Interference of the T cell and antigen-presenting cell costimulatory pathway using CTLA4-Ig (abatacept) prevents Staphylococcal enterotoxin B pathology

Abstract Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology. In this article, we demonstrate mice treated with a single dose of abatacept 8 h post SEB exposure had reduced pathology compared with control SEB-exposed mice. SEB-exposed mice showed significant reductions in body weight between days 4 and 9, whereas mice exposed to SEB and also treated with abatacept showed no weight loss for the duration of the study, suggesting therapeutic mitigation of SEB-induced morbidity. Histopathology and magnetic resonance imaging demonstrated that SEB mediated lung damage and edema, which were absent after treatment with abatacept. Analysis of plasma and lung tissues from SEB-exposed mice treated with abatacept demonstrated significantly lower levels of IL-6 and IFN-γ (p &amp;lt; 0.0001), which is likely to have resulted in less pathology. In addition, exposure of human and mouse PBMCs to SEB in vitro showed a significant reduction in levels of IL-2 (p &amp;lt; 0.0001) after treatment with abatacept, indicating that T cell proliferation is the main target for intervention. Our findings demonstrate that abatacept is a robust and potentially credible drug to prevent toxic effects from SEB exposure.</jats:p

Tight-binding study of the influence of the strain on the electronic properties of InAs/GaAs quantum dots

We present an atomistic investigation of the influence of strain on the electronic properties of quantum dots (QD's) within the empirical $s p^{3} s^{*}$ tight-binding (ETB) model with interactions up to 2nd nearest neighbors and spin-orbit coupling. Results for the model system of capped pyramid-shaped InAs QD's in GaAs, with supercells containing $10^{5}$ atoms are presented and compared with previous empirical pseudopotential results. The good agreement shows that ETB is a reliable alternative for an atomistic treatment. The strain is incorporated through the atomistic valence force field model. The ETB treatment allows for the effects of bond length and bond angle deviations from the ideal InAs and GaAs zincblende structure to be selectively removed from the electronic-structure calculation, giving quantitative information on the importance of strain effects on the bound state energies and on the physical origin of the spatial elongation of the wave functions. Effects of dot-dot coupling have also been examined to determine the relative weight of both strain field and wave function overlap.Comment: 22 pages, 7 figures, submitted to Phys. Rev. B (in press) In the latest version, added Figs. 3 and 4, modified Fig. 5, Tables I and II,.and added new reference

Carbon clusters near the crossover to fullerene stability

The thermodynamic stability of structural isomers of $\mathrm{C}_{24}$, $\mathrm{C}_{26}$, $\mathrm{C}_{28}$ and $\mathrm{C}_{32}$, including fullerenes, is studied using density functional and quantum Monte Carlo methods. The energetic ordering of the different isomers depends sensitively on the treatment of electron correlation. Fixed-node diffusion quantum Monte Carlo calculations predict that a $\mathrm{C}_{24}$ isomer is the smallest stable graphitic fragment and that the smallest stable fullerenes are the $\mathrm{C}_{26}$ and $\mathrm{C}_{28}$ clusters with $\mathrm{C}_{2v}$ and $\mathrm{T}_{d}$ symmetry, respectively. These results support proposals that a $\mathrm{C}_{28}$ solid could be synthesized by cluster deposition.Comment: 4 pages, includes 4 figures. For additional graphics, online paper and related information see http://www.tcm.phy.cam.ac.uk/~prck

Dissecting HSV-1-induced host shut-off at RNA level

Herpes simplex virus 1 (HSV-1) installs a profound host shut-off during lytic infection. The virion host shut-off (vhs) protein plays a key role in this process by efficiently cleaving both host and viral mRNAs in a translation-initiation-dependent manner. Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in transcriptional activity of the host genome. Both mechanisms have tremendous impact on the RNA expression profile of the infected cells. To dissect their relative contributions and elucidate gene-specific host transcriptional responses throughout the first 8h of lytic HSV-1 infection, we here employed RNA-seq of total, newly transcribed (4sU-labelled) and chromatin-associated RNA in wild-type (WT) and Δvhs infection of primary human fibroblasts. Following virus entry, vhs activity rapidly plateaued at an elimination rate of around 30% of cellular mRNAs per hour until 8h p.i. In parallel, host transcriptional activity dropped down to 10-20%. While the combined effects of both phenomena dominated infection-induced changes in total RNA, extensive gene-specific transcriptional regulation was observable in chromatin-associated RNA. This was surprisingly concordant between WT HSV-1 and its Δvhs mutant and at least in parts mediated by the embryonic transcription factor DUX4. Furthermore, both WT and Δvhs infection induced strong transcriptional up-regulation of a small subset of genes. Most of these were either poorly or not at all expressed prior to infection but already primed by H3K4me3 histone marks at their promoters. Most interestingly, analysis of chromatin-associated RNA revealed vhs-nuclease-activity-dependent transcriptional down-regulation of at least 150 cellular genes, in particular of many genes encoding integrin adhesome and extracellular matrix components. This was accompanied by a vhs-dependent reduction in protein levels by 8h p.i. for many of these genes. In summary, our study provides a comprehensive picture of the molecular mechanisms that govern cellular RNA metabolism during the first 8h of lytic HSV-1 infection

A tetragonal-to-monoclinic phase transition in a ferroelectric perovskite: the structure of PbZr(0.52)Ti(0.48)O3

The perovskite-like ferroelectric system PbZr(1-x)Ti(x)O3 (PZT) has a nearly vertical morphotropic phase boundary (MPB) around x=0.45-0.50. Recent synchrotron x-ray powder diffraction measurements by Noheda et al. [Appl. Phys. Lett. 74, 2059 (1999)] have revealed a new monoclinic phase between the previously-established tetragonal and rhombohedral regions. In the present work we describe a Rietveld analysis of the detailed structure of the tetragonal and monoclinic PZT phases on a sample with x= 0.48 for which the lattice parameters are respectively: at= 4.044 A, ct= 4.138 A, at 325 K, and am= 5.721 A, bm= 5.708 A, cm= 4.138 A, beta= 90.496 deg., at 20K. In the tetragonal phase the shifts of the atoms along the polar [001] direction are similar to those in PbTiO3 but the refinement indicates that there are, in addition, local disordered shifts of the Pb atoms of ~0.2 A perpendicular to the polar axis.. The monoclinic structure can be viewed as a condensation along one of the directions of the local displacements present in the tetragonal phase. It equally well corresponds to a freezing-out of the local displacements along one of the directions recently reported by Corker et al.[J. Phys. Condens. Matter 10, 6251 (1998)] for rhombohedral PZT. The monoclinic structure therefore provides a microscopic picture of the MPB region in which one of the "locally" monoclinic phases in the "average" rhombohedral or tetragonal structures freezes out, and thus represents a bridge between these two phases.Comment: REVTeX, 7 figures. Modifications after referee's suggestion: new figure (figure 5), comments in 2nd para. (Sect.III) and in 2nd & 3rd para. (Sect. IV-a), in the abstract: "...of ~0.2 A perpendicular to the polar axis.

Generating Sustainable Value from Open Data in a Sharing Society

Part 1: Creating ValueInternational audienceOur societies are in the midst of a paradigm shift that transforms hierarchal markets into an open and networked economy based on digital technology and information. In that context, open data is widely presumed to have a positive effect on social, environmental and economic value; however the evidence to that effect has remained scarce. Subsequently, we address the question how the use of open data can stimulate the generation of sustainable value. We argue that open data sharing and reuse can empower new ways of generating value in the sharing society. Moreover, we propose a model that describes how different mechanisms that take part within an open system generate sustainable value. These mechanisms are enabled by a number of contextual factors that provide individuals with the motivation, opportunity and ability to generate sustainable value

Functional diversity of chemokines and chemokine receptors in response to viral infection of the central nervous system.

Encounters with neurotropic viruses result in varied outcomes ranging from encephalitis, paralytic poliomyelitis or other serious consequences to relatively benign infection. One of the principal factors that control the outcome of infection is the localized tissue response and subsequent immune response directed against the invading toxic agent. It is the role of the immune system to contain and control the spread of virus infection in the central nervous system (CNS), and paradoxically, this response may also be pathologic. Chemokines are potent proinflammatory molecules whose expression within virally infected tissues is often associated with protection and/or pathology which correlates with migration and accumulation of immune cells. Indeed, studies with a neurotropic murine coronavirus, mouse hepatitis virus (MHV), have provided important insight into the functional roles of chemokines and chemokine receptors in participating in various aspects of host defense as well as disease development within the CNS. This chapter will highlight recent discoveries that have provided insight into the diverse biologic roles of chemokines and their receptors in coordinating immune responses following viral infection of the CNS

Multiband tight-binding theory of disordered ABC semiconductor quantum dots: Application to the optical properties of alloyed CdZnSe nanocrystals

Zero-dimensional nanocrystals, as obtained by chemical synthesis, offer a broad range of applications, as their spectrum and thus their excitation gap can be tailored by variation of their size. Additionally, nanocrystals of the type ABC can be realized by alloying of two pure compound semiconductor materials AC and BC, which allows for a continuous tuning of their absorption and emission spectrum with the concentration x. We use the single-particle energies and wave functions calculated from a multiband sp^3 empirical tight-binding model in combination with the configuration interaction scheme to calculate the optical properties of CdZnSe nanocrystals with a spherical shape. In contrast to common mean-field approaches like the virtual crystal approximation (VCA), we treat the disorder on a microscopic level by taking into account a finite number of realizations for each size and concentration. We then compare the results for the optical properties with recent experimental data and calculate the optical bowing coefficient for further sizes

Social Network Analysis: Recent Achievements and Current Controversies

Network analysis has grown rapidly over the past two decades, but criticisms of the approach have increased as well This article focuses on several accomplishments and unresolved problems of the network approach In the first section. I illustrate the value of the network model in several substantive areas. focusing on studies of centrahty and power, network subgroups, and interorganizational relations I then discuss three issues over which the approach has provoked controversy the relation between network analysis and rational choice theory; the role of norms and culture, and the question of human agency I conclude with some examples of how network theorists are addressing these problemsPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68023/2/10.1177_000169939403700403.pd