A beta2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

beta2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta2-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the b2-integrin (TTT/AAA-b2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-b2-integrin KI dendritic cells, which leads to a failure ofMRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of b2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of b2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.Peer reviewe

NIPA Defines an SCF-Type Mammalian E3 Ligase that Regulates Mitotic Entry

SummaryThe regulated oscillation of protein expression is an essential mechanism of cell cycle control. The SCF class of E3 ubiquitin ligases is involved in this process by targeting cell cycle regulatory proteins for degradation by the proteasome, with the F-box subunit of the SCF specifically recruiting a given substrate to the SCF core. Here we identify NIPA (nuclear interaction partner of ALK) as a human F-box-containing protein that defines an SCF-type E3 ligase (SCFNIPA) controlling mitotic entry. Assembly of this SCF complex is regulated by cell-cycle-dependent phosphorylation of NIPA, which restricts substrate ubiquitination activity to interphase. We show nuclear cyclin B1 to be a substrate of SCFNIPA. Inactivation of NIPA by RNAi results in nuclear accumulation of cyclin B1 in interphase, activation of cyclin B1-Cdk1 kinase activity, and premature mitotic entry. Thus, SCFNIPA-based ubiquitination may regulate S-phase completion and mitotic entry in the mammalian cell cycle

Simulating Black Hole White Dwarf Encounters

The existence of supermassive black holes lurking in the centers of galaxies and of stellar binary systems containing a black hole with a few solar masses has been established beyond reasonable doubt. The idea that black holes of intermediate masses ($\sim 1000$ \msun) may exist in globular star clusters has gained credence over recent years but no conclusive evidence has been established yet. An attractive feature of this hypothesis is the potential to not only disrupt solar-type stars but also compact white dwarf stars. In close encounters the white dwarfs can be sufficiently compressed to thermonuclearly explode. The detection of an underluminous thermonuclear explosion accompanied by a soft, transient X-ray signal would be compelling evidence for the presence of intermediate mass black holes in stellar clusters. In this paper we focus on the numerical techniques used to simulate the entire disruption process from the initial parabolic orbit, over the nuclear energy release during tidal compression, the subsequent ejection of freshly synthesized material and the formation process of an accretion disk around the black hole.Comment: 9 pages, 4 figures, Computer Physics Communications, accepted; movie can be found at http://www.faculty.iu-bremen.de/srosswog/; reference correcte

Soft capacitor fibers using conductive polymers for electronic textiles

A novel, highly flexible, conductive polymer-based fiber with high electric capacitance is reported. In its crossection the fiber features a periodic sequence of hundreds of conductive and isolating plastic layers positioned around metallic electrodes. The fiber is fabricated using fiber drawing method, where a multi-material macroscopic preform is drawn into a sub-millimeter capacitor fiber in a single fabrication step. Several kilometres of fibers can be obtained from a single preform with fiber diameters ranging between 500um -1000um. A typical measured capacitance of our fibers is 60-100 nF/m and it is independent of the fiber diameter. For comparison, a coaxial cable of the comparable dimensions would have only ~0.06nF/m capacitance. Analysis of the fiber frequency response shows that in its simplest interrogation mode the capacitor fiber has a transverse resistance of 5 kOhm/L, which is inversely proportional to the fiber length L and is independent of the fiber diameter. Softness of the fiber materials, absence of liquid electrolyte in the fiber structure, ease of scalability to large production volumes, and high capacitance of our fibers make them interesting for various smart textile applications ranging from distributed sensing to energy storage

Learning health ‘safety’ within non-technical skills interprofessional simulation education: a qualitative study

Background: Healthcare increasingly recognises and focusses on the phenomena of ‘safe practice’ and ‘patient safety.’ Success with non-technical skills (NTS) training in other industries has led to widespread transposition to healthcare education, with communication and teamwork skills central to NTS frameworks. Objective: This study set out to identify how the context of interprofessional simulation learning influences NTS acquisition and development of ‘safety’ amongst learners. Methods: Participants receiving a non-technical skills (NTS) safety focussed training package were invited to take part in a focus group interview which set out to explore communication, teamwork, and the phenomenon of safety in the context of the learning experiences they had within the training programme. The analysis was aligned with a constructivist paradigm and took an interactive methodological approach. The analysis proceeded through three stages, consisting of open, axial, and selective coding, with constant comparisons taking place throughout each phase. Each stage provided categories that could be used to explore the themes of the data. Additionally, to ensure thematic saturation, transcripts of observed simulated learning encounters were then analysed. Results: Six themes were established at the axial coding level, i.e., analytical skills, personal behaviours, communication, teamwork, context, and pedagogy. Underlying these themes, two principal concepts emerged, namely: intergroup contact anxiety – as both a result of and determinant of communication – and teamwork, both of which must be considered in relation to context. These concepts have subsequently been used to propose a framework for NTS learning. Conclusions: This study highlights the role of intergroup contact anxiety and teamwork as factors in NTS behaviour and its dissipation through interprofessional simulation learning. Therefore, this should be a key consideration in NTS education. Future research is needed to consider the role of the affective non-technical attributes of intergroup contact anxiety and teamwork as focuses for education and determinants of safe behaviour

Conformally Flat Smoothed Particle Hydrodynamics: Application to Neutron Star Mergers

We present a new 3D SPH code which solves the general relativistic field + hydrodynamics equations in the conformally flat approximation. Several test cases are considered to test different aspects of the code. We finally apply then the code to the coalescence of a neutron star binary system. The neutron stars are modeled by a polytropic equation of state (EoS) with adiabatic indices $\Gamma=2.0$, $\Gamma=2.6$ and $\Gamma=3.0$. We calculate the gravitational wave signals, luminosities and frequency spectra by employing the quadrupole approximation for emission and back reaction in the slow motion limit. In addition, we consider the amount of ejected mass.Comment: 23 pages, 12 figures. Accepted for publication in Phys. Rev. D. v3: Final Versio

Nonperturbative renormalization group approach to frustrated magnets

This article is devoted to the study of the critical properties of classical XY and Heisenberg frustrated magnets in three dimensions. We first analyze the experimental and numerical situations. We show that the unusual behaviors encountered in these systems, typically nonuniversal scaling, are hardly compatible with the hypothesis of a second order phase transition. We then review the various perturbative and early nonperturbative approaches used to investigate these systems. We argue that none of them provides a completely satisfactory description of the three-dimensional critical behavior. We then recall the principles of the nonperturbative approach - the effective average action method - that we have used to investigate the physics of frustrated magnets. First, we recall the treatment of the unfrustrated - O(N) - case with this method. This allows to introduce its technical aspects. Then, we show how this method unables to clarify most of the problems encountered in the previous theoretical descriptions of frustrated magnets. Firstly, we get an explanation of the long-standing mismatch between different perturbative approaches which consists in a nonperturbative mechanism of annihilation of fixed points between two and three dimensions. Secondly, we get a coherent picture of the physics of frustrated magnets in qualitative and (semi-) quantitative agreement with the numerical and experimental results. The central feature that emerges from our approach is the existence of scaling behaviors without fixed or pseudo-fixed point and that relies on a slowing-down of the renormalization group flow in a whole region in the coupling constants space. This phenomenon allows to explain the occurence of generic weak first order behaviors and to understand the absence of universality in the critical behavior of frustrated magnets.Comment: 58 pages, 15 PS figure

Integrating data and analysis technologies within leading environmental research infrastructures: Challenges and approaches

When researchers analyze data, it typically requires significant effort in data preparation to make the data analysis ready. This often involves cleaning, pre-processing, harmonizing, or integrating data from one or multiple sources and placing them into a computational environment in a form suitable for analysis. Research infrastructures and their data repositories host data and make them available to researchers, but rarely offer a computational environment for data analysis. Published data are often persistently identified, but such identifiers resolve onto landing pages that must be (manually) navigated to identify how data are accessed. This navigation is typically challenging or impossible for machines. This paper surveys existing approaches for improving environmental data access to facilitate more rapid data analyses in computational environments, and thus contribute to a more seamless integration of data and analysis. By analysing current state-of-the-art approaches and solutions being implemented by world‑leading environmental research infrastructures, we highlight the existing practices to interface data repositories with computational environments and the challenges moving forward. We found that while the level of standardization has improved during recent years, it still is challenging for machines to discover and access data based on persistent identifiers. This is problematic in regard to the emerging requirements for FAIR (Findable, Accessible, Interoperable, and Reusable) data, in general, and problematic for seamless integration of data and analysis, in particular. There are a number of promising approaches that would improve the state-of-the-art. A key approach presented here involves software libraries that streamline reading data and metadata into computational environments. We describe this approach in detail for two research infrastructures. We argue that the development and maintenance of specialized libraries for each RI and a range of programming languages used in data analysis does not scale well. Based on this observation, we propose a set of established standards and web practices that, if implemented by environmental research infrastructures, will enable the development of RI and programming language independent software libraries with much reduced effort required for library implementation and maintenance as well as considerably lower learning requirements on users. To catalyse such advancement, we propose a roadmap and key action points for technology harmonization among RIs that we argue will build the foundation for efficient and effective integration of data and analysis.This work was supported by the European Union’s Horizon 2020 research and innovation program under grant agreements No. 824068 (ENVRI-FAIR project) and No. 831558 (FAIR- sFAIR project). NEON is a project sponsored by the National Science Foundation (NSF) and managed under cooperative support agreement (EF-1029808) to Battell

Rare variant collapsing in conjunction with mean log p-value and gradient boosting approaches applied to Genetic Analysis Workshop 17 data

In addition to methods that can identify common variants associated with susceptibility to common diseases, there has been increasing interest in approaches that can identify rare genetic variants. We use the simulated data provided to the participants of Genetic Analysis Workshop 17 (GAW17) to identify both rare and common single-nucleotide polymorphisms and pathways associated with disease status. We apply a rare variant collapsing approach and the usual association tests for common variants to identify candidates for further analysis using pathway-based and tree-based ensemble approaches. We use the mean log p-value approach to identify a top set of pathways and compare it to those used in simulation of GAW17 dataset. We conclude that the mean log p-value approach is able to identify those pathways in the top list and also related pathways. We also use the stochastic gradient boosting approach for the selected subset of single-nucleotide polymorphisms. When compared the result of this tree-based method with the list of single-nucleotide polymorphisms used in dataset simulation, in addition to correct SNPs we observe number of false positives