Mechanical characterization of rigid discrete interlocking materials

Les matériaux discrets entrecroisés (DIM) rigides sont une classe de matériaux qui se distinguent par la manière unique par laquelle ils se déforment: les DIMs sont composés d’éléments (connectés par entrecroisements) qui peuvent se déplacer librement à l’intérieur d’une amplitude définie par les contacts avec leurs éléments voisins. Ceci donne une réponse biphasique aux déformations unique à ces structures où soit aucune résistance n’est fournie à une déformation, soit un arrêt complet à la déformation se présente. Il n’est pas clair comment l’ensemble de paramètres discrets et continus décrivant un DIM influence ce comportement biphasique. De plus, nous ne possédons pas les outils pour le charactériser correctement. Dans le but d’élucider ce comportement, nous présentons une méthode qui s’inspire de techniques d’homogénisation qui peut détecter les contacts physiques entre éléments composés de tores. En définissant une énergie adéquate, nous pouvons minimiser les intersections entre éléments tout en déformant le DIM d’une façon arbitraire en utilisant des techniques d’optimisation standardes. Nous explorons les déformations auxquelles des arrangements planaires de DIMs peuvent être assujettis et investiguons comment le couplage de contraintes dans deux directions orthogonales influence ces déformations. Nos résultats permettent de mieux comprendre comment différents paramètres décrivant un DIM influence ces déformations.Rigid discrete interlocking materials (DIMs) are a class of materials that distinguish themselves by the unique way in which they deform: in DIMs, elements (connected through interlocking) can move freely within a range defined through contacts with neighbouring elements. This results in a biphasic deformation behaviour unique to these structures where no resistance is provided to deformation or a hard stop to deformation is met. It is yet unclear how the set of discrete and continuous parameters describing a DIM influences this biphasic behaviour. Likewise, we lack tools to properly characterize it. To that effect, we present a method which takes inspiration from homogenization and handles contacts by leveraging the definition of implicit surfaces, specifically tori, making up our elements. By defining an adequate energy function, we can minimize intersection between elements while deforming the DIM in an arbitrary way using standard optimization approaches. We explore the deformations that planar sheets of DIM can be subjected to and investigate how the coupling of constraints in two orthogonal directions affects these deformations. Our results give insights on how the tuning of various parameters describing the DIM affects these deformations

Un nouveau paradigme pour l’orientation : perspectives, limites, et défis

Dans leur discussion de l’article qui fait l’objet du présent numéro, les auteurs présentent dans un premier temps une appréciation générale et critique du texte. Ils s’arrêtent ensuite brièvement à trois aspects en rapport avec la problématique développée par Savickas et ses collègues, à savoir l’aspect individuel du développement de carrière, la notion de carrière et de counseling de carrière, et la formation des conseillers d’orientation, notamment au plan de la collaboration interprofessionnelle.In their discussion of the central article presented in this special issue, the authors first present a general and critical assessment of the text. They then consider briefly three aspects related to the issues raised by Savickas et al., namely, the individual aspect of career development, the notions of career and career counseling, and the training of career counselors, particularly with respect to multidisciplinary collaboration

A novel therapeutic strategy for pancreatic neoplasia using a novel RNAi platform targeting PDX-1

Bi-functional shRNA (bi-shRNA), a novel RNA interference (RNAi) effector platform targeting PDX-1 utilizing a systemic DOTAP-Cholesterol delivery vehicle, was studied in three mouse models of progressive pancreatic neoplasia. Species-specific bi-functional PDX-1 shRNA (bi-shRNAPDX-1) lipoplexes inhibited insulin expression and secretion while also substantially inhibiting proliferation of mouse and human cell lines via disruption of cell cycle proteins in vitro. Three cycles of either bi-shRNA<sup>mousePDX-1</sup> or shRNA<sup>mousePDX-1</sup> lipoplexes administered intravenously prevented death from hyperinsulinemia and hypoglycemia in a lethal insulinoma mouse model. Three cycles of shRNA<sup>mousePDX-1</sup> lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of pancreatic neoplasia. Moreover, three cycles of the bi-shRNA<sup>humanPDX-1</sup> lipoplexes resulted in near complete ablation of tumor volume and considerably improved survival in a human PANC-1 implanted SCID-mouse model. Human pancreatic neoplasia specimens also stained strongly for PDX-1 expression. Together, these data support the clinical development of a novel therapeutic strategy using systemic bi-shRNA<sup>PDX-1</sup> lipoplexes against pancreatic neoplasia

Professionals’ perspectives on viewing child sexual abuse images to improve response to victims

The complexity of the phenomenon of child sexual abuse images online (CSAIO) benefits from cross-disciplinary collaboration across law enforcement, child protection, and children's mental health. Through focus groups with professionals working in these fields, this article focuses on when and whether professionals who work with child sexual abuse cases should be exposed to viewing CSAIO and if so under what circumstances doing so would benefit investigations and support services for victims. In a broader sense, this article is about professional experience, decision making, training, and collaboration around a particularly difficult professional experience, namely exposure to viewing CSAIO

The C terminus of talin links integrins to cell cycle progression

Talin recruits and activates focal adhesion proteins required for cell cycle progression

A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism

BACKGROUND: HIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors. METHODS AND FINDINGS: We have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy. CONCLUSIONS: HIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy

The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis

The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of cell-surface molecules that control inflammation, bone homeostasis, neurological development and blood coagulation. TREM-1 and TREM-2, the best-characterized receptors so far, play divergent roles in several infectious diseases. In the intestine, TREM-1 is highly expressed by macrophages, contributing to inflammatory bowel disease (IBD) pathogenesis. Contrary to current understanding, TREM-2 also promotes inflammation in IBD by fueling dendritic cell functions. This review will focus specifically on recent insights into the role of TREM proteins in IBD development, and discuss opportunities for novel treatment approaches

Systematic exploration of essential yeast gene function with temperature-sensitive mutants

Conditional temperature-sensitive (ts) mutations are valuable reagents for studying essential genes in the yeast Saccharomyces cerevisiae. We constructed 787 ts strains, covering 497 (~45%) of the 1,101 essential yeast genes, with ~30% of the genes represented by multiple alleles. All of the alleles are integrated into their native genomic locus in the S288C common reference strain and are linked to a kanMX selectable marker, allowing further genetic manipulation by synthetic genetic array (SGA)–based, high-throughput methods. We show two such manipulations: barcoding of 440 strains, which enables chemical-genetic suppression analysis, and the construction of arrays of strains carrying different fluorescent markers of subcellular structure, which enables quantitative analysis of phenotypes using high-content screening. Quantitative analysis of a GFP-tubulin marker identified roles for cohesin and condensin genes in spindle disassembly. This mutant collection should facilitate a wide range of systematic studies aimed at understanding the functions of essential genes

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH -Mutant Molecular Profiles

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance