Political Institutions, Discourse and Imagination in China at Tiananmen

Summary The weakness of official institutions in China renders formal political discourse unreal and thwarts any attempts by organised social groups to engage in dialogue with those in political control. This is true of the structures of both the state and the Chinese Communist Party, which Deng Xiaoping and his reformist colleagues claimed to be (and at first, were) strengthening from 1978 onwards. When economic and political crises struck in the late 1980s, the circle of aged leaders round Deng used their personalised networks of clients to brush these institutions aside. Whatever institution?building had occurred since 1978 was swiftly undone. This wrecked any chance of dialogue between the young people of Tiananmen and those in political control, and reduced the two sides to manipulating symbols and discourse in highly theatrical exercises. Résumé Les Organismes Politiques, les Discours et l'Imagination à Tiananmen en Chine La faiblesse des institutions offidelles en Chine donne un aspect irréel aux discours politiques formels et contrecarre les efforts effectués par des groupes sociaux organisés pour engager le dialogue avec les dirigeants politiques. Ceci est vrai pour les structures de l'état et celles du Parti Communiste Chinois, que Deng Xiaoping et ses collègues réformistes (et ils l'étaient, au début) revendiquent d'avoir renforcées depuis 1978. Lors de la crise économique et politique à la fin des années 80, le cercle des anciens dirigeants autour de Deng ont utilisé leur réseau personnel de clients pour balayer ces institutions. Toutes les institutions établies depuis 1978 ont été rapidement détruites. Ceci a eu pour effet de ruiner toute possibilité de dialogue entre les jeunes gens de Tiananmen et les dirigeants politiques, et a réduit les deux parties à manipuler les symboles et les discours comme un exercise hautement théâtral. Resumen Instituciones Políticas, Discurso e Imaginación en Tiananmen, China La debilidad de las instituciones oficiales políticas en la China hace imposible la existencia del discurso político e impiden a cualquier grupo social entrar en diálogo con los dirigentes políticos. Este es el caso de ambos el estado y el Partido Comunista Chino, el cual Deng Xiaoping y sus colegas reformistas proclamaron ir (y al principio fueron) fortaleciendo desde 1978. Cuando a finales de los años 80 estalló la crisis económica y política, el círculo de ancianos que rodeaban a Deng utilizaron sus contactos personales para relegar estas instituciones a un lado. Todas las instituciones establecidas desde 1978 fueron rápidamente derrumbadas. Esto destruyó cualquier intento al diálogo entre los jóvenes de Tiananmen y los dirigentes políticos, reduciendo a los partidos a manipular símbolos y discursos de una forma sumamente teatral

ICSPEA

The covariance matrix adaptation (CMA) is a concept originally introduced for improving the single-objective evolution strategy (ES). CMA varies the classical ES-mutation operator by utilising a mutation distribution adaptation scheme and an evolution path, which takes the evolutionary history into account. SPEA2 surely belongs to the most popular multi-objective evolutionary algorithms. It uses the strength Pareto concept and a special distribution measure for the evaluation of offspring individuals. An archive collects non-dominated individuals, which are used during selection, making the SPEA2 a typical elitist strategy. The new ICSPEA (Integrated CMA-SPEA) combines the powerful mutation concept of the CMA-ES with the evaluation scheme of the SPEA2. Tests on selected benchmark functions show the promising features of this new multi-objective optimisation algorithm

A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP.

Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Aβ peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aβ peptides have been discovered such as γ-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Aβ levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative

Direct correlation of crystal structure and optical properties in wurtzite/zinc-blende GaAs nanowire heterostructures

A novel method for the direct correlation at the nanoscale of structural and optical properties of single GaAs nanowires is reported. Nanowires consisting of 100% wurtzite and nanowires presenting zinc-blende/wurtzite polytypism are investigated by photoluminescence spectroscopy and transmission electron microscopy. The photoluminescence of wurtzite GaAs is consistent with a band gap of 1.5 eV. In the polytypic nanowires, it is shown that the regions that are predominantly composed of either zinc-blende or wurtzite phase show photoluminescence emission close to the bulk GaAs band gap, while regions composed of a nonperiodic superlattice of wurtzite and zinc-blende phases exhibit a redshift of the photoluminescence spectra as low as 1.455 eV. The dimensions of the quantum heterostructures are correlated with the light emission, allowing us to determine the band alignment between these two crystalline phases. Our first-principles electronic structure calculations within density functional theory, employing a hybrid-exchange functional, predict band offsets and effective masses in good agreement with experimental results

Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials

Deconstructing sarcomeric structure-function relations in titin-BioID knock-in mice

Proximity proteomics has greatly advanced the analysis of native protein complexes and subcellular structures in culture, but has not been amenable to study development and disease in vivo. Here, we have generated a knock-in mouse with the biotin ligase (BioID) inserted at titin's Z-disc region to identify protein networks that connect the sarcomere to signal transduction and metabolism. Our census of the sarcomeric proteome from neonatal to adult heart and quadriceps reveals how perinatal signaling, protein homeostasis and the shift to adult energy metabolism shape the properties of striated muscle cells. Mapping biotinylation sites to sarcomere structures refines our understanding of myofilament dynamics and supports the hypothesis that myosin filaments penetrate Z-discs to dampen contraction. Extending this proof of concept study to BioID fusion proteins generated with Crispr/CAS9 in animal models recapitulating human pathology will facilitate the future analysis of molecular machines and signaling hubs in physiological, pharmacological, and disease context

Bewertung der SGB II-Umsetzung aus gleichstellungspolitischer Sicht: Jahresbericht 2007 des Gender-Projekts; Kurzfassung - 5. Oktober 2007; Projektnr. 03/06

Im Zentrum der vorliegenden Kurzfassung des ersten Jahresberichtes stehen die Ergebnisse einer Online-Befragung der Personen, die bei den SGB II-Trägereinheiten für Chancengleichheit, Gleichstellung oder Gender Mainstreaming zuständig sind. Die Befragung diente in erster Linie dem Ziel, ein Bild vom Ausmaß der konzeptionellen, organisatorischen und personellen Verankerung des Gleichstellungszieles zu erhalten. Darüber hinaus enthält der Bericht eine erste geschlechterdifferenzierende Bestandsaufnahme des Leistungsbezugs im SGB II auf Basis von öffentlich zugänglichen Statistiken und Befragungsergebnissen. Neben dem Umfang und der Zusammensetzung der Bezieher/innen von Grundsicherungsleistungen nach SGB II wird analysiert, inwieweit geschlechtsspezifische Unterschiede in Bezug auf die Arbeitslosigkeit, die Abgangsdynamik, die Erwerbstätigkeit und die Maßnahmeteilnahme festzustellen sind

Regeneration of the Exocrine Pancreas Is Delayed in Telomere-Dysfunctional Mice

INTRODUCTION: Telomere shortening is a cell-intrinsic mechanism that limits cell proliferation by induction of DNA damage responses resulting either in apoptosis or cellular senescence. Shortening of telomeres has been shown to occur during human aging and in chronic diseases that accelerate cell turnover, such as chronic hepatitis. Telomere shortening can limit organ homeostasis and regeneration in response to injury. Whether the same holds true for pancreas regeneration in response to injury is not known. METHODS: In the present study, pancreatic regeneration after acute cerulein-induced pancreatitis was studied in late generation telomerase knockout mice with short telomeres compared to telomerase wild-type mice with long telomeres. RESULTS: Late generation telomerase knockout mice exhibited impaired exocrine pancreatic regeneration after acute pancreatitis as seen by persistence of metaplastic acinar cells and markedly reduced proliferation. The expression levels of p53 and p21 were not significantly increased in regenerating pancreas of late generation telomerase knockout mice compared to wild-type mice. CONCLUSION: Our results indicate that pancreatic regeneration is limited in the context of telomere dysfunction without evidence for p53 checkpoint activation

Aerosolized BC-819 Inhibits Primary but Not Secondary Lung Cancer Growth

Despite numerous efforts, drug based treatments for patients suffering from lung cancer remains poor. As a promising alternative, we investigated the therapeutic potential of BC-819 for the treatment of lung cancer in mouse tumor models. BC-819 is a novel plasmid DNA which encodes for the A-fragment of Diphtheria toxin and has previously been shown to successfully inhibit tumor growth in human clinical study of bladder carcinoma. In a first set of experiments, we examined in vitro efficacy of BC-819 in human lung cancer cell-lines NCI-H460, NCI-H358 and A549, which revealed >90% reduction of cell growth. In vivo efficacy was examined in an orthotopic mouse xenograft lung cancer model and in a lung metastasis model using luminescent A549-C8-luc adenocarcinoma cells. These cells resulted in peri- and intra-bronchiolar tumors upon intrabronchial application and parenchymal tumors upon intravenous injection, respectively. Mice suffering from these lung tumors were treated with BC-819, complexed to branched polyethylenimine (PEI) and aerosolized to the mice once per week for a period of 10 weeks. Using this regimen, growth of intrabronchially induced lung tumors was significantly inhibited (p = 0.01), whereas no effect could be observed in mice suffering from lung metastasis. In summary, we suggest that aerosolized PEI/BC-819 is capable of reducing growth only in tumors arising from the luminal part of the airways and are therefore directly accessible for inhaled BC-819