A Comprehensive Case Study of Macrosegregation in a Steel Ingot

This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11663-015-0386-yA case study is presented that examines the macrosegregation and grain structure present in a 12-tonne steel ingot, which was cast for experimental purposes. Details of the casting procedure were well documented and the resulting ingot was characterized using a number of techniques that measured chemical segregation, shrinkage, and porosity. The formation of the porosity and segregation patterns is discussed in reference to the particular grain structure observed in the ingot. It is hoped that this case study can be used as a tool for the validation of future macromodels.This work was undertaken as part of a Project sponsored by Rolls-Royce Power Nuclear plc in collaboration with Sheffield Forgemasters International

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced >= 1 treatment-emergent adverse event (TEAE), with = 3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients

Tubulin inhibitors targeting the colchicine binding site: a perspective of privileged structures

The vital roles of microtubule in mitosis and cell division make it an attractive target for antitumor therapy. Colchicine binding site of tubulin is one of the most important pockets that have been focused on to design tubulin-destabilizing agents. Over the past few years, a large number of colchicine binding site inhibitors (CBSIs) have been developed inspired by natural products or synthetic origins, and many moieties frequently used in these CBSIs are structurally in common. In this review, we will classify the CBSIs into classical CBSIs and nonclassical CBSIs according to their spatial conformations and binding modes with tubulin, and highlight the privileged structures from these CBSIs in the development of tubulin inhibitors targeting the colchicine binding site

Individual Actin Filaments in a Microfluidic Flow Reveal the Mechanism of ATP Hydrolysis and Give Insight Into the Properties of Profilin

A novel microfluidic approach allows the analysis of the dynamics of individual actin filaments, revealing both their local ADP/ADP-Pi-actin composition and that Pi release is a random mechanism

Insight into the Assembly Properties and Functional Organisation of the Magnetotactic Bacterial Actin-like Homolog, MamK

Magnetotactic bacteria (MTB) synthesize magnetosomes, which are intracellular vesicles comprising a magnetic particle. A series of magnetosomes arrange themselves in chains to form a magnetic dipole that enables the cell to orient itself along the Earth’s magnetic field. MamK, an actin-like homolog of MreB has been identified as a central component in this organisation. Gene deletion, fluorescence microscopy and in vitro studies have yielded mechanistic differences in the filament assembly of MamK with other bacterial cytoskeletal proteins within the cell. With little or no information on the structural and behavioural characteristics of MamK outside the cell, the mamK gene from Magnetospirillium gryphiswaldense was cloned and expressed to better understand the differences in the cytoskeletal properties with its bacterial homologues MreB and acitin. Despite the low sequence identity shared between MamK and MreB (22%) and actin (18%), the behaviour of MamK monitored by light scattering broadly mirrored that of its bacterial cousin MreB primarily in terms of its pH, salt, divalent metal-ion and temperature dependency. The broad size variability of MamK filaments revealed by light scattering studies was supported by transmission electron microscopy (TEM) imaging. Filament morphology however, indicated that MamK conformed to linearly orientated filaments that appeared to be distinctly dissimilar compared to MreB suggesting functional differences between these homologues. The presence of a nucleotide binding domain common to actin-like proteins was demonstrated by its ability to function both as an ATPase and GTPase. Circular dichroism and structural homology modelling showed that MamK adopts a protein fold that is consistent with the ‘classical’ actin family architecture but with notable structural differences within the smaller domains, the active site region and the overall surface electrostatic potential

O manuscrito e o iconográfico em cartões-postais belicosos: da apologia cavalheiresca à contestação da Grande Guerra (1914-1918) na França

O trabalho analisa mensagens transmitidas por cartões-postais produzidos e circulados na França no contexto da Primeira Guerra Mundial (1914-1918), apresentando temática associada ao conflito. O objetivo é contrapor as mensagens iconográficas e textuais neles impressas à quelas que foram manuscritas por seus remetentes, de modo a evidenciar formas de expressão e percepções do conflito, conforme empregadas por civis e militares, em diferentes momentos de seu desenvolvimento.The paper analyzes messages conveyed by postcards produced and circulated in France during the First World War (1914-1918), with themes referring to the conflict. The intention is to compare the iconographic and textual messages printed with handwritten messages, to display forms of expression and perception of war, used by civilian and military on different occasions

The structure of bovine F(1)-ATPase inhibited by ADP and beryllium fluoride

The structure of bovine F(1)-ATPase inhibited with ADP and beryllium fluoride at 2.0 Å resolution contains two ADP.BeF(3)(−) complexes mimicking ATP, bound in the catalytic sites of the β(TP) and β(DP) subunits. Except for a 1 Å shift in the guanidinium of αArg373, the conformations of catalytic side chains are very similar in both sites. However, the ordered water molecule that carries out nucleophilic attack on the γ-phosphate of ATP during hydrolysis is 2.6 Å from the beryllium in the β(DP) subunit and 3.8 Å away in the β(TP) subunit, strongly indicating that the β(DP) subunit is the catalytically active conformation. In the structure of F(1)-ATPase with five bound ADP molecules (three in α-subunits, one each in the β(TP) and β(DP) subunits), which has also been determined, the conformation of αArg373 suggests that it senses the presence (or absence) of the γ-phosphate of ATP. Two catalytic schemes are discussed concerning the various structures of bovine F(1)-ATPase

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Upscaling mesoscopic simulation results to develop constitutive relations for macroscopic modeling of equiaxed dendritic solidification

International audienceMacroscale solidification models incorporate the microscale and mesoscale phenomena of dendritic grain growth using constitutive relations. These relations can be obtained by simulating those phenomena inside a Representative Elementary Volume (REV) and then upscaling the results to the macroscale. In the present study, a previously developed mesoscopic envelope model is used to perform three-dimensional simulations of equiaxed dendritic growth at a spatial scale that corresponds to a REV. The mesoscopic results are upscaled by averaging them over the mesoscopic simulation domain. The upscaled results are used to develop new constitutive relations, which, unlike the currently available relations, do not rely on highly simplified assumptions about the grain envelope shape or the solute diffusion conditions around it. The relations are verified by comparing the predictions of the macroscopic model with the upscaled mesoscopic results at different solidification conditions. These relations can now be used in macroscopic models of equiaxed solidification to incorporate more realistically the microscale and mesoscale phenomena