B Cells with a Senescent-Associated Secretory Phenotype Accumulate in the Adipose Tissue of Individuals with Obesity

Senescent cells accumulate in the adipose tissue (AT) of individuals with obesity and secrete multiple factors that constitute the senescence-associated secretory phenotype (SASP). This paper aimed at the identification of B cells with a SASP phenotype in the AT, as compared to the peripheral blood, of individuals with obesity. Our results show increased expression of SASP markers in AT versus blood B cells, a phenotype associated with a hyper-metabolic profile necessary to support the increased immune activation of AT-derived B cells as compared to blood-derived B cells. This hyper-metabolic profile is needed for the secretion of the pro-inflammatory mediators (cytokines, chemokines, micro-RNAs) that fuel local and systemic inflammation.     

A miniature triaxial apparatus for investigating the micromechanics of granular soils with in situ X-ray micro-tomography scanning

The development of a miniature triaxial apparatus is presented. In conjunction with an X-ray micro-tomography (termed as X-ray μCT hereafter) facility and advanced image processing techniques, this apparatus can be used for in situ investigation of the micro-scale mechanical behavior of granular soils under shear. The apparatus allows for triaxial testing of a miniature dry sample with a size of \mathrm{8}\hspace{0.17em}\mathrm{mm}\times \mathrm{16}\hspace{0.17em}\mathrm{mm} (diameter \times height). In situ triaxial testing of a 0.4–0.8 mm Leighton Buzzard sand (LBS) under a constant confining pressure of 500 kPa is presented. The evolutions of local porosities (i.e., the porosities of regions associated with individual particles), particle kinematics (i.e., particle translation and particle rotation) of the sample during the shear are quantitatively studied using image processing and analysis techniques. Meanwhile, a novel method is presented to quantify the volumetric strain distribution of the sample based on the results of local porosities and particle tracking. It is found that the sample, with nearly homogenous initial local porosities, starts to exhibit obvious inhomogeneity of local porosities and localization of particle kinematics and volumetric strain around the peak of deviatoric stress. In the post-peak shear stage, large local porosities and volumetric dilation mainly occur in a localized band. The developed triaxial apparatus, in its combined use of X-ray μCT imaging techniques, is a powerful tool to investigate the micro-scale mechanical behavior of granular soils.     

A self‐scalable load injection service

Load testing of applications is an important and costly activity for software provider companies. Classical solutions are very difficult to set up statically, and their cost is prohibitive in terms of both human and hardware resources. Virtualized cloud computing platforms provide new opportunities for stressing an application's scalability, by providing a large range of flexible and less expensive (pay‐per‐use model) computation units. On the basis of these advantages, load testing solutions could be provided on demand in the cloud. This paper describes a Benchmark‐as‐a‐Service solution that automatically scales the load injection platform and facilitates its setup according to load profiles. Our approach is based on: (i) virtualization of the benchmarking platform to create self‐scaling injectors; (ii) online calibration to characterize the injector's capacity and impact on the benched application; and (iii) a provisioning solution to appropriately scale the load injection platform ahead of time. We also report experiments on a benchmark illustrating the benefits of this system in terms of cost and resource reductions. Copyright © 2013 John Wiley & Sons, Ltd.     

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Understanding trust in ms-commerce: The roles of reported experience,linguistic style,profile photo,emotional, and cognitive trust

This paper examines what influences trust in mobile social commerce environment. Drawing on trust-based acceptance model (i.e. cognitive and emotional trust) and online review features (i.e. profile photo, linguistic style, and reported experience), we examine how these factors affect trust in mobile social commerce. Hypotheses were tested using survey data. The results of our model showed that there are significant influences of profile photo, reported experience, cognitive, and emotional trust towards trust in ms-commerce. This work contributes to existing literature by examining the roles of previous trust in mobile payments and online reviews on trust in mobile social commerce.     

Automated and Continuous Production of Microstructured Metallic Plates via Cold Embossing

Many critical issues need to be addressed when microstructured reactors are manufactured in large unit volumes. The most crucial of these are cost, ease of production, and reliability. The lack of breakthrough manufacturing technology to provide high‐efficiency, low‐cost, high‐precision plates is a hindrance to the early market implementation of systems requiring metallic microstructured plates. This contribution focuses on the development and optimization of a combined embossing and bending tool for the quick and continuous manufacture of easily machined plates.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.