Stopping Brain Tumours in Their Tracks- The Role of RhoGTPase Activating Proteins (ARHGAPs) in Glioma Cell Migration and Invasion

Glioblastoma (GBM) is a highly aggressive form of brain cancer that is difficult to treat. Despite efforts to improve treatment outcomes, patients have a median survival of only 12-15 months as tumours will eventually recur leading to patient death. The RhoGTPase activating proteins (ARHGAPs) are a family of proteins that have been associated with various diseases including cancers. A recent microarray screen in the established GBM cell line U251 showed that expression levels of five ARHGAPs significantly changed when exposed to (2'Z,3'E)-6-Bromoindirubin-3'-oxime (BIO), an established migrastatic drug. Of the five ARHGAPs, ARHGAP4, 22 and 25 were investigated here as regulators of cell migration in view of improved treatment options in GBM. Using 2D and 3D migration/invasion assays with established and patient derived cell lines as well as in vivo models and human GBM tissue, the role of ARHGAPs in cell migration and dissemination was investigated. The expression and localisation of ARHGAPs in different GBM subtypes in normoxic and hypoxic conditions were established. Migration studies after gene knockdown in the patient derived cell line G9 revealed that the three ARHGAPs had pro-or-anti-migratory activity. Preliminary in vivo studies with the knockdowns uncovered novel phenotypes after orthoptic intracranial injection leading to tumours with limited migratory activity and highly aggressive tumours. Clinical relevance of the ARHGAPs was determined by an association of ARHGAP expression and survival after treatment. The study's findings enhance our understanding of GBM cell migration, providing potential targets for therapeutic intervention. Overall, the discoveries made represent an important step forward in the development of new treatments for this devastating disease

INDOT Prequalification & Compliance

Doing business with INDOT on construction contracts involves complying with numerous state and federal laws and INDOT specifications and contract requirements. As part of the INDOT Legal Department’s 2023 strategic plan, the agency is reviewing all areas of compliance and working to produce administrative policy directives that explain the requirements of each rule and regulation. This presentation will provide an overview of INDOT construction compliance, including a review of the specific requirements of the most commonly used regulations. Discussion time will be available so that vendors and government stakeholders can ask questions and express their opinion on INDOT construction compliance

A Perfect Kiss : Un Baiser Parfait

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Modelling Zn (II) sorption onto clayey sediments using a multi-site ion-exchange model

International audienceIn environmental studies, we need to be able to predict the behaviour of contaminants in more or less complex physico-chemical contexts. The improvement of this prediction partly depends on establishing thermodynamic models that can describe the behaviour of these contaminants and, in particular, the sorption reactions on mineral surfaces. In this way, based on the mass action law, it is possible to use surface complexation models and ion exchange models. Therefore, the aim of this study is i) to develop an ion-exchange model able to describe the sorption of transition metal onto pure clay minerals and ii) to test the ability of this approach to predict the sorption of these elements onto natural materials containing clay minerals (i.e. soils/sediments) under various chemical conditions. This study is focused on the behaviour of Zn(II) in the presence of clayey sediments. Considering that clay minerals are cation exchangers containing multiple sorption sites, it is possible to interpret the sorption of Zn(II), as well as competitor cations, by ion-exchange equilibria with the clay minerals. This approach is applied with success to interpret the experimental data obtained previously in the Zn(II)-H+-Na+-montmorillonite system [Baeyens, B., Bradbury, M.H., 1997. A mechanistic description of Ni and Zn sorption on Na-montmorillonite. Part I: Titration and sorption measurements. J. Contam. Hydrol. 27, 199–222]. Our research team has already studied the behaviour of Na+, K+, Ca2+ and Mg2+ versus pH in terms of ion exchange onto pure montmorillonite, leading us to develop a thermodynamic database including the exchange site concentrations associated with montmorillonite and the selectivity coefficients of Na+, K+, Ca2+, Mg2+, and Zn2+ versus H+. In the present study, we report experimental isotherms of Zn(II) on two different sediments in batch reactors at different pH and ionic strengths, using NaCl and CaSO4 as electrolytes. Assuming clay minerals are the main ion-exchanging phases, it is possible to predict Zn(II) sorption onto sediments under different experimental conditions, using the previously obtained data base on montmorillonite. Whatever the physico-chemical conditions tested, we observe a relatively good agreement between experimental results and the predicted sorption behaviour

Sorption Properties of Peat for U(VI) and 226Ra in U Mining Areas

AbstractUnderstanding the environmental behavior of U and 226Ra is important for remediation of former mining sites and assessment of their durability. The aim of this study is to determine the sorption properties of an acidic peat for U and 226Ra, located near a former U mine. A 90% retention of U over a pH range of 3 to 10 was observed in Na- conditioned peat samples issued from the mesotelm, with a Rd between 1000 and 12000 mL/g. It seems that U sorption in peat is not only governed by organic matter. The Kd for 226Ra adsorption increases with pH from zero to 4849 mL/g. However in this mining environment, the peat bog proved to be significantly impacted by anthropogenic activities, with the presence of detrital components in the peat material that can also contribute to U and Ra sorption

Statistical tolerance analysis of over-constrained mechanisms with gaps using system reliability methods

One of the aims of statistical tolerance analysis is to evaluate a predicted quality level at the design stage. One method consists of computing the defect probability PD expressed in parts per million (ppm). It represents the probability that a functional requirement will not be satisfied in mass production. This paper focuses on the statistical tolerance analysis of over-constrained mechanisms containing gaps. In this case, the values of the functional characteristics depend on the gap situations and are not explicitly formulated with respect to part deviations. To compute PD, an innovative methodology using system reliability methods is presented. This new approach is compared with an existing one based on an optimization algorithm and Monte Carlo simulations. The whole approach is illustrated using two industrial mechanisms: one inspired by a producer of coaxial connectors and one prismatic pair. Its major advantage is to considerably reduce computation time

Statistical tolerance analysis of a hyperstatic mechanism, using system reliability methods

The quality level of a mechanism can be evaluated a posteriori after several months by following the number of warranty returns. However, it is more interesting to evaluate a predicted quality level in the design stage: this is one of the aims of statistical tolerance analysis. A possible method consists of computing the defect probability (PD) expressed in ppm. It represents the probability that a functional requirement will not be satisfied in mass production. For assembly reasons, many hyperstatic mechanisms require gaps, which their functional requirements depend on. The defect probability assessment of such mechanisms is not straightforward, and requires advanced numerical methods. This problem particularly interests the VALEO W.S. company, which experiences problems with an assembly containing gaps. This paper proposes an innovative methodology to formulate and compute the defect probability of hyperstatic mechanisms with gaps in two steps. First, a complex feasibility problem is converted into a simpler problem. Then the defect probability is efficiently computed thanks to system reliability methods and the m-dimensional multivariate normal distribution Um. Finally, a sensitivity analysis is provided to improve the original design. The whole approach is illustrated with an industrial case study, but can be adapted to other similar problems

Processus d'ajustement social de la performance de genre chez les femmes immigrantes à Montréal

La présente recherche porte sur la performance de genre des femmes immigrantes à Montréal. Ces femmes, en immigrant à Montréal, rencontrent dans leur quotidien de nouvelles conceptions du genre ainsi que de nouvelles pratiques genrées. Ce contexte particulier révèle la présence d'enjeux touchant la rencontre de ces conceptions. C'est dans l'optique d'éclaircir l'impact de ces rencontres et de ces enjeux chez les femmes immigrantes que nous tâcherons de répondre à la question centrale suivante : comment le processus d'ajustement social de la performance de genre est-il vécu par les femmes immigrantes depuis leur établissement à Montréal? La performance de genre correspond à une série de pratiques quotidiennes qui, apparaissant au sein d'une scène culturelle spécifique, est associée soit au genre féminin, soit au genre masculin. Afin d'offrir un premier éclairage sur cette situation particulière, nous dressons un portrait des femmes immigrantes à Montréal, ainsi qu'un portrait des impacts de l'immigration sur le genre. De plus, nous présentons un cadre théorique composé de quatre concepts permettant d'éclairer certaines dimensions relatives au phénomène étudié. Plus précisément, nous présentons le processus d'ajustement social, le modèle culturel, la performance de genre et le monde intersubjectif du quotidien. Puis, c'est en nous basant sur une approche qualitative ainsi que sur une position féministe que nous avons réalisé une série d'entretiens individuels auprès de quatre femmes immigrantes établies à Montréal. Nous souhaitions à travers la réalisation de ces entretiens éclairer le phénomène à l'étude à partir du sens qu'y accordent ces femmes. Les données recueillies au fil des entretiens nous conduisent à dresser un portrait des conceptions du genre des participantes ainsi que de leurs pratiques genrées en les classant en trois sections, soit leur conception du genre dans leur pays d'origine, leur conception du genre dans la société d'accueil, puis leurs conceptions actuelles du genre et la façon dont ces conceptions se traduisent dans leur vie quotidienne à Montréal. Les résultats de la recherche nous permettent d'identifier quatre pistes d'interprétation. D'abord, le processus d'ajustement social de la performance de genre semble favorisé chez les participantes par une posture réflexive particulière. De plus, il semble que les participantes n'aient pas rencontré au sein du quotidien montréalais une diversité de conception du genre, mais plutôt une seule conception. D'autre part, ce processus semble influencé par la composition de leur réseau, les personnes rencontrées au quotidien, ainsi que par leurs expériences quotidiennes. Enfin, il semble que ce processus ait mené les participantes à vivre une série d'ajustements divers, où toutes eurent le sentiment qu'un plus grand nombre de possibilités s'offraient à elles. Finalement, nous achevons ce mémoire en proposant plusieurs pistes qui, dans le cadre de futures recherches, enrichiront la compréhension du processus d'ajustement social de la performance de genre vécu par les femmes immigrantes.\ud ______________________________________________________________________________ \ud MOTS-CLÉS DE L’AUTEUR : performance de genre, femme, immigration, modèle culturel, quotidien

A statistical tolerance analysis approach for over-constrained mechanism based on optimization and Monte Carlo simulation

Tolerancing decisions can profoundly impact the quality and cost of the mechanism. To evaluate the impact of tolerance on mechanism quality, designers need to simulate the influences of tolerances with respect to the functional requirements. This paper proposes a mathematical formulation of tolerance analysis which integrates the notion of quantifier: ‘‘For all acceptable deviations (deviations which are inside tolerances), there exists a gap configuration such as the assembly requirements and the behavior constraints are verified’’ & ‘‘For all acceptable deviations (deviations which are inside tolerances), and for all admissible gap configurations, the assembly and functional requirements and the behavior constraints are verified’’. The quantifiers provide a univocal expression of the condition corresponding to a geometrical product requirement. This opens a wide area for research in tolerance analysis. To solve the mechanical problem, an approach based on optimization is proposed. Monte Carlo simulation is implemented for the statistical analysis. The proposed approach is tested on an over-constrained mechanism

Preclinical models of glioblastoma:limitations of current models and the promise of new developments

Acknowledgements. The authors thank members of the Speirs group for helpful comments. Financial support. This study was supported by the University of Aberdeen Development Trust and a University of Huddersfield PhD studentship (PV-B).Peer reviewedPostprin