LNCS

Concurrent accesses to shared data structures must be synchronized to avoid data races. Coarse-grained synchronization, which locks the entire data structure, is easy to implement but does not scale. Fine-grained synchronization can scale well, but can be hard to reason about. Hand-over-hand locking, in which operations are pipelined as they traverse the data structure, combines fine-grained synchronization with ease of use. However, the traditional implementation suffers from inherent overheads. This paper introduces snapshot-based synchronization (SBS), a novel hand-over-hand locking mechanism. SBS decouples the synchronization state from the data, significantly improving cache utilization. Further, it relies on guarantees provided by pipelining to minimize synchronization that requires cross-thread communication. Snapshot-based synchronization thus scales much better than traditional hand-over-hand locking, while maintaining the same ease of use

Effect of base–acid properties of the mixtures of water with methanol on the solution enthalpy of selected cyclic ethers in this mixture at 298.15 K

The enthalpies of solution of cyclic ethers: 1,4- dioxane, 12-crown-4 and 18-crown-6 in the mixture of water and methanol have been measured within the whole mole fraction range at T = 298.15 K. Based on the obtained data, the effect of base–acid properties of water– methanol mixtures on the solution enthalpy of cyclic ethers in these mixtures has been analyzed. The solution enthalpy of cyclic ethers depends on acid properties of water– methanol mixtures in the range of high and medium water contents in the mixture. Based on the analysis performed, it can be assumed that in the mixtures of high methanol contents, cyclic ethe

Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models

The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4–FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4–mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease

Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

Delivery of Dark Material to Vesta via Carbonaceous Chondritic Impacts

NASA's Dawn spacecraft observations of asteroid (4) Vesta reveal a surface with the highest albedo and color variation of any asteroid we have observed so far. Terrains rich in low albedo dark material (DM) have been identified using Dawn Framing Camera (FC) 0.75 {\mu}m filter images in several geologic settings: associated with impact craters (in the ejecta blanket material and/or on the crater walls and rims); as flow-like deposits or rays commonly associated with topographic highs; and as dark spots (likely secondary impacts) nearby impact craters. This DM could be a relic of ancient volcanic activity or exogenic in origin. We report that the majority of the spectra of DM are similar to carbonaceous chondrite meteorites mixed with materials indigenous to Vesta. Using high-resolution seven color images we compared DM color properties (albedo, band depth) with laboratory measurements of possible analog materials. Band depth and albedo of DM are identical to those of carbonaceous chondrite xenolith-rich howardite Mt. Pratt (PRA) 04401. Laboratory mixtures of Murchison CM2 carbonaceous chondrite and basaltic eucrite Millbillillie also show band depth and albedo affinity to DM. Modeling of carbonaceous chondrite abundance in DM (1-6 vol%) is consistent with howardite meteorites. We find no evidence for large-scale volcanism (exposed dikes/pyroclastic falls) as the source of DM. Our modeling efforts using impact crater scaling laws and numerical models of ejecta reaccretion suggest the delivery and emplacement of this DM on Vesta during the formation of the ~400 km Veneneia basin by a low-velocity (<2 km/sec) carbonaceous impactor. This discovery is important because it strengthens the long-held idea that primitive bodies are the source of carbon and probably volatiles in the early Solar System.Comment: Icarus (Accepted) Pages: 58 Figures: 15 Tables:

Cyr61/CCN1 Displays High-Affinity Binding to the Somatomedin B 1–44 Domain of Vitronectin

OV) family of extracellular-associated (matricellular) proteins that present four distinct functional modules, namely insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C (vWF), thrombospondin type 1 (TSP), and C-terminal growth factor cysteine knot (CT) domain. While heparin sulphate proteoglycans reportedly mediate the interaction of Cyr61 with the matrix and cell surface, the role of other extracellular associated proteins has not been revealed. at high concentrations attenuate Cyr61 binding to immobilized VTNC, while monomeric VTNC was ineffective. Therefore, immobilization of VTNC exposes cryptic epitopes that recognize Cyr61 with high affinity, as reported for a number of antibodies, β-endorphin, and other molecules. domain suggests that VTNC represent a point of anchorage for CCN family members to the matrix. Results are discussed in the context of the role of CCN and VTNC in matrix biology and angiogenesis

Aortic valvuloplasty of calcific aortic stenosis with monofoil and trefoil balloon catheters: practical considerations

In order to evaluate the relation between balloon design (monofoil, trefoil) and valvular configuration, experimental aortic valvuloplasty was performed in four post-mortem hearts with calcific aortic sten

Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18

<p>Abstract</p> <p>Background</p> <p>Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.</p> <p>Methods</p> <p>Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack <it>in vitro</it>. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated <it>in vivo </it>in mice bearing ID8-Vegf tumors.</p> <p>Results</p> <p>While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death <it>in vitro</it>. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy <it>in vivo </it>and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.</p> <p>Conclusion</p> <p>These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 <it>in vivo</it>.</p