3,735 research outputs found
Police legitimacy among immigrants in Europe: institutional frames and group position
Research on the antecedents of police legitimacy has begun to stress the relevance of a wide range of factors – beyond performance – in shaping public judgements of police (e.g. Jackson et al 2012; Antrobus et al 2015; Mehozay and Factor 2016; Weitzer and Tuch 2006). The ways in which people experience not just policing and but also their wider social, cultural and economic environment – and the location of both police and policed within structures of power, authority and affect – have important effects on lay judgements of police which, in turn, constitute the empirical legitimacy of this foundational state institution
A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation.
BACKGROUND: The mammalian DNA-damage response (DDR) has evolved to protect genome stability and maximize cell survival following DNA-damage. One of the key regulators of the DDR is p53, itself tightly regulated by MDM2. Following double-strand DNA breaks (DSBs), mediators including ATM are recruited to the site of DNA-damage. Subsequent phosphorylation of p53 by ATM and ATM-induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53-responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis.
METHODS: In the current study, we investigated the stabilization and activation of p53 and associated DDR proteins in response to treatment of human colorectal cancer cells (HCT116p53+/+) with the MDM2 antagonist, Nutlin-3.
RESULTS: Using immunoblotting, Nutlin-3 was observed to stabilize p53, and activate p53 target proteins. Unexpectedly, Nutlin-3 also mediated phosphorylation of p53 at key DNA-damage-specific serine residues (Ser15, 20 and 37). Furthermore, Nutlin-3 induced activation of CHK2 and ATM - proteins required for DNA-damage-dependent phosphorylation and activation of p53, and the phosphorylation of BRCA1 and H2AX - proteins known to be activated specifically in response to DNA damage. Indeed, using immunofluorescent labeling, Nutlin-3 was seen to induce formation of γH2AX foci, an early hallmark of the DDR. Moreover, Nutlin-3 induced phosphorylation of key DDR proteins, initiated cell cycle arrest and led to formation of γH2AX foci in cells lacking p53, whilst γH2AX foci were also noted in MDM2-deficient cells.
CONCLUSION: To our knowledge, this is the first solid evidence showing a secondary role for Nutlin-3 as a DDR triggering agent, independent of p53 status, and unrelated to its role as an MDM2 antagonist
Prediction of Optimal Folding Routes of Proteins That Satisfy the Principle of Lowest Entropy Loss: Dynamic Contact Maps and Optimal Control
An optimization model is introduced in which proteins try to evade high energy regions of the folding landscape, and prefer low entropy loss routes during folding. We make use of the framework of optimal control whose convenient solution provides practical and useful insight into the sequence of events during folding. We assume that the native state is available. As the protein folds, it makes different set of contacts at different folding steps. The dynamic contact map is constructed from these contacts. The topology of the dynamic contact map changes during the course of folding and this information is utilized in the dynamic optimization model. The solution is obtained using the optimal control theory. We show that the optimal solution can be cast into the form of a Gaussian Network that governs the optimal folding dynamics. Simulation results on three examples (CI2, Sso7d and Villin) show that folding starts by the formation of local clusters. Non-local clusters generally require the formation of several local clusters. Non-local clusters form cooperatively and not sequentially. We also observe that the optimal controller prefers “zipping” or small loop closure steps during folding. The folding routes predicted by the proposed method bear strong resemblance to the results in the literature
Spatial and topological organization of DNA chains induced by gene co-localization
Transcriptional activity has been shown to relate to the organization of
chromosomes in the eukaryotic nucleus and in the bacterial nucleoid. In
particular, highly transcribed genes, RNA polymerases and transcription factors
gather into discrete spatial foci called transcription factories. However, the
mechanisms underlying the formation of these foci and the resulting topological
order of the chromosome remain to be elucidated. Here we consider a
thermodynamic framework based on a worm-like chain model of chromosomes where
sparse designated sites along the DNA are able to interact whenever they are
spatially close-by. This is motivated by recurrent evidence that there exists
physical interactions between genes that operate together. Three important
results come out of this simple framework. First, the resulting formation of
transcription foci can be viewed as a micro-phase separation of the interacting
sites from the rest of the DNA. In this respect, a thermodynamic analysis
suggests transcription factors to be appropriate candidates for mediating the
physical interactions between genes. Next, numerical simulations of the polymer
reveal a rich variety of phases that are associated with different topological
orderings, each providing a way to increase the local concentrations of the
interacting sites. Finally, the numerical results show that both
one-dimensional clustering and periodic location of the binding sites along the
DNA, which have been observed in several organisms, make the spatial
co-localization of multiple families of genes particularly efficient.Comment: Figures and Supplementary Material freely available on
http://dx.doi.org/10.1371/journal.pcbi.100067
"The California critical thinking instruments for benchmarking, program assessment, and directing curricular change"
Charles R. Phillips is an Associate Professor of Pharmacy Administration/Dept. Chair of Pharmacy Practice, Renae J. Chesnut is Associate Dean for Academic and Student Affairs. Raylene M. Rospond is Dean, Pharmacy and Health Sciences. All three are in the College of Pharmacy and Health Sciences at Drake University. They can be contacted at: [email protected], [email protected], and [email protected]. To assess pharmacy students’ critical thinking (CT) measures and identify areas for curricular reform.
Methods. Pharmacy students were given the California Critical Thinking Skills Test and Disposition Index at various points in the PharmD program. Scores were compared with a national referent group and evaluated for changes across the curriculum and between classes.
Results. Students were comparable to national norms. Pretest and posttest scores for total disposition showed improvement. Scores in all subcategories except for truth-seeking were consistently above 40. The CT skills of the pharmacy students varied compared with those of referent students, but the pharmacy students’ overall score of 18 was in the 73rd percentile. Pre- and post-skills scores showed improvement. Students scoring low on the pretest improved more than those scoring high.
Conclusions. Students had a consistent disposition towards CT and compared favorably to national
norms. Both disposition and skills improved across the curriculum. Dimensions of critical thinking on
which students score low should be areas for curricular and other program changes
Thermal and electrical conductivity of iron at Earth's core conditions
The Earth acts as a gigantic heat engine driven by decay of radiogenic
isotopes and slow cooling, which gives rise to plate tectonics, volcanoes, and
mountain building. Another key product is the geomagnetic field, generated in
the liquid iron core by a dynamo running on heat released by cooling and
freezing to grow the solid inner core, and on chemical convection due to light
elements expelled from the liquid on freezing. The power supplied to the
geodynamo, measured by the heat-flux across the core-mantle boundary (CMB),
places constraints on Earth's evolution. Estimates of CMB heat-flux depend on
properties of iron mixtures under the extreme pressure and temperature
conditions in the core, most critically on the thermal and electrical
conductivities. These quantities remain poorly known because of inherent
difficulties in experimentation and theory. Here we use density functional
theory to compute these conductivities in liquid iron mixtures at core
conditions from first principles- the first directly computed values that do
not rely on estimates based on extrapolations. The mixtures of Fe, O, S, and Si
are taken from earlier work and fit the seismologically-determined core density
and inner-core boundary density jump. We find both conductivities to be 2-3
times higher than estimates in current use. The changes are so large that core
thermal histories and power requirements must be reassessed. New estimates of
adiabatic heat-flux give 15-16 TW at the CMB, higher than present estimates of
CMB heat-flux based on mantle convection; the top of the core must be thermally
stratified and any convection in the upper core driven by chemical convection
against the adverse thermal buoyancy or lateral variations in CMB heat flow.
Power for the geodynamo is greatly restricted and future models of mantle
evolution must incorporate a high CMB heat-flux and explain recent formation of
the inner core.Comment: 11 pages including supplementary information, two figures. Scheduled
to appear in Nature, April 201
Beyond Gross-Pitaevskii Mean Field Theory
A large number of effects related to the phenomenon of Bose-Einstein
Condensation (BEC) can be understood in terms of lowest order mean field
theory, whereby the entire system is assumed to be condensed, with thermal and
quantum fluctuations completely ignored. Such a treatment leads to the
Gross-Pitaevskii Equation (GPE) used extensively throughout this book. Although
this theory works remarkably well for a broad range of experimental parameters,
a more complete treatment is required for understanding various experiments,
including experiments with solitons and vortices. Such treatments should
include the dynamical coupling of the condensate to the thermal cloud, the
effect of dimensionality, the role of quantum fluctuations, and should also
describe the critical regime, including the process of condensate formation.
The aim of this Chapter is to give a brief but insightful overview of various
recent theories, which extend beyond the GPE. To keep the discussion brief,
only the main notions and conclusions will be presented. This Chapter
generalizes the presentation of Chapter 1, by explicitly maintaining
fluctuations around the condensate order parameter. While the theoretical
arguments outlined here are generic, the emphasis is on approaches suitable for
describing single weakly-interacting atomic Bose gases in harmonic traps.
Interesting effects arising when condensates are trapped in double-well
potentials and optical lattices, as well as the cases of spinor condensates,
and atomic-molecular coupling, along with the modified or alternative theories
needed to describe them, will not be covered here.Comment: Review Article (19 Pages) - To appear in 'Emergent Nonlinear
Phenomena in Bose-Einstein Condensates: Theory and Experiment', Edited by
P.G. Kevrekidis, D.J. Frantzeskakis and R. Carretero-Gonzalez (Springer
Verlag
An Intermittent Live Cell Imaging Screen for siRNA Enhancers and Suppressors of a Kinesin-5 Inhibitor
Kinesin-5 (also known as Eg5, KSP and Kif11) is required for assembly of a bipolar mitotic spindle. Small molecule inhibitors of Kinesin-5, developed as potential anti-cancer drugs, arrest cell in mitosis and promote apoptosis of cancer cells. We performed a genome-wide siRNA screen for enhancers and suppressors of a Kinesin-5 inhibitor in human cells to elucidate cellular responses, and thus identify factors that might predict drug sensitivity in cancers. Because the drug's actions play out over several days, we developed an intermittent imaging screen. Live HeLa cells expressing GFP-tagged histone H2B were imaged at 0, 24 and 48 hours after drug addition, and images were analyzed using open-source software that incorporates machine learning. This screen effectively identified siRNAs that caused increased mitotic arrest at low drug concentrations (enhancers), and vice versa (suppressors), and we report siRNAs that caused both effects. We then classified the effect of siRNAs for 15 genes where 3 or 4 out of 4 siRNA oligos tested were suppressors as assessed by time lapse imaging, and by testing for suppression of mitotic arrest in taxol and nocodazole. This identified 4 phenotypic classes of drug suppressors, which included known and novel genes. Our methodology should be applicable to other screens, and the suppressor and enhancer genes we identified may open new lines of research into mitosis and checkpoint biology
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