Interprocedural Reachability for Flat Integer Programs

We study programs with integer data, procedure calls and arbitrary call graphs. We show that, whenever the guards and updates are given by octagonal relations, the reachability problem along control flow paths within some language w1* ... wd* over program statements is decidable in Nexptime. To achieve this upper bound, we combine a program transformation into the same class of programs but without procedures, with an Np-completeness result for the reachability problem of procedure-less programs. Besides the program, the expression w1* ... wd* is also mapped onto an expression of a similar form but this time over the transformed program statements. Several arguments involving context-free grammars and their generative process enable us to give tight bounds on the size of the resulting expression. The currently existing gap between Np-hard and Nexptime can be closed to Np-complete when a certain parameter of the analysis is assumed to be constant.Comment: 38 pages, 1 figur

Enhancing Protocols to Improve Consistency Across Nanotoxicology Studies

In current nanotoxicology research, there is a lack of standardization in reporting of zebrafish exposure media and sonication practices. This lack of standardization in use and reporting methods has made reproducing nanoparticle (NP) toxicity results between labs a common issue. It is important to have a standardized way of reporting of exposure media recipe used as media can impact the agglomeration behavior of NPs which can directly impact toxicity results. The objective of this study was to characterize and implement a fish water media recipe to replace the fish water currently used in our laboratory. We conducted a literature review to see how and if exposure media was being reported and determined that a majority of labs did not report media used and in ones that did only a few had enough detail to replicate the recipe. We chose 5 media recipes to analyze along with ultrapure water, and my lab’s current exposure media (Instant Ocean’s simulated fresh water) in order to determine the stability of the particles and media’s impact on agglomeration size after sonication. When the 7 medias containing TiO2 NPs were characterized and measured using dynamic light scattering (DLS), a difference in agglomeration behavior was observed between each media. A difference was also seen in HDD between placing the samples directly into the DLS after sonication, time 0, and allowing the sample to rest for 48 hours before measurement. It is also important to have a standardized way of reporting sonication methods in nanotoxicology as the range of energies found in papers spans from 450J to 1728000J which directly impacts the agglomerates size and resulting toxicity. We hypothesized that when we were able to calculate and hold energy constant during sonication that we would see a decrease in the HDD of CeO2 and TiO2 NPs. We chose to investigate three commonly used ultrasonication systems (cup horn, probe and bath). We calibrated the three systems using calorimetry calibration to hold each treatment to an equivalent energy of 8400J. The bath sonicator has a single programmed amplitude and the cup horn and probe sonicators have programmed amplitudes of 20%, 30% and 40%. This was to see if when energy was held constant, whether the agglomerates size would be similar no matter the ultrasonication system used. We saw that when energy was held constant between the three systems there was no statistical difference between the different sonicators. We also saw a statistically significant difference between NPs that were sonicated vs unsonicated in the 3 medias with both NPs. We chose to use NPs CeO2 and TiO2 in our lab’s simulated fresh water, ultrapure water and recipe 10 medium chosen from the Fish Exposure Media study. We also wanted to observe the effects of energy input and its impact on HDD. To do this we varied the energy using ultrapure water to determine whether an increase in energy would decrease the NP agglomerate size. The HDD of CeO2 decreased as sonication energy was increased while TiO2 did not exhibit this same energy dependent agglomeration

CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity

During CNS autoimmunity, brain endothelial cell CXCR7 internalizes CXCL12 from the perivascular space, thereby permitting leukocyte migration into the CNS parenchyma

The first total synthesis of (+)-mucosin

The first total synthesis of (+)-mucosin has been completed allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core

Microfluidic Endothelium for Studying the Intravascular Adhesion of Metastatic Breast Cancer Cells

BACKGROUND:The ability to properly model intravascular steps in metastasis is essential in identifying key physical, cellular, and molecular determinants that can be targeted therapeutically to prevent metastatic disease. Research on the vascular microenvironment has been hindered by challenges in studying this compartment in metastasis under conditions that reproduce in vivo physiology while allowing facile experimental manipulation. METHODOLOGY/PRINCIPAL FINDINGS:We present a microfluidic vasculature system to model interactions between circulating breast cancer cells with microvascular endothelium at potential sites of metastasis. The microfluidic vasculature produces spatially-restricted stimulation from the basal side of the endothelium that models both organ-specific localization and polarization of chemokines and many other signaling molecules under variable flow conditions. We used this microfluidic system to produce site-specific stimulation of microvascular endothelium with CXCL12, a chemokine strongly implicated in metastasis. CONCLUSIONS/SIGNIFICANCE:When added from the basal side, CXCL12 acts through receptor CXCR4 on endothelium to promote adhesion of circulating breast cancer cells, independent of CXCL12 receptors CXCR4 or CXCR7 on tumor cells. These studies suggest that targeting CXCL12-CXCR4 signaling in endothelium may limit metastases in breast and other cancers and highlight the unique capabilities of our microfluidic device to advance studies of the intravascular microenvironment in metastasis

Plugging a hole and lightening the burden: A process evaluation of a practice education team

Aim: To investigate the perceptions of clinical and senior managers about the role of Practice Educators employed in one acute hospital in the UK. Background: Producing nurses who are fit for practice, purpose and academic award is a key issue for nurse education partnership providers in the UK. Various new models for practice learning support structures and new roles within health care institutions have been established. To sustain funding and policy support for these models, there is a need for evaluation research. Design: A process evaluation methodology was employed to determine the current value of a practice education team and to provide information to guide future direction. Methods: Data were collected through semi-structured telephone interviews using a previously designed schedule. All senior nurse managers (N=5) and a purposive sample of clinical managers (n=13) who had personal experience of and perceptions about the role of practice educators provided the data. Interview notes were transcribed, coded and a thematic framework devised to present the results. Results: A number of key themes emerged including: qualities needed for being a successful practice educator; visibility and presence of practice educators; providing a link with the university; ‘plugging a hole’ in supporting learning needs; providing relief to practitioners in dealing with ‘the burden of students’; alleviating the ‘plight of students’; and effects on student attrition. Conclusions: Findings provided evidence for the continued funding of the practice educator role with improvements to be made in dealing with stakeholder expectations and outcomes. Relevance to clinical practice: In the UK, there still remain concerns about the fitness for practice of newly registered nurses, prompting a recent national consultation by the professional regulating body. Despite fiscal pressures, recommendations for further strengthening of all systems that will support the quality of practice learning may continue to sustain practice learning support roles

The diacylglycerol kinase α/Atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells