P2Y\u3csub\u3e12\u3c/sub\u3e or P2Y\u3csub\u3e1\u3c/sub\u3e Inhibitors Reduce Platelet Deposition in a Microfluidic Model of Thrombosis while Apyrase Lacks Efficacy Under Flow Conditions

Determination of the patient-specific response to antiplatelet agents facilitates proper dosing for both acute and chronic prophylaxis. Closed systems (with or without flow) may fail to predict pharmacological potency in situations where platelets rapidly accumulate under flow conditions at the site of thrombosis ( Open systems). Using an 8-channel microfluidic flow assay of human whole blood with corn trypsin inhibitor (± PPACK) perfused over focul zones of collagen, dose-response curves were measured for pharmacological agents at a wall shear rate of 210 s-1. The P2Y1 inhibitor MRS 2179 (IC50 = 0.233 ± 0.132 µM) and P2Y12 inhibitor 2-MeSAMP (IC50 = 2.558 ± 0.799 µM) were potent blockers of secondary platelet accumulation under flow, while the P2X1 inhibitor (NF 449) and apyrase failed to reduce platelet accumulation. MRS 2179 and 2-MeSAMP and undetectable effects on initial platelet adhesion to collagen. Numerical simulation of convective-diffusive transport and apyrase-mediated catalytic degradation of ADP indicated that ultra-high concentrations of apyrase (~ 2000 U mL-1) would be required to have the same effect under flow as much lower concentrations (1 U mL-1) currently used in closed systems (aggregometry or cone-and-plate viscometer). This is the first evaluation of IC50 values for P2Y12 and P2Y1 antagonists under controlled flow conditions. Evaluation of antiplatelet agents in open flow systems demonstrates that inhibition of either ADP by apyrase or antagonism of P2X1 signaling had no inhibitory effect on platelet accumulation. This technique provides a platform for rapidly investigating effects of antithrombotic therapies simultaneously in a model injury system

Cost accounting for brass manufacturers, Final report on the preparation of a uniform cost accounting system

The following report of the Special Cost Committee, appointed by the Permanent Cost Committee at the meeting held at the Congress Hotel, Chicago, May 22nd and 23rd, 1917, outlines a Uniform Cost Finding System that will adequately meet the needs of Brass Manufacturers. It has been constantly borne in mind by this Committee that this Uniform Cost Finding System must be as applicable to the small manufacturer as to the large one, and we believe that a careful study of this report will bear out the statement that it will meet the requirements of any brass manufacturer, regardless of the size of his plant. In considering a Uniform Cost Finding System, its relation to other phases of the business of manufacturing must be taken into consideration. There is production work, which consists of planning the work to be performed in the factory, and the issuing of instructions covering it; control of labor and pay-roll department. Then there is Purchasing, Inspecting, Receiving, General Accounting and Shipping. It has been the aim of this Committee to confine its recommendations to actual cost finding as much as possible, although occasional references to Production and General Accounting will be found. By this is meant, the general books should reflect in total what the cost accounts represent in detailâ⠡¬â€�in other words, the accounts in the general books must be so arranged that the detailed charges and credits turned in monthly by the Cost Department can be posted directly to the general account affected. The accounts in the general books must be of sufficient detail to overcome the bad practice of charging many items to General Expense that really deserve separate accounts

Simultaneous Embeddings with Few Bends and Crossings

A simultaneous embedding with fixed edges (SEFE) of two planar graphs $R$ and $B$ is a pair of plane drawings of $R$ and $B$ that coincide when restricted to the common vertices and edges of $R$ and $B$. We show that whenever $R$ and $B$ admit a SEFE, they also admit a SEFE in which every edge is a polygonal curve with few bends and every pair of edges has few crossings. Specifically: (1) if $R$ and $B$ are trees then one bend per edge and four crossings per edge pair suffice (and one bend per edge is sometimes necessary), (2) if $R$ is a planar graph and $B$ is a tree then six bends per edge and eight crossings per edge pair suffice, and (3) if $R$ and $B$ are planar graphs then six bends per edge and sixteen crossings per edge pair suffice. Our results improve on a paper by Grilli et al. (GD'14), which proves that nine bends per edge suffice, and on a paper by Chan et al. (GD'14), which proves that twenty-four crossings per edge pair suffice.Comment: Full version of the paper "Simultaneous Embeddings with Few Bends and Crossings" accepted at GD '1

Governance and Policy Cooperation on the Cyber Security of the Internet of Things

This report was based on a workshop. The impetus for this workshop was the recognition that international policy cooperation on the cybersecurity aspects of the IoT has made little progress. This is due in part to a failure to establish a functioning community of technicians and policymakers who are jointly focusing on these issues. From a technical perspective, the IoT will significantly increase opportunities to breach security via new attack surfaces. For policymakers, the heightened insecurity created by the rapid expansion of the IoT marks a significant governance challenge. Addressing these security deficiencies will require an increase in the capacity to share threat information as well as a range of innovative technical and policy solutions. The workshop marked a starting point in building a global community of security practitioners and policymakers who are interested in these issues and who are working on similar topics

GTP and Ca2+ Modulate the Inositol 1,4,5-Trisphosphate-Dependent Ca2+ Release in Streptolysin O-Permeabilized Bovine Adrenal Chromaffin Cells

The inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release was studied using streptolysin O-permeabilized bovine adrenal chromaffin cells. The IP3-induced Ca2+ release was followed by Ca2+ reuptake into intracellular compartments. The IP3-induced Ca2+ release diminished after sequential applications of the same amount of IP3. Addition of 20 μM GTP fully restored the sensitivity to IP3. Guanosine 5'-O-(3-thio)triphosphate (GTPγS) could not replace GTP but prevented the action of GTP. The effects of GTP and GTPγS were reversible. Neither GTP nor GTPγS induced release of Ca2+ in the absence of IP3. The amount of Ca2+ whose release was induced by IP3 depended on the free Ca2+ concentration of the medium. At 0.3 μM free Ca2+, a half-maximal Ca2+ release was elicited with ∼0.1 μM IP3. At 1 μM free Ca2+, no Ca2+ release was observed with 0.1 μM IP3; at this Ca2+ concentration, higher concentrations of IP3 (0.25 μM) were required to evoke Ca2+ release. At 8 μM free Ca2+, even 0.25 μM IP3 failed to induce release of Ca2+ from the store. The IP3-induced Ca2+ release at constant low (0.2 μM) free Ca2+ concentrations correlated directly with the amount of stored Ca2+. Depending on the filling state of the intracellular compartment, 1 mol of IP3 induced release of between 5 and 30 mol of Ca2+

Equine protease inhibitor system as a marker for the diagnosis of chronic obstructive pulmonary disease (COPD).

Polymorphism in programming languages enables code reuse. Here, we show that polymorphism has broad applicability far beyond computations for technical computing: parallelism in distributed computing, presentation of visualizations of runtime data flow, and proofs for formal verification of correctness. The ability to reuse a single codebase for all these purposes provides new ways to understand and verify parallel programs.Comment: 10 pages, 3 figures. Proceedings of HPTCDL, the 1st Workshop on High Performance Technical Computing in Dynamic Languages, November 17, 2014, New Orleans, Louisiana, USA. Supporting Information available at http://jiahao.github.io/parallel-prefi

The strong thirteen spheres problem

The thirteen spheres problem is asking if 13 equal size nonoverlapping spheres in three dimensions can touch another sphere of the same size. This problem was the subject of the famous discussion between Isaac Newton and David Gregory in 1694. The problem was solved by Schutte and van der Waerden only in 1953. A natural extension of this problem is the strong thirteen spheres problem (or the Tammes problem for 13 points) which asks to find an arrangement and the maximum radius of 13 equal size nonoverlapping spheres touching the unit sphere. In the paper we give a solution of this long-standing open problem in geometry. Our computer-assisted proof is based on a enumeration of the so-called irreducible graphs.Comment: Modified lemma 2, 16 pages, 12 figures. Uploaded program packag

Requirements of SLP76 tyrosines in ITAM and integrin receptor signaling and in platelet function in vivo

Src homology 2 domain–containing leukocyte phosphoprotein of 76 kD (SLP76), an adaptor that plays a critical role in platelet activation in vitro, contains three N-terminal tyrosine residues that are essential for its function. We demonstrate that mice containing complementary tyrosine to phenylalanine mutations in Y145 (Y145F) and Y112 and Y128 (Y112/128F) differentially regulate integrin and collagen receptor signaling. We show that mutation of Y145 leads to severe impairment of glycoprotein VI (GPVI)–mediated responses while preserving outside-in integrin signaling. Platelets from Y112/128F mice, although having mild defects in GPVI signaling, exhibit defective actin reorganization after GPVI or αIIbβ3 engagement. The in vivo consequences of these signaling defects correlate with the mild protection from thrombosis seen in Y112/128F mice and the near complete protection observed in Y145F mice. Using genetic complementation, we further demonstrate that all three phosphorylatable tyrosines are required within the same SLP76 molecule to support platelet activation by GPVI

TYMSTR, a putative chemokine receptor selectively expressed in activated T cells, exhibits HIV-1 coreceptor function

AbstractBackground: Chemokines bind to specific receptors and mediate leukocyte migration to sites of inflammation. Recently, some chemokine receptors, notably CXCR4 and CCR5, have been shown to be essential fusion factors on target cells for infection by human immunodeficiency virus (HIV); the chemokines bound by these receptors have also been shown to act as potent inhibitors of HIV infection. Here, we describe the isolation of a novel, putative chemokine receptor.Results: We have isolated the cDNA for a putative human chemokine receptor, which we have termed TYMSTR (T-lymphocyte-expressed seven-transmembrane domain receptor). The TYMSTR gene is localized to human chromosome 3 and encodes a protein that has a high level of identity with chemokine receptors. TYMSTR mRNA was selectively expressed in interleukin-2-stimulated T lymphocytes but not in freshly isolated lymphocytes and leukocytes or related cell lines. The natural ligand for TYMSTR was not identified among 32 human chemokines and other potential ligands. Cells co-expressing TYMSTR and human CD4 fused with cells expressing envelope glycoproteins of macrophage (M)-tropic HIV-1 as well as T-cell line (T)-tropic HIV-1 isolates. Addition of infectious, T-tropic HIV-1 particles to TYMSTR/CD4-expressing cells resulted in viral entry and proviral DNA formation.Conclusions: Our findings demonstrate that TYMSTR, in combination with CD4, mediates HIV-1 fusion and entry. The high-level expression of TYMSTR in CD4+ T lymphocytes and the selectivity of this receptor for T-tropic and M-tropic HIV-1 strains indicates that TYMSTR might function as HIV coreceptor at both early and late stages of infection