独立激励评估法在车身功能测试中的应用

车辆硬件在环仿真测试时,目前使用预先定义的测试结构,即测试结构将特定的测试激励与单独的测试步骤耦合到固定的、预先定义的测试体系中,测试后给出通过或不通过的结果。此方法中的每项测试都有其特定的功能测试重点,但无法适用于多项功能同时测试。未来的测试方法需要尽可能地完成全面性功能评估,并使评估资源得到有效利用,即应该在独立激励和现实环境中可同时对多项功能进行评估,因此,需要采用与之前不同的方法在独立激励的情况下进行测试。由于测试环境事先无法确定激励序列,因而也无法对每个测试步骤进行单独验证。激励的确切序列在测试运行开始时是未知的,从而可模拟出一个尽可能真实的现实环境,为此介绍一种独立激励的测试方法。该方法将组合法与基于模型法相结合,与相应功能测试要求联系起来,用于车身领域的系统性功能评估。该方法同样也支持现有的方法,并实现了比普通测试方法更广泛、更深入的评估覆盖面。该方法将在一家德国汽车制造商的车辆硬件在环舒适性功能测试中得到验证。     

New record and southern range extension for the Mearn's grasshopper mouse ( Onychomys arenicola Mearns, 1896) in Veracruz, Mexico

Mearn’s grasshopper mouse ( Onychomys arenicola ) in Mexico is found primarily in the central and northern states. This is the first report of the genus Onychomys in the state of Veracruz, based on 7 captured specimens (3 collected). This finding extends the species’ known distribution by approximately 470 km east-southeast. In addition, this record increases the alpha diversity of terrestrial mammals for the state of Veracruz to 192 species.     

Using accounting‐based information on young firms to predict bankruptcy

This study analyzes the nonlinear relationships between accounting‐based key performance indicators and the probability that the firm in question will become bankrupt or not. The analysis focuses particularly on young firms and examines whether these nonlinear relationships are affected by a firm's age. The analysis of nonlinear relationships between various predictors of bankruptcy and their interaction effects is based on a structured additive regression model and on a comprehensive data set on German firms. The results of this analysis provide empirical evidence that a firm's age has a considerable effect on how accounting‐based key performance indicators can be used to predict the likelihood that a firm will go bankrupt. More specifically, the results show that there are differences between older firms and young firms with respect to the nonlinear effects of the equity ratio, the return on assets, and the sales growth on their probability of bankruptcy.     

Replacement of huntingtin exon 1 by trans-splicing

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminus of huntingtin (HTT). HD offers unique opportunities for promising RNA-based therapeutic approaches aimed at reducing mutant HTT expression, since the HD mutation is considered to be a “gain-of-function” mutation. Allele-specific strategies that preserve expression from the wild-type allele and reduce the levels of mutant protein would be of particular interest. Here, we have conducted proof-of-concept studies to demonstrate that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically repair the HTT allele. We employed a dual plasmid transfection system consisting of a pre-mRNA trans-splicing module (PTM) containing HTT exon 1 and a HTT minigene to demonstrate that HTT exon 1 can be replaced in trans. We detected the presence of the trans-spliced RNA in which PTM exon 1 was correctly joined to minigene exons 2 and 3. Furthermore, exon 1 from the PTM was trans-spliced to the endogenous HTT pre-mRNA in cultured cells as well as disease-relevant models, including HD patient fibroblasts and primary neurons from a previously described HD mouse model. These results suggest that the repeat expansion of HTT can be repaired successfully not only in the context of synthetic minigenes but also within the context of HD neurons. Therefore, pre-mRNA trans-splicing may be a promising approach for the treatment of HD and other dominant genetic disorders.     

Action Research for Emancipation Informed by Habermas and Hierarchy of Systems: Case Study on Environmental Education and Management of Water Resources in Brazil

Technology is used in order to emancipate. Emancipation for social and environmental justice ought to shape the way technology is designed and used. The relationships across action research, action research spiral, and the General Systems Theory was investigated. The case study refers to environmental education activities as part of a participative management approach to water resources on the Hydrographic Basin of the Upper Maranhão River (Brazil). By introducing action research spiral as a search of rationality in social practices, and describing the nature of lower and higher hierarchical level in General Systems Theory, the higher hierarchical level was associated with Habermasian emancipatory interest, whereas lower hierarchic levels were associated with the specific instrumental concern. To conclude, it is said that the articulation between action research spiral and General System Theory can be the means to strengthen the dialectical potential of the action research spiral in order to achieve both individual and collective empowerment.     

The Epistemological Functions of Symbolization in Leibniz’s Universal Characteristic

Leibniz’s universal characteristic is a fundamental aspect of his theory of cognition. Without symbols or characters it would be difficult for the human mind to define several concepts and to achieve many demonstrations. In most disciplines, and particularly in mathematics, the mind must then focus on symbols and their combinatorial rules rather than on mental contents. For Leibniz, mental perception is most of the time too confused for attaining distinct notions and valid deductions. In this paper, I argue that the functions of symbolization differ depending upon the kind of concepts that are replaced with characters. In my view, most commentators did not sufficiently underline the distinction between two main functions of formal substitution in Leibniz’s characteristic: either increasing our knowledge or simply structuring it. In the first case, we complete our knowledge because formal substitution makes sensible and imaginary concepts more distinct. In the second case, symbolization helps to organize contents that are already conceived of by reason. Thus the process of substitution is not always identically applicable, for symbols replace different types of concepts.     

Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells

Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr?231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr?231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.     

Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision

Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.     

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.