A conceptual framework to assess the impact of training on equipment cost and availability in the military context

Designing military support is challenging and current practices need to be reviewed and improved. This paper gives an overview of the Industry current practices in designing military support under Ministry of Defence/Industry agreements (in particular for Contracting for Availability (CfA)), and identifies challenges and opportunities for improvement. E.g. training delivery was identified as an important opportunity for improving the CfA in-service phase. Thus, an innovative conceptual framework is presented to assess the impact of training on the equipment availability and cost. Additionally, guidelines for improving the current training delivery strategies are presented, which can also be applied to other Industry contexts

GSK3-mediated raptor phosphorylation supports amino acid-dependent Q2 mTORC1-directed signalling

The mammalian or mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a ubiquitously expressed multimeric protein kinase complex that integrates nutrient and growth factor signals for the co-ordinated regulation of cellular metabolism and cell growth. Herein, we demonstrate that suppressing the cellular activity of glycogen synthase kinase-3 (GSK3), by use of pharmacological inhibitors or shRNA-mediated gene silencing, results in substantial reduction in amino acid (AA)-regulated mTORC1-directed signalling, as assessed by phosphorylation of multiple downstream mTORC1 targets. We show that GSK3 regulates mTORC1 activity through its ability to phosphorylate the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Ser(859). We further demonstrate that either GSK3 inhibition or expression of a S859A mutated raptor leads to reduced interaction between mTOR and raptor and under these circumstances, irrespective of AA availability, there is a consequential loss in phosphorylation of mTOR substrates, such as p70S6K1 (ribosomal S6 kinase 1) and uncoordinated-51-like kinase (ULK1), which results in increased autophagic flux and reduced cellular proliferation

Review of the modelling approaches for availability contracts in the military context

The defence context more recently has been experiencing a significant shift towards servitization. As competition has increased, commercial strategies are increasingly moving towards providing through-life solutions for complex engineering products such as submarines. Within such a context value for money is an essential driver in a life cycle sense for selecting a bid. The defence sector has largely been affected by this change in the business environment. Industrial Product Service System (IPS2) is a model of providing services that satisfy industrial customers and aims to reduce lifecycle impacts of products and services through product servicing, remanufacturing and recycling. This approach has proved to be an effective solution to enhance the services support in military projects. IPS2 offers client value by responding more efficiently to the client demands with reduced prices; it is delivered in the form of contracting approaches between Ministry of Defence (MoD) and industry; these contracts can differ in several aspects as risk sharing, application level, ownership policy and supportability specifications vary. This research focuses on Contracting for Availability (CfA), which is a particular approach of IPS2.The paper aims to present the review of literature in designing support strategies for CfA, identifying the good practices and challenges, and to propose a systematic approach to fill the industrial and academic gap towards an optimization of the current modelling process. This work starts by presenting a literature review in IPS2; it then moves into the optimization processes, describing how contractors currently design a long term service support contract in the military context with better value for money and high level of system readiness. The key cost and performance drivers are identified and a framework is presented to enhance the design process of CfA. The methodology of the paper relies on literature. This research aims to extend the work of several authors in predicting the cost of services in the military contracts

Une approche multi-méthodes (TL, OSL, IRSL) et multi-matérielles (silex, quartz et feldspath) pour de nouvelles données chronologiques de gisements moustériens (MIS 5-3) du sud-ouest de la France

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Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization

LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients. Since a common mutation that replaces Gly(2019) with a serine residue enhances kinase catalytic activity, small-molecule LRRK2 inhibitors might have utility in treating Parkinson's disease. However, the effectiveness of inhibitors is difficult to assess, as no physiological substrates or downstream effectors have been identified that could be exploited to develop a robust cell-based assay. We recently established that LRRK2 bound 14-3-3 protein isoforms via its phosphorylation of Ser(910) and Ser(935). In the present study we show that treatment of Swiss 3T3 cells or lymphoblastoid cells derived from control or a Parkinson's disease patient harbouring a homozygous LRRK2(G2019S) mutation with two structurally unrelated inhibitors of LRRK2 (H-1152 or sunitinib) induced dephosphorylation of endogenous LRRK2 at Ser(910) and Ser(935), thereby disrupting 14-3-3 interaction. Our results suggest that H-1152 and sunitinib induce dephosphorylation of Ser(910) and Ser(935) by inhibiting LRRK2 kinase activity, as these compounds failed to induce significant dephosphorylation of a drug-resistant LRRK2(A2016T) mutant. Moreover, consistent with the finding that non-14-3-3-binding mutants of LRRK2 accumulated within discrete cytoplasmic pools resembling inclusion bodies, we observed that H-1152 causes LRRK2 to accumulate within inclusion bodies. These findings indicate that dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and/or monitoring LRRK2 cytoplasmic localization can be used as an assay to assess the relative activity of LRRK2 inhibitors in vivo. These results will aid the elaboration and evaluation of LRRK2 inhibitors. They will also stimulate further research to understand how phosphorylation of Ser(910) and Ser(935) is controlled by LRRK2, and establish any relationship to development of Parkinson's disease