The rockefeller university

Environmental variables and husbandry practices can influence physiology and alter behavior in mice. Our study evaluated the effects of cage change on serum corticosterone levels and anxiety-like behaviors in C57BL/6 male mice. We examined the effects of 3 different methods of performing cage transfer and of transferring mice to a clean or a dirty familiar cage microenvironment. The 3 different handling methods were forceps transfer, gentle transfer with gloved hands, and a passive transfer technique that did not involve active handling. Active handling methods and transfer to both clean and dirty cage microenvironments significantly increased serum corticosterone 15 min after cage change; however, at 60 min after cage change, levels were comparable to those of unmanipulated mice. Although the effects were transient, cage change altered anxiety-like behaviors in the open field when behavioral testing was performed on the same day. These results demonstrate that the timing of cage change can influence behavioral results, an effect that is an important consideration for rodent behavioral studies.

Platelets are a remarkable mammalian adaptation that are required for human survival by virtue of their ability to prevent and arrest bleeding. Ironically, however, in the past century, the platelets' hemostatic activity became maladaptive for the increasingly large percentage of individuals who develop age-dependent progressive atherosclerosis. As a result, platelets also make a major contribution to ischemic thrombotic vascular disease, the leading cause of death worldwide. In this brief review, I provide historical descriptions of a highly selected group of topics to provide a framework for understanding our current knowledge and the trends that are likely to continue into the future of platelet research. For convenience, I separate the eras of platelet research into the "Descriptive Period" extending from similar to 1880-1960 and the "Mechanistic Period" encompassing the past similar to 50 years since 1960. We currently are reaching yet another inflection point, as there is a major shift from a focus on traditional biochemistry and cell and molecular biology to an era of single molecule biophysics, single cell biology, single cell molecular biology, structural biology, computational simulations, and the high-throughput, data-dense techniques collectively named with the "omics postfix". Given the progress made in understanding, diagnosing, and treating many rare and common platelet disorders during the past 50 years, I think it appropriate to consider it a Golden Age of Platelet Research and to recognize all of the investigators who have made important contributions to this remarkable achievement..

The generation of metameric body plans is a key process in development. In Drosophila segmentation, periodicity is established rapidly through the complex transcriptional regulation of the pair-rule genes. The 'primary' pair-rule genes generate their 7-stripe expression through stripe-specific cis-regulatory elements controlled by the preceding non-periodic maternal and gap gene patterns, whereas 'secondary' pair-rule genes are thought to rely on 7-stripe elements that read off the already periodic primary pair-rule patterns. Using a combination of computational and experimental approaches, we have conducted a comprehensive systems-level examination of the regulatory architecture underlying pair-rule stripe formation. We find that runt (run), fushi tarazu (ftz) and odd skipped (odd) establish most of their pattern through stripe-specific elements, arguing for a reclassification of ftz and odd as primary pair-rule genes. In the case of run, we observe long-range cis-regulation across multiple intervening genes. The 7-stripe elements of run, ftz and odd are active concurrently with the stripe-specific elements, indicating that maternal/gap-mediated control and pair-rule gene cross-regulation are closely integrated. Stripe-specific elements fall into three distinct classes based on their principal repressive gap factor input; stripe positions along the gap gradients correlate with the strength of predicted input. The prevalence of cis-elements that generate two stripes and their genomic organization suggest that single-stripe elements arose by splitting and subfunctionalization of ancestral dual-stripe elements. Overall, our study provides a greatly improved understanding of how periodic patterns are established in the Drosophila embryo.

High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1-2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings'. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in alpha 2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209)(2-4). Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC-SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc-treated hDC-SIGN(+) macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor Fc gamma RIIB on effector macrophages. Systemic administration of the T(H)2 cytokines IL-33 or IL-4 upregulates Fc gamma RIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN-T(H)2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases.

Generation of infectious retroviral particles rely on the targeting of all structural components to the correct cellular sites at the correct time. Gag, the main structural protein, orchestrates the assembly process and the mechanisms that trigger its targeting to assembly sites are well described. Gag is also responsible for the packaging of the viral genome and the molecular details of the Gag/RNA interaction are well characterized. Until recently, much less was understood about the cell biology of retrovirus RNA packaging. However, novel biochemical and live-cell microscopic approaches have identified where in the cell the initial events of genome recognition by Gag occur. These recent developments have shed light on the role played by the viral genome during virion assembly. Other central issues of the cell biology of RNA packaging, such as how the Gag-RNA complex traffics through the cytoplasm toward assembly sites, await characterization.

Despite significant recent advances in molecular and structural studies of G protein-coupled receptors (GPCRs), an understanding of transmembrane signal transduction with chemical precision requires new approaches. Simple binary receptor-ligand or receptor-G protein complex models cannot adequately describe the relevant macromolecular signaling machineries. GPCR signalosomes undergo complex dynamic assembly-disassembly reactions to create allosteric signaling conduits whose properties cannot necessarily be predicted from individual elements alone. The combinatorial possibilities inherent in a system with hundreds of potential components suggest that high-content miniaturized experimental platforms and computational approaches will be required. To study allosteric effects involved in signalosome reaction pathways, a bottom-up approach using multicolor single-molecule detection fluorescence experiments in biochemically defined systems and complemented by molecular dynamics models of macromolecular complexes is proposed. In bridging the gap between molecular and systems biology, this synthetic approach suggests a way forward from the flatlands to multi-dimensional data collection.

A search for groups of collimated muons is performed using a data sample collected by the CMS experiment at the LHC, at a centre-of-mass energy of 7TeV, and corresponding to an integrated luminosity of 35 pb(-1). The analysis searches for production of new low-mass states decaying into pairs of muons and is designed to achieve high sensitivity to a broad range of models predicting leptonic jet signatures. With no excess observed over the background expectation, upper limits on the production cross section times branching fraction times acceptance are set, ranging from 0.1 to 0.5 pb at the 95% CL depending on event topology. In addition, the results are interpreted in several benchmark models in the context of supersymmetry with a new light dark sector exploring previously inaccessible parameter space.

We derive a model of a neuron's interspike interval probability density through analysis of the first passage problem. The fit of our expression to retinal ganglion cell laboratory data extracts three physiologically relevant parameters, with which our model yields input-output features that conform to laboratory results. Preliminary analysis suggests that under common circumstances, local circuitry readjusts these parameters with changes in firing rate and so endeavors to faithfully replicate an input signal. Further results suggest that the so-called principle of sloppy workmanship also plays a role in evolution's choice of these parameters.

Several pathogenic bacteria utilize type Ill secretion systems (TTSS) to deliver into host cells bacterial virulence proteins with the capacity to modulate a variety of cellular pathways. Once delivered into host cells, the accurate targeting of bacterial effectors to specific locations is critical for their proper function. However, little is known about the mechanisms these virulence effectors use to reach their subcellular destination. Here we show that the Salmonella TTSS effector proteins SspH2 and Ssel are localized to the plasma membrane of host cells, a process dependent on S-palmitoylation of a conserved cysteine residue within their N-terminal domains. We also show that effector protein lipidation is mediated by a specific subset of host-cell palmitoyltransferases and that lipidation is critical for effector function. This study describes a remarkable mechanism by which a pathogen exploits host-cell machinery to properly target its virulence factors.