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Accumulation of conformationally altered cellular proteins (i.e., prion protein) is the common feature of prions and other neurodegenerative diseases. Previous studies demonstrated that the lack of terminal sequence of cellular prion protein (PrPC), necessary for the addition of glycosylphosphatidylinositol lipid anchor, leads to a protease-resistant conformation that resembles scrapie-associated isoform of prion protein. Moreover, mice overexpressing the truncated form of PrPC showed late-onset, amyloid deposition, and the presence of a short protease-resistant PrP fragment in the brain similar to those found in Gerstmann–Straussler–Scheinker disease patients. Therefore, the physiopathological function of truncated_/anchorless 23–230 PrPC (Δ23–230 PrPC) has come into focus of attention. The present study aims at revealing the physiopathological function of the anchorless PrPC form by identifying its interacting proteins. The truncated_/anchorless Δ23–230 PrPC along with its interacting proteins was affinity purified using STrEP-Tactin chromatography, in-gel digested, and identified by quadrupole time-of-flight tandem mass spectrometry analysis in prion protein-deficient murine hippocampus (HpL3-4) neuronal cell line. Twenty-three proteins appeared to interact with anchorless Δ23–230 PrPC in HpL3-4 cells. Out of the 23 proteins, one novel protein, pyruvate kinase isozymes M1/M2 (PKM2), exhibited a potential interaction with the anchorless Δ23–230 form of PrPC. Both reverse co-immunoprecipitation and confocal laser-scanning microscopic analysis confirmed an interaction of PKM2 with the anchorless Δ23–230 form of PrPC. Furthermore, we provide the first evidence for co-localization of PKM2 and PrPC as well as PrPC-dependent PKM2 expression regulation. In addition, given the involvement of PrPC in the regulation of apoptosis, we exposed HpL3-4 cells to staurosporine (STS)-mediated apoptotic stress. In response to STS-mediated apoptotic stress, HpL3-4 cells transiently expressing 23–230-truncated PrPC were markedly less viable, were more prone to apoptosis and exhibited significantly higher PKM2 expressional regulation as compared with HpL3-4 cells transiently expressing full-length PrPC (1–253 PrPC). The enhanced STS-induced apoptosis was shown by increased caspase-3 cleavage. Together, our data suggest that the misbalance or over expression of anchorless Δ23–230 form of PrPC in association with the expressional regulation of interacting proteins could render cells more prone to cellular insults-stress response, formation of aggregates and may ultimately be linked to the cell death.

The present study investigates whether posttranslational modifications of cellular prion protein (PrP(C)) in the cerebrospinal fluid (CSF) of humans with prion diseases are associated with methionine (M) and/or valine (V) polymorphism at codon 129 of the prion protein gene (PRNP), scrapie prion protein (PrP(Sc)) type in sporadic Creutzfeldt-Jakob disease (sCJD), or PRNP mutations in familial Creutzfeldt-Jakob disease (fCJD/E200K), and fatal familial insomnia (FFI). We performed comparative 2-dimensional immunoblotting of PrP(C) charge isoforms in CSF samples from cohorts of diseased and control donors. Mean levels of total PrP(C) were significantly lower in the CSF from fCJD patients than from those with sCJD or FFI. Of the 12 most abundant PrP(C) isoforms in the examined CSF, one (IF12) was relatively decreased in (1) sCJD with VV (vs. MM or MV) at PRNP codon 129; (2) in sCJD with PrP(Sc) type 2 (vs. PrP(Sc) type 1); and (3) in FFI versus sCJD or fCJD. Furthermore, truncated PrP(C) species were detected in sCJD and control samples without discernible differences. Finally, serine 43 of PrP(C) in the CSF and brain tissue from CJD patients showed more pronounced phosphorylation than in control donors.

Alone among modern European thinkers, Rousseau (1712–78) was both a great moralist and a significant moral philosopher. As a moralist, he developed an original vision of human nature and human fulfillment along with an analysis of the forces hindering people from achieving happiness in the modern world; as a moral philosopher, he presented a theory of right action and the grounds of moral obligation that has shaped centuries of debate about rights, duties, and authority. Both aspects of his ethical thought have provoked widely divergent interpretations and they remain controversial, both as to their meaning and the soundness of their argumentation. Born in Geneva but living most of his adult life in France, Rousseau identified the decay beneath the glittering facade both of the ancien regime and of the intellectual culture of the Enlightenment. In the end, he was persecuted by both camps and was inspired to create, as one scholar put it, “a dazzling one-man alternative Enlightenment” (Hulliung 1994: 4). His works remain notable for their originality, depth, influence, and style. Keywords: authenticity; autonomy; Enlightenment; ethics; philosophy; Rousseau, Jean-Jacques

We discuss relevant aspects in two siblings with a neurodegenerative process of unclear aetiology who developed progressive dementia with global aphasia and hyperoral behaviour at the ages of 39 and 46 years and who died 6 and 5 years after disease onset. The cases were reported to the National Reference Center for TSE Surveillance in Gottingen, Germany. Detailed clinical examinations, CSF, blood samples, and copies of the important diagnostic tests (magnetic resonance imaging, electroencephalogram, laboratory tests) were obtained. Further neuropathological and genetic analyses were performed. Cerebral magnetic resonance imaging of both siblings showed prominent changes in signal intensity, especially in the left medial temporal cortex, but also the hippocampal formation. Neuropathological examination revealed spongiform changes, neuronal loss, and astrocytic gliosis, which are typical in Creutzfeldt-Jakob disease. However, no prion protein deposits were detectable by immunohistochemical analysis, Western blot, or PET blot, though abundant tau protein deposits were observed. A mutation in the coding region of the prion protein genes of both siblings was excluded. A detailed search of the literature revealed no other cases with a similar clinical and neuropathological appearance. While the disease aetiology remains unclear, the findings point to a neurodegenerative process and most likely a genetic disease.

Sporadic inclusion body myositis is a chronic progressive, inflammatory disorder of the skeletal muscle. No effective treatment is available for this debilitating condition and the complex disease pathology is far from being understood. The major hallmark of the pathomechanisms is the co-occurrence of inflammatory as well as degenerative cascades including aggregates consisting of β-amyloid within skeletal muscle fibers. Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to be upregulated via the proinflammatory cytokine TNF-α in human skeletal muscle cells. In a human cell line from rhabdomyosarcoma as a model to study muscle cells, we here show that TNF-α-mediated upregulation of macroautophagy modulates APP and β-amyloid load and can be blocked by inhibition of macroautophagy. Thus, macroautophagy may be a crucial mediator between inflammation and β-amyloid-associated degeneration in skeletal muscle.

The rise in the usage of sustainable energy conversion technologies has been remarkable. However, the growth of these technologies poses several problems, mainly concerning the net integration of intermittent energy sources, like wind and solar power, by means of advanced storage systems and the land consumption the use of these energy sources implies. Furthermore, the economic viability of these solutions is in question, as they are to date still often heavily supported by financial subsidies. The Powership concept attempts to tackle these shortcomings by harvesting wind energy offshore using an alternative infrastructural approach which features a special-purpose ship towed by a high-flying kite. The ship’s resulting kinetic energy is partially converted by a water repeller and can either be used to compress and store air in steel tubes (Alternative 1) or to drive a generator which in turn delivers electrical energy to produce hydrogen (Alternative 2). In this study, the economic feasibility of each of the two alternatives is investigated and compared with the other using real options analysis, including both R&D and market risks as stochastic variables driving the option’s value. In order to determine the strategic value of managerial flexibility in the face of uncertainty, assumptions concerning the change of the economic environment are made and motivated.

Background: The detection of a 14-3-3 elevated level in cerebrospinal fluid (CSF) is a part of the diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease (sCJD), as defined by the WHO. However, some pathological conditions associated with acute neuronal damage may result in a positive 14-3-3 test and thereby reduce test specificity in sCJD. Objective: Desmoplakin has been previously identified as up-regulated CSF protein in sCJD and these studies aimed to investigate its diagnostic utility and compare it with two known CSF markers, 14-3-3 and tau. Methods and Results: We tested CSF levels of 14-3-3, tau and desmoplakin in 58 sCJD patients and 81 control patients including 45 cases with an elevated 14-3-3 level due to other disease than sCJD. We detected an elevated CSF level of desmoplakin in 78% of the sCJD patients, while 14-3-3 (88%) and tau (91%) showed a higher positive rate. However, the false positive rate of newly tested desmoplakin was significantly lower in comparison to 14-3-3 and tau, and it accounted for only 11% versus 56% and 35%, respectively. Further reduction of false positive rates was achieved by combination of elevated tau level with a positive desmoplakin test. Moreover, in the non-sCJD group, desmoplakin level did not correlate with the level of both above-mentioned CSF markers, whereas a clear correlation was observed in the sCJD group. Conclusion: Desmoplakin showed a low positive rate accompanied by a very low false positive rate. Thus, we conclude that desmoplakin is a promising candidate for supportive CSF marker to rule out 14-3-3 false positive cases in sCJD differential diagnosis.

Caveolin and caveolin containing rafts are involved in the signaling of growth factors in various cell types. Previous reports of our lab indicated a co-localization of caveolin and the high affinity nerve growth factor (NGF) receptor tyrosine kinase A (TrkA). Mutual effects have been observed among which a caveolin-1 knock-down resulted in an impairment of the NGF signaling cascade rather than in an increase of activity as expected from other growth factor reports. On the other hand, an over-expression of caveolin-1 impaired the NGF stimulated activity of p42/44 mitogen activated protein kinases (MAPK). In this study, we used a caveolin-1 scaffolding domain (CSD) peptide (cavtratin) of which an inhibitory effect on growth factor receptors was reported. Our data showed that cavtratin suppresses the NGF-induced phosphorylation of TrkA as well as the activation of MAPK in porcine oligodendrocytes significantly. peerReviewed

The presence of apolipoprotein E (ApoE) e4 allele is a risk factor for Alzheimer's disease (AD) and associated with a more pronounced reduction of amyloid-β 1-42 (Aβ1-42) in the cerebrospinal fluid (CSF). Because a decrease of Aβ1-42 and increase of tau protein levels, both important biomarkers for AD, are also reported in Creutzfeldt-Jakob disease (CJD), we analyzed if a similar relationship can be observed in this rapid progressive dementia. Our study included 309 patients with sporadic CJD (147 neuropathologically confirmed and 162 probable cases). We analyzed the role of ApoE e4 in sporadic CJD (sCJD), in particular the influence on the CSF-markers 14-3-3 protein, tau protein, neuron-specific enolase, S100 protein, Aβ1-42, and Aβ1-40. No differences in the ApoE e4 allele frequency and ApoE genotype distribution between sCJD and published healthy controls were observed. The ApoE e4 allele had no effect on disease duration or age at onset. We detected a dose-dependent ApoE e4 effect on the decrease of Aβ1-42 in sCJD. ApoE e4 carriers with one ApoE e4 allele showed significantly reduced Aβ1-42 values (p < 0.0001) in comparison with non-carriers. ApoE e4 allele is not a risk factor for sCJD but modifies the Aβ1-42 levels in CSF in a similar manner as in AD. Based on our results in sCJD patients, we hypothesize that the ApoE e4 effect on Aβ1-42 values might not be disease-specific.

The cellular prion protein (PrP(c)) is a multifunctional, highly conserved and ubiquitously expressed protein. It undergoes a number of modifications during its post-translational processing, resulting in different PrP(c) glycoforms and truncated PrP(c) fragments. Limited data are available in humans on the expression and cleavage of PrP(c). In this study we investigated the PrP(c) isoform composition in the cerebrospinal fluid from patients with different human prion diseases. The first group of patients was affected by sporadic Creutzfeldt-Jakob disease exhibiting different PrP codon 129 genotypes. The second group contained patients with a genetic form of Creutzfeldt-Jakob disease (E200K). The third group consisted of patients with fatal familial insomnia and the last group comprised cases with the Gerstmann-Sträussler-Scheinker syndrome. We examined whether the PrP codon 129 polymorphism in sporadic Creutzfeldt-Jakob disease as well as the type of prion disease in human patients has an impact on the glycosylation and processing of PrP(c). Immunoblotting analyses using different monoclonal PrP(c) antibodies directed against various epitopes of PrP(c) revealed, for all examined groups of patients, a consistent predominance of the glycosylated PrP(c) isoforms as compared with the unglycosylated form. In addition, the antibody SAF70 recognized a variety of PrP(c) fragments with sizes of 21, 18, 13 and 12 kDa. Our findings indicate that the polymorphisms at PrP codon 129, the E200K mutation at codon 200 or the examined types of human transmissible spongiform encephalopathies do not exert a measurable effect on the glycosylation and processing of PrP(c) in human prion diseases.

Embedded systems in robotics or mechatronics need flexibility since they are working in dynamic environments. We consider an embedded modular multi-microcontroller system. Each module includes a microcontroller and special purpose hardware like a motor driver. Usually a change of the embedded software necessitates a direct access to all the devices (microcontrollers) to reload the code.

The definite physiological role of the cellular prion protein (PrP(c)) remains elusive. There is ample in vitro and in vivo evidence suggesting a neuroprotective role for PrP(c). On the other hand, several in vitro and in vivo studies demonstrated detrimental effects of PrP(c) overexpression through activation of a p53 pathway. Recently, we reported that transient overexpression of PrP(c) in human embryonic kidney 293 cells elicits proteome expression changes which point to deregulation of proteins involved in energy metabolism and cellular homeostasis. Here we report proteome expression changes following stable PrP(c) overexpression in human neuronal SH-SY5Y cells. In total 18 proteins that are involved in diverse biological processes were identified as differentially regulated. The majority of these proteins is involved in cell signaling, cytoskeletal organization and protein folding. Annexin V exhibited a several fold up-regulation following stable PrP(c) overexpression in SH-SY5Y cells. This finding has been reproduced in alternative, mouse N2a and human SK-N-LO neuroblastoma cell lines transiently overexpressing PrP(c). Annexin V plays an important role in maintenance of calcium homeostasis which when disturbed can activate a p53-dependent cell death. Although we did not detect changes in p53 expression between PrP(c) overexpressing SH-SY5Y and control cells, deregulation of several proteins including annexin V, polyglutamine tract-binding protein-1, spermine synthase and transgelin 2 indicates disrupted cellular equilibrium. We conclude that stable PrP(c) overexpression in SH-SY5Y cells is sufficient to perturb cellular balance but insufficient to affect p53 expression.

Signaling of growth factors may depend on the recruitment of their receptors to specialized microdomains. Previous reports on PC12 cells indicated an interaction of raft-organized caveolin and TrkA signaling. Because porcine oligodendrocytes (OLs) respond to nerve growth factor (NGF), we were interested to know whether caveolin also plays a role in oligodendroglial NGF/TrkA signaling. OLs expressed caveolin at the plasma membrane but also intracellularly. This was partially organized in the classically Ω-shaped invaginations, which may represent caveolae. We could show that caveolin and TrkA colocalize by using a discontinuous sucrose gradient (Song et al. [1996] J. Biol. Chem. 271:9690–9697), MACS technology, and immunoprecipitation. However, differential extraction of caveolin and TrkA with Triton X-100 at 4°C indicated that caveolin and TrkA are probably not exclusively present in detergent-resistant, caveolin-containing rafts (CCRs). NGF treatment of OLs up-regulated the expression of caveolin-1 (cav-1) and stimulated tyrosine-14 phosphorylation of cav-1. Furthermore, OLs were transfected with cav-1-specific small interfering RNA (siRNA). A knockdown of cav-1 resulted in a reduced activation of downstream components of the NGF signaling cascade, such as p21Ras and mitogen-activated protein kinase (MAPK) after NGF exposure of OLs. Subsequently, increased oligodendroglial process formation via NGF was impaired. The present study indicates that CCRs/caveolin could play a modulating role during oligodendroglial differentiation and regeneration. © 2009 Wiley-Liss, Inc.

Statins are widely prescribed drugs in cardiovascular diseases. Recent studies also demonstrated anti-inflammatory and immunomodulatory properties of statins by modulating the activity of small GTPases. Statins are thus considered as potential therapeutic drug for the inflammatory demyelinating disease multiple sclerosis (MS). However, little is known about the effects of statins on myelin-forming oligodendrocytes. Here, we show that statins hamper process and myelin formationin vitroby interfering with Ras and Rho signaling in mature oligodendrocytes and provide evidence that statins impair ongoing remyelinationin vivo. Our findings may have significant implications for the application of statins in MS patients and in other demyelinating diseases of the CNS.

Infrared (IR) spectroscopy is a most important technique for identifying compounds and monitoring their reactions in bio-chemistry. Usually spectra are obtained from condensed-phase samples containing molecules embedded in solvents of varying polarity or in complex and polar protein environments. Upon transfer from the gas phase to the condensed phase, the vibrational frequencies may become sizeably shifted and the lines inhomogeneuosly broadened. For molecules comprising up to about 100 atoms, accurate computations of their gas-phase IR spectra were enabled by the development and widespread accessibility of density functional theory (DFT) about a decade ago. Concerning molecules in the condensed phase, however, the art of accurately computing the IR spectra is an ongoing development, whose computational basis is provided by hybrid methods combining DFT descriptions of molecules with molecular mechanics (MM) models of their condensed phase environment. Here we review the involved physics, the available computational procedures, the achievements, and the perspectives of this DFT/MM based development, which promises to provide detailed insights into the structural dynamics of condensed phase bio-chemical reactions by quantitative descriptions of corresponding IR spectra.

The midinfrared (MIR) spectra of molecules in polar solvents exhibit inhomogeneously broadened bands whose spectral positions are shifted as compared to the gas phase. The shifts are caused by interactions with structured solvation shells and the broadenings by fluctuations of these interactions. The MIR spectra can be calculated from hybrid molecular dynamics (MD) simulations, which treat the solute molecule by density functional theory and the solvent by molecular mechanics by the so-called instantaneous normal mode analysis (INMA) or by Fourier transforming the time correlation function (FTTCF) of the molecular dipole moment. In Paper I of this work [M. Schmitz and P. Tavan, J. Chem. Phys. 121, 12233 (2004)] we explored an alternative method based on generalized virial (GV) frequencies noting, however, that GV systematically underestimates frequencies. As shown by us these artifacts are caused by solvent-induced fluctuations of the (i) equilibrium geometry, (ii) force constants, and (iii) normal mode directions as well as by (iv) diagonal and (v) off-diagonal anharmonicities. Here we now show, by analyzing the time scales of fluctuations and sample MD trajectories of formaldehyde in the gas phase and in water, that all these sources of computational artifacts can be made visible by a Fourier analysis of the normal coordinates. Correspondingly, the error sources (i) and (iii)-(v) can be removed by bandpass filtering, as long as the spectral signatures of the respective effects are well separated from the fundamental band. Furthermore, the artifacts arising from effect (ii) can be strongly diminished by a time-resolved version of the GV approach (TF-GV). The TF-GV method then yields for each mode j a trajectory of the vibrational frequency omega(j)(tmid R:tau) at a time resolution tautau(j), which is only limited by the corresponding oscillation time tau(j)=2pi/omega(j) and, thus, is in the femtosecond range. A correlation analysis of these trajectories clearly separates the librational motions from the conformational dynamics of the solvation shells and yields the inhomogeneously broadened MIR spectra, if the theory of motional narrowing is properly included. The MIR spectrum of formaldehyde in solution obtained by TF-GV agrees very well with the FTTCF result, if one applies the so-called "harmonic approximation" quantum correction factor and a temperature scaling to the FTTCF intensities. Also for INMA an excellent agreement is achieved if one disregards a slight INMA overestimate of linewidths.

Allmorgendliches Wecken mit Musik, Erziehung ohne Zwang und fruhzeitige Forderung vorhandener Anlagen durch selbstandiges Lernen nach dem Prinzip Erfahrung — auf seine Weise suchte M.s Vater Pierre Eyquem in den Grundsatzen der Erziehung seines eigensinnigen Sohnes die humanistischen Ideale seiner Zeit umzusetzen. Diese hatte der erste und letzte Ritter einer im Handel mit Wein, Farbstoffen und Heringen reichgewordenen Groskaufmannsfamilie burgerlichen Standes kennengelernt, als er an den italienischen Feldzugen Franz’ I. teilgenommen hatte. Nach der humanistischen Ausbildung durch einen des Franzosischen unkundigen deutschen Hofmeister wurde M., dessen Mutter aus einer reichen Kaufmannsfamilie judisch-portugiesischer Herkunft stammte, mit sechs Jahren fur eine standesgemase Erziehung zum Edelmann auf das neugegrundete College de Guyenne geschickt. Obwohl eine der angesehenen Adelsschulen, auf der glanzende humanistische Gelehrte der Zeit wirkten, blieb sie fur M. »immer noch eine offentliche Lehranstalt«: »Mit dreizehn hatte ich meinen Kursus beendet (wie sie es nennen) und zwar in Wirklichkeit ohne irgend einen Nutzen, den ich heute in Anschlag bringen konnte.« Die strenge Buchererziehung widerstrebte M., der in einem spateren Essay uber die Kindererziehung im Vertrauen auf die Kraft der Natur jegliche Pedanterie oder schulischen Zwang ablehnte und seine padagogischen Ratschlage einer »Wesensbildung im Angesicht der Fulle der Welt« (Hugo Friedrich) an der Herausbildung einer selbstandig urteilenden und weltoffenen Personlichkeit orientierte.

»Kraft aus dem Ursprung ziehen?... Aus der Fremde habe ich meine Krafte gezogen« (Besuch im Hades, 1967) — jener Fremde, die nicht nur einen wechselnden geographischen, sondern auch den gesellschaftlichen Ort des wahrend des Nationalsozialismus politisch und rassisch Verfolgten, seit den 50er Jahren des unerwunschten Warners vor der »atomaren Drohung« meint. Schon 1917 wurde A. in Frankreich als Zwangsmitglied eines paramilitarischen Schulerverbandes mit den Folgen des Ersten Weltkrieges konfrontiert und war als Sohn judischer Eltern, des Psychologenpaars Clara und William Stern, antisemitischen Qualereien ausgesetzt. Trotzdem folgte dem Abitur (1920) ein »politikfreies Intermezzo« mit vorwiegend philosophischen und kunstlerischen Interessen. Sein Studium der Philosophie, zunachst in Hamburg bei Ernst Cassirer und Eduard Spranger in Berlin, dann u.a. bei Martin Heidegger sowie Edmund Husserl in Freiburg, schlos A. mit einer Dissertation uber Die Rolle der Situationskategorie bei den »Logischen Satzen« (Freiburg 1924) ab. Es folgten Seminare und Semester bei Heidegger, Max Scheler, dessen Assistent er wurde, Karl Mannheim und Paul Tillich. Zugleich arbeitete er fur den Rundfunk, schrieb an einem Versepos uber Berlin und begann seine Tatigkeiten als Journalist und Rezensent bei der kurzlebigen Monatszeitschrift Das Dreieck.

Nein, als Philosoph hat er sich nicht gesehen. Auch kam ihm wohl niemals in den Sinn, seine Studien der wahren Philosophie zuzuordnen, wie er sie verstand und zeitlebens mit der Philosophie Kants und ihrer Aufgabenstellung der Bestimmung der Grenzen reiner Vernunfterkenntnis identifizierte. Von ihr glaubte H. auch dort noch auszugehen, wo er sich von Anfang an von ihr entfernte, indem er jenseits ihrer restriktiven Resultate das Gebiet der ihn interessierenden, immer auch empirisch bedeutsamen Fragen zu den Bereichen Individualitat, Bildung, Sprache, historische Zeit sowie Staat und Gesellschaft ausschritt. Oberflachlicher Betrachtung entzieht sich diese ungewohnliche Themenvielfalt seines fruh entworfenen, prinzipiell bis zu den spaten Sprachstudien festgehaltenen Projekts einer »Synthese von Philosophie und Anthropologie« (Jurgen Trabant) einer uberzeugenden Systematisierung und tragt weitgehend fragmentarischen Charakter, so das H. wie »eine Sphinx (erscheint), welche jeden Betrachter anders ansieht und welche jeder Betrachter anders ansieht« (Friedrich Meinecke). Doch erlangen seine wenigen abgeschlossenen wie die Vielzahl der abgebrochenen Schriften »eine innere Vollendung« (Tilman Borsche) gerade dadurch, das sie alle auf den Mittelpunkt einer umfassend gedachten Theorie der Bildung des Menschen (1794/95) bezogen sind, die sich in Abgrenzung zu Kants Bestimmung des transzendentalen Subjekts an einem philosophisch und empirisch zugleich gemeinten Begriff des Menschen orientiert.

Introduction: The definitive diagnosis of genetic prion diseases (gPrD) requires pathological confirmation. To date, diagnosis has relied upon the finding of the biomarkers 14-3-3 protein and total tau (t-tau) protein in the cerebrospinal fluid (CSF), but many researchers have reported that these markers are not sufficiently elevated in gPrD, especially in Gerstmann-Sträussler-Scheinker syndrome (GSS). We recently developed a new in vitro amplification technology, designated "real-time quaking-induced conversion (RT-QUIC)", to detect the abnormal form of prion protein in CSF from sporadic Creutzfeldt-Jakob disease (sCJD) patients. In the present study, we aimed to investigate the presence of biomarkers and evaluate RT-QUIC assay in patients with gPrD, as the utility of RT-QUIC as a diagnostic tool in gPrD has yet to be determined. Method/Principal Findings: 56 CSF samples were obtained from gPrD patients, including 20 cases of GSS with P102L mutation, 12 cases of fatal familial insomnia (FFI; D178N), and 24 cases of genetic CJD (gCJD), comprising 22 cases with E200K mutation and 2 with V203I mutation. We subjected all CSF samples to RT-QUIC assay, analyzed 14-3-3 protein by Western blotting, and measured t-tau protein using an ELISA kit. The detection sensitivities of RT-QUIC were as follows: GSS (78%), FFI (100%), gCJD E200K (87%), and gCJD V203I (100%). On the other hand the detection sensitivities of biomarkers were considerably lower: GSS (11%), FFI (0%), gCJD E200K (73%), and gCJD V203I (67%). Thus, RT-QUIC had a much higher detection sensitivity compared with testing for biomarkers, especially in patients with GSS and FFI. Conclusion/Significance: RT-QUIC assay is more sensitive than testing for biomarkers in gPrD patients. RT-QUIC method would thus be useful as a diagnostic tool when the patient or the patient's family does not agree to genetic testing, or to confirm the diagnosis in the presence of a positive result for genetic testing., PLoS ONE, 8(1), e54915; 2013

Nur schwer last sich H.s geistesgeschichtliche Stellung beschreiben, weil sein Denken ohne offensichtlich einheitlichen Grundris blieb. Schon zu Lebzeiten wurde daher »der edle Geist… verkannt; doch nicht ganz ohne seine Schuld; denn er hatte den Fehler, das er kein Stern erster oder sonstiger Grose war, sondern ein Bund von Sternen, aus welchem sich dann jeder ein beliebiges Sternbild buchstabiert« (Jean Paul). Thematische Vielfalt und Umfang des herderschen Lebenswerks spiegeln jedoch nicht nur die Weite seiner Bestrebungen als protestantischer Theologe, Prediger und Padagoge, als Philosoph der Geschichte und Kunst, der Poesie und Sprache wider, der selbst als Dichter und bedeutender Sammler von Volksliedern hervortrat. Es zeichnet sich darin auch sein lebenslanges Bemuhen um die Deutung und selbstandige Weiterfuhrung einer »Universalgeschichte der Bildung der Welt« ab. Diese hochgespannte Aufgabe fuhrte ihn endlich zu seiner eigentumlichen Leistung, Geschichte in ihrem inneren Zusammenhang mit dem psychologischen und biologischen Geschehen als neue Lebensdimension zu erschliesen. In der Entfaltung seiner historischen Denkweise, die sich an den Kategorien der Individualitat und Entwicklung orientiert, um dabei Kontingenz und Uberlieferung zu betonen, wurde H. weniger seiner Ergebnisse, als der Vielfalt seiner Einflusse methodischer Art wegen zum grosen Anreger vor allem in der Sprach- und Geschichtsphilosophie, aber auch der Anthropologie und Literaturgeschichte.

Die in den Hauptkapiteln D. und E. konzipierten (Teil-) Losungsansatze fur die Bewertung flexibel automatisierter Fertigungssysteme in der rechnerintegrierten Produktion beziehen sich sowohl auf die Fertigung als auch auf den fertigungsnahen Bereich. Fur den Bereich der Fertigung wurde neben der prozesorientierten Grenzplankostenrechnung eine auf Kosten basierende Investitionsrechnung konzipiert, welche die erforderlichen Daten in der Planungsphase aus einer Simulation des flexibel automatisierten Fertigungssystems ableitet bzw. in der Betriebsphase mit Hilfe der Betriebsdatenerfassung ermittelt. Die so ermittelten Kosten werden mit Hilfe des Theorems von Lucke auf die Investitionsrechnung ubertragen. Zwar wird versucht, auch den fertigungsnahen Bereich durch eine Abschatzung der dort auftretenden Kostenwirkungen — als Folge der Eingliederung z.B. eines FFS in die rechnerintegrierte Produktion — in die Betrachtung einzubeziehen, doch gelingt dies nur unvollstandig. So sind z.B. weiterhin exakte Kalkulationen im fertigungsnahen Bereich nicht moglich. Weiterhin konnen Investitionen im fertigungsnahen Bereich Auswirkungen auf die Wirtschaftlichkeit des flexibel automatisierten Fertigungssystems durch unternehmungsexterne Faktoren (z.B. kurzere Entwicklungs- und somit auch Durchlaufzeiten eines Auftrages bei Investition in ein CAD-System und in der Folge hohere Auftragseingange infolge dieses Wettbewerbsvorteils) haben, die infolge unklarer Ursache-/Wirkungs-Relationen nicht berucksichtigt werden konnen. Um auch den fertigungsnahen Bereich in die Betrachtung einzubeziehen, wurde die Prozeskostenrechnung als Instrument des Gemeinkostenmanagements diskutiert und eine Erganzung der Grenzplankostenrechnung durch dieses Kostenrechnungssystem befurwortet. Zwar handelt es sich bei der Prozeskostenrechnung um eine Vollkostenrechnung, doch bietet sie gerade im Hinblick auf die veranderte Aufbau- und Ablaufstruktur der rechnerintegrierten Produktion infolge ihrer Prozesorientierung gewisse Vorteile. Eine Erganzung der Grenzplankostenrechnung um Elemente der Prozeskostenrechnung erscheint auch vor dem Hintergrund vorteilhaft und praktikabel, da beide Systeme derartig viele Gemeinsamkeiten haben, das die Prozeskostenrechnung durchaus als eine Modifikation bzw. Weiterentwicklung der Grenzplankostenrechnung angesehen werden kann. Gewisse Veranderungen z.B. im BAB oder der Kostenstellenstruktur sind fur die Einfuhrung der Prozeskostenrechnung jedoch erforderlich.

Im Rahmen von Hauptkapitel B. sollen die mit der Integration flexibel automatisierter Fertigungssysteme in die rechnerintegrierte Produktion verbundenen Implikationen analysiert werden. Zunachst wird in Abschnitt I. naher auf die Grundlagen der Allgemeinen Systemtheorie eingegangen. Die Grunde Ihr die Anwendung der Allgemeinen Systemtheorie ergeben sich aus dem Bemuhen, die Komplexitat der Problemstellung durch einen Ansatz zu bewaltigen, der die gesamte Realitat erfassen kann, dabei aber so praktikabel bleibt, das auch konkrete Einzelprobleme damit diskutiert werden konnen. Im Hinblick auf die Bewertung flexibel automatisierter Fertigungssysteme in der rechnerintegrierten Produktion eroffnet die Allgemeine Systemtheorie die Moglichkeit, die realen Wirkungszusammenhange auf der Basis eines integrierenden Bezugsrahmens unter Einbeziehung der gesamten Unternehmung eingehend zu untersuchen. Aus der Sicht der Allgemeinen Systemtheorie werden dann in den Abschnitten H. und III. die rechnerintegrierte Produktion bzw. das flexibel automatisierte Fertigungssystem naher untersucht. Weiterhin werden in Abschnitt IV. die mit dem Einsatz flexibel automatisierter Fertigungssysteme verbundenen Veranderungen in der Organisationsstruktur der Unternehmung betrachtet. Abschliesend wird in Abschnitt V. die Einbindung flexibel automatisierter Fertigungssysteme in die Wettbewerbsstrategie der Unternehmung am Beispiel von FFS diskutiert.

Im Rahmen von Hauptkapitel A. wird in Abschnitt I. zunachst ein Uberblick uber die Problemstellung dieser Untersuchung gegeben. Anschliesend wird in Abschnitt II. die Zielsetzung definiert und die weitere Vorgehensweise bestimmt.

Im Rahmen von Hauptkapitel D. wird ein Konzept fur die Bewertung flexibel automatisierter Fertigungssysteme entworfen, das in der Planungs- und auch in der Betriebsphase als Entscheidungshilfe dienen soll. Hierbei wird grundsatzlich zwischen der strategischen und der taktisch/operativen Bewertung unterschieden. Die strategische Bewertung ist erforderlich, weil das flexibel automatisierte Fertigungssystem Bestandteil der rechnerintegrierten Produktion ist und mit einer derartigen Investitionsentscheidung die grundsatzliche strategische Orientierung der Unternehmung festgelegt wird.1 Aufgrund der Wettbewerbsrelevanz flexibel automatisierter Fertigungssysteme, und dabei insbesondere von FFS, sind fur die strategische Bewertung Produkt-Markt-Strategien erforderlich, die auf der Basis von Produkt-, Markt- und Technologie-Portfolios die Chancen und Risiken nicht nur des Marktsegments bewerten, welches von der Einfuhrung des FFS betroffen ist, sondern auch die der gesamten Unternehmung. Die auf die mittlere Erfolgswirkung ausgelegte taktische Bewertung des flexibel automatisierten Fertigungssystems umfast sowohl die Bewertung von Konfigurationsentscheidungen als auch von Entscheidungen uber das Produktionsprogramm. Bei der Bewertung von Konfigurationsentscheidungen soll im Vergleich mit Alternativen die wirtschaftlichste Losung ausgewahlt werden. Hier sind Entscheidungen insbesondere im Hinblick auf den Automatisierungsgrad und die Flexibilitat z.B. eines FFS zu treffen, die durch Ausstattungsparameter wie z.B. die Anzahl der Maschinen, die Anzahl der Transportfahrzeuge etc. determiniert sind. Mit Hilfe der operativen Bewertung soll eine moglichst optimale Durchfuhrung des Fertigungsprozesses gewahrleistet werden. Hier kann ein Einflus auf die Fertigungskosten durch verschiedene Strategien zur Reihenfolgeplanung und -steuereng von Werkstucken ausgeubt werden.

Der in Hauptkapitel D. dargestellte Losungsansatz zur Bewertung flexibel automatisierter Fertigungssysteme in der rechnerintegrierten Produktion bezieht sich ausschlieslich auf die Bewertung des flexibel automatisierten Fertigungssystems und vernachlassigt weitgehend die Auswirkungen im fertigungsnahen Bereich. Infolge der fertigungsubergreifenden Auswirkungen des Einsatzes von flexibel automatisierten Fertigungssystemen, die Veranderungen in der Aufbau- und Ablaufstruktur (Prozesorientierung mit Daten- und Vorgangsintegration) nach sich ziehen und auch Kostenstrukturveranderungen in der gesamten Produktion zur Folge haben, konnen die vorzunehmenden Betrachtungen jedoch nicht allein auf das Fertigungssystem beschrankt bleiben. Zwar wird bei dem in Hauptkapitel D. dargestellten Ansatz versucht, auch diese Auswirkungen mit Hilfe von Schatzungen zusatzlich entstandener bzw. eingesparter Kosten im fertigungsnahen Bereich in die Betrachtung einzubeziehen, doch werden die Ergebnisse ausschlieslich fur die Bewertung des FFS verwendet und lassen keine weiteren Schlusse uber die gesamtbetrieblichen Overhead-Kosten zu. Hier bedarf es einer Erweiterung des bestehenden Ansatzes.

Im Rahmen von Hauptkapitel C. sollen jene Auswirkungen auf das betriebliche Rechnungswesen naher untersucht werden, die sich infolge der Integration flexibel automatisierter Fertigungssysteme in die rechnerintegrierte Produktion ergeben. Zunachst wird in Abschnitt I. das betriebliche Rechnungswesen in seiner Eigenschaft als funktionelles Instrument zur Steuerung der Unternehmung in knapper Form erlautert. Weiterhin wird die These aufgestellt, das das betriebliche Rechnungswesen infolge der Integration flexibel automatisierter Fertigungssysteme in die rechnerintegrierte Produktion und der damit einhergehenden Auswirkungen in seiner Aussagefahigkeit und somit in seiner Funktion der Informationsbereitstellung zur Steuerung der Unternehmung eingeschrankt ist. Die Auswirkungen der Integration flexibel automatisierter Fertigungssysteme in die rechnerintegrierte Produktion auf das betriebliche Rechnungswesen werden anschliesend in den Abschnitten II. (Marktinduzierte Auswirkungen), III. (Fertigungssysteminduzierte Auswirkungen) und IV. (Organisationsinduzierte Auswirkungen) dargestellt und diskutiert. Die Ergebnisse werden in Abschnitt V. (“Erfordernis zur Umgestaltung des betrieblichen Rechnungswesens”) in tabellarischer Form zusammengefast; auserdem werden bereits Hinweise auf mogliche Losungsansatze gegeben.

Hybrid molecular dynamics (MD) simulations, which combine density functional theory (DFT) descriptions of a molecule with a molecular mechanics (MM) modeling of its solvent environment, have opened the way towards accurate computations of solvation effects in the vibrational spectra of molecules. Recently, Wheeler et al. [ChemPhysChem 4, 382 (2002)] have suggested to compute these spectra from DFT/MM-MD trajectories by diagonalizing the covariance matrix of atomic fluctuations. This so-called principal mode analysis (PMA) allegedly can replace the well-established approaches, which are based on Fourier transform methods or on conventional normal mode analyses. By scrutinizing and revising the PMA approach we identify five conditions, which must be guaranteed if PMA is supposed to render exact vibrational frequencies. Besides specific choices of (a) coordinates and (b) coordinate systems, these conditions cover (c) a harmonic intramolecular potential, (d) a complete thermal equilibrium within the molecule, and (e) a molecular Hamiltonian independent of time. However, the PMA conditions [(c)-(d)] and [(c)-(e)] are generally violated in gas phase DFT-MD and liquid phase DFT/MM-MD trajectories, respectively. Based on a series of simple analytical model calculations and on the analysis of MD trajectories calculated for the formaldehyde molecule in the gas phase (DFT) and in liquid water (DFT/MM) we show that in both phases the violation of condition (d) can cause huge errors in PMA frequency computations, whereas the inevitable violations of conditions (c) and (e), the latter being generic to the liquid phase, imply systematic and sizable underestimates of the vibrational frequencies by PMA. We demonstrate that the huge errors, which are caused by an incomplete thermal equilibrium violating (d), can be avoided if one introduces mode-specific temperatures T(j) and calculates the frequencies from a "generalized virial" (GV) expression instead from PMA. Concerning ways to additionally remove the remaining errors, which GV still shares with PMA, we refer to Paper II of this work [M. Schmitz and P. Tavan, J. Chem. Phys. 121, 12247 (2004)].

On decrit la synthese, en six etapes a partir de l′acide dibromo-4,6-isophtalique, de l′amino-11-cis-fluorenacene ou amino-4-[indeno-2′,1′:2,3-fluorene].

On decrit la synthese, en quatre etapes a partir de l'acide dibromo- 4, 6-isophtalique, de derives di- et tetramethyles du cis-fluorbnackne ([indeno-2′, 1′: 2,3-fluorkne]). Ce sont le dimethyl-3,6-cis-fluorknacbne ou dimethyl-6,6′-[indho-2′, 1′ : 2,3-fluorene], le teramehyl-1, 3,6,8- cis-fluorenackne ou tetramethyl-6,8,4′, 6′-[indeno-2′, 1′: 2,3-fluorene] et le tetramethyl-1,4,5,8-cis-fluorenseene ou tetramethyl-5,8,4′7′- [indeno-2′, 1′: 2,S-fluorenel].

Cholesterol is an essential component of eukaryotic plasma membranes and plays an important role in membrane organization and signaling processes. It is the major lipid component of detergent resistant caveolin-1 containing rafts which previously had been reported as a platform for nerve growth factor (NGF) signaling in oligodendrocytes (OL). Surprisingly, a knockdown of caveolin-1 attenuated the process formation of OL (Schmitz et al. J Neurosci Res 88:572–588, 2010), for which a loss of cholesterol could be responsible. In the present report, we could show that a caveolin-1 knockdown resulted in an elevation of cellular cholesterol level; it may indicate an important role of caveolin-1 in cholesterol trafficking to the plasma membrane. Treatment with exogenous PEG cholesterol, which was incorporated to the plasma membrane, supported oligodendroglial process formation, in particular when OL were stimulated by NGF. In this context we have found that OL express NPC1L1 (Niemann–Pick disease type C1-Like 1) which could modulate cholesterol uptake. In contrast, depletion of membrane-bound cholesterol diminished NGF-induced process formation concomitant with a reduced activity of p42/44 mitogen-activated protein kinases. peerReviewed

A perovskite material, CaMn0.9Mg0.1O3-δ, has been investigated as oxygen carrier in a 10kW chemical looping pilot using sulphurous fuels. Operation with inert gas in the fuel reactor showed that the material released significant amounts of gas-phase oxygen, indicating CLOU properties. Stable operation with fuel was performed during 29hours with performance superior to previously tested oxygen carriers like ilmenite. A slight deterioration of the conversion was detected during the experiments, which can be attributed to the accumulation of sulphur in the oxygen carrier. However, a regeneration test with non-sulphurous fuel showed that this process is reversible and that the oxygen carrier can be regenerated after being subjected to sulphurous fuels.

The development of in vitro amplification systems allows detecting femtomolar amounts of prion protein scrapie (PrPSc) in human cerebrospinal fluid (CSF). We performed a CSF study to determine the effects of prion disease type, codon 129 genotype, PrPSc type, and other disease-related factors on the real-time quaking-induced conversion (RT-QuIC) response. We analyzed times to 10,000 relative fluorescence units, areas under the curve and the signal maximum of RT-QuIC response as seeding parameters of interest. Interestingly, type of prion disease (sporadic vs. genetic) and the PRNP mutation (E200K vs. V210I and FFI), codon 129 genotype, and PrPSc type affected RT-QuIC response. In genetic forms, type of mutation showed the strongest effect on the observed outcome variables. In sporadic CJD, MM1 patients displayed a higher RT-QuIC signal maximum compared to MV1 and VV1. Age and gender were not associated with RT-QuIC signal, but patients with a short disease course showed a higher seeding efficiency of the RT-QuIC response. This study demonstrated that PrPSc characteristics in the CSF of human prion disease patients are associated with disease subtypes and rate of decline as defined by disease duration. Electronic supplementary material The online version of this article (doi:10.1007/s12035-014-8709-6) contains supplementary material, which is available to authorized users.

The rise in the usage of renewable energy technologies in recent years has been remarkable. Still, the growth of these technologies poses formidable problems, mainly concerning the grid integration of intermittent energy sources, such as wind and solar power, by means of advanced storage systems, as well as the land use requirements implied by these low energy density resources. Furthermore, the economic viability of these solutions is in question, which is why to date they are often still heavily subsidized. The Powership concept attempts to tackle some of these shortcomings by harvesting wind energy offshore using an alternative infrastructural approach featuring a special-purpose ship towed by a high-flying kite. The ship's resulting kinetic energy is partially converted by a water repeller and can either be used to compress and store air in steel tubes (Alternative 1) or to drive a generator which in turn delivers electrical energy to produce hydrogen (Alternative 2). In this study, the economic feasibility of each of the two alternatives is investigated and compared with each other using real options analysis, including both R&D and market risks as stochastic variables driving the option value. For determining the strategic value of managerial flexibility under uncertainty, assumptions about changes of the economic environment are made and motivated.

Introduction Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown. Methods Cerebrospinal fluid NFL levels were quantified in nonprimarily neurodegenerative neurological and psychiatric diseases (n = 122), mild cognitive impairment (n = 48), Alzheimer's disease (n = 108), dementia with Lewy bodies/Parkinson's disease dementia (n = 53), vascular dementia (n = 46), frontotemporal dementia (n = 41), sporadic Creutzfeldt-Jakob disease (sCJD, n = 132), and genetic prion diseases (n = 182). Results The highest NFL levels were detected in sCJD, followed by vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease dementia, Alzheimer's disease, and mild cognitive impairment. In sCJD, NFL levels correlated with cerebrospinal fluid tau and disease duration. NFL levels were able to differentiate sCJD from nonprimarily neurodegenerative neurological and psychiatric diseases (area under the curve = 0.99, 95% confidence interval: 0.99–1) and from the other diagnostic groups showing cognitive impairment/dementia of a non-CJD etiology (area under the curve = 0.90, 95% confidence interval: 0.87–0.92). Compared to nonprimarily neurodegenerative neurological and psychiatric diseases, NFL was also elevated in genetic prion diseases associated with the E200K, V210I, P102L, and D178N prion protein gene mutations. Discussion Increased NFL levels are a common feature in neurodegenerative dementias.