277 research outputs found

    Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib.

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    Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated

    Association of transcriptomic signatures of inflammatory response with viral control after dendritic cell-based therapeutic vaccination in hiv-1 infected individuals

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    Systems vaccinology has seldomly been used in therapeutic HIV-1 vaccine research. Our aim was to identify early gene ‘signatures’ that predicted virus load control after analytical therapy interruption (ATI) in participants of a dendritic cell-based HIV-1 vaccine trial (DCV2). mRNA and miRNA were extracted from frozen post-vaccination PBMC samples; gene expression was determined by microarray method. In gene set enrichment analysis, responders showed an up-regulation of 14 gene sets (TNF-alpha/NFkB pathway, inflammatory response, the complement system, Il6 and Il2 JAK-STAT signaling, among others) and a down-regulation of 7 gene sets (such as E2F targets or interferon alpha response). The expression of genes regulated by three (miR-223-3p, miR-1183 and miR-8063) of the 9 differentially expressed miRNAs was significantly down-regulated in responders. The deregulation of certain gene sets related to inflammatory processes seems fundamental for viral control, and certain miRNAs may be important in fine-tuning these processes.</p

    Clay mineral formation in Permian rocks of a geothermal borehole at Northern Upper Rhine Graben, Germany

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    &lt;jats:title&gt;Abstract&lt;/jats:title&gt;&lt;jats:p&gt;Hydrothermally altered rhyolite rocks in the Permian Donnersberg Formation of a geothermal borehole in the Northern Upper Rhine Graben (Germany) were investigated to find out answers for the low hydraulic conductivity of the rocks. The composition of clay minerals and the temperature of smectite–illite transformation were carried out using X-ray diffraction, X-ray fluorescence, transmission electron microscopy, Fourier transform infrared spectroscopy, and polarized-light microscopy analyses. Clay mineral (CM) composition includes illite/muscovite (1&lt;jats:italic&gt;M&lt;/jats:italic&gt;and 2&lt;jats:italic&gt;M&lt;/jats:italic&gt;&lt;jats:sub&gt;1&lt;/jats:sub&gt;polytypes), illite–smectite interstratifications (IS-ml), smectite, and chlorite; and non-clay minerals such as quartz, feldspars, epidote, calcite, dolomite, and hematite were detected. The 2&lt;jats:italic&gt;M&lt;/jats:italic&gt;&lt;jats:sub&gt;1&lt;/jats:sub&gt;-polytype mica might be the only primary sheet silicates from the parent rocks, while the others occur as authigenic neo-formed CMs under heat flow and geothermal gradient. The development of CMs indicates different mechanisms of illitization and smectitization. Based on the texture, morphology, structure/polytype, and chemistry of rocks and minerals, in particular CMs, the study grouped the CM formation into three transformation processes: smectitization during magma cooling and possible contact metamorphisms with decreasing and low temperature, smectite illitization controlled by burial diagenesis and hydrothermal alteration, and illite smectitization followed exhumation and Cenozoic subsidence with decreasing temperature. The rhyolites were altered to all of the orders IS-R0, IS-R1, and IS-R3 by the dissolution-precipitation and layer-to-layer mechanisms. The first one supported small xenomorphic plates and flakes of 1&lt;jats:italic&gt;M&lt;/jats:italic&gt;&lt;jats:sub&gt;&lt;jats:italic&gt;d&lt;/jats:italic&gt;&lt;/jats:sub&gt;, elongated particles of 1&lt;jats:italic&gt;M&lt;/jats:italic&gt;, and pseudo-hexagonal forms of 2&lt;jats:italic&gt;M&lt;/jats:italic&gt;&lt;jats:sub&gt;1&lt;/jats:sub&gt;. The second one could lead to the platy particles of 1&lt;jats:italic&gt;M&lt;/jats:italic&gt;&lt;jats:sub&gt;&lt;jats:italic&gt;d&lt;/jats:italic&gt;&lt;/jats:sub&gt;and 2&lt;jats:italic&gt;M&lt;/jats:italic&gt;&lt;jats:sub&gt;1&lt;/jats:sub&gt;polytypes. The dominant temperature range for the transformation in the area has been 140–170 °C– ~ 230 °C.&lt;/jats:p&gt

    Sensor and actuator placement for proportional feedback control in advection-diffusion equations

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    In this letter, advection-diffusion equations with constant coefficients on infinite 1-D and 2-D spatial domains are considered. Suitable sensor and/or actuator locations are determined for which high-gain and low-gain proportional feedback can effectively reduce the influence of a disturbance at a point of interest. These locations are characterized by simple analytic expressions which can be used as guidelines for control system design. The obtained analytic expressions are validated by numerical results

    Range maximisation of electric vehicles through active cell balancing using reachability analysis

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    Due to internal differences between cells inside a battery pack, active cell balancing during discharging potentially leads to an extension of the range of electric vehicles. This paper poses range maximisation of electric vehicles as a reachability problem. It is solved by converting this reachability problem into a feasibility problem for a given range. This leads to a large-scale nonlinear feasibility/optimisation problem, which we propose to solve using sequential linearisation of the dynamics and a dual decomposition. This method provides the necessary balancing currents to extend and maximise the range of the vehicle, if the drive cycle, and the model parameters and states are completely known. This result shows the maximum potential for range maximisation through active balancing and can serve as a benchmark for evaluating controllers which are applicable in real-time

    Understanding battery aging mechanisms

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    \u3cp\u3eThe aging mechanisms of Li-ion batteries are introduced in this chapter, and are experimentally investigated and modeled. From SEM it is found that the thickness of the solid electrolyte interface layers at the graphite electrode surface increase upon aging. Deformation of the graphite structure is confirmed by Raman spectroscopy. XPS analyses show that transition metals dissolved from cathode are deposited onto the graphite electrode. Cathode dissolution at elevated temperatures is further confirmed by ICP measurements. Apart from postmortem analyses, a novel non-destructive approach is proposed to quantify the graphite electrode decay. A comprehensive electrochemistry model is proposed to simulate the irreversible capacity loss under various aging conditions. The dependence of the capacity loss on aging conditions, such as storage state of charge, cycling current, temperature, etc. is simulated and the simulations are in good agreement with the experiments. The degradation model allows researchers to have an in-depth understanding of aging mechanisms and therefore helps manufacturers to improve battery performance by optimizing manufacturing procedures. Moreover, the model can be further used to predict the battery cycle life, which can be used to develop more accurate battery management systems to increase battery efficiency and safety.\u3c/p\u3

    Optimal thermal actuation for mitigation of heat-induced wafer deformation

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    An important step in the production of integrated circuits is the projection of the pattern of electronic connections on a silicon wafer. The light used to project the pattern moves over the wafer and induces a local temperature increase. The resulting thermal expansion of the wafer leads to a significant reduction in the imaging quality of next-generation wafer scanners. Thermal actuators that move together with the projection light can be used to improve the imaging quality. Because the placement of these actuators largely determines the performance of the resulting control system, a method to support the design of an effective thermal actuator layout is presented. The proposed method computes the smallest actuation heat load that consists of a single spatial shape and respects certain constraints on wafer deformations. A gradient-based optimization algorithm is presented to compute the optimal actuation heat load. The proposed method is applied to a wafer heating problem for which the resulting shapes of the actuation heat load have a clear physic
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