Reverse Hall-Petch effect in ultra nanocrystalline diamond

We present atomistic simulations for the mechanical response of ultra nanocrystalline diamond, a polycrystalline form of diamond with grain diameters of the order of a few nm. We consider fully three-dimensional model structures, having several grains of random sizes and orientations, and employ state-of-the-art Monte Carlo simulations. We calculate structural properties, elastic constants and the hardness of the material; our results compare well with experimental observations for this material. Moreover, we verify that this material becomes softer at small grain sizes, in analogy to the observed reversal of the Hall-Petch effect in various nanocrystalline metals. The effect is attributed to the large concentration of grain boundary atoms at smaller grain sizes. Our analysis yields scaling relations for the elastic constants as a function of the average grain size.Comment: Proceedings of the IUTAM Symposium on Modelling Nanomaterials and Nanosystems, Aalborg, Denmark, May 19-22 2008; to be published in the IUTAM Bookseries by Springe

Ocean temperature and salinity components of the Madden-Julian oscillation observed by Argo floats

New diagnostics of the Madden-Julian Oscillation (MJO) cycle in ocean temperature and, for the first time, salinity are presented. The MJO composites are based on 4 years of gridded Argo float data from 2003 to 2006, and extend from the surface to 1,400 m depth in the tropical Indian and Pacific Oceans. The MJO surface salinity anomalies are consistent with precipitation minus evaporation fluxes in the Indian Ocean, and with anomalous zonal advection in the Pacific. The Argo sea surface temperature and thermocline depth anomalies are consistent with previous studies using other data sets. The near-surface density changes due to salinity are comparable to, and partially offset, those due to temperature, emphasising the importance of including salinity as well as temperature changes in mixed-layer modelling of tropical intraseasonal processes. The MJO-forced equatorial Kelvin wave that propagates along the thermocline in the Pacific extends down into the deep ocean, to at least 1,400 m. Coherent, statistically significant, MJO temperature and salinity anomalies are also present in the deep Indian Ocean

WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response

There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel also activates endoplasmic reticulum (ER) stress. Here, we examine the role of WWOX (WW domain containing oxidoreductase), a gene frequently lost in several cancers, in mediating paclitaxel response. We examine the ER stress-mediated apoptotic response to paclitaxel in WWOX-transfected epithelial ovarian cancer (EOC) cells and following siRNA knockdown of WWOX. We show that WWOX-induced apoptosis following exposure of EOC cells to paclitaxel is related to ER stress and independent of the antimitotic action of taxanes. The apoptotic response to ER stress induced by WWOX re-expression could be reversed by WWOX siRNA in EOC cells. We report that paclitaxel treatment activates both the IRE-1 and PERK kinases and that the increase in paclitaxel-mediated cell death through WWOX is dependent on active ER stress pathway. Log-rank analysis of overall survival (OS) and progression-free survival (PFS) in two prominent EOC microarray data sets (Tothill and The Cancer Genome Atlas), encompassing ~800 patients in total, confirmed clinical relevance to our findings. High WWOX mRNA expression predicted longer OS and PFS in patients treated with paclitaxel, but not in patients who were treated with only cisplatin. The association of WWOX and survival was dependent on the expression level of glucose-related protein 78 (GRP78), a key ER stress marker in paclitaxel-treated patients. We conclude that WWOX sensitises EOC to paclitaxel via ER stress-induced apoptosis, and predicts clinical outcome in patients. Thus, ER stress response mechanisms could be targeted to overcome chemoresistance in cancer

FLPe functions in zebrafish embryos

To assay the efficiency of the FLP/FRT site-specific recombination system in Danio rerio, a construct consisting of a muscle-specific promoter driving EGFP flanked by FRT sites was developed. FLPe capped RNA was microinjected into transgenic single cell stage zebrafish embryos obtained by crossing hemizygous transgenic males with wild-type females. By 48 h post fertilization (hpf), the proportion of embryos displaying green fluorescence following FLPe RNA microinjection was significantly lower (7.7%; P < 0.001) than would be expected from a cross in the absence of the recombinase (50%). Embryos that retained fluorescence displayed marked mosaicism. Inheritance of the excised transgene in non-fluorescent, transgenic embryos was verified by PCR analysis and FLPe-mediated recombination was confirmed by DNA sequencing. Sperm derived from confirmed transgenic males in these experiments was used to fertilize wild-type eggs to determine whether germline excision of the transgene had occurred. Clutches sired by FLPe-microinjected males contained 0–4% fluorescent embryos. Transgenic males that were phenotypically wild-type produced no fluorescent progeny, demonstrating complete excision of the transgene from their germline. FLPe microinjected males that retained some fluorescent muscle expression produced a small proportion of fluorescent offspring, suggesting that in mosaic males not all germline cells had undergone FLPe-mediated transgene excision. Our results show that FLPe, which is derived from Saccharomyces cerevisiae, is an efficient recombinase in zebrafish maintained at 28.5°C

The effect of turbulent viscous shear stress on red blood cell hemolysis

[[abstract]]Non-physiologic turbulent flow occurs in medical cardiovascular devices resulting in hemodynamic stresses that may damage red blood cells (RBC) and cause hemolysis. Hemolysis was previously thought to result from Reynolds shear stress (RSS) in turbulent flows. A more recent hypothesis suggests that turbulent viscous shear stresses (TVSS) at spatial scales similar in size to RBCs are related to their damage. We applied two-dimensional digital particle image velocimetry to measure the flow field of a free-submerged axisymmetric jet that was utilized to hemolyze porcine RBCs in selected locations. Assuming a dynamic equilibrium for the sub-grid scale (SGS) energy flux between the resolved and the sub-grid scales, the SGS energy flux was calculated from the strain rate tensor computed from the resolved velocity fields. The SGS stress was determined by the Smagorinsky model, from which the turbulence dissipation rate and then TVSS were estimated. Our results showed the hemolytic threshold of the Reynolds stresses was up to 517 Pa, and the TVSSs were at least an order of magnitude less than the RSS. The results provide further insight into the relationship between turbulence and RBC damage.[[incitationindex]]SCI[[booktype]]紙本[[countrycodes]]JP

Checkpoint Signaling, Base Excision Repair, and PARP Promote Survival of Colon Cancer Cells Treated with 5-Fluorodeoxyuridine but Not 5-Fluorouracil

The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor

Suppression of Allograft Rejection by Tim-1-Fc through Cross-Linking with a Novel Tim-1 Binding Partner on T Cells

Engagement of T-cell immunoglobulin mucin (Tim)-1 on T cells with its ligand, Tim-4, on antigen presenting cells delivers positive costimulatory signals to T cells. However, the molecular mechanisms for Tim-1-mediated regulation of T-cell activation and differentiation are relatively poorly understood. Here we investigated the role of Tim-1 in T-cell responses and allograft rejection using recombinant human Tim-1 extracellular domain and IgG1-Fc fusion proteins (Tim-1-Fc). In vitro assays confirmed that Tim-1-Fc selectively binds to CD4+ effector T cells, but not dendritic cells or natural regulatory T cells (nTregs). Tim-1-Fc was able to inhibit the responses of purified CD4+ T cells that do not express Tim-4 to stimulation by anti-CD3/CD28 mAbs, and this inhibition was associated with reduced AKT and ERK1/2 phosphorylation, but it had no influence on nTregs. Moreover, Tim-1-Fc inhibited the proliferation of CD4+ T cells stimulated by allogeneic dendritic cells. Treatment of recipient mice with Tim-1-Fc significantly prolonged cardiac allograft survival in a fully MHC-mismatched strain combination, which was associated with impaired Th1 response and preserved Th2 and nTregs function. Importantly, the frequency of Foxp3+ cells in splenic CD4+ T cells was increased, thus shifting the balance toward regulators, even though Tim-1-Fc did not induce Foxp3 expression in CD4+CD25− T cells directly. These results indicate that Tim-1-Fc can inhibit T-cell responses through an unknown Tim-1 binding partner on T cells, and it is a promising immunosuppressive agent for preventing allograft rejection

The Role of Perfusion Computed Tomography in the Prediction of Cerebral Hyperperfusion Syndrome

Hyperperfusion syndrome (HPS) following carotid angioplasty with stenting (CAS) is associated with significant morbidity and mortality. At present, there are no reliable parameters to predict HPS. The aim of this study was to clarify whether perfusion computed tomography (CT) is a feasible and reliable tool in predicting HPS after CAS.We performed a retrospective case-control study of 54 patients (11 HPS patients and 43 non-HPS) with unilateral severe stenosis of the carotid artery who underwent CAS. We compared the prevalence of vascular risk factors and perfusion CT parameters including regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and time to peak (TTP) within seven days prior to CAS. Demographic information, risk factors for atherosclerosis, and perfusion CT parameters were evaluated by multivariable logistic regression analysis. The rCBV index was calculated as [(ipsilateral rCBV - contralateral rCBV)/contralateral rCBV], and indices of rCBF and TTP were similarly calculated. We found that eleven patients had HPS, including five with intracranial hemorrhages (ICHs) of whom three died. After a comparison with non-HPS control subjects, independent predictors of HPS included the severity of ipsilateral carotid artery stenosis, 3-hour mean systolic blood pressure (3 h SBP) after CAS, pre-stenting rCBV index >0.15 and TTP index >0.22.The combination of severe ipsilateral carotid stenosis, 3 h SBP after CAS, rCBV index and TTP index provides a potential screening tool for predicting HPS in patients with unilateral carotid stenosis receiving CAS. In addition, adequate management of post-stenting blood pressure is the most important treatable factor in preventing HPS in these high risk patients