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The aim of this study was to identify sex-dependent expression of renal transporter mRNA in lean and obese Zucker spontaneously hypertensive fatty (ZSF1) rats and to investigate the interaction of the most altered transporter, organic anion transporter 2 (Oat2), with diabetes-relevant metabolites and drugs. Higher incidence of glomerulosclerosis, tubulointerstitial fibrosis, and protein casts in Bowman’s space and tubular lumen was detected by PAS staining in obese male compared to female ZSF1 rats. Real-time PCR on RNA isolated from kidney cortex revealed that Sglt1-2, Oat1-3, and Oct1 were higher expressed in kidneys of lean females. Oct2 and Mrp2 were higher expressed in obese males. Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1β and Hnf4α in both sexes. The highest difference between lean and obese ZSF1 rats was found for Oat2. Therefore, we have tested the interaction of human OAT2 with various substances using tritium-labeled cGMP. Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors. However, OAT2-dependent uptake of cGMP was inhibited by furosemide. The strongly decreased expression of Oat2 and other transporters in female diabetic ZSF1 rats could possibly impair renal drug excretion, for example, of furosemide.
The impact of (long-term) drought acclimation and (short-term) heat stress and their combination on fast chlorophyll fluorescence induction curves (OJIP) and grain yield was tested using pot-grown plants of wild barley (Hordeum spontaneum) originating from Northern Egypt. Concerning agronomic traits, the main effect of drought was decreased biomass accumulation and grain yield, while heat specifically affected floral development. The treatments caused specific inhibitions of photosystem II (PSII) functionality. While heat stressed plants showed a reduction of maximum quantum efficiency of PSII (φP0), an indication of effects on oxygen evolving complex (OEC) functionality, and the connectivity of PSII units, these features were entirely missing in drought acclimated plants. Drought caused a reduction of the Performance Index (PIabs) and of the relative amplitude of the IP-phase of the OJIP induction curve (ΔVIP). Individuals suffering from a combination of drought and heat showed a better ability to recover photosynthetic electron transport after the relief of stress in comparison to heat stressed plants. However, this improved capacity to recover was not accompanied by an increased grain yield. Thus, we conclude that chlorophyll fluorescence measurements provide valuable physiological data; however, their use in agronomic studies for the prediction of agronomic traits should be done with some precaution.
Debattieren wir in der Rechtsgeschichte zu wenig über Grundsätzliches und über Methodenfragen – oder lässt sich im Gegenteil eine gewisse Ermüdung feststellen, weil die Vielzahl übergreifender Diskussionen nur von der Quellenlektüre und der inhaltlichen Arbeit ablenkt? Die Antwort fällt schwer. Im Anschluss an einige Gespräche auf dem Rechtshistorikertag in Tübingen haben wir uns entschlossen, in Rechtsgeschichte – Legal History den Raum für genau diese Erörterung zur Verfügung zu stellen. Um die Debatte anzustoßen, haben wir den einleitenden Beitrag über Normengeschichte, Wissenschaftsgeschichte und Praxisgeschichte an knapp 30 Kolleginnen und Kollegen versandt und sie eingeladen, ihre Sicht der Dinge knapp und zugespitzt darzulegen. ...
Macroautophagy requires membrane trafficking and remodelling to form the autophagosome and deliver its contents to lysosomes for degradation. We have previously identified the TBC domain‐containing protein, TBC1D14, as a negative regulator of autophagy that controls delivery of membranes from RAB11‐positive recycling endosomes to forming autophagosomes. In this study, we identify the TRAPP complex, a multi‐subunit tethering complex and GEF for RAB1, as an interactor of TBC1D14. TBC1D14 binds to the TRAPP complex via an N‐terminal 103 amino acid region, and overexpression of this region inhibits both autophagy and secretory traffic. TRAPPC8, the mammalian orthologue of a yeast autophagy‐specific TRAPP subunit, forms part of a mammalian TRAPPIII‐like complex and both this complex and TBC1D14 are needed for RAB1 activation. TRAPPC8 modulates autophagy and secretory trafficking and is required for TBC1D14 to bind TRAPPIII. Importantly, TBC1D14 and TRAPPIII regulate ATG9 trafficking independently of ULK1. We propose a model whereby TBC1D14 and TRAPPIII regulate a constitutive trafficking step from peripheral recycling endosomes to the early Golgi, maintaining the cycling pool of ATG9 required for initiation of autophagy.
Background: Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib.
Results: The tozasertib concentration that reduces cell viability by 50 % (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3ABCG2 cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3ABCG2 cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression.
Conclusions: Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds.
Tamar Herzog arbeitet seit Jahren an einer Rechtsgeschichte der Praxis. In ihren Publikationen zur Strafrechtsgeschichte im frühneuzeitlichen Quito beschrieb sie das Funktionieren der Strafjustiz anhand zahlreicher Fallstudien und strich dabei die nicht-juristischen Faktoren als entscheidende Orientierung für die Entscheidungsfindung heraus (zuletzt in Upholding justice, 2004). In Defining Nations (2003) rekonstruierte sie das System der Bestimmung von Zugehörigkeit und ergo der Zuweisung von materiellen und immateriellen Ressourcen auf ähnliche Weise. Auch dort hat sie die komplexe Interaktion zwischen Normsetzung und -aneignung unterstrichen und damit die Rechtsgeschichten der Staatsangehörigkeit in imperialen Räumen neu akzentuiert. Das Besondere an ihren Arbeiten liegt nicht zuletzt darin, dass sie ihre Beobachtung stets in eine unaufgeregte Theorie des frühneuzeitlichen Rechts einordnet. Recht gibt für sie schlicht einen großen Teil der Regeln vor, in deren Horizont die Akteure handeln. Es sind nicht die einzigen, aber es sind wichtige Teile des normativen Universums. Die Spieler mögen sich – so ein in der Zusammenfassung benutztes Bild (264) – an diese Regeln halten, ihre eigenen Strategien im Umgang mit ihnen entwickeln oder sie schlicht missachten. Doch ganz unabhängig von diesen Regeln wird niemand sein Spiel treiben können. Der Zuschauer, der die Regeln kennt, kann das Ergebnis ebenfalls nicht vorhersagen. Er wird auch ratlos sein, wenn seine Mannschaft verliert. Aber er versteht das Spiel besser. Wer die Regeln nicht kennt, sieht nur Bewegung. In Frontiers of Possession bleibt Herzog dieser Methode treu. Sie schaut ins Archiv, auf den Einzelfall, von dort auf das Recht. Sie blickt von innen nach außen, kommt deswegen zu teilweise anderen Befunden als die Forschung und zeichnet damit ein klares – und zugleich komplexes – Bild. ...
Objectives: To evaluate the multinational medical-student-delivered tobacco prevention programme for secondary schools for its effectiveness to reduce the smoking prevalence among adolescents aged 11–15 years in Germany at half year follow-up.
Setting: We used a prospective quasi-experimental study design with measurements at baseline (t1) and 6 months postintervention (t2) to investigate an intervention in 8 German secondary schools. The participants were split into intervention and control classes in the same schools and grades.
Participants: A total of 1474 eligible participants of both genders at the age of 11–15 years were involved within the survey for baseline assessment of which 1200 completed the questionnaire at 6-month follow-up (=longitudinal sample). The schools participated voluntarily. The inclusion criteria were age (10–15 years), grade (6–8) and school type (regular secondary schools).
Intervention: Two 60 min school-based modules delivered by medical students.
Primary and secondary outcome measures: The primary end point was the difference from t1 to t2 of the smoking prevalence in the control group versus the difference from t1 to t2 in the intervention group (difference of differences approach). The percentage of former smokers and new smokers in the two groups were studied as secondary outcome measures.
Results: In the control group, the percentage of students who claimed to be smokers doubled from 4.2% (t1) to 8.1% (t2), whereas it remained almost the same in the intervention group (7.1% (t1) to 7.4% (t2); p=0.01). The likelihood of quitting smoking was almost six times higher in the intervention group (total of 67 smokers at t1; 27 (4.6%) and 7 (1.1%) in the control group; OR 5.63; 95% CI 2.01 to 15.79; p<0.01). However, no primary preventive effect was found.
Conclusions: We report a significant secondary preventive (smoking cessation) effect at 6-month follow-up. Long-term evaluation is planned.
Rpn13 is an intrinsic ubiquitin receptor of the 26S proteasome regulatory subunit that facilitates substrate capture prior to degradation. Here we show that the C-terminal region of Rpn13 binds to the tetratricopeptide repeat (TPR) domain of SGTA, a cytosolic factor implicated in the quality control of mislocalised membrane proteins (MLPs). The overexpression of SGTA results in a substantial increase in steady-state MLP levels, consistent with an effect on proteasomal degradation. However, this effect is strongly dependent upon the interaction of SGTA with the proteasomal component Rpn13. Hence, overexpression of the SGTA-binding region of Rpn13 or point mutations within the SGTA TPR domain both inhibit SGTA binding to the proteasome and substantially reduce MLP levels. These findings suggest that SGTA can regulate the access of MLPs to the proteolytic core of the proteasome, implying that a protein quality control cycle that involves SGTA and the BAG6 complex can operate at the 19S regulatory particle. We speculate that the binding of SGTA to Rpn13 enables specific polypeptides to escape proteasomal degradation and/or selectively modulates substrate degradation.
Bone marrow mononuclear cells (BMCs) are suitable for bone tissue engineering. Comparative data regarding the needs of BMC for the adhesion on biomaterials and biocompatibility to various biomaterials are lacking to a large extent. Therefore, we evaluated whether a surface coating would enhance BMC adhesion and analyze the biocompatibility of three different kinds of biomaterials. BMCs were purified from human bone marrow aspirate samples. Beta tricalcium phosphate (β-TCP, without coating or coated with fibronectin or human plasma), demineralized bone matrix (DBM), and bovine cancellous bone (BS) were assessed. Seeding efficacy on β-TCP was 95% regardless of the surface coating. BMC demonstrated a significantly increased initial adhesion on DBM and β-TCP compared to BS. On day 14, metabolic activity was significantly increased in BMC seeded on DBM in comparison to BMC seeded on BS. Likewise increased VEGF-synthesis was observed on day 2 in BMC seeded on DBM when compared to BMC seeded on BS. The seeding efficacy of BMC on uncoated biomaterials is generally high although there are differences between these biomaterials. Beta-TCP and DBM were similar and both superior to BS, suggesting either as suitable materials for spatial restriction of BMC used for regenerative medicine purposes in vivo.
Mitochondria are involved in the aging processes that ultimately lead to neurodegeneration and the development of Alzheimer’s disease (AD). A healthy lifestyle, including a diet rich in antioxidants and polyphenols, represents one strategy to protect the brain and to prevent neurodegeneration. We recently reported that a stabilized hexanic rice bran extract (RBE) rich in vitamin E and polyphenols (but unsuitable for human consumption) has beneficial effects on mitochondrial function in vitro and in vivo (doi:10.1016/j.phrs.2013.06.008, 10.3233/JAD-132084). To enable the use of RBE as food additive, a stabilized ethanolic extract has been produced. Here, we compare the vitamin E profiles of both extracts and their effects on mitochondrial function (ATP concentrations, mitochondrial membrane potential, mitochondrial respiration and mitochondrial biogenesis) in PC12 cells. We found that vitamin E contents and the effects of both RBE on mitochondrial function were similar. Furthermore, we aimed to identify components responsible for the mitochondria-protective effects of RBE, but could not achieve a conclusive result. α-Tocotrienol and possibly also γ-tocotrienol, α-tocopherol and δ-tocopherol might be involved, but hitherto unknown components of RBE or a synergistic effect of various components might also play a role in mediating RBE’s beneficial effects on mitochondrial function.
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is overactivated in malignant glioma and plays a key role in promoting cell survival, thereby increasing the acquired apoptosis resistance of these tumors. Here we investigated the STAT3/myeloid cell leukemia 1 (MCL1) signaling pathway as a target to overcome the resistance of glioma cells to the Bcl-2-inhibiting synthetic BH3 mimetic ABT-737. Stable lentiviral knockdown of MCL1 sensitized LN229 and U87 glioma cells to apoptotic cell death induced by single-agent treatment with ABT-737 which was associated with an early activation of DEVDase activity, cytochrome c release, and nuclear apoptosis. Similar sensitizing effects were observed when ABT-737 treatment was combined with the multikinase inhibitor sorafenib which effectively suppressed levels of phosphorylated STAT3 and MCL1 in MCL1-proficient LN229 and U87 glioma cells. In analogous fashion, these synergistic effects were observed when we combined ABT-737 with the STAT3 inhibitor WP-1066. Lentiviral knockdown of the activating transcription factor 5 combined with subsequent quantitative polymerase chain reaction analysis revealed that sorafenib-dependent suppression of MCL1 occurred at the transcriptional level but did not depend on activating transcription factor 5 which previously had been proposed to be essential for MCL1-dependent glioma cell survival. In contrast, the constitutively active STAT3 mutant STAT3-C was able to significantly enhance MCL1 levels under sorafenib treatment to retain cell survival. Collectively, these data demonstrate that sorafenib targets MCL1 in a STAT3-dependent manner, thereby sensitizing glioma cells to treatment with ABT-737. They also suggest that targeting STAT3 in combination with inducers of the intrinsic pathway of apoptosis may be a promising novel strategy for the treatment of malignant glioma.
Newly emerging influenza A viruses (IAV) pose a major threat to human health by causing seasonal epidemics and/or pandemics, the latter often facilitated by the lack of pre-existing immunity in the general population. Early recognition of candidate pandemic influenza viruses (CPIV) is of crucial importance for restricting virus transmission and developing appropriate therapeutic and prophylactic strategies including effective vaccines. Often, the pandemic potential of newly emerging IAV is only fully recognized once the virus starts to spread efficiently causing serious disease in humans. Here, we used a novel phylogenetic algorithm based on the informational spectrum method (ISM) to identify potential CPIV by predicting mutations in the viral hemagglutinin (HA) gene that are likely to (differentially) affect critical interactions between the HA protein and target cells from bird and human origin, respectively. Predictions were subsequently validated by generating pseudotyped retrovirus particles and genetically engineered IAV containing these mutations and characterizing potential effects on virus entry and replication in cells expressing human and avian IAV receptors, respectively. Our data suggest that the ISM-based algorithm is suitable to identify CPIV among IAV strains that are circulating in animal hosts and thus may be a new tool for assessing pandemic risks associated with specific strains.
Study Design: Survey of 100 worldwide spine surgeons.
Objective: To develop a spine injury score for the AOSpine Thoracolumbar Spine Injury Classification System.
Methods: Each respondent was asked to numerically grade the severity of each variable of the AOSpine Thoracolumbar Spine Injury Classification System. Using the results, as well as limited input from the AOSpine Trauma Knowledge Forum, the Thoracolumbar AOSpine Injury Score was developed.
Results: Beginning with 1 point for A1, groups A, B, and C were consecutively awarded an additional point (A1, 1 point; A2, 2 points; A3, 3 points); however, because of a significant increase in the severity between A3 and A4 and because the severity of A4 and B1 was similar, both A4 and B1 were awarded 5 points. An uneven stepwise increase in severity moving from N0 to N4, with a substantial increase in severity between N2 (nerve root injury with radicular symptoms) and N3 (incomplete spinal cord injury) injuries, was identified. Hence, each grade of neurologic injury was progressively given an additional point starting with 0 points for N0, and the substantial difference in severity between N2 and N3 injuries was recognized by elevating N3 to 4 points. Finally, 1 point was awarded to the M1 modifier (indeterminate posterolateral ligamentous complex injury).
Conclusion: The Thoracolumbar AOSpine Injury Score is an easy-to-use, data-driven metric that will allow for the development of a surgical algorithm to accompany the AOSpine Thoracolumbar Spine Injury Classification System.
Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.
A current challenge in life sciences is to image cell membrane receptors while characterizing their specific interactions with various ligands. Addressing this issue has been hampered by the lack of suitable nanoscopic methods. Here we address this challenge and introduce multifunctional high-resolution atomic force microscopy (AFM) to image human protease-activated receptors (PAR1) in the functionally important lipid membrane and to simultaneously localize and quantify their binding to two different ligands. Therefore, we introduce the surface chemistry to bifunctionalize AFM tips with the native receptor-activating peptide and a tris-N-nitrilotriacetic acid (tris-NTA) group binding to a His10-tag engineered to PAR1. We further introduce ways to discern between the binding of both ligands to different receptor sites while imaging native PAR1s. Surface chemistry and nanoscopic method are applicable to a range of biological systems in vitro and in vivo and to concurrently detect and localize multiple ligand-binding sites at single receptor resolution.
Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance.
Cell death and survival programs are controlled by the cellular redox state, which is typically dysregulated during oncogenesis. A recent study reports that the inhibition of antioxidant defenses resulting from glutathione depletion can prime acute lymphoblastic leukemia cells for death induced by Smac mimetics.
Als Band zwei der neuen Reihe Religion and Law in Medieval and Muslim Societies (von der inzwischen schon mehrere Titel vorliegen) erschien dieser bemerkenswerte Band. Die Rolle der Juden im Recht des frühen Mittelalters ist natürlich schon mehrfach untersucht worden, doch ist man dankbar für einen Band, der die Forschung widerspiegelt und an vielen Punkten weiter voranbringt. Die einzelnen Beiträge sind in der Regel auch bibliographisch à jour, so dass dieser Sammelband durchaus auch die Eigenschaften eines Handbuchs aufweist. ...
The extracellular matrix is rapidly emerging as a prominent contributor to various fundamental processes of tumorigenesis. In particular, decorin, a member of the small leucine-rich proteoglycan gene family, is assuming a central role as a potent soluble tumor repressor. Decorin binds and antagonizes various receptor tyrosine kinases and inhibits downstream oncogenic signaling in several solid tumors. Among other functions, decorin evokes cell cycle arrest, apoptosis, and antimetastatic, and antiangiogenic programs. Recent work has revealed a paradigmatic shift in our understanding of the molecular mechanisms underlying its tumoricidal properties. Decorin adversely compromises the genetic signature of the tumor microenvironment and induces endothelial cell autophagy downstream of VEGFR2. Moreover, decorin selectively evokes destruction of tumor cell mitochondria downstream of Met through mitophagy. Acting as a partial agonist, decorin signals via proautophagic receptors and triggers procatabolic processes that parallel the classical tumoricidal properties of this multifaceted proteoglycan.
Dass das Papsttum und sein jurisdiktioneller Anspruch letztlich auf dem Apostel Petrus basieren, der, wie man bei Matthäus lesen kann, der Fels ist, auf dem Christus seine Kirche errichten wollte (Matth. 16,18), ist eine bekannte Tatsache, auf die hier nicht eingegangen werden soll. Der in Rom zentrierte Rechtsraum der lateinischen Kirche stand schon bald, spätestens im 5. Jahrhundert, im Gegensatz zum sich seit dem 4. Jahrhundert konstituierenden Rechtsraum der griechischen Kirche(n) mit Antiocheia, Alexandreia, Jerusalem (ab 451) und schließlich Konstantinopel, der zweiten Hauptstadt des Römischen Reiches und ab 476 der einzigen Hauptstadt. Das kanonische Recht beider Bereiche entwickelte sich im Verlaufe der Jahrhunderte auseinander. Trotz gemeinsamer Grundlagen (der sieben bzw. acht ökumenischen Konzilien und deren Rechtssetzung) gab es Konflikte, die sich schließlich seit dem 11. Jahrhundert in einem bis heute andauernden Schisma niederschlugen. Ein steter Stein des Anstoßes (neben den anderen bekannten Differenzen – Azymen, Filioque usw.) war der römische Primatsanspruch, den man in Konstantinopel nie anerkannte und dem man etwa die sog. Pentarchietheorie entgegensetzte. Erst spät, wie hier gezeigt werden soll, um 800, setzte man in Konstantinopel Petrus seinen Bruder Andreas entgegen, den "Erstberufenen" (vgl. Joh. 1,35–42). Jedenfalls versuchte man dies, vermutlich nach römischem Vorbild. Wann genau und warum dies geschah, ist Gegenstand der folgenden Ausführungen. ...
Background: Microarray analysis represents a powerful way to test scientific hypotheses on the functionality of cells. The measurements consider the whole genome, and the large number of generated data requires sophisticated analysis. To date, no gold-standard for the analysis of microarray images has been established. Due to the lack of a standard approach there is a strong need to identify new processing algorithms.
Methods: We propose a novel approach based on hyperbolic partial differential equations (PDEs) for unsupervised spot segmentation. Prior to segmentation, morphological operations were applied for the identification of co-localized groups of spots. A grid alignment was performed to determine the borderlines between rows and columns of spots. PDEs were applied to detect the inflection points within each column and row; vertical and horizontal luminance profiles were evolved respectively. The inflection points of the profiles determined borderlines that confined a spot within adapted rectangular areas. A subsequent k-means clustering determined the pixels of each individual spot and its local background.
Results: We evaluated the approach for a data set of microarray images taken from the Stanford Microarray Database (SMD). The data set is based on two studies on global gene expression profiles of Arabidopsis Thaliana. We computed values for spot intensity, regression ratio, and coefficient of determination. For spots with irregular contours and inner holes, we found intensity values that were significantly different from those determined by the GenePix Pro microarray analysis software. We determined the set of differentially expressed genes from our intensities and identified more activated genes than were predicted by the GenePix software.
Conclusions: Our method represents a worthwhile alternative and complement to standard approaches used in industry and academy. We highlight the importance of our spot segmentation approach, which identified supplementary important genes, to better explains the molecular mechanisms that are activated in a defense responses to virus and pathogen infection.
This article was republished on October 14, 2015, to correct the order of Figs 8–13. The publisher apologizes for the error. Please download this article again to view the correct version. The originally published, uncorrected article and the republished, corrected article are provided here for reference.
Recent advances in the diagnostic of myeloproliferative neoplasms (MPNs) discovered CALRETICULIN (CALR) mutations as a major driver in these disorders. In contrast to JAK2 mutations being mainly associated with polycythaemia vera, CALR mutations are only associated with primary myelofibrosis (PMF) and essential thrombocythaemia (ET). CALR mutations are present in the majority of PMF and ET patients lacking JAK2 and MPL mutations. As these CALR mutations are absent from reactive bone marrow (BM) lesions their presence indicates ET or PMF. So far these mutations are detectable only by molecular assays. Their molecular detection is cumbersome because of the great CALR mutation heterogeneity. Therefore, the availability of a simple assay would be of great help. All CALR mutations reported lead to a frameshift generating a new 36 amino-acid C-terminus. We generated a monoclonal antibody (CAL2) to this C-neoterminus by immunizing mice with a representative peptide and compared its performance with Sanger sequencing data in 173 MPNs and other BM diseases. There was a 100% correlation between the molecular and the CAL2 immunohistochemical (IHC) assays. Thus, the detection of CALR mutations by the CAL2 IHC is a specific, sensitive, rapid, simple and low-cost method.
IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis
(2015)
Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-κB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKβ/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkβ stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4+Foxp3+ regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkβ-deficient fibroblasts, transcription of negative regulators of TGFβ signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFβ gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkβ-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF–Met signaling in mucosa of Ikkβ-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKβ/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.
Haematopoietic stem cells (HSCs) require the right composition of microRNAs (miR) for proper life-long balanced blood regeneration. Here we show a regulatory circuit that prevents excessive HSC self-renewal by upregulation of miR-193b upon self-renewal promoting thrombopoietin (TPO)-MPL-STAT5 signalling. In turn, miR-193b restricts cytokine signalling, by targeting the receptor tyrosine kinase c-KIT. We generated a miR-193b knockout mouse model to unravel the physiological function of miR-193b in haematopoiesis. MiR-193b−/− mice show a selective gradual enrichment of functional HSCs, which are fully competent in multilineage blood reconstitution upon transplantation. The absence of miR-193b causes an accelerated expansion of HSCs, without altering cell cycle or survival, but by decelerating differentiation. Conversely, ectopic miR-193b expression restricts long-term repopulating HSC expansion and blood reconstitution. MiR-193b-deficient haematopoietic stem and progenitor cells exhibit increased basal and cytokine-induced STAT5 and AKT signalling. This STAT5-induced microRNA provides a negative feedback for excessive signalling to restrict uncontrolled HSC expansion.
Background: Emerging evidence indicates that mesenchymal stromal cells (MSCs) isolated from different tissue sources may be used in vivo as tissue restorative agents. To date, there is no evidence, however, on migration and proliferation ("wound healing") potential of different subsets of MSCs. The main goal of this study was therefore to compare the in vitro "wound healing" capacity of MSCs generated from positively selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs generated by plastic adherence (PA-MSCs).
Methods: The in vitro model of wound healing (CytoSelect™ 24-Well Wound Healing Assay) was used in order to compare the migration and proliferation potential of CD271-MSCs and PA-MSCs of passage 2 and 4 cultured in presence or absence of growth factors or cytokines.
Results: CD271-MSCs of both passages when compared to PA-MSCs demonstrated a significantly higher potential to close the wound 12 and 24 h after initiation of the wound healing assay (P < 0.003 and P < 0.002, respectively). Noteworthy, the migration capacity of PA-MSCs of second passage was significantly improved after stimulation with FGF-2 (P < 0.02), PDGF-BB (P < 0.006), MCP-1 (P < 0.002) and IL-6 (P < 0.03), whereas only TGF-β enhanced significantly migration process of PA-MSCs of P4 12 h after the treatment (P < 0.02). Interestingly, treatment of CD271-MSCs of both passages with growth factors or cytokines did not affect their migratory potential.
Conclusions: Our in vitro data provide the first evidence that CD271-MSCs are significantly more potent in "wound healing" than their counterparts PA-MSCs.
Background: Hypoxia is a key driver for infiltrative growth in experimental gliomas. It has remained elusive whether tumor hypoxia in glioblastoma patients contributes to distant or diffuse recurrences. We therefore investigated the influence of perioperative cerebral ischemia on patterns of progression in glioblastoma patients.
Methods: We retrospectively screened MRI scans of 245 patients with newly diagnosed glioblastoma undergoing resection for perioperative ischemia near the resection cavity. 46 showed relevant ischemia nearby the resection cavity. A control cohort without perioperative ischemia was generated by a 1:1 matching using an algorithm based on gender, age and adjuvant treatment. Both cohorts were analyzed for patterns of progression by a blinded neuroradiologist.
Results: The percentage of diffuse or distant recurrences at first relapse was significantly higher in the cohort with perioperative ischemia (61.1%) compared to the control cohort (19.4%). The results of the control cohort matched well with historical data. The change in patterns of progression was not associated with a difference in survival.
Conclusions: This study reveals an unrecognized association of perioperative cerebral ischemia with distant or diffuse recurrence in glioblastoma. It is the first clinical study supporting the concept that hypoxia is a key driver of infiltrative tumor growth in glioblastoma patients.
Members of the Sm protein family are important for the cellular RNA metabolism in all three domains of life. The family includes archaeal and eukaryotic Lsm proteins, eukaryotic Sm proteins and archaeal and bacterial Hfq proteins. While several studies concerning the bacterial and eukaryotic family members have been published, little is known about the archaeal Lsm proteins. Although structures for several archaeal Lsm proteins have been solved already more than ten years ago, we still do not know much about their biological function, however one can confidently propose that the archaeal Lsm proteins will also be involved in RNA metabolism. Therefore, we investigated this protein in the halophilic archaeon Haloferax volcanii. The Haloferax genome encodes a single Lsm protein, the lsm gene overlaps and is co-transcribed with the gene for the ribosomal L37.eR protein. Here, we show that the reading frame of the lsm gene contains a promoter which regulates expression of the overlapping rpl37R gene. This rpl37R specific promoter ensures high expression of the rpl37R gene in exponential growth phase. To investigate the biological function of the Lsm protein we generated a lsm deletion mutant that had the coding sequence for the Sm1 motif removed but still contained the internal promoter for the downstream rpl37R gene. The transcriptome of this deletion mutant was compared to the wild type transcriptome, revealing that several genes are down-regulated and many genes are up-regulated in the deletion strain. Northern blot analyses confirmed down-regulation of two genes. In addition, the deletion strain showed a gain of function in swarming, in congruence with the up-regulation of transcripts encoding proteins required for motility.
In search for the elusive schizophrenia pathway, candidate genes for the disorder from a discovery sample were localized within the energy-delivering and ischemia protection pathway. To test the adult vascular-ischemic (AVIH) and the competing neurodevelopmental hypothesis (NDH), functional genomic analyses of practically all available schizophrenia-associated genes from candidate gene, genome-wide association and postmortem expression studies were performed. Our results indicate a significant overrepresentation of genes involved in vascular function (P<0.001), vasoregulation (that is, perivascular (P<0.001) and shear stress (P<0.01), cerebral ischemia (P<0.001), neurodevelopment (P<0.001) and postischemic repair (P<0.001) among schizophrenia-associated genes from genetic association studies. These findings support both the NDH and the AVIH. The genes from postmortem studies showed an upregulation of vascular-ischemic genes (P=0.020) combined with downregulated synaptic (P=0.005) genes, and ND/repair (P=0.003) genes. Evidence for the AVIH and the NDH is critically discussed. We conclude that schizophrenia is probably a mild adult vascular-ischemic and postischemic repair disorder. Adult postischemic repair involves ND genes for adult neurogenesis, synaptic plasticity, glutamate and increased long-term potentiation of excitatory neurotransmission (i-LTP). Schizophrenia might be caused by the cerebral analog of microvascular angina.
Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIFα subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIFα by ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitylases. Here, we show that expression of HIF2α (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2α gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2α transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2α, demonstrating that the HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression through control of E2F1 levels. Our results thus suggest that HIF2α is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling.
This article intends to give an overview about developments in European Regulatory and Health Technology Assessment (HTA) of new cancer drugs. As background information, it will refer to an overview article by Bergmann et al. [1], which pointed out the status and the limitations of the current system. The authors discussed possible steps to improve the interface between regulators and HTA bodies but stated that this alone will not be sufficient to overcome heterogeneous HTA assessments between HTA agencies. Major issues and challenges for the foreseeable future will be to overcome the heterogeneity of patient access decisions of pharmaceutical payers across Europe which is due to (i) considerably different scientific approaches and methodology to the more or less formal evaluation of cost-effectiveness; (ii) differing health priorities across the countries that reflect historically developed cultural differences and values or different unmet medical needs and (iii) different economic strengths among nations, regions and locales that necessarily drive health care budgetary decisions. The authors consider that this needs a science-based common position on methodology, greater commitments by politicians and health care decision makers to ensure equal access for patients across the EU to anti-tumour medicines. ...
The PKCβ inhibitor enzastaurin was tested in parental neuroblastoma and rhabdomyosarcoma cell lines, their vincristine-resistant sub-lines, primary neuroblastoma cells, ABCB1-transduced, ABCG2-transduced, and p53-depleted cells. Enzastaurin IC50s ranged from 3.3 to 9.5 μM in cell lines and primary cells independently of the ABCB1, ABCG2, or p53 status. Enzastaurin 0.3125 μM interfered with ABCB1-mediated drug transport. PKCα and PKCβ may phosphorylate and activate ABCB1 under the control of p53. However, enzastaurin exerted similar effects on ABCB1 in the presence or absence of functional p53. Also, enzastaurin inhibited PKC signalling only in concentrations ≥ 1.25 μM. The investigated cell lines did not express PKCβ. PKCα depletion reduced PKC signalling but did not affect ABCB1 activity. Intracellular levels of the fluorescent ABCB1 substrate rhodamine 123 rapidly decreased after wash-out of extracellular enzastaurin, and enzastaurin induced ABCB1 ATPase activity resembling the ABCB1 substrate verapamil. Computational docking experiments detected a direct interaction of enzastaurin and ABCB1. These data suggest that enzastaurin directly interferes with ABCB1 function. Enzastaurin further inhibited ABCG2-mediated drug transport but by a different mechanism since it reduced ABCG2 ATPase activity. These findings are important for the further development of therapies combining enzastaurin with ABC transporter substrates.
Die Lektüre des Buchs beginnt mit dem Titel. Er ist offenbar bewusst vage gehalten. "Die Juristen", als Gattung oder Stand, als Denktypus, als wissenschaftliche Formation? Geht es um Juristen aller Herren und Länder? Und was bedeutet "kritische Geschichte" – ist eine unkritische denkbar? Handelt es sich um eine soziologische historische Studie zur Ausbreitung der Juristen und eine Analyse ihres Einflusses? "The Jurists" ist also ein anspruchsvolles Portal, hinter dem sich jedenfalls kein Juristenlexikon verbirgt. Treten wir also ein und sehen wir zunächst, welchen Ballast Gordley abwerfen musste, um sein Schiff flott zu bekommen. ...
Aussagen über den "Zustand" der Rechtsgeschichte in verschiedenen Ländern sind schwer zu gewinnen und zu gewichten. Akademische Fächer als reale Verbandspersönlichkeiten sind ohnehin eine luftige Konstruktion. Die Zahlen der Professuren in Relation zur Zahl der Universitäten, die Abschlussexamina der Juristenausbildung (mit oder ohne rechtshistorischen Anteil, mit oder ohne Bologna-Modell), die Zahl der Dissertationen, die Ausstattung der Bibliotheken und viele andere Daten lassen sich natürlich erheben. Aber schon die Ausgangspunkte sind unterschiedlich. In den meisten Ländern widmen sich die Rechtshistoriker nur ihrem Fach, während sie in Deutschland in der Lehre auch geltendes Recht vorzutragen und im Examen zu prüfen haben. ...
L’autore ricostruisce l’impatto del saggio di Max Weber sulla città nella storiografia tedesca a partire dalla fine degli anni Ottanta. Esso indica altresì il significato politico della "scoperta" weberiana della città come nucleo genetico della politica occidentale, con il suo universalismo che Weber data addirittura all’incontro tra gli apostoli Pietro e Paolo ad Antiochia. La "città" è per Weber la sede della possibilità teorica e fattuale di creare un diritto autonomo e nuovo. Essa è certamente il luogo di origine della predominanza politica della borghesia, ma nel paradigma weberiano basato sulla razionalizzazione come processo tipico della cultura occidentale, essa indica un percorso che prosegue ancora oggi nell’epoca delle migrazioni e della globalizzazione.
Postface
(2015)
Enfondant l’Académie française en 1635, le cardinal de Richelieu, Premier ministre de Louis XIII, lui avait assigné deux missions : la création d’undictionnaire de langue française etl'élaboration d’une poétique, d’une théorie littéraire analogue à celles qui existaient en Italie. Assurément, il souhaitait soutenir les écrivains français et leur donner une tribune, mais cette initiative n'était cependant pas exempte de considérations politiques. Bien qu'il n'ait pas envisagé la création d’une académie artistique, Richelieu n’excluait guère, de ses préoccupations, l'art : en 1627, il rappela à Paris Simon Vouet, alors à Rome, dans l’idée de développer un art typiquement français, qui serait indépendant des influences italiennes et flamandes. Il estimait qu’un État territorial modernese définissait toutautant par son art et sa littérature que par sa langue. La fondation de l’Académie royale de peinture et de sculpture en 1648, dans le contexte tourmenté de la Fronde, par le cardinal Mazarin, successeur de Richelieu, assignait à la nouvelle institution des tâches plus complexes quoiqu'assez voisines de celles de l’Académie française. Il s'agissait non seulement de témoigner de la noblesse de la peinture et de la sculpture, mais également de prodiguer aux générations successives une formation leur assurant de réelles qualités artistiques. ...
Seit Oktober 2010 reflektiert im Italienisch-Deutschen Historischen Institut in Trient eine Gruppe von Historikern über ein zentrales Problem der Geschichtswissenschaften, demjenigen der Epochen und der "Transitionen" zwischen diesen. Vom 11.–14. September 2012 veranstaltete das Institut hierzu eine Tagung, auf der erste Ergebnisse und Gedanken vorgestellt wurden. Der Sammelband versammelt die meisten der damaligen Vorträge. ...
Au milieu du beau livre d’Anna Karla, le lecteur tombe sur les réflexions du général François-Amédée Doppet qui, dans sa préface aux »Mémoires politiques et militaires«(1797), rapporte les conditions nécessaires pour écrire une histoire véritable de la Révolution française. À son avis, il faudra un écrivain impartial, éloigné du chaos des événements, qui, tout d’abord, rassemblera tous les souvenirs écrits par les protagonistes de la Révolution, jusque-là encore dominés par l’esprit de parti. Seul cet écrivain pourra, avec l’impartialité de l’historien, extraire de ces mémoires une histoire complète des bouleversements révolutionnaires. La vérité sur la Révolution, donc, ne pourra être formulée que longtemps après la fin de celle-ci. ...
Le genre des questions-et-réponses dans la littérature grecque chrétienne se laisse mieux comprendre si l'on le définit comme une série de questions-et-réponses, présentées comme telles (et non comme des lettres ou des dialogues, par exemple) abordant des sujets variés et qui ne se réduisent pas à une seule catégorie de contenu (exégèse biblique ou explications scientifiques, par exemple). Ainsi restreint, le genre des questions-et-réponses dans la littérature grecque chrétienne connaît sa période la plus faste aux Ve-VIIIe s. dans des milieux monastiques ouverts sur les problèmes et les interrogations du monde. Ce genre, d'une grande souplesse et d'une grande vitalité, permet de traiter des questions d'une façon plus accessible et plus libre qu'il ne serait possible de le faire dans une homélie ou un traité théologique.
We present an overview on the resonance dynamics within the microscopic parton-hadron-string dynamics (PHSD) approach which incorporates explicit partonic degrees-of-freedom in terms of strongly interacting quasiparticles (quarks and gluons) in line with an equation-of-state from lattice QCD as well as the dynamical hadronization and hadronic collision dynamics in the final reaction phase. We discuss how the vector meson resonances can be used as a probe of the in-medium effects and demostrate that the low mass dilepton spectra show visible in-medium effects from dynamical vector-meson spectral functions from SIS to SPS energies whereas at RHIC and LHC energies such medium effects become more moderate. We show also that the intermediate mass spectra are dominated by the radiation from the partonic degrees of freedom at RHIC and LHC energies.
An overview is given on the experimental study of physics with relativistic heavy-ion collisions, with emphasis on recent measurements at the Large Hadron Collider (LHC) and the Relativistic Heavy Ion Collider (RHIC). The focus here is laid on p–Pb collisions at the LHC and the corresponding d–Au measurements at RHIC. The topics touched are “collectivity and approach to equilibrium”, “high pT and jets”, “heavy flavour and electroweak bosons” and “search for exotic objects”.
We discuss the effects of the final hadronic state, in ultra-relativistic nuclear collisions, on hadronic resonance properties and measurable production rates. In particular we will compare our results with recent ALICE data on resonance production. We show that the hadronic phase of the system evolution has a considerable impact on the measured resonance ratios and pT spectra. We also discuss some of the remaining uncertainties in the model and how they may be addressed in future studies.
The dynamics of strange vector meson resonances (K* and K̄*) is investigated within the Parton-Hadron-String Dynamics (PHSD) transport approach. We present the time evolution of the production of K*− resonances from the QGP phase by quark fusion as well as from hadronic sources. We also give a brief overview of the modification of the K* through Kπ decay and K*N interaction in a hot and dense nuclear medium.
Der vorliegende Band vereint insgesamt 33 Beiträge von Archäologen, Historikern und Kunsthistorikern zur Geschichte kultureller Wechselbeziehungen zwischen Skandinaviern und den lokalen Gesellschaften vorwiegend in Altrussland und der Normandie in französischer und englischer Sprache. Er geht zurück auf die im Jahre 2009 in Sankt-Petersburg, Nowgorod, Staraja Russa und Caen veranstaltete Doppeltagung eines Projekts, das nicht umsonst "Deux Normandies" getauft wurde: Sein Ziel ist es, auf dem Stand aktueller methodologischer und theoretischer Erkenntnisse über kulturelle Interaktion eine vergleichende Perspektive auf zwei sehr unterschiedlich strukturierte Randzonen der viking world – die Normandie und die nordwestliche Rusʼ – und ihre Entwicklung zu eröffnen. Dabei wird auch die spätere kollektive, regionale Erinnerung an Beziehungen zu Skandinavien und damit ihre Politisierung thematisiert. Aus dieser empirischen Ausrichtung und der daraus resultierenden Vielstimmigkeit bezieht der voluminöse Band einen Großteil seines innovativen und ausgesprochen anregenden Charakters. Zudem stellt allein schon die hier versammelte Expertise zu den wikingerzeitlichen skandinavischen "Diasporen" mehr als genug Grund zur intensiven Lektüre dar. Insbesondere gilt dies für den vermittelten Überblick über die einschlägige russischsprachige Forschung der letzten Jahrzehnte; hier erfüllen die jeweiligen Aufsätze eine unverzichtbare Brückenfunktion. ...
Freundschaftsvorstellungen des Mittelalters und die politisch-soziale Bedeutung der Freundschaft sind keine "jungen" Gegenstände mehr: Schon in den 1990er Jahren unterstrich Gerd Althoff die Bedeutung der hochmittelalterlichen amicitiae, und seinen Pionierarbeiten folgten weitere Studien, die das Mittelalter räumlich und zeitlich recht breit erfassten. In dieser Forschungslandschaft müssen sich neue Beiträge entsprechend sorgfältig positionieren. ...
Krieg und physische Gewalt sind seit jeher präsente Themen der Frühmittelalterforschung, trotz gewisser konjunktureller Schwankungen. Über die letzten Jahre lässt sich eine intensivere Auseinandersetzung mit diesem Bereich beobachten, wohl ein Reflex auf aktuelle Ereignisse und die von ihnen ausgelösten wissenschaftlichen Debatten in stärker gegenwartsorientierten Disziplinen. Gerade in der deutschen Mittelalterforschung wird dabei eine Hinwendung zu einer "Kulturgeschichte des Krieges" (Hans-Henning Kortüm) vollzogen, was einerseits in den Schwierigkeiten begründet liegt, auf Basis des größtenteils sehr fragmentarischen Quellenmaterials "klassische" Militärgeschichte für das Frühmittelalter zu schreiben, andererseits aber auch Entwicklungen in den Kulturwissenschaften aufnimmt und den pazifistischen Grundtenor der deutschen Nachkriegsgesellschaft spiegelt. In diesen Kontext gehört das zu besprechende Buch von Laury Sarti, das auf ihrer 2012 bei Hans-Werner Goetz in Hamburg eingereichten Dissertation beruht. ...
Newsletter FamilyPlus 2/2015
(2015)