. It is characterized by the association of obesity, hypertension, and atherogenic dyslipidemia, which lead to premature morbidity and mortality due to cardiovascular disease (CVD). Male infertility is another common condition which accounts for about 50% of cases of couple infertility worldwide. Interestingly, male infertility and MetS shares several risk factors (e.g., smoking, ageing, physical inactivity, and excessive alcohol consumption), leading to reactive oxygen species (ROS) production and increased oxidative stress (OS), and resulting in endothelial dysfunction and altered semen quality. Thus, the present narrative review aims to discuss the pathophysiological mechanisms which link male infertility and MetS and to investigate the latest available evidence on the reproductive consequences of MetS. 相似文献