Model simplification and validation of virtual prototypes for vehicular antenna design

Wireless connectivity is becoming an important feature in cars, which together with recent developments in car design point to the need to accurately predict the performance of real antennas in simulation, to speed up the design cycle. However, it is challenging to accurately represent structurally complex real cars in simulation. This paper proposes a car model simplification approach for designing vehicular antennas, exemplified using three progressively simplified models of a hatchback car. For validation, a monopole and a PIFA operating at 800 MHz and 2.4 GHz, respectively, were mounted and simulated at two locations on these prototypes. The proposed scheme reduced the computational time to less than a third, while maintaining similar simulated antenna performance. Specifically, the antenna patterns of the simplest prototype and original one are correlated by 84% and 59% at 800 MHz and 2.4 GHz, respectively. Therefore, the proposed scheme is promising for real application

Tracing a Route and Finding a Shortcut: The Working Memory, Motivational, and Personality Factors Involved

Wayfinding (WF) is the ability to move around efficiently and find the way from a starting point to a destination. It is a component of spatial navigation, a coordinate and goal-directed movement of one\u2019s self through the environment. In the present study, the relationship between WF tasks (route tracing and shortcut finding) and individual factors were explored with the hypothesis that WF tasks would be predicted by different types of cognitive, affective, motivational variables, and personality factors. A group of 116 university students (88 F.) were conducted along a route in a virtual environment and then asked first to trace the same route again, and then to find a shortcut between the start and end points. Several instruments assessing visuospatial working memory, mental rotation ability, self-efficacy, spatial anxiety, positive attitude to exploring, and personality traits were administered. The results showed that a latent spatial ability factor (measured with the visuospatial working memory and mental rotations tests) \u2013 controlled for gender \u2013 predicted route-tracing performance, while self-report measures of anxiety, efficacy, and pleasure in exploring, and some personality traits were more likely to predict shortcut-finding performance. We concluded that both personality and cognitive abilities affect WF performance, but differently, depending on the requirements of the task

Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation

introduction: To generate biomarkers of target engagement or predictive response for multi-target drugs is challenging. One such compound is the multi-AGC kinase inhibitor AT13148. Metabolic signatures of selective signal transduction inhibitors identified in preclinical models have previously been confirmed in early clinical studies. This study explores whether metabolic signatures could be used as biomarkers for the multi-AGC kinase inhibitor AT13148.Objectives: To identify metabolomic changes of biomarkers of multi-AGC kinase inhibitor AT13148 in cells, xenograft / mouse models and in patients in a Phase I clinical study.Methods: HILIC LC–MS/MS methods and Biocrates AbsoluteIDQ™ p180 kit were used for targeted metabolomics; followed by multivariate data analysis in SIMCA and statistical analysis in Graphpad. Metaboanalyst and String were used for network analysis.Results: BT474 and PC3 cells treated with AT13148 affected metabolites which are in a gene protein metabolite network associated with Nitric oxide synthases (NOS). In mice bearing the human tumour xenografts BT474 and PC3, AT13148 treatment did not produce a common robust tumour specific metabolite change. However, AT13148 treatment of non-tumour bearing mice revealed 45 metabolites that were different from non-treated mice. These changes were also observed in patients at doses where biomarker modulation was observed. Further network analysis of these metabolites indicated enrichment for genes associated with the NOS pathway. The impact of AT13148 on the metabolite changes and the involvement of NOS-AT13148- Asymmetric dimethylarginine (ADMA) interaction were consistent with hypotension observed in patients in higher dose cohorts (160-300 mg).Conclusion: AT13148 affects metabolites associated with NOS in cells, mice and patients which is consistent with the clinical dose-limiting hypotension

Critical Points of Tumor Necrosis Factor Action in Central Nervous System Autoimmune Inflammation Defined by Gene Targeting

Tumor necrosis factor (TNF)–dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35–55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF−/− mice. However, in the TNF−/− mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF−/− and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF−/− mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF−/− mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE

A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.

Background Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss.Patients and methods mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated.Results Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples.Conclusions The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway.Clinical trial number NCT02525068

Presidential Election Laws and Multipartism in Latin America

This article examines the interaction between the rules governing presidential elections and multipartism in Latin America. Data from 16 Latin American systems are examined through the use of a multivariate model to gain an understanding of the independent impact of presidential electoral formula (plurality vs. majority), the timing of presidential and legislative elections (concurrent vs. nonconcurrent) and legislative district magnitude on legislative multipartism, and by extension, on the number of relevant political parties operating in the nation. The findings demonstrate the strong and significant impact which formula and timing have on multipartism. They also point to the importance of examining the interaction between elections for different constituent institutions. Finally, they underscore the applicability of Duverger's law to presidential elections.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68710/2/10.1177_106591299404700103.pd