1,745 research outputs found
A mixed-mode cohesive model accounting for small to large openings transition
No full textThis work addresses the formulation of a new mixed-mode cohesive model, able to handle the transition from small to large openings: the proposed model is an extension of the isotropic damage model formulated in [Confalonieri and Perego, JSSCM, 11-2, 2017] for the simulation of mixed-mode delamination with variable mode-ratio, under the assumption of small relative displacements
Multiscale Molecular Modelling of ATP‐Fueled Supramolecular Polymerisation and Depolymerisation**
No full textRaw research data supporting the publication Perego C. et al., ChemSystemsChem 2021, DOI: https://doi.org/10.1002/syst.20200003
Searching the Optimal Folding Routes of a Complex Lasso Protein
No full textUnderstanding how polypeptides can efficiently and reproducibly attain a self-entangled conformation is a compelling biophysical challenge that might shed new light on our general knowledge of protein folding. Complex lassos, namely self-entangled protein structures characterized by a covalent loop sealed by a cysteine bridge, represent an ideal test system in the framework of entangled folding. Indeed, because cysteine bridges form in oxidizing conditions, they can be used as on/off switches of the structure topology to investigate the role played by the backbone entanglement in the process. In this work, we have used molecular dynamics to simulate the folding of a complex lasso glycoprotein, granulocyte-macrophage colony-stimulating factor, modeling both reducing and oxidizing conditions. Together with a well-established Gō-like description, we have employed the elastic folder model, a coarse-grained, minimalistic representation of the polypeptide chain driven by a structure-based angular potential. The purpose of this study is to assess the kinetically optimal pathways in relation to the formation of the native topology. To this end, we have implemented an evolutionary strategy that tunes the elastic folder model potentials to maximize the folding probability within the early stages of the dynamics. The resulting protein model is capable of folding with high success rate, avoiding the kinetic traps that hamper the efficient folding in the other tested models. Employing specifically designed topological descriptors, we could observe that the selected folding routes avoid the topological bottleneck by locking the cysteine bridge after the topology is formed. These results provide valuable insights on the selection of mechanisms in self-entangled protein folding while, at the same time, the proposed methodology can complement the usage of established minimalistic models and draw useful guidelines for more detailed simulations
Computational methods in the study of self-entangled proteins: a critical appraisal
No full textThe existence of self-entangled proteins, the native structure of which features a complex topology, unveils puzzling, and thus fascinating, aspects of protein biology and evolution. The discovery that a polypeptide chain can encode the capability to self-entangle in an efficient and reproducible way during folding, has raised many questions, regarding the possible function of these knots, their conservation along evolution, and their role in the folding paradigm. Understanding the function and origin of these entanglements would lead to deep implications in protein science, and this has stimulated the scientific community to investigate self-entangled proteins for decades by now. In this endeavour, advanced experimental techniques are more and more supported by computational approaches, that can provide theoretical guidelines for the interpretation of experimental results, and for the effective design of new experiments. In this review we provide an introduction to the computational study of self-entangled proteins, focusing in particular on the methodological developments related to this research field. A comprehensive collection of techniques is gathered, ranging from knot theory algorithms, that allow detection and classification of protein topology, to Monte Carlo or molecular dynamics strategies, that constitute crucial instruments for investigating thermodynamics and kinetics of this class of proteins
Vocatives in subitles: A survey across genre
No full textThe purpose of this contribution is to investigate the function of vocatives and their translation in interlinguistic subtitles over different film genres. Our previous investigation (Bruti, Perego 2005) was based on a small corpus that included 2 British and 2 American films, belonging approximately to the same genre, i.e. COMEDY (with the exception of "The Talented Mr Ripley", which begins as a COMEDY but turns into a DRAMATIC MYSTERY STORY). This project aims to investigate the various roles vocatives play in the construction of the narrative according to the different needs that different film genres aim to fulfil. The corpus has therefore been extended to include: a full-length animated feature from Walt Disney Pictures ("Bambi", D. Hand, 1942), an action film ("Lethal Weapon 4", R. Donner, 1998), an adaptation from a literary masterpiece ("Sense and Sensibility", A. Lee, 1996), a popular comedy series (two episodes of "Sex and the City", Season 4, “The Agony and the Ex-tasy”, M.P. King, 2001 and “I heart NY”, M.P. King 2002) and an animated series (two episodes of "The Simpsons", “Homer in the night”, R. Moore, 1989-90; “Homer the Moe”, J. Kamerman, 2001-02)
N- and C-terminal isoforms of Arg quantified by real time PCR are specifically expressed in human normal and neoplastic cells, in neoplastic cell lines, and in HL-60 cell differentiation
No full textThe human ABL2 (or ARG) gene codes for a nonreceptor tyrosine kinase is involved in translocation with the ETV6 gene in human leukemia and has an altered expression in several human carcinomas. Two isoforms of Arg with different N-termini (1A and 1B) have been described. The C-terminal domain of Arg contains two F-actin-binding sequences that perform a number of actions related to cell morphology and motility by interacting with actin filaments. We have identified different-sized specific cDNAs in hematopoietic, epithelial, nervous, and fibroblastic cells by means of the reverse transcription (RT)-polymerase chain reaction (PCR) analysis of human Arg mRNA. Some of these cDNAs showed an adjunctive alternative splice event involving the 63 bp sequence of exon II, thus leading to four cDNA types with different N-termini: 1A long and short, and 1B long and short. Other cDNAs lacked a 309 bp sequence in the last exon involving one of the C-terminal F-actin binding domains, thus giving rise to two cDNA types: C-termini long and short. Quantified by real-time PCR - quantitative RT-PCR - these Arg transcript isoforms have specific expression patterns not only in different normal and tumor cell types, but also during cell differentiation and growth arrest. These isoforms maintained the open reading frames, and eight putative proteins were predicted. The different C-termini isoforms seem to retain the same quantitative reciprocal ratio of their respective transcripts. The Arg protein isoforms with different C-terminal actin-binding domains and different N-termini might have specific cellular localizations/concentrations, and differently regulated catalytic activity with different implications in normal and neoplastic cells
Study on local effects of aggressive environmental conditions on masonry strengthened with FRCM
No full textAggressive environmental conditions as moisture, temperature and presence of salts, may affect the interfacial behaviour of FRCM bonded to masonry. To check the effectiveness of intervention solid clay brick samples and masonry assemblages including mortar joints were investigated. Strips of carbon fibre nets were applied with a cementitious or a lime based matrices. Specimens were exposed to salt crystallisation tests, according to a RILEM procedure, and to thermal cycles with a temperature variation ranging between -10°C and +70°C. The characteristic size of damage of the samples were monitored by visual observation and laser profilometer; the loss of bond of the composites was verified by pull-off test. Tests results showed different behaviour between the inorganic matrices applied on bricks having different strengths. Moreover, the adhesion strength was affected by the presence of bed joints. The adherence of the specimens of cement matrix depends from the type of substrate and his damage. Specimens of lime matrix do not seem to have a relation between damage of the substrate and adherence, as the failure occurred at the interface matrix/strengthening
Mammalian LIN-7 PDZ proteins associate with beta-catenin at the cell junctions of epithelia and neurons
No full textThe heterotrimeric PDZ complex containing LIN-2, LIN-7 and LIN-10 is known to be involved in the organization of epithelial and neuronal junctions in Caenorhabditis elegans and mammals. We report here that mammalian LIN-7 PDZ proteins form a complex with cadherin and β-catenin in epithelia and neurons. The association of LIN-7 with cadherin and β-catenin is Ca2+ dependent and is mediated by the direct binding of LIN-7 to the C-terminal PDZ target sequence of β-catenin, as demonstrated by means of co-immunoprecipitation experiments and in vitro binding assays with the recombinant glutathione S-transferase:LIN-7A. The presence of β-catenin at the junction is required in order to relocate LIN-7 from the cytosol to cadherin-mediated adhesions, thus indicating that LIN-7 junctional recruitment is β-catenin dependent and that one functional role of the binding is to localize LIN-7. Moreover, when LIN-7 is present at the β-catenin-containing junctions, it determines the accumulation of binding partners, thus suggesting the mechanism by which β-catenin mediates the organization of the junctional domai
Protein self-entanglement modulates successful folding to the native state: A multi-scale modeling study
No full textThe computer-aided investigation of protein folding has greatly benefited from coarse-grained models, that is, simplified representations at a resolution level lower than atomistic, providing access to qualitative and quantitative details of the folding process that would be hardly attainable, via all-atom descriptions, for medium to long molecules. Nonetheless, the effectiveness of low-resolution models is itself hampered by the presence, in a small but significant number of proteins, of nontrivial topological self-entanglements. Features such as native state knots or slipknots introduce conformational bottlenecks, affecting the probability to fold into the correct conformation; this limitation is particularly severe in the context of coarse-grained models. In this work, we tackle the relationship between folding probability, protein folding pathway, and protein topology in a set of proteins with a nontrivial degree of topological complexity. To avoid or mitigate the risk of incurring in kinetic traps, we make use of the elastic folder model, a coarse-grained model based on angular potentials optimized toward successful folding via a genetic procedure. This light-weight representation allows us to estimate in silico folding probabilities, which we find to anti-correlate with a measure of topological complexity as well as to correlate remarkably well with experimental measurements of the folding rate. These results strengthen the hypothesis that the topological complexity of the native state decreases the folding probability and that the force-field optimization mimics the evolutionary process these proteins have undergone to avoid kinetic traps
Noninvasive electrocardiographic parameters to assess interventricular dyssynchrony in dogs with bundle branch blocks
No full textObjectives: To define electrocardiographic features of complete left bundle branch block (LBBB) and right bundle branch block (RBBB), and the use of R-peak time (RPT) to identify interventricular dyssynchrony in dogs with BBB.
Animals, materials and methods: Twelve-lead ECG tracings of 20 dogs with RBBB, 20 with LBBB, and 60 healthy dogs were retrospectively analyzed and RPT was measured in precordial leads. Interventricular dyssynchrony index (IDI) was than calculated.
Results: In RBBB, mean electrical axis (MEA) was 111 [120/100], V1RPTwas significantly longer (61 ms [55e72 ms]) than left precordial leads RPT (V2:25 ms [22e30 ms]; V3:25 ms [22e29 ms]; V4:24 ms [21e29 ms]; V5:25 ms [22e29 ms]; V6:25 ms [22e29 ms]) and when compared to normal dogs (P < 0.001). In LBBB, MEA was 76 [70/81], RPT in left precordial leads was significantly longer (V2:49 ms [34e58 ms]; V3:49 ms [43e57 ms]; V4:52 ms [45e62 ms]; V5:53 ms [45e63 ms]; V6:55 ms [45e63 ms]) than V1RPT (17 ms [15e20 ms]) and when compared to normaldogs (P<0.001). V1RPT>28 ms and V5RPT>36 ms were found to predict the presence of RBBB and LBBB with a sensitivity of 100% and 96.7%, and a specificity of 96.7% and 99.5%, respectively. The IDI was 23% [16e29%] in normal dogs and significantly greater in dogs with RBBB (33% [30e38%]; P < 0.001) and LBBB (32% [23e41%]; P 1⁄4 0.006).
Conclusions: This study defines ECG features and RPT in dogs with BBB. Electrical interventricular dyssynchrony can be defined using IDI in dogs with BBB
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