5,096 research outputs found
Recommended from our members
Universality of filamentous aggregation phenomena.
We use perturbative renormalization group theory to study the kinetics of protein aggregation phenomena in a unified manner across multiple timescales. Using this approach, we find that, irrespective of the specific molecular details or experimental conditions, filamentous assembly systems display universal behavior in time. Moreover, we show that the universality classes for protein aggregation correspond to simple autocatalytic processes and that the diversity of behavior in these systems is determined solely by the reaction order for secondary nucleation with respect to the protein concentration, which labels all possible universality classes. We validate these predictions on experimental data for the aggregation of several different proteins at several different initial concentrations, which by appropriate coordinate transformations we are able to collapse onto universal kinetic growth curves. These results establish the power of the perturbative renormalization group in distilling the ultimately simple temporal behavior of complex protein aggregation systems, creating the possibility to study the kinetics of general self-assembly phenomena in a unified fashion
A Graph-Based Semantics Workbench for Concurrent Asynchronous Programs
A number of novel programming languages and libraries have been proposed that
offer simpler-to-use models of concurrency than threads. It is challenging,
however, to devise execution models that successfully realise their
abstractions without forfeiting performance or introducing unintended
behaviours. This is exemplified by SCOOP---a concurrent object-oriented
message-passing language---which has seen multiple semantics proposed and
implemented over its evolution. We propose a "semantics workbench" with fully
and semi-automatic tools for SCOOP, that can be used to analyse and compare
programs with respect to different execution models. We demonstrate its use in
checking the consistency of semantics by applying it to a set of representative
programs, and highlighting a deadlock-related discrepancy between the principal
execution models of the language. Our workbench is based on a modular and
parameterisable graph transformation semantics implemented in the GROOVE tool.
We discuss how graph transformations are leveraged to atomically model
intricate language abstractions, and how the visual yet algebraic nature of the
model can be used to ascertain soundness.Comment: Accepted for publication in the proceedings of FASE 2016 (to appear
Trauma as counter-revolutionary colonisation: narratives from (post)revolutionary Egypt
We argue that multiple levels of trauma were present in Egypt before, during and after the 2011 revolution. Individual, social and political trauma constitute a triangle of traumatisation which was strategically employed by the Egyptian counter-revolutionary forces – primarily the army and the leadership of the Muslim Brotherhood – to maintain their political and economic power over and above the social, economic and political interests of others. Through the destruction of physical bodies, the fragmentation and polarisation of social relations and the violent closure of the newly emerged political public sphere, these actors actively repressed the potential for creative and revolutionary transformation. To better understand this multi-layered notion of trauma, we turn to Habermas’ ‘colonisation of the lifeworld’ thesis which offers a critical lens through which to examine the wider political and economic structures and context in which trauma occurred as well as its effects on the personal, social and political realms. In doing so, we develop a novel conception of trauma that acknowledges individual, social and political dimensions. We apply this conceptual framing to empirical narratives of trauma in Egypt’s pre- and post-revolutionary phases, thus both developing a non-Western application of Habermas’ framework and revealing ethnographic accounts of the revolution by activists in Cairo
Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice
INTRODUCTION: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis. METHODS: Healthy C57Bl/6 mice (n = 66) or BALB/c mice (n = 66) were ventilated (tidal volume = 7.5 ml/kg or 15 ml/kg; positive end-expiratory pressure = 2 cmH2O; fraction of inspired oxygen = 0.5) for five hours. Normal saline or sodium bicarbonate were used to correct for hypovolaemia. Lung histopathology, lung wet-to-dry ratio, bronchoalveolar lavage fluid protein content, neutrophil influx and levels of proinflammatory cytokines and coagulation factors were measured. RESULTS: Animals remained haemodynamically stable throughout the whole experiment. Lung histopathological changes were minor, although significantly more histopathological changes were found after five hours of MV with a larger tidal volume. Lung histopathological changes were no different between the strains. In both strains and with both ventilator settings, MV caused higher wet-to-dry ratios, higher bronchoalveolar lavage fluid protein levels and more influx of neutrophils, and higher levels of proinflammatory cytokines and coagulation factors. Also, with MV higher systemic levels of cytokines were measured. All parameters were higher with larger tidal volumes. Correcting for metabolic acidosis did not alter endpoints. CONCLUSIONS: MV induces VILI, in the absence of a priming pulmonary insult and even with use of relevant (least injurious) ventilator settings. This model offers opportunities to study the pathophysiological mechanisms behind VILI and the contribution of MV to lung injury in the absence of pre-existing lung injury
Recommended from our members
Fluctuations in the Kinetics of Linear Protein Self-Assembly.
Biological systems are characterized by compartmentalization from the subcellular to the tissue level, and thus reactions in small volumes are ubiquitous in living systems. Under such conditions, statistical number fluctuations, which are commonly negligible in bulk reactions, can become dominant and lead to stochastic behavior. We present here a stochastic model of protein filament formation in small volumes. We show that two principal regimes emerge for the system behavior, a small fluctuation regime close to bulk behavior and a large fluctuation regime characterized by single rare events. Our analysis shows that in both regimes the reaction lag-time scales inversely with the system volume, unlike in bulk. Finally, we use our stochastic model to connect data from small-volume microdroplet experiments of amyloid formation to bulk aggregation rates, and show that digital analysis of an ensemble of protein aggregation reactions taking place under microconfinement provides an accurate measure of the rate of primary nucleation of protein aggregates, a process that has been challenging to quantify from conventional bulk experiments.We are grateful to St. John’s College, Cambridge
(T. C. T. M., J. B. K.), the Schiff Foundation (A. J. D.),
the EPSRC (K. L. S.), NSF Grant No. DMR-1310266 (D. A. W.), the Harvard MRSEC Grant No. DMR1420570 (D. A. W.), BBSRC (T. P. J. K.), ERC (T. C. T. M., T. P. J. K.), and Frances and Augustus Newman Foundation (T. P. J. K.) for financial support
Recommended from our members
A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.
Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers
- …