Riverine sustainment 2012

Student Integrated ProjectIncludes supplementary materialThis technical report analyzed the Navy's proposed Riverine Force (RF) structure and capabilities for 2012. The Riverine Sustainment 2012 Team (RST) examined the cost and performance of systems of systems which increased RF sustainment in logistically barren environments. RF sustainment was decomposed into its functional areas of supply, repair, and force protection. The functional and physical architectures were developed in parallel and were used to construct an operational architecture for the RF. The RST used mathematical, agent-based and queuing models to analyze various supply, repair and force protection system alternatives. Extraction of modeling data revealed several key insights. Waterborne heavy lift connectors such as the LCU-2000 are vital in the re-supply of the RF when it is operating up river in a non-permissive environment. Airborne heavy lift connectors such as the MV-22 were ineffective and dominated by the waterborne variants in the same environment. Increase in manpower and facilities did appreciable add to the operational availability of the RF. Mean supply response time was the biggest factor effecting operational availability and should be kept below 24 hours to maintain operational availability rates above 80%. Current mortar defenses proposed by the RF are insufficient.N

Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia

PTEN (phosphatase and tensin homologue deleted on chromosome TEN) is the major negative regulator of phosphatidylinositol 3-kinase signaling and has cell-specific functions including tumor suppression. Nuclear localization of PTEN is vital for tumor suppression; however, outside of cancer, the molecular and physiological events driving PTEN nuclear entry are unknown. In this paper, we demonstrate that cytoplasmic Pten was translocated into the nuclei of neurons after cerebral ischemia in mice. Critically, this transport event was dependent on a surge in the Nedd4 family–interacting protein 1 (Ndfip1), as neurons in Ndfip1-deficient mice failed to import Pten. Ndfip1 binds to Pten, resulting in enhanced ubiquitination by Nedd4 E3 ubiquitin ligases. In vitro, Ndfip1 overexpression increased the rate of Pten nuclear import detected by photobleaching experiments, whereas Ndfip1⁻/⁻ fibroblasts showed negligible transport rates. In vivo, Ndfip1 mutant mice suffered larger infarct sizes associated with suppressed phosphorylated Akt activation. Our findings provide the first physiological example of when and why transient shuttling of nuclear Pten occurs and how this process is critical for neuron survival.Jason Howitt, Jenny Lackovic, Ley-Hian Low, Adam Naguib, Alison Macintyre, Choo-Peng Goh, Jennifer K. Callaway, Vicki Hammond, Tim Thomas, Matthew Dixon, Ulrich Putz, John Silke, Perry Bartlett, Baoli Yang, Sharad Kumar, Lloyd C. Trotman, and Seong-Seng Ta

U.S. Army tactical wheeled vehicles modernization strategy an optimization model

This thesis addresses the issue of optimal budget allocation in the modernization of the U.S. Army's Light Tactical Wheeled Vehicles (LTWV). To achieve the objective for this research, a decision optimization tool was requested by the U.S. Tank-Automotive and Armaments Life Cycle Management Command (TACOM LCMC) and Program Executive Office, Combat Support / Combat Service Support (PEO CS/CSS) to provide an analytical tool to serve as the underpinning for modernization strategies for the LTWV over the next fifteen fiscal years. The optimization tool was implemented in Excel, using Excel Premium Solver Platform as the solver engine. An initial analysis was done to demonstrate the validity of the model, using notional data and the weighted values from the Value Model. Sensitivity analyses were also performed on the model by varying the inputs, such as the budgetary and average age requirements, to look at the capabilities that can be provided during the modernization period.http://archive.org/details/usarmytacticalwh109453173Technology Agency author (civilian).Approved for public release; distribution is unlimited

Rab5 and Ndfip1 Are Involved in Pten Ubiquitination and Nuclear Trafficking

The spatial regulation of Pten is critical for its role as a tumour suppressor with both nuclear and cytoplasmic locations being implicated with distinct functions. In the cytoplasm, Pten plays a central role in opposing PI3K/Akt cell signalling, whereas in the nucleus, Pten is important for maintaining genome stability and enhancing the tumour suppressor activity of APC-CDH1. Despite this diversity in protein function at different subcellular locations, there is limited knowledge on how Pten is able to find different cellular niches. Here, we report that Rab5 GTPase is required for efficient trafficking and ubiquitination of Pten on endosomes inside the cytosol. Using bimolecular fluorescence complementation (BiFC) for imaging protein interactions, we observed that ubiquitinated Pten is localized to peri-nuclear and nuclear regions of the cell. Nuclear trafficking of Pten required both Rab5 as well as the E3 ligase adaptor protein Ndfip1. Rab5 colocalization with Pten was observed on endosomes and expression of a dominant negative form of Rab5 significantly reduced Pten ubiquitination and nuclear trafficking. Genomic deletion of Ndfip1 abrogated nuclear trafficking of ubiquitinated Pten, even in the presence of Rab5. Our findings show that endosomal trafficking and ubiquitination are important mechanisms for the subcellular distribution of Pten. The subcellular distribution of Pten is critical for its multiple roles as a tumour suppressor. Here we describe the trafficking of Pten on both early and recycling endosomes using bimolecular fluorescence complementation. We show that both Rab5 GTPase and the E3 ligase adaptor protein Ndfip1 are required for ubiquitination and nuclear trafficking of Pten

Nuclear trafficking of Pten after brain injury leads to neuron survival not death

There is controversy whether accumulation of the tumor suppressor PTEN protein in the cell nucleus under stress conditions such as trauma and stroke causes cell death. A number of in vitro studies have reported enhanced apoptosis in neurons possessing nuclear PTEN, with the interpretation that its nuclear phosphatase activity leads to reduction of the survival protein phospho-Akt. However, there have been no in vivo studies to show that nuclear PTEN in neurons under stress is detrimental. Using a mouse model of injury, we demonstrate here that brain trauma altered the nucleo-cytoplasmic distribution of Pten, resulting in increased nuclear Pten but only in surviving neurons near the lesion. This event was driven by Ndfip1, an adaptor and activator of protein ubiquitination by Nedd4 E3 ligases. Neurons next to the lesion with nuclear PTEN were invariably negative for TUNEL, a marker for cell death. These neurons also showed increased Ndfip1 which we previously showed to be associated with neuron survival. Biochemical assays revealed that overall levels of Pten in the affected cortex were unchanged after trauma, suggesting that Pten abundance globally had not increased but rather Pten subcellular location in affected neurons had changed. Following experimental injury, the number of neurons with nuclear Pten was reduced in heterozygous mice (Ndfip1+/-) although lesion volumes were increased. We conclude that nuclear trafficking of Pten following injury leads to neuron survival not death

Third generation EGFR TKIs: current data and future directions

Abstract Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care

Clinical phenotypes and heath-related quality of life of COPD patients in a rural setting in Malaysia – a cross-sectional study

Background: The Spanish chronic obstructive pulmonary disease (COPD) guideline phenotypes patients according to the exacerbation frequency and COPD subtypes. In this study, we compared the patients’ health-related quality of life (HRQoL) according to their COPD phenotypes. Methods: This was a cross-sectional study of COPD patients who attended the outpatient clinic of the Serian Divisional Hospital and Bau District Hospital from 23th January 2018 to 22th January 2019. The HRQoL was assessed using modified Medical Research Council (mMRC), COPD Assessment Test (CAT), and St George’s Respiratory Questionnaire for COPD (SGRQ-c). Results: Of 185 patients, 108 (58.4%) were non-exacerbators (NON-AE), 51 (27.6%) were frequent exacerbators (AE), and the remaining 26 (14.1%) had asthma-COPD overlap (ACO). Of AE patients, 42 (82.4%) had chronic bronchitis and only 9 (17.6%) had emphysema. Of the 185 COPD patients, 65.9% had exposure to biomass fuel and 69.1% were ex- or current smokers. The scores of mMRC, CAT, and SGRQ-c were significantly different between COPD phenotypes (p < 0.001). There were significantly more patients with mMRC 2–4 among AE (68.6%) (p < 0.001), compared to those with ACO (38.5%) and NON-AE (16.7%). AE patients had significantly higher total CAT (p=0.003; p < 0.001) and SGRQ-c (both p < 0.001) scores than those with ACO and NON-AE. Patients with ACO had significantly higher total CAT and SGRQ-c (both p< 0.001) scores thanthose with NON-AE. AE patients had significantly higher score in each item of CAT and component of SGRQ-c compared to those with NON-AE (all p < 0.001), and ACO [(p = 0.003–0.016; p=<0.001–0.005) except CAT 1, 2 and 7. ACO patients had significantly higher score in each item of CAT and component of SGRQ-c (p=<0.001–0.040; p < 0.001) except CAT 2 and activity components of SGRQ-c. Conclusions: The HRQoL of COPD patients was significantly different across different COPD phenotypes. HRQoL was worst in AE, followed by ACO and NON-AE. This study supports phenotyping COPD patients based on their exacerbation frequency and COPD subtypes. The treatment of COPD should be personalised according to these two factors