352 research outputs found

    Ambidexterity as historically embedded process : evidence from NASA, 1958-2016

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    Even though the growing ambidexterity literature has delivered useful insights, this theme has been researched largely in static and a-contextual terms, without adequate attention to how an organization’s history and context can shape its present. In this paper we employ NASA as an in-depth case study to trace how its historical trajectory has shaped its current propensity to be ambidextrous. Our study reveals organizational ambidexterity as a path-dependent, contingent process rather than something necessarily achievable via the more generic prescriptions of structural, temporal or contextual ambidexterity models

    Computational investigation of copper-mediated conformational changes in α-synuclein dimer †

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    We report molecular dynamics simulation of dimers of α-synuclein, the peptide closely associated with onset of Parkinson's disease, both as metal-free dimer and with inter-chain bridging provided by Cu(ii) ions. Our investigation reveals that the presence of copper-induced inter-chain bridging not only stabilizes α-synuclein dimers, but also leads to enhanced ÎČ-sheet formation at critical regions within the N-terminal and NAC regions of the protein. These contacts are larger and longer-lived in the presence of copper, and as a result each peptide chain is more extended and less flexible than in the metal-free dimer. The persistence of these inter-peptide contacts underscores their significance in stabilising the dimers, potentially influencing the aggregation pathway. Moreover, the increased flexibility in the two termini, as well as the absence of persistent contacts in the metal-free dimer, correlates with the presence of amorphous aggregates. This phenomenon is known to mitigate fibrillation, while their absence in the metal-bound dimer suggests an increased propensity to form fibrils in the presence of copper ions

    Exploring the impact of mutation and post-translational modification on α-Synuclein: Insights from molecular dynamics simulations with and without copper

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    We report molecular dynamics simulations of two modifications to α-Synuclein, namely A53T mutation and phosphorylation at Ser129, which have been observed in Parkinson's disease patients. Both modifications are close to known metal binding sites, so as well as each modified peptide we also study Cu(II) bound to N-terminal and C-terminal residues. We show that A53T is predicted to cause increased ÎČ-sheet content of the peptide, with a persistent ÎČ-hairpin between residues 35–55 particularly notable. Phosphorylation has less effect on secondary structure but is predicted to significantly increase the size of the peptide, especially when bound to Cu(II), which is ascribed to reduced interaction of C-terminal sequence with central non-amyloid component. In addition, estimate of binding free energy to Cu(II) indicates A53T has little effect on metal-ion affinity, whereas phosphorylation markedly enhances the strength of binding. We suggest that the predicted changes in spatial extent and secondary structure of α-Synuclein may have implications for aggregation into Lewy bodies

    How Cu(II) binding affects structure and dynamics of α-synuclein revealed by molecular dynamics simulations

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    We report accelerated molecular dynamics simulations of α-Synuclein and its complex with two Cu(II) ions bound to experimentally determined binding sites. Adding two Cu(II) ions, one bound to the N-terminal region and one to the C-terminus, decreases size and flexibility of the peptide while introducing significant new contacts within and between N-terminus and non-AÎČ component (NAC). Cu(II) ions also alter the pattern of secondary structure within the peptide, inducing more and longer-lasting elements of secondary structure such as ÎČ-strands and hairpins. Free energy surfaces, obtained from reweighting the accelerated molecular dynamics boost potential, further demonstrate the restriction on size and flexibility that results from binding of copper ions

    Constraints on the dark sector from electroweak precision observables

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    We revisit the constraints on the parameter space for dark photons arising from electroweak precision observables in light of the recent W boson mass anomaly reported by the CDF Collaboration. We also extend previous work by placing the first electroweak precision observable constraints on the coupling of dark photons to the fermionic dark matter sector.Comment: 14 pages, 2 figures, 4 table

    Recommendation of RILEM TC237-SIB on cohesion test of recycled asphalt

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    This recommendation describes how to evaluate the presence of potentially active bitumen in recycled asphalt (RA) materials through the cohesion test. The experimental protocol is designed according to the research performed by the RILEM Technical Committee 237-SIB ‘‘Testing and characterization of sustainable innovative bituminous materials and systems’’ with the purpose, to develop a new, simple and fast method for the characterization of RA while limiting the need for conventional rheological tests. The guidelines in this recommendation focus on the testing procedure including specimen preparation, data analysis and provide information on the preparation of a tests report

    “Those songs were the ones that made me, nobody asked me this question before”: Music Elicitation with ex-gang involved men about their experiences of childhood domestic violence and abuse

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    This article describes the use of music and music videos as an elicitation tool within life-story narrative interviews. The study focused on the lives of men who had experienced domestic violence and abuse in childhood and become involved on road and/or with gangs. Music elicitation was used as participants were asked to select three music tracks that aided them telling their life stories, with particular reference to their experiences of domestic violence in childhood and their involvement on road and in gangs. The music tracks and in many cases the accompanying music videos were viewed in the interview space by both the researcher and participant together. In this case, music elicitation was found to be a very valuable element to the interviews and enhanced the experience for both the participant and researcher. Music elicitation operated in three main ways. Firstly, music often had been used as a personal coping mechanism, and this was recalled in the interview, acting as an anchor to the memory. Secondly, at points, both the music lyrics and their accompanying music videos were used as tools for communication by the participant, through them being used as metaphors, or as illustrations of the past. Lastly, the music was used by the participants as a narrative tool to structure and pace the interviews, giving them greater control over the interview space. This article shows promising results in using music as an elicitation tool for research with this participant group discussing sensitive issues

    Forcefield evaluation and accelerated molecular dynamics simulation of Zn(II) binding to N-terminus of amyloid-ÎČ

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    We report conventional and accelerated molecular dynamics simulation of Zn(II) bound to the N-terminus of amyloid-ÎČ. By comparison against NMR data for the experimentally determined binding mode, we find that certain combinations of forcefield and solvent model perform acceptably in describing the size, shape and secondary structure, and that there is no appreciable difference between implicit and explicit solvent models. We therefore used the combination of ff14SB forcefield and GBSA solvent model to compare the result of different binding modes of Zn(II) to the same peptide, using accelerated MD to enhance sampling and comparing the free peptide simulated in the same way. We show that Zn(II) imparts significant rigidity to the peptide, disrupts the secondary structure and pattern of salt bridges seen in the free peptide, and induces closer contact between residues. Free energy surfaces in 1 or 2 dimensions further highlight the effect of metal coordination on peptide’s spatial extent. We also provide evidence that accelerated MD provides improved sampling over conventional MD by visiting as many or more configurations in much shorter simulation times

    Synthesis of Specimen Preparation and Curing Processes for Cold Recycled Asphalt Mixes

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    The process of cold recycling (CR) is becoming method of choice for pavement rehabilitation due to significantly added environmental and economic benefits. Understanding and standardization of specimen preparation and curing processes are critical to replicate field conditions in lab. This paper presents an extensive synthesis of various specimen preparation and curing processes for cold recycled asphalt mixes. Topics synthesized include RAP, emulsion/bitumen and aggregate preparation, mixing processes, pre- and post- compaction curing, compaction and mechanical testing. This paper was developed through efforts of cold recycling task group (TG6) of RILEM Technical Committee on Testing and Characterization of Sustainable Innovative Bituminous Materials and Systems (TC-SIB)
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