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Background: The peroneal muscles are the most effective lateral stabilisers whose tension braces the ankle joint complex against excessive supination. The purpose of this study was to identify the morphological and biomechanical effects of two machine-based shank muscle training methods.
Methods: Twenty-two healthy male recreationally active sports students performed ten weeks of single-set high resistance strength training with 3 training sessions per week. The subjects conducted subtalar pronator/supinator muscle training (ST) with the right leg by using a custom-made apparatus; the left foot muscles were exercised with machine-based talocrural plantar and dorsiflexor training (TT). Muscle strength (MVIC), muscle volume and foot biomechanics (rearfoot motion, ground reaction forces, muscle reaction times) during a sudden ankle supination were recorded before and after the intervention.
Results: Compared to TT, ST resulted in significantly higher pronator (14% vs. 8%, P<0.01) and supinator MVIC (25% vs. 12%, P<0.01). During sudden foot inversions, both ST and TT resulted in reduced supination velocity (-12%; P<0.01). The muscle reaction onset time was faster after the training in peroneus longus (PL) (P<0.01). Muscle volume of PL (P<0.01) and TA (P<0.01) increased significantly after both ST and TT.
Conclusion: After both ST and TT, the ankle joint complex is mechanically more stabilised against sudden supinations due to the muscle volume increase of PL and TA. As the reduced supination velocities indicate, the strength training effects are already present during free-fall. According to a sudden ankle supination in standing position, both machine-based dorsiflexor and pronator strength training is recommended for enhancing the mechanical stability of the ankle.
Cognitive stability and flexibility are core functions in the successful pursuit of behavioral goals. While there is evidence for a common frontoparietal network underlying both functions and for a key role of dopamine in the modulation of flexible versus stable behavior, the exact neurocomputational mechanisms underlying those executive functions and their adaptation to environmental demands are still unclear. In this work we study the neurocomputational mechanisms underlying cue based task switching (flexibility) and distractor inhibition (stability) in a paradigm specifically designed to probe both functions. We develop a physiologically plausible, explicit model of neural networks that maintain the currently active task rule in working memory and implement the decision process. We simplify the four-choice decision network to a nonlinear drift-diffusion process that we canonically derive from a generic winner-take-all network model. By fitting our model to the behavioral data of individual subjects, we can reproduce their full behavior in terms of decisions and reaction time distributions in baseline as well as distractor inhibition and switch conditions. Furthermore, we predict the individual hemodynamic response timecourse of the rule-representing network and localize it to a frontoparietal network including the inferior frontal junction area and the intraparietal sulcus, using functional magnetic resonance imaging. This refines the understanding of task-switch-related frontoparietal brain activity as reflecting attractor-like working memory representations of task rules. Finally, we estimate the subject-specific stability of the rule-representing attractor states in terms of the minimal action associated with a transition between different rule states in the phase-space of the fitted models. This stability measure correlates with switching-specific thalamocorticostriatal activation, i.e., with a system associated with flexible working memory updating and dopaminergic modulation of cognitive flexibility. These results show that stochastic dynamical systems can implement the basic computations underlying cognitive stability and flexibility and explain neurobiological bases of individual differences.
El artículo, después de haber tratado la cuestión del tiranicidio en Tomás de Aquino y en Bartolo de Sassoferrato, muestra cómo Francisco de Vitoria, consciente de las soluciones que ofrecen los autores anteriores a él, afronta el argumento de forma innovadora, aunque en línea con la tradición anterior. En la base de la solución que propone Vitoria, se encuentra, en efecto, la afirmación de un derecho a la auto-defensa, entendido como derecho natural inalienable que reside en los individuos y en las comunidades; un derecho que siempre lo pueden ejercer los súbditos en relación con un gobernante que se convierte en tirano. Vitoria expresa de este modo el principio de resistencia a la autoridad injusta e ilegal en los términos de un derecho subjetivo, el de la auto-defensa, pero, al mismo tiempo, señala los límites afirmando la necesidad de cada individuo de respetar y someterse a un orden de justicia objetivo. De aquí su prohibición a un particular de matar a un hombre, aunque sea un tirano, sin un justo procedimiento jurídico. Así pues, el artículo muestra, a través del debate sobre la licitud del tiranicidio cómo en la obra de Vitoria se encuentra una teoría sólida de la soberanía juntamente con la afirmación tenaz de derechos naturales individuales. En efecto, Vitoria retoma, por una parte, una tradición de pensamiento para la que la formación de las sociedades políticas era la consecuencia de la sociabilidad natural de los hombres; y por otra, desarrollaba una teoría coherente de los derechos subjetivos a partir de la necesidad misma de los individuos de asociarse los unos con los otros para los fines de una vida éticamente justa y gratificante.
kurz und kn@pp news : Nr. 34
(2015)
Die Frage was ein Fach ausmacht ist keinesfalls leicht zu beantworten. Dennoch haben sich in den letzten Wochen auf FAZ.net Kolleginnen und Kollegen verschiedenster Fächer daran versucht. Für Schülerinnen und Schülern dürfte dies bei der Studienfachwahl hilfreich sein. Doch der Versuch von Prof. Korte zur Politikwissenschaft stellt das Fach zu eingeschränkt dar.
Es gibt Neuigkeiten von Chinas bekanntestem Dissidenten und Künstler Ai Weiwei. Aber dieses Mal ist es nicht die chinesische Regierung, die sich Fragen stellen lassen muss, sondern die britische. Denn Ai erhielt kein 6-Monatsvisum, weil er „straffällig“ sei. Doch der Künstler wurde niemals angeklagt. Was steckt hinter der Verweigerung? Ein Kommentar.
This master thesis will consider the question how far American history influenced, and is mirrored in, (American) science fiction literature. The main work of reference for this endeavor will be the award-winning Mars Trilogy by the aforementioned, renowned science fiction author Kim Stanley Robinson.
Chapter one will deal specifically with the topic of how certain events of American history – especially the War of Independence, its origins and its aftermath – are more or less mirrored in the Mars novels, often with only minor changes (and adapted into a sci-fi setting, of course). The historic concepts of ‘the Frontier’ and ‘Manifest Destiny’ will find some minor mention here.
The second chapter of this paper will be exclusively about one of the early main characters of the trilogy, one with a lasting influence even though he dies early. The leading thesis will be that this ‘all-American hero’ is, more or less, a fusion of two major figures of early American history, specifically Captain John Smith and legendary ‘frontiersman’ Daniel Boone. The name of this character alone – John Boone – should serve easily as an indicator for the truth of this thesis.
The final chapter of this thesis then leaves the Mars Trilogy behind in order to look at the whole wide field of science fiction literature. Selected works will serve to illustrate the pervasive presence of American history in this genre. The concept of the ‘frontier’ will be of considerable importance to this endeavor, and will feature significantly in this section.
Concluding the paper will be a short overview of the paper’s major points and a few final thoughts will then round out this thesis and mark its end.
Challenging voluntary CSR-initiatives – a case study on the effectiveness of the Equator Principles
(2015)
The Equator Principles (EPs) are a voluntary and self-regulatory Corporate Social Responsibility (CSR) initiative in the field of project finance. The EPs provide a number of principles to businesses to reduce the negative impacts of lending practices linked to environment-damaging projects. The paper argues that the actual impact of the EPs even now as revised version is still limited. This is due to their voluntary nature and their lack of adequate governance mechanisms, that is, enforcement, monitoring and sanctioning. With the help of RepRisk, which provides a database capturing third-party criticism as well as a company’s or project’s exposure to controversial socio-environmental issues, the paper evaluates the on-the-ground performances of the two ‘Equator banks’ Barclays and JPMorgan Chase and compares their performance with the one of the two non-Equator banks Deutsche Bank and UBS. The paper shows that the EPs do not have a substantial influence on the broader CSR-performance of multinational banks due to the EPs’ limited scope – focusing mainly on project finance – and the (still) existing various loopholes, grey areas and discretionary leeway. The paper also gives an overview of the main institutional shortcomings of the EPs and their association and discusses some potential reform steps which should be taken to further strengthen and ‘harden’ this ‘soft law’ EP-framework. The paper thus argues in favor of (more) mandatory and legally binding rules and standards at the transnational level to overcome the EPs’ ‘voluntariness bias’.
Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Defects in flow-induced NO formation go along with endothelial dysfunction, initiation and progression of atherosclerosis as well as with arterial hypertension. Previous work has identified several mechanotransducing signaling processes involved in fluid shear stress-induced endothelial effects. But how fluid shear stress initiates the response is poorly understood. Here, I show in human and bovine endothelial cells that the G-protein Gq/G11 and the purinergic receptor P2Y2 mediate fluid shear stress-induced endothelial responses such as Ca2+ release, nitric oxide (NO) formation and the phosphorylation of platelet-endothelial-cell-adhesion-molecule-1 (PECAM-1), vascular endothelial growth factor-2 (VEGFR-2) and Akt kinase as well as activation of the endothelial NO synthase (eNOS). P2Y2 receptor is activated by adenosine triphosphate (ATP) which is released from endothelial cells under the influence of fluid shear stress. Arteries with P2Y2 or Gαq/Gα11 deficiency have impaired flow-induced dilatation. Mice with induced endothelium-specific deficiency of P2Y2 or Gαq/Gα11 develop hypertension which is accompanied by reduced eNOS activation. My data identify P2Y2 and Gq/G11 as a critical endothelial mechano-signaling pathway located upstream of mechanotransducing processes described so far. Moreover, I demonstrate that P2Y2 and Gq/G11 are required for basal endothelial NO formation, vascular tone and blood pressure.
Die vorliegende Arbeit beschäftigt sich mit den Arbeitsgedächtnisleistungen zweier sprachlicher Sondergruppen und der Möglichkeit über die Leistung des Arbeitsgedächtnisses validere Prognosen des weiteren sprachlichen bzw. schriftsprachlichen Entwicklungsverlaufs zu erreichen, als dies über eine ausschließliche Erhebung der Sprachleistung möglich ist. Die Basis dieser Untersuchungen bilden zwei Längsschnittstudien. Die Daten der sprachlichen Sondergruppe der Late Talker (kognitive Aspekte) wurden in Heidelberg an der Universität und dem Frühinterventionszentrum (FRIZ) zwischen dem zweiten und dem neunten Lebensjahr der Kinder (N=93 mit n1=59 Late Talkers und n2=34 Kontrollkindern) in bestimmten Abständen erhoben. Neben den sprachlichen und kognitiven Leistungstests wurde zum letzten Messzeitpunkt zusätzlich die Arbeitsgedächtnisleistung erfasst. Dabei sollte untersucht werden, ob die Leistungen im Arbeitsgedächtnis valide unterscheiden können zwischen Kindern mit persistierenden Sprachentwicklungsproblemen und Kindern, die das Defizit im weiteren Entwicklungsverlauf aufholen (Late Bloomer). Die Ergebnisse zeigen, dass mithilfe der Leistungen in der Phonologischen Schleife eine sehr gute Trennung der Late Bloomer von den Kindern, die weiter eine Sprachproblematik aufweisen, vorgenommen werden kann. Ein Hinzuziehen der zentral-exekutiven Leistungen bringt hingegen keine Verbesserung in der Vorhersagegenauigkeit.
Der zweiten Untersuchung liegen zum einen die Daten der Normierung der Arbeitsgedächtnistestbatterie für Kinder von fünf bis zwölf Jahren (AGTB 5-12 {Hasselhorn et al., 2012}) zugrunde (N=1.669 davon 243 Kinder mit Migrationshintergrund), anhand derer überprüft wurde, ob Kinder mit Migrationshintergrund in irgendeiner Weise durch die Nutzung der Testbatterie benachteiligt werden, sei es 1. Durch die ungeprüfte Übernahme des Arbeitsgedächtnismodells (nach dem Vorbild von Baddeley (1986)), dass für Muttersprachler bereits bestätigt werden konnte, 2. Durch Benachteiligungen in bestimmten Untertests und 3. Durch die Testbatterie im Allgemeinen, die Art der Testung und die Wahl bestimmter Items. Zur Überprüfung, inwieweit Prädiktoren, die bei Muttersprachlern valide Prognosen der späteren schriftsprachlichen Leistungen erlauben, auch bei Kindern mit Migrationshintergrund genutzt werden können, wird ein weiterer längsschnittlicher Datensatz herangezogen. Von den 127 Kindern der Längsschnittstudie des Projekts ANNA „Gedächtnis und Schulfähigkeit“ (Individual Development and Adaptive Education of Children at Risk am Deutschen Institut für internationale pädagogische Forschung - DIPF) weisen 60 Kinder einen Migrationshintergrund auf. Auf Basis beider Datensätze konnte nachgewiesen werden, dass das Modell des Arbeitsgedächtnisses auch bei Kindern mit Migrationshintergrund Anwendung findet und die Benachteiligungen bei der Testung besonders gering ausfallen, je früher die Kinder untersucht werden. Es zeigt sich aber auch, dass die AGTB 5-12 an manchen Stellen überarbeitet werden sollte, um mögliche Benachteiligungen noch weiter zu verringern. Außerdem konnte gezeigt werden, dass sich auch bei Kindern mit Migrationshintergrund valide Prognosen späterer schriftsprachlicher Leistungen anhand ihrer Arbeitsgedächtnisleistungen treffen lassen und hier hauptsächlich auf Basis der phonologischen Gesamtleistungen (alle Untertests).
Background: Cardiovascular magnetic resonance (CMR) offers quantification of phasic atrial functions based on volumetric assessment and more recently, on CMR feature tracking (CMR-FT) quantitative strain and strain rate (SR) deformation imaging. Inter-study reproducibility is a key requirement for longitudinal studies but has not been defined for CMR-based quantification of left atrial (LA) and right atrial (RA) dynamics.
Methods: Long-axis 2- and 4-chamber cine images were acquired at 9:00 (Exam A), 9:30 (Exam B) and 14:00 (Exam C) in 16 healthy volunteers. LA and RA reservoir, conduit and contractile booster pump functions were quantified by volumetric indexes as derived from fractional volume changes and by strain and SR as derived from CMR-FT. Exam A and B were compared to assess the inter-study reproducibility. Morning and afternoon scans were compared to address possible diurnal variation of atrial function.
Results: Inter-study reproducibility was within acceptable limits for all LA and RA volumetric, strain and SR parameters. Inter-study reproducibility was better for volumetric indexes and strain than for SR parameters and better for LA than for RA dynamics. For the LA, reservoir function showed the best reproducibility (intraclass correlation coefficient (ICC) 0.94–0.97, coefficient of variation (CoV) 4.5–8.2 %), followed by conduit (ICC 0.78–0.97, CoV 8.2–18.5 %) and booster pump function (ICC 0.71–0.95, CoV 18.3–22.7). Similarly, for the RA, reproducibility was best for reservoir function (ICC 0.76–0.96, CoV 7.5–24.0 %) followed by conduit (ICC 0.67–0.91, CoV 13.9–35.9) and booster pump function (ICC 0.73–0.90, CoV 19.4–32.3). Atrial dynamics were not measurably affected by diurnal variation between morning and afternoon scans.
Conclusions: Inter-study reproducibility for CMR-based derivation of LA and RA functions is acceptable using either volumetric, strain or SR parameters with LA function showing higher reproducibility than RA function assessment. Amongst the different functional components, reservoir function is most reproducibly assessed by either technique followed by conduit and booster pump function, which needs to be considered in future longitudinal research studies.
Immunohistochemical assessment of phosphorylated mTORC1-pathway proteins in human brain tumors
(2015)
Background: Current pathological diagnostics include the analysis of (epi-)genetic alterations as well as oncogenic pathways. Deregulated mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in a variety of cancers including malignant gliomas and is considered a promising target in cancer treatment. Monitoring of mTORC1 activity before and during inhibitor therapy is essential. The aim of our study is to provide a recommendation and report on pitfalls in the use of phospho-specific antibodies against mTORC1-targets phospho-RPS6 (Ser235/236; Ser240/244) and phospho-4EBP1 (Thr37/46) in formalin fixed, paraffin embedded material.
Methods and findings: Primary, established cell lines and brain tumor tissue from routine diagnostics were assessed by immunocyto-, immunohistochemistry, immunofluorescent stainings and immunoblotting. For validation of results, immunoblotting experiments were performed. mTORC-pathway activation was pharmacologically inhibited by torin2 and rapamycin. Torin2 treatment led to a strong reduction of signal intensity and frequency of all tested antibodies. In contrast phospho-4EBP1 did not show considerable reduction in staining intensity after rapamycin treatment, while immunocytochemistry with both phospho-RPS6-specific antibodies showed a reduced signal compared to controls. Staining intensity of both phospho-RPS6-specific antibodies did not show considerable decrease in stability in a timeline from 0–230 minutes without tissue fixation, however we observed a strong decrease of staining intensity in phospho-4EBP1 after 30 minutes. Detection of phospho-signals was strongly dependent on tissue size and fixation gradient. mTORC1-signaling was significantly induced in glioblastomas although not restricted to cancer cells but also detectable in non-neoplastic cells.
Conclusion: Here we provide a recommendation for phospho-specific immunohistochemistry for patient-orientated therapy decisions and monitoring treatment response.
Objectives: Previous studies investigating speech perception in noise have typically been conducted with static masker positions. The aim of this study was to investigate the effect of spatial separation of source and masker (spatial release from masking, SRM) in a moving masker setup and to evaluate the impact of adaptive beamforming in comparison with fixed directional microphones in cochlear implant (CI) users.
Design: Speech reception thresholds (SRT) were measured in S0N0 and in a moving masker setup (S0Nmove) in 12 normal hearing participants and 14 CI users (7 subjects bilateral, 7 bimodal with a hearing aid in the contralateral ear). Speech processor settings were a moderately directional microphone, a fixed beamformer, or an adaptive beamformer. The moving noise source was generated by means of wave field synthesis and was smoothly moved in a shape of a half-circle from one ear to the contralateral ear. Noise was presented in either of two conditions: continuous or modulated.
Results: SRTs in the S0Nmove setup were significantly improved compared to the S0N0 setup for both the normal hearing control group and the bilateral group in continuous noise, and for the control group in modulated noise. There was no effect of subject group. A significant effect of directional sensitivity was found in the S0Nmove setup. In the bilateral group, the adaptive beamformer achieved lower SRTs than the fixed beamformer setting. Adaptive beamforming improved SRT in both CI user groups substantially by about 3 dB (bimodal group) and 8 dB (bilateral group) depending on masker type.
Conclusions: CI users showed SRM that was comparable to normal hearing subjects. In listening situations of everyday life with spatial separation of source and masker, directional microphones significantly improved speech perception with individual improvements of up to 15 dB SNR. Users of bilateral speech processors with both directional microphones obtained the highest benefit.
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
Species recognition in lichen-forming fungi has been a challenge because of unsettled species concepts, few taxonomically relevant traits, and limitations of traditionally used morphological and chemical characters for identifying closely related species. Here we analyze species diversity in the cosmopolitan genus Protoparmelia s.l. The ~25 described species in this group occur across diverse habitats from the boreal -arctic/alpine to the tropics, but their relationship to each other remains unexplored. In this study, we inferred the phylogeny of 18 species currently assigned to this genus based on 160 specimens and six markers: mtSSU, nuLSU, ITS, RPB1, MCM7, and TSR1. We assessed the circumscription of species-level lineages in Protoparmelia s. str. using two coalescent-based species delimitation methods – BP&P and spedeSTEM. Our results suggest the presence of a tropical and an extra-tropical lineage, and eleven previously unrecognized distinct species-level lineages in Protoparmelia s. str. Several cryptic lineages were discovered as compared to phenotype-based species delimitation. Many of the putative species are supported by geographic evidence.
The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph+ leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. The co-expression of p96ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185BCR/ABL. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and Ph+ ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96ABL/BCR and p185BCR/ABL in hematopoietic stem cells. Co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph+ ALL.
Little work has been done on large-scale patterns of stream insect richness in China. We explored the influence of climatic and catchment-scale factors on stream insect (Ephemeroptera, Plecoptera, Trichoptera; EPT) richness across mid-latitude China. We assessed the predictive ability of climatic, catchment land cover and physical structure variables on genus richness of EPT, both individually and combined, in 80 mid-latitude Chinese streams, spanning a 3899-m altitudinal gradient. We performed analyses using boosted regression trees and explored the nature of their influence on richness patterns. The relative importance of climate, land cover, and physical factors on stream insect richness varied considerably between the three orders, and while important for Ephemeroptera and Plecoptera, latitude did not improve model fit for any of the groups. EPT richness was linked with areas comprising high forest cover, elevation and slope, large catchments and low temperatures. Ephemeroptera favoured areas with high forest cover, medium-to-large catchment sizes, high temperature seasonality, and low potential evapotranspiration. Plecoptera richness was linked with low temperature seasonality and annual mean, and high slope, elevation and warm-season rainfall. Finally, Trichoptera favoured high elevation areas, with high forest cover, and low mean annual temperature, seasonality and aridity. Our findings highlight the variable role that catchment land cover, physical properties and climatic influences have on stream insect richness. This is one of the first studies of its kind in Chinese streams, thus we set the scene for more in-depth assessments of stream insect richness across broader spatial scales in China, but stress the importance of improving data availability and consistency through time.
Is postoperative imaging mandatory after meningioma removal? : results of a prospective study
(2015)
Background: Routine postoperative imaging (PI) following surgery for intracranial meningiomas is common practice in most neurosurgical departments. The purpose of this study was to determine the role of routine PI and its impact on clinical decision making after resection of meningioma.
Methods: Patient and tumor characteristics, details of radiographic scans, symptoms and alteration of treatment courses were prospectively collected for patients undergoing removal of a supratentorial meningioma of the convexity, falx, tentorium, or lateral sphenoid wing at the authors’ institution between January 1st, 2010 and March 31st, 2012. Patients with infratentorial manifestations or meningiomas of the skull base known to be surgically difficult (e.g. olfactory groove, petroclival, medial sphenoid wing) were not included. Maximum tumor diameter was divided into groups of < 3cm (small), 3 to 6 cm (medium), and > 6 cm (large).
Results: 206 patients with meningiomas were operated between January 2010 and March 2012. Of these, 113 patients met the inclusion criteria and were analyzed in this study. 83 patients (73.5%) did not present new neurological deficits, whereas 30 patients (26.5%) became clinically symptomatic. Symptomatic patients had a change in treatment after PI in 21 cases (70%), while PI was without consequence in 9 patients (30%). PI did not result in a change of treatment in all asymptomatic patients (p<0.001) irrespective of tumor size (p<0.001) or localization (p<0.001).
Conclusions: PI is mandatory for clinically symptomatic patients but it is safe to waive it in clinically asymptomatic patients, even if the meningioma was large in size.
Background and aims: Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions.
Methods: In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated.
Results: Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%.
Conclusion: The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable.
The α-defensins, human neutrophil peptides (HNPs) are the predominant antimicrobial peptides of neutrophil granules. They are synthesized in promyelocytes and myelocytes as proHNPs, but only processed in promyelocytes and stored as mature HNPs in azurophil granules. Despite decades of search, the mechanisms underlying the posttranslational processing of neutrophil defensins remain unidentified. Thus, neither the enzyme that processes proHNPs nor the localization of processing has been identified. It has been hypothesized that proHNPs are processed by the serine proteases highly expressed in promyelocytes: Neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3), all of which are able to process recombinant proHNP into HNP in vitro. We investigated whether serine proteases are in fact responsible for processing of proHNP in human bone marrow cells and in human and murine myeloid cell lines. Subcellular fractionation of the human promyelocytic cell line PLB-985 demonstrated proHNP processing to commence in fractions containing endoplasmic reticulum. Processing of 35S-proHNP was insensitive to serine protease inhibitors. Simultaneous knockdown of NE, CG, and PR3 did not decrease proHNP processing in primary human bone marrow cells. Furthermore, introduction of NE, CG, and PR3 into murine promyelocytic cells did not enhance the proHNP processing capability. Finally, two patients suffering from Papillon–Lefèvre syndrome, who lack active neutrophil serine proteases, demonstrated normal levels of fully processed HNP in peripheral neutrophils. Contradicting earlier assumptions, our study found serine proteases dispensable for processing of proHNPs in vivo. This calls for study of other protease classes in the search for the proHNP processing protease(s).
Background: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
Methods: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.
Results: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.
Conclusion: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.
Elementar für eine zukunftsfähige Verkehrsplanung ist eine möglichst detaillierte Kenntnis des Mobilitätsverhaltens der Bevölkerung in der Region. Zur Analyse des Mobilitätsverhaltens der Bevölkerung in Deutschland wurden in der Vergangenheit auf verschiedenen räumlichen Ebenen mehrere größtenteils voneinander unabhängige Datenerhebungen durchgeführt. Für die Region Frankfurt Rhein-Main besonders relevant sind dabei zum einen die Längsschnitt- bzw. Panelerhebungen des „Rhein-Main-Panels“ (RMP) und des „Deutschen Mobilitätspanels“ (MOP), zum anderen die Querschnittserhebungen der Befragung „Mobilität in Deutschland“ (MiD) und speziell für Frankfurt auch „Mobilität in Städten – SrV“ (SrV).
Ziel dieser Publikation ist es, diese vier unterschiedlichen Erhebungen in einem kurzen Vergleich vorzustellen. Dabei sollen die jeweiligen spezifischen Potentiale, aber auch Einschränkungen aufgezeigt werden, die diese Mobilitätsdatensätze bezüglich der Auswertung und weiteren Nutzung aufweisen. Danach werden in knapper Form mögliche Kombinationsmöglichkeiten dieser Datensätze untereinander, aber auch mit ergänzenden Datenbeständen dargestellt. Anschließend werden die aus den verschiedenen Mobilitätsdatensätzen ermittelten zentralen regionalen Mobilitätskennziffern in einem Vergleich veranschaulicht. Als Abschluss soll schließlich ein kurzer Blick auf mögliche Anwendungsfelder der Mobilitätsdaten in Politik und Planung geworfen werden.
Since the domestication of the urus, 10.000 years ago, mankind utilizes bovine milk for different purposes. Besides usage as a nutrient also the external application of milk on skin has a long tradition going back to at least the ancient Aegypt with Cleopatra VII as a great exponent. In order to test whether milk has impact on skin physiology, cultures of human skin fibroblasts were exposed to commercial bovine milk. Our data show significant induction of proliferation by milk (max. 2,3-fold, EC50: 2,5% milk) without toxic effects. Surprisingly, bovine milk was identified as strong inducer of collagen 1A1 synthesis at both, the protein (4-fold, EC50: 0,09% milk) and promoter level. Regarding the underlying molecular pathways, we show functional activation of STAT6 in a p44/42 and p38-dependent manner. More upstream, we identified IGF-1 and insulin as key factors responsible for milk-induced collagen synthesis. These findings show that bovine milk contains bioactive molecules that act on human skin cells. Therefore, it is tempting to test the herein introduced concept in treatment of atrophic skin conditions induced e.g. by UV light or corticosteroids.
Thrombopoietin (Thpo) signals via its receptor Mpl and regulates megakaryopoiesis, hematopoietic stem cell (HSC) maintenance and post-transplant expansion. Mpl expression is tightly controlled and deregulation of Thpo/Mpl-signaling is linked to hematological disorders. Here, we constructed an intracellular-truncated, signaling-deficient Mpl protein which is presented on the cell surface (dnMpl). The transplantation of bone marrow cells retrovirally transduced to express dnMpl into wildtype mice induced thrombocytopenia, and a progressive loss of HSC. The aplastic BM allowed the engraftment of a second BM transplant without further conditioning. Functional analysis of the truncated Mpl in vitro and in vivo demonstrated no internalization after Thpo binding and the inhibition of Thpo/Mpl-signaling in wildtype cells due to dominant-negative (dn) effects by receptor competition with wildtype Mpl for Thpo binding. Intracellular inhibition of Mpl could be excluded as the major mechanism by the use of a constitutive-dimerized dnMpl. To further elucidate the molecular changes induced by Thpo/Mpl-inhibition on the HSC-enriched cell population in the BM, we performed gene expression analysis of Lin-Sca1+cKit+ (LSK) cells isolated from mice transplanted with dnMpl transduced BM cells. The gene expression profile supported the exhaustion of HSC due to increased cell cycle progression and identified new and known downstream effectors of Thpo/Mpl-signaling in HSC (namely TIE2, ESAM1 and EPCR detected on the HSC-enriched LSK cell population). We further compared gene expression profiles in LSK cells of dnMpl mice with human CD34+ cells of aplastic anemia patients and identified similar deregulations of important stemness genes in both cell populations. In summary, we established a novel way of Thpo/Mpl inhibition in the adult mouse and performed in depth analysis of the phenotype including gene expression profiling.
Inverted perceptual judgment of nociceptive stimuli at threshold level following inconsistent cues
(2015)
Objective: The perception of pain is susceptible to modulation by psychological and contextual factors. It has been shown that subjects judge noxious stimuli as more painful in a respective suggestive context, which disappears when the modifying context is resolved. However, a context in which subjects judge the painfulness of a nociceptive stimulus in exactly the opposite direction to that of the cues has never been shown so far.
Methods: Nociceptive stimuli (300 ms intranasal gaseous CO2) at the individual pain threshold level were applied after a visual cue announcing the stimulus as either "no pain", merely a "stimulus", or "pain". Among the stimuli at threshold level, other CO2 stimuli that were clearly below or above pain threshold were randomly interspersed. These were announced beforehand in 12 subjects randomly with correct or incorrect cues, i.e., clearly painful or clearly non-painful stimuli were announced equally often as not painful or painful. By contrast, in a subsequent group of another 12 subjects, the stimuli were always announced correctly with respect to the evoked pain.
Results: The random and often incorrect announcement of stimuli clearly below or above pain threshold caused the subjects to rate the stimuli at pain-threshold level in the opposite direction of the cue, i.e., when the stimuli were announced as "pain" significantly more often than as non-painful and vice versa (p < 10-4). By contrast, in the absence of incongruence between announcement and perception of the far-from-threshold stimuli, stimuli at pain threshold were rated in the cued direction.
Conclusions: The present study revealed the induction of associations incongruent with a given message in the perception of pain. We created a context of unreliable cues whereby subjects perceived the stimulus opposite to that suggested by a prior cue, i.e., potentially nociceptive stimuli at pain threshold level that were announced as painful were judged as non-painful and vice versa. These findings are consistent with reported data on the effects of distrust on non-painful cognitive responses.
Membranes are central for cells as borders to the environment or intracellular organelle definition. They are composed of and harbor different molecules like various lipid species and sterols, and they are generally crowded with proteins. The membrane system is very dynamic and components show lateral, rotational and translational diffusion. The consequence of the latter is that phase separation can occur in membranes in vivo and in vitro. It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched. Furthermore, current discussions favor the idea that proteins are sorted into the liquid-disordered phase of model membranes, but experimental support for the behavior of isolated proteins in native membranes is sparse. To gain insight into the protein behavior we built a model of the red blood cell membrane with integrated glycophorin A dimer. The sorting and the dynamics of the dimer were subsequently explored by coarse-grained molecular dynamics simulations. In addition, we inspected the impact of lipid head groups and the presence of cholesterol within the membrane on the dynamics of the dimer within the membrane. We observed that cholesterol is important for the formation of membrane areas with Lo and Ld character. Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment. The protein dimer was exclusively sorted into the domain of Ld character in the model red blood cell plasma membrane. Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution.
Even though the microevolution of plant hosts and pathogens has been intensely studied, knowledge regarding macro-evolutionary patterns is limited. Having the highest species diversity and host-specificity among Oomycetes, downy mildews are a useful a model for investigating long-term host-pathogen coevolution. We show that phylogenies of Bremia and Asteraceae are significantly congruent. The accepted hypothesis is that pathogens have diverged contemporarily with their hosts. But maximum clade age estimation and sequence divergence comparison reveal that congruence is not due to long-term coevolution but rather due to host-shift driven speciation (pseudo-cospeciation). This pattern results from parasite radiation in related hosts, long after radiation and speciation of the hosts. As large host shifts free pathogens from hosts with effector triggered immunity subsequent radiation and diversification in related hosts with similar innate immunity may follow, resulting in a pattern mimicking true co-divergence, which is probably limited to the terminal nodes in many pathogen groups.
Translation elongation factor Tuf of Acinetobacter baumannii is a plasminogen-binding protein
(2015)
Acinetobacter baumannii is an important nosocomial pathogen, causing a variety of opportunistic infections of the skin, soft tissues and wounds, urinary tract infections, secondary meningitis, pneumonia and bacteremia. Over 63% of A. baumannii infections occurring in the United States are caused by multidrug resistant isolates, and pan-resistant isolates have begun to emerge that are resistant to all clinically relevant antibiotics. The complement system represents the first line of defense against invading pathogens. However, many A. baumannii isolates, especially those causing severe bacteremia are resistant to complement-mediated killing, though the underlying mechanisms remain poorly understood. Here we show for the first time that A. baumannii binds host-derived plasminogen and we identify the translation elongation factor Tuf as a moonlighting plasminogen-binding protein that is exposed on the outer surface of A. baumannii. Binding of plasminogen to Tuf is at least partly dependent on lysine residues and ionic interactions. Plasminogen, once bound to Tuf can be converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component C3b. Thus, Tuf acts as a multifunctional protein that may contribute to virulence of A. baumannii by aiding in dissemination and evasion of the complement system.
Background and aims: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes.
Methods: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization.
Results: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period.
Conclusions: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.
Introduction: Organ dysfunction or failure after the first days of ICU treatment and subsequent mortality with respect to the type of intensive care unit (ICU) admission is poorly elucidated. Therefore we analyzed the association of ICU mortality and admission for medical (M), scheduled surgery (ScS) or unscheduled surgery (US) patients mirrored by the occurrence of organ dysfunction/failure (OD/OF) after the first 72h of ICU stay.
Methods: For this retrospective cohort study (23,795 patients; DIVI registry; German Interdisciplinary Association for Intensive Care Medicine (DIVI)) organ dysfunction or failure were derived from the Sequential Organ Failure Assessment (SOFA) score (excluding the Glasgow Coma Scale). SOFA scores were collected on admission to ICU and 72h later. For patients with a length of stay of at least five days, a multivariate analysis was performed for individual OD/OF on day three.
Results: M patients had the lowest prevalence of cardiovascular failure (M 31%; ScS 35%; US 38%), and the highest prevalence of respiratory (M 24%; ScS 13%; US 17%) and renal failure (M 10%; ScS 6%; US 7%). Risk of death was highest for M- and ScS-patients in those with respiratory failure (OR; M 2.4; ScS 2.4; US 1.4) and for surgical patients with renal failure (OR; M 1.7; ScS 2.7; US 2.4).
Conclusion: The dynamic evolution of OD/OF within 72h after ICU admission and mortality differed between patients depending on their types of admission. This has to be considered to exclude a systematic bias during multi-center trials.
Die Spinozerebelläre Ataxie Typ 2 (SCA2) ist eine autosomal dominant vererbte neurodegenerative Krankheit, welche durch die Expansion des Trinukleotids Cytosin-Adenin-Guanin von ~22/23 auf >32 im Ataxin-2 Gen (ATXN2) verursacht wird. Dieses Trinukleotid codiert für die Aminosäure Glutamin weshalb SCA2 auch zu den Polyglutaminerkrankungen zählt. Zu dieser Gruppe zählen außerdem fünf weitere SCA-Subtypen sowie drei weitere neurodegenerative Erkrankungen, darunter die Huntington-Krankheit.
SCA2 wurde 1971 zum ersten Mal von Wadia und Swami beschrieben und unterscheidet sich von den anderen SCAs aufgrund der typischen Störung der sakkadischen Augenbewegungen. Weitere klinische Symptome von SCA2 sind Ataxie, Tremor, Dysmetrie, Dysarthrie, Hyporeflexie und Dysdiadochokinese. Die Symptome gehen auf einen neuronalen Verlust insbesondere im Cerebellum, aber auch in anderen Hirnregionen wie zum Beispiel dem Hirnstamm zurück.
Atxn2 wird in weiten Teilen des Zentralnervensystems aber auch in vielen nicht-neuronalen Geweben exprimiert. Es handelt sich um ein überwiegend cytoplasmatisch lokalisiertes Protein, welches im Gegensatz zu vielen anderen SCA-Proteinen cytoplasmatische und nur selten nukleäre Aggregate bildet. Die exakte Funktion von Atxn2 ist bisher unklar, es wurde allerdings mehrfach gezeigt, dass es in die mRNA Translation involviert ist aufgrund seiner Interaktion mit dem PolyA-bindenden Protein PABPC1.
Eine Expansion des Trinukleotids in Ataxin-2 kann nicht nur zu SCA2 führen, sondern stellt bei Wiederholungen zwischen 27 und 32 CAGs auch ein erhöhtes Risiko für eine Erkrankung an Amyotropher Lateralsklerose (ALS) und anderen neurodegenerativen Krankheiten dar. Eine Interaktion zwischen ATXN2 und dem ALS-verursachenden TDP43 (Tardbp) wurde bereits zahlreich beforscht, da Aggregate von ATXN2 in Motoneuronen des Rückenmarks von ALS-Patienten und aggregiertes TDP43 in SCA2-Neuronen beobachtet wurden.
Generell sind die Mechanismen, die zur Pathologie von SCA2 und ALS führen, noch weitgehend unklar. Ziel dieser Arbeit war es daher auf der einen Seite einen Einblick in den Pathomechanismus von SCA2 zu erhalten, indem mögliche oder bereits bekannte Interaktoren in etablierten Atxn2-Mausmodellen untersucht wurden. Auf der anderen Seite wurden zwei neue Mausmodelle charakterisiert, um ihre Eignung für die Erforschung von ALS und SCA2 zu prüfen.
Für den ersten Teil der Arbeit dienten Daten aus mehreren Transkriptomstudien von Atxn2-Knock-Out (KO) und Atxn2-CAG42-Knock-In (KIN) Mäusen als Grundlage. Konnten die Daten mit einer unabhängigen Methode bestätigt werden, folgten weitere Untersuchungen auf mRNA und Proteinebene sowie unter zusätzlicher Verwendung von Zellkultur und Patientenmaterial. Dadurch konnten neue Interaktionspartner von ATXN2 identifiziert und bereits bekannte in diesen Mausmodellen bestätigt werden.
So wurde zum Beispiel eine Interaktion von ATXN2 mit der E3-Ubiquitin-Protein-Ligasekomponente FBXW8 gezeigt und deren Beteiligung am Abbau von expandiertem ATXN2. Außerdem wurde eine Interaktion von FBXW8 mit dem bereits bekannten ATXN2-degradierenden Protein PARK2 gezeigt. Eine Hochregulierung des Fbxw8 Transkripts wurde sowohl im Atxn2-CAG42-KIN-Mausmodell als auch in SCA2-Patientenfibroblasten gefunden, während Park2 in keinem der Modelle signifikant veränderte Transkriptspiegel aufwies. Diese Daten belegen die Relevanz von Fbxw8 für den Abbau von moderat-expandiertem Atxn2 und begründen weitere Studien zur genauen Funktion dieses Proteins im Pathomechanismus von Atxn2.
Des Weiteren wurden diverse Kalziumhomöostasefaktoren untersucht, welche eine konsistente Herunterregulierung der Transkripte in beiden Mausmodellen aufwiesen. Auf Proteinebene zeigten sich jedoch Unterschiede zwischen den Modellen. Diese Daten belegen, dass zwar ähnliche Transkriptveränderungen im KIN- und KO-Modell auftreten, diesen aber vermutlich verschiedene Mechanismen zugrunde liegen. Welche Mechanismen dies genau sind bleibt zu klären, es ist jedoch wahrscheinlich, dass im KIN-Modell die Aggregatbildung sowie in beiden Modellen die Beteiligung von ATXN2 an der Translationregulation eine Rolle spielen. Die Ergebnisse dieser Studie unterstreichen die Relevanz des Ca2+ Signalwegs für die Entwicklung von SCA2.
Der zweite Teil der Arbeit beinhaltet die Charakterisierung einer ATXN2/TDP43 Doppelmutante auf Verhaltensebene sowie die gründliche Evaluierung des Phänotyps einer vollkommen neuen SCA2 Mausmutante. Während in der Doppelmutante trotz doppelter Genmutation nur ein sehr schwacher Phänotyp auf Verhaltensebene festgestellt werden konnte und bis zu einem Alter von 12 Monaten keine Potenzierung der Mutationen zu beobachten war, zeigte die Atxn2-CAG100-KIN Maus signifikante und früh auftretende Pathologie. Neben einer verminderten Überlebensrate, einem Gewichtsverlust und diversen motorischen Störungen, konnten auch Aggregate des mutierten Proteins in diversen Hirnregionen identifiziert werden. Der Atxn2-CAG100-KIN Phänotyp spiegelt die humanen Symptome daher recht gut wider, weshalb diese Mausmutante ein wertvolles Modell für die weitere SCA2-Forschung darstellt.
Zusammengefasst zeigt diese Arbeit die Bedeutung des ATXN2-Interaktors FBXW8 im SCA2-Mausmodell als auch im Patientenmaterial. Sie betont die Relevanz des Atxn2-KO-Modells in Bezug auf Störungen der Kalziumhomöostase und dokumentiert die Alters- und Gewebespezifität dieser Veränderungen. Außerdem beinhaltet sie die vorläufige Beschreibung eines kombinierten Atxn2/TDP43-Mausmodells und schließlich die ausführliche Charakterisierung eines vollkommen neuen und äußerst wertvollen SCA2-Mausmodells.