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  • Article
    Open Access
    Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants
    (2015-07-03) Griffin, Helen R.; Töpf, Ana; Glen, Elise; Zweier, Christiane; Stuart, A. Graham; Parsons, Jonathan; Peart, Ian; Deanfield, John; O'Sullivan, John; Rauch, Anita; Scambler, Peter; Burn, John; Cordell, Heather J.; Keavney, Bernard; Goodship, Judith A.
    Background Tetralogy of Fallot (TOF) is common in individuals with hemizygous deletions of chromosome 22q11.2 that remove the cardiac transcription factor TBX1. Objective To assess the contribution of common and rare TBX1 genetic variants to TOF. Design Rare TBX1 variants were sought by resequencing coding exons and splice-site boundaries. Common TBX1 variants were investigated by genotyping 20 haplotype-tagging SNPs capturing all the common variations present at the locus. Association analysis was performed using the program UNPHASED. Patients TBX1 exons were sequenced in 93 patients with non-syndromic TOF. Single nucleotide polymorphism analysis was performed in 356 patients with TOF, their parents and healthy controls. Results Three novel variants not present in 1000 chromosomes from healthy ethnically matched controls were identified. One of these variants, an in-frame 57 base-pair deletion in the third exon which removed 19 evolutionarily conserved residues, decreased transcriptional activity by 40% in a dual luciferase assay (p=0.008). Protein expression studies demonstrated that this mutation affected TBX1 protein stability. After correction for multiple comparisons, no significant associations between common genetic variants and TOF susceptibility were found. Conclusion This study demonstrates that rare TBX1 variants with functional consequences are present in a small proportion of non-syndromic TOF.
  • Article
    Open Access
    Clinical and molecular delineation of the 17q21.31 microdeletion syndrome
    (2015-07-03) Koolen, D. A.; Sharp, A. J.; Hurst, J. A.; Firth, H. V.; Knight, S. J. L.; Goldenberg, A.; Saugier--Veber, P.; Pfundt, R.; Vissers, L. E. L. M.; Destree, A.; Grisart, B.; Rooms, L.; Van der Aa, N.; Field, M.; Hackett, A.; Bell, K.; Nowaczyk, M. J. M.; Mancini, G. M. S.; Poddighe, P. J.; Schwartz, C. E.; Rossi, E.; De Gregori, M.; Antonacci-Fulton, L. L.; McLellan II, M. D.; Garrett, G. M.; Wiechert, M. A.; Miner, T. L.; Crosby, S.; Ciccione, R.; Willatt, L.; Rauch, A.; Zenker, M.; Aradhya, S.; Manning, M. A.; Strom, T. M.; Wagenstaller, J.; Krepischi-Santos, A. C.; Vianna-Morgante, A. M.; Rosenberg, C.; Price, S. M.; Stewart, H.; Shaw-Smith, C.; Brunner, H. G.; Wilkie, A. O. M.; Veltman, J. A.; Zuffardi, O.; Eichler, E. E.; de Vries, B. B. A.
    Background: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. Aim: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. Results: We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729–41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10−5). Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
  • Article
    Open Access
    Disruption of ST5 is associated with mental retardation and multiple congenital anomalies
    (2015-06-26) Göhring, Ina; Tagariello, Andreas; Endele, Sabine; Stolt, Claus C.; Ghassibe, Michaella; Vikkula, Miika; Winterpacht, Andreas; FitzPatrick, David R.; Rauch, Anita
    Background The authors observed a patient with a cryptic subtelomeric de novo balanced translocation 46,XY.ish t(11;20)(p15.4;q13.2) presenting with severe mental retardation, muscular hypotonia, seizures, bilateral sensorineural hearing loss, submucous cleft palate, persistent ductus Botalli, unilateral cystic kidney dysplasia and frequent infections. Methods and Results Fluorescence in situ hybridisation mapping and sequencing of the translocation breakpoints showed that no known genes are disrupted at 20q13.2 and that ST5 (suppression of tumorigenicity 5; MIM 140750) is disrupted on 11p15.4. By quantitative PCR from different human tissues, the authors found ST5 to be relatively evenly expressed in fetal tissues. ST5 expression was more pronounced in adult brain, kidney and muscle than in the corresponding fetal tissues, whereas expression in other tissues was generally lower than in the fetal tissue. Using RNA in situ hybridisation in mouse, the authors found that St5 is expressed in the frontal cortex during embryonic development. In adult mouse brain, expression of St5 was especially high in the hippocampal area and cerebellum. Conclusion Hence, the authors suppose that ST5 plays an important role in central nervous system development probably due to disturbance of DENN-domain-mediated vesicle formation and neurotransmitter trafficking. Thus, these findings implicate ST5 in the aetiology of mental retardation, seizures and multiple congenital anomalies.
  • Article
    Open Access
    Comprehensive genotype–phenotype analysis in 230 patients with tetralogy of Fallot
    (2015-06-26) Rauch, Ralf; Hofbeck, Michael; Zweier, Christiane; Koch, Andreas; Zink, Stefan; Trautmann, Udo; Hoyer, Juliane; Kaulitz, Renate; Singer, Helmut; Rauch, Anita
    Background Tetralogy of Fallot (ToF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. In order to get further insight into genotype–phenotype correlation, a large cohort of 230 unselected patients with ToF was comprehensively investigated. Methods and results 230 patients with ToF were studied by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Pathogenic genetic aberrations were found in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic ToF (0.9%). One patient showed a recurrent polyalanine stretch elongation within TBX1 which represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation. Conclusion This study shows that 22q11.2 deletion represents the most common known cause of ToF, and that the associated cardiac phenotype is distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with ToF is very suggestive of trisomy 21 and almost excludes 22q11.2 deletion. We report a further patient with a recurrent polyalanine stretch elongation within TBX1 and for the first time link TBX1 cytoplasmatic protein aggregation to congenital heart defects.
  • Article
    Open Access
    V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours
    (2015-06-26) Agaimy, Abbas; Terracciano, L. M.; Dirnhofer, S.; Tornillo, L.; Foerster, A.; Hartmann, A.; Bihl, M. P.
    Background: A small subset (10–15%) of gastrointestinal stromal tumours (GISTs) lack mutations in KIT and PDGFRA (wild-type GIST). Recently, a novel BRAF exon 15 mutation (V600E) was detected in imatinib-naive wild-type high-risk intestinal GISTs (4%). However, the frequency and distribution of BRAF mutations within the spectrum of GISTs, and whether they might represent secondary events acquired during tumour progression, remain unknown. Methods: 69 GISTs (39 KIT mutants, 2 PDGFRA mutants and 28 wild-type) were analysed for mutations in BRAF exon 15 and KRAS exon 2. To assess the stage at which these mutations might occur in GIST, a considerable number of incidental gastric (n = 23) and intestinal (n = 2) tumours were included. Results: BRAF mutations (V600E) were detected in 2 of 28 wild-type GISTs (7%), but in none of the 41 KIT/PDGFRA mutants. No KRAS mutation was detected. The two BRAF-mutated GISTs measured 4 mm in diameter and originated in the gastric body and the jejunum in two men (mean age, 76 years). Both tumours were mitotically inactive KIT-positive spindle-cell GISTs that were indistinguishable histologically from their more common KIT-mutated counterparts. Conclusion: BRAF mutations represent an alternative molecular pathway in the early tumorigenesis of a subset of KIT/PDGFRA wild-type GISTs and are per se not associated with a high risk of malignancy. Mutations in KIT, PDGFRA and BRAF were mutually exclusive in this study. Results from this and a previous study indicate that BRAF-mutated GISTs show a predilection for the small bowel (four of five tumours), but this needs further evaluation in larger studies.
  • Article
    Open Access
    Evaluation of low-cost computer monitors for the detection of cervical spine injuries in the emergency room: an observer confidence-based study
    (2015-06-25) Brem, H. M.; Böhner, C.; Brenning, A.; Gelse, K.; Radkow, T.; Blanke, M.; Schlechtweg, P. M.; Neumann, G.; Wu, I. Y.; Bautz, W.; Hennig, F. F.; Richter, H.
    Background: To compare the diagnostic value of low-cost computer monitors and a Picture Archiving and Communication System (PACS) workstation for the evaluation of cervical spine fractures in the emergency room. Methods: Two groups of readers blinded to the diagnoses (2 radiologists and 3 orthopaedic surgeons) independently assessed–digital radiographs of the cervical spine (anterior–posterior, oblique and trans-oral-dens views). The radiographs of 57 patients who arrived consecutively to the emergency room in 2004 with clinical suspicion of a cervical spine injury were evaluated. The diagnostic values of these radiographs were scored on a 3-point scale (1 = diagnosis not possible/bad image quality, 2 = diagnosis uncertain, 3 = clear diagnosis of fracture or no fracture) on a PACS workstation and on two different liquid crystal display (LCD) personal computer monitors. The images were randomised to avoid memory effects. We used logistic mixed-effects models to determine the possible effects of monitor type on the evaluation of x ray images. To determine the overall effects of monitor type, this variable was used as a fixed effect, and the image number and reader group (radiologist or orthopaedic surgeon) were used as random effects on display quality. Group-specific effects were examined, with the reader group and additional fixed effects as terms. A significance level of 0.05 was established for assessing the contribution of each fixed effect to the model. Results: Overall, the diagnostic score did not differ significantly between standard personal computer monitors and the PACS workstation (both p values were 0.78). Conclusion: Low-cost LCD personal computer monitors may be useful in establishing a diagnosis of cervical spine fractures in the emergency room.
  • Article
    Open Access
    Transient postoperative vascular endothelial growth factor (VEGF)-neutralisation improves graft survival in corneas with partly regressed inflammatory neovascularisation
    (2015-06-24) Bachmann, B. O.; Lütjen-Drecoll, Elke; Bock, F.; Wiegand, S. J.; Hos, D.; Dana, R.; Kruse, F. E.; Cursiefen, C.
    Background: High-risk keratoplasties are usually performed after an uninflamed and quiescent interval in corneas with partly regressed blood and lymphatic vessels. We analysed whether the inhibition of post-keratoplasty revascularisation in mice with partly regressed corneal vessels (“intermediate-risk”) improves graft survival. Methods: Three interrupted stromal sutures (11-0) in corneas of Balb/c mice (6–8 weeks old) were placed for 6 weeks. Six months after suture removal, penetrating keratoplasty was performed with C57BL/6 donors. The treatment group received a vascular endothelial growth factor-A specific cytokine trap (VEGF Trap) intraperitoneally at days 0, 4, 7 and 14 after keratoplasty (25 mg/kg per mouse; controls received equal amounts of Fc protein). Pathological haemangiogenesis and lymphangiogenesis prior to as well as 3 days or 8 weeks after keratoplasty and graft survival were analysed. Results: Three days after keratoplasty corneal revascularisation was sufficiently reduced by VEGF Trap (haem-vascularised areas 42.7% reduction; lymph-vascularised areas 54.7% reduction). Survival proportions 8 weeks after keratoplasty were 36% in the treatment group compared with 9% in the control group (n = 11; p<0.05). At that time no differences in haemangiogenesis or lymphangiogenesis were observed between the two groups. Conclusion: Early transient postoperative induction of haemangiogenesis and lymphangiogenesis and reformation of regressed corneal blood and lymphatic vessels are important for transplant rejections after “intermediate-risk” corneal transplantation.
  • Article
    Open Access
    Tumour-associated lymphangiogenesis in conjunctival malignant melanoma
    (2015-06-24) Zimmermann, P.; Dietrich, T.; Bock, F.; Horn, F. K.; Hofmann-Rummelt, C.; Kruse, F. E.; Cursiefen, C.
    Background: To evaluate whether tumour-associated lymphangiogenesis, that is the formation of new lymphatic vessels (LVs) induced by a tumour, occurs in and around conjunctival malignant melanoma (MM). Methods: Clinical files and conjunctival specimens of 20 patients with histologically diagnosed conjunctival MM were analysed. Sections were stained with LYVE-1 and podoplanin antibodies as specific lymphatic endothelial markers and Ki67 as proliferation marker. The tumour area and the area covered by LV (LVA), LV number (LVN) and LV density (LVD) were measured within the tumour and in the peritumoural area in digital images of the specimen. The LV results were correlated with the histopathological characteristics, tumour location, recurrence rate, mitomycin C therapy and presence of metastases. Results: LVs were detected in all specimens within the tumour and peritumourally. Significantly more Ki67+ proliferating lymphatic endothelial cells were detected in the tumour and in the peritumoural tissue up to 300 μm compared with the surrounding normal conjunctiva (>300 μm distance). There was a slightly positive correlation between the tumour size and the LVN and LVA in the 50 μm zone adjacent to the tumour. We did not find any significant correlations between LVs and histopathological and clinical characteristics (location, shape, relapses, metastases), possibly due to the small sample sizes. Non-limbal tumours with involvement of tarsus or fornix showed a tendency towards a higher LVD compared with limbal tumours. Conclusion: Conjunctival MMs display tumour-associated LV within and around the tumour. The MM seems to induce lymphangiogenesis not only in the tumour, but also in its proximity.
  • Article
    Open Access
    IgG autoantibodies bound to surfaces of necrotic cells and complement C4 comprise the phagocytosis promoting activity for necrotic cells of systemic lupus erythaematosus sera
    (2015-06-24) Grossmayer, Gerhard; Munoz, L. E.; Weber, C. K.; Franz, S.; Voll, R. E.; Kern, P. M.; Kalden, Joachim R.; Schett, Georg; Herrmann, M.; Gaipl, Udo S.
    Objective: Accumulation of dying and dead cells is thought to be involved in the etiopathogenesis of systemic lupus erythaematosus (SLE). Clearance has been described mainly for apoptotic cells; however, the knowledge of serum factors participating in the phagocytosis of necrotic cells is limited. Patients and methods: Sera from 18 patients with SLE and 10 normal healthy donors (NHD), and macrophages from 3 NHD were included. Autoantibodies and complement were measured by ELISA and phagocytosis by flow cytometry. Binding of serum IgG to necrotic cells was assessed by flow cytometry and confocal microscopy. Results: Sera from patients with SLE and NHD generally promoted the phagocytosis of necrotic cells by macrophages isolated from NHD. Five independent experiments with macrophages from three different NHD led to similar results. The sera from healthy controls displayed a homogeneous activity, whereas sera from patients with SLE showed a dichotomic behaviour. Only sera containing autoantibodies binding to the surfaces of necrotic cells and sufficient complement showed increased phagocytosis promoting activities. In SLE sera, C4 turned out to be the critical complement component in this process. Sera de-complemented by heat treatment strongly reduced phagocytosis of necrotic cells. Conclusions: Serum components influence the uptake of necrotic cells by phagocytosis competent macrophages from NHD. Complement is required for this process and autoantibodies binding to the surfaces of necrotic cells additionally promote their phagocytosis.
  • Article
    Open Access
    Physiological responses to rock climbing in young climbers
    (2015-06-24) Morrison, Audry Birute; Schöffl, Volker Rainer
    Key questions regarding the training and physiological qualities required to produce an elite rock climber remain inadequately defined. Little research has been done on young climbers. The aim of this paper was to review literature on climbing alongside relevant literature characterising physiological adaptations in young athletes. Evidence-based recommendations were sought to inform the training of young climbers. Of 200 studies on climbing, 50 were selected as being appropriate to this review, and were interpreted alongside physiological studies highlighting specific common development growth variables in young climbers. Based on injury data, climbers younger than 16 years should not participate in international bouldering competitions and intensive finger strength training is not recommended. The majority of climbing foot injuries result from wearing too small or unnaturally shaped climbing shoes. Isometric and explosive strength improvements are strongly associated with the latter stages of sexual maturation and specific ontogenetic development, while improvement in motor abilities declines. Somatotyping that might identify common physical attributes in elite climbers of any age is incomplete. Accomplished adolescent climbers can now climb identical grades and compete against elite adult climbers aged up to and >40 years. High-intensity sports training requiring leanness in a youngster can result in altered and delayed pubertal and skeletal development, metabolic and neuroendocrine aberrations and trigger eating disorders. This should be sensitively and regularly monitored. Training should reflect efficacious exercises for a given sex and biological age.
  • Article
    Open Access
    Quantitative Transduction of Excited-State Energy inFluorophore-Heterofullerene Conjugates
    (2013-07-17) Hauke, Frank; Hirsch, Andreas; Atalick, Stefan; Guldi, Dirk M.
    A novel series of fluorophore-heterofullerene conjugates 10–14 — the fluorophores range from benzene, naphthalene, phenanthrene, and fluorene to pyrene — was synthesized. NMR spectroscopy and quantum mechanical calculations demonstrate that the flexibility of the acetyl-group linker opens the way for conformations with π–π stacking interactions between the chromophores. This leads to favorable electronic communication between the two subsystems and is reflected in a series of ground- and excited-state assays ranging from fluorescence to fast transient absorption measurements. It was found that a common deactivation process of the photoexcited fluorophores takes place, namely, a quanti-tative transduction of singlet excited state, yielding the hetero-fullerene singlet excited state. This reaction pathway leads to the long-lived and highly reactive fullerene triplet state, which forms, in a reaction with molecular oxygen, a cytotoxic oxygen species (i.e. singlet oxygen).
  • Article
    Open Access
    Metal-Induced Chiral Folding of Depsipeptide Dendrimers
    (2013-07-17) Buschhaus, Boris; Hampel, Frank; Grimme, Stefan; Hirsch, Andreas
    The synthesis and metal complexation of chiral depsipeptide dendrimers 3 and 7 containing an ethylenediaminetetraacetic acid (EDTA) ester-derived core is reported. The EDTA ester cavity of these dendrimers selectively complexes Zn2+ and Cu2+ ions leading to diastereoselective folding. To elucidate the coordination motif in the resulting “foldamers” of 3-ZnCl2, 7-ZnCl2, 3-CuCl2, and 7-CuCl2, the coordination behavior of the tetramethyl ester of EDTA (8) has been investigated as a model case. The corresponding complexes 8-ZnCl2 and 8-CuCl2 have been structurally characterized by 1H NMR spectroscopy and X-ray analysis. The complexes involve the inherently chiral octahedral cis-α coordination motif, in which 8 serves as a tetradentate ligand. In the case of the ZnII complex 8-ZnCl2, both Δcis-α(S,S,λ) and Λcis-α(R,R,λ) stereoisomers were found in the unit cell. For the CuII complex 8-CuCl2, only one stereoisomer, namely Δcis-α(S,S,λ) was found in the crystal under investigation. 1H NMR spectroscopy has shown that the same coordination motif is diastereoselectively formed in the chiral Zn2+ dendrimers 3-ZnCl2 and 7-ZnCl2. Likewise, the calculated CD spectrum of the Δcis-α(S,S,λ) stereoisomer of the model complex 8-CuCl2 shows good agreement with the experimental spectrum of the CuII dendrimers 3-CuCl2 and 7-CuCl2, allowing assignment of the absolute configurations of the preferred foldamers as Λcis-α(R,R,λ) for 3-CuCl2 and Δcis-α(S,S,λ) for 7-CuCl2. This work represents the first example of metal-complexation-mediated diastereoselective folding of chiral dendrimers with known absolute configuration.
  • Article
    Open Access
    Switchable Supramolecular Organization of Structurally Defined Micelles Based on an Amphiphilic Fullerene
    (2013-07-17) Burghardt, Stephan; Hirsch, Andreas; Schade, Boris; Ludwig, Kai; Böttcher, Christoph
    Exactly eight amphiphilic fullerene dendrimer molecules form a globular micelle spontaneously in aqueous solution. This supramolecular organization can be turned on and off by an external stimulus (pH). Owing to the remarkable structure persistence of the micelles, their three-dimensional structure could be determined from cryogenic transmission electron micrographic images and the molecular architecture was subsequently modeled.
  • Article
    Open Access
    Complete Self-Assembly of Discrete Supramolecular Dendrimers
    (2013-07-17) Franz, Alexander; Bauer, Walter; Hirsch, Andreas
    Simply mixing a core (black) with defined amounts of branching units (red) and end caps (blue) leads to programmed complete self-assembly of supramolecular dendrimers through complimentary and multiple hydrogen bonding.
  • Article
    Open Access
    Diastereoselective Assembly of Chiral RuII-Coordinated Depsipeptide-Dendrimers
    (2013-07-17) Buschhaus, Boris; Hirsch, Andreas
    The synthesis, characterization and chiroptical properties of chiral dendrimers 11–14 formed by ruthenium coordination of2,2′-bipyridine (bpy*) ligands 4, 7, 8 and 10 involving two pairs of enantiomerically pure depsipeptide dendrons bound in 4,4′-position are described. In the case of the first and second generation ligands 4, 7 and 8 the metallodendrimers 11, 12 and 13 are formed containing a central [Ru(bpy*)3]2+ core. After coordination of the third generation dendritic ligand 10 the metallodendrimer 14 with two bpy* ligands, {[Ru(bpy*)2Cl2] core} was isolated. The corresponding metallodendrimer 15 with three bpy* ligands was formed in traces only. Dendrimers 11, 12 and 13 are the first chiral metallodendrimers involving an [Ru(bpy*)3]2+ core. This chiral coordination motif can have either a Δ or a Λ configuration. To elucidate if there is a preference for a certain configuration 1H NMR and CD spectroscopy and analytical HPLC were applied. It was found that for the first generation dendrimer 11 the corresponding diastereoisomers with Δ and Λ configuration are formed in equal amounts. On the other hand the Λ diastereoisomers of 12 and 13 are preferably formed upon coordination of the second generation dendrons 7 and 8 with all-(R,R) configuration (8) or mixed (S,S)1-(R,R)2 configuration (7). This demonstrates that the configuration of the outer rather than the inner layer within the depsipeptide dendrons determines which isomer is preferably formed.
  • Article
    Open Access
    Vollständiger Selbstaufbau von diskreten supramolekularen Dendrimeren
    (2013-07-17) Franz, Alexander; Bauer, Walter; Hirsch, Andreas
    Einfaches Mischen eines Kernbausteins (schwarz) mit definierten Mengen an Verzweigungseinheiten (rot) und Endstücken (blau), die jeweils komplementär sind und durch mehrfache Wasserstoffbrücken miteinander verknüpft werden, führt zu einem programmierten Selbstaufbau von supramolekularen Dendrimeren.
  • Article
    Open Access
    New concepts for regio- and stereoselective bis- and triscyclopropanations of C60
    (2013-07-17) Hirsch, Andreas
    The synthesis of isomerically multiple adducts of C60 with a defined three-dimensional structure is still one of the most challenging tasks of exohedral fullerene chemistry. The inherent regioselectivity of successive additions of addends such as malonates to the fullerene's [6,6]-double bonds is only moderate. In most cases difficult-to-isolate mixtures of regioisomers are obtained. The regioselectivity can be significantly improved if multifunctional addends able to undergo two or more additions are allowed to react with C60. Preorganization and minimization of strain energy within the addend skeleton reduce the number of sterically allowed addition patterns. Improved concepts for highly regio- and stereoselective bis- and triscyclopropanations of C60 are described. Two examples of the bisadditions with complete regioselectivity leading to trans-2- and cis-2 are presented. Here, the two malonate binding sites are linked by rigid tetraphenylporphyrin and calix-[4]-arene spacers. Selective trisadditions were achieved with the easy-to-synthesize and easy-to-modify tripodal addends 5–7, where the malonates are held together by a focal aryl moiety. Another very elegant approach for bis- and trisadditions involves cyclo-[n]-alkylmalonates. Selection between addition patterns with and without rotational axes is possible by choosing the right combinations of the flexible alkyl chains connecting the malonates. If alkyl chains of identical lengths are used bis- and trisadducts such as 19–21 and 25 with rotational symmetry are formed with high regioselectivity. These addition patterns are avoided if cyclo-[n]-malonates containing alkyl chains of different lengths are employed. In this case adducts such as 26 and 27 with Cs-symmetry are formed. The use of the chiral cyclo-[3]-malonate 28 allows for the regio- and stereoselective synthesis of the enantiomerically pure e,e,e-trisadducts 29 and 30 containing an inherently chiral addition pattern with C3-symmetry.
  • Article
    Open Access
    Schaltbare supramolekulare Organisation strukturdefinierter Micellen basierend auf einem amphiphilen Fulleren
    (2013-07-17) Burghardt, Stephan; Hirsch, Andreas; Schade, Boris; Ludwig, Kai; Böttcher, Christoph
    Jeweils exakt acht amphiphile Fullerendendrimer-Moleküle bilden spontan in wässriger Lösung Micellen, deren Auf- und Abbau durch einen externen Stimulus (pH-Wert) geschaltet werden kann. Die bemerkenswerte Strukturpersistenz der Micellen ermöglicht die Bestimmung ihrer dreidimensionalen Organisation aus kryo-transmissionselektronenmikroskopischen Aufnahmen und damit die Modellierung der molekularen Architektur.
  • Article
    Open Access
    Polymorphisms in the Hsp70 gene locus are genetically associated with systemic lupus erythematosus
    (2013-05-16) Fürnrohr, Barbara G.; Wach, Sven; Kelly, Jennifer A.; Haslbeck, Martin; Weber, Christian K.; Stach, Christian M.; Hueber, Axel J.; Graef, Daniela; Spriewald, Bernd M.; Manger, Karin; Herrmann, Martin; Kaufman, Kenneth M.; Frank, Summer G.; Goodmon, Ellen; James, Judith A.; Schett, Georg; Winkler, Thomas H.; Harley, John B.; Voll, Reinhard E.
    Background: Heat shock proteins (Hsps) play a role in the delivery and presentation of antigenic peptides and are thought to be involved in the pathogenesis of multifactorial diseases. Objective: To investigate genes encoding cytosolic Hsp70 proteins for associations of allelic variants with systemic lupus erythematosus (SLE). Methods: Case–control studies of two independent Caucasian SLE cohorts were performed. In a haplotype-tagging single-nucleotide polymorphism approach, common variants of HspA1L, HspA1A and HspA1B were genotyped and principal component analyses were performed for the cohort from the Oklahoma Medical Research Foundation (OMRF). Relative quantification of mRNA was carried out for each Hsp70 gene in healthy controls. Conditional regression analysis was performed to determine if allelic variants in Hsp70 act independently of HLA-DR3. Results: On analysis of common genetic variants of HspA1L, HspA1A and HspA1B, a haplotype significantly associated with SLE in the Erlangen-SLE cohort was identified, which was confirmed in the OMRF cohort. Depending on the cohorts, OR ranging from 1.43 to 1.88 and 2.64 to 3.16 was observed for individuals heterozygous and homozygous for the associated haplotype, respectively. Patients carrying the risk haplotype or the risk allele more often displayed autoantibodies to Ro and La in both cohorts. In healthy controls bearing this haplotype, the amount of HspA1A mRNA was significantly increased, whereas total Hsp70 protein concentration was not altered. Conclusions: Allelic variants of the Hsp70 genes are significantly associated with SLE in Caucasians, independently of HLA-DR3, and correlate with the presence of autoantibodies to Ro and La. Hence, the Hsp70 gene locus appears to be involved in SLE pathogenesis.
  • Article
    Open Access
    Ethical opinions and personal attitudes of young adults conceived by in vitro fertilisation
    (2013-05-16) Siegel, Stefan; Dittrich, Ralf; Vollmann, Jochen
    Background: Today in vitro fertilisation (IVF) is a widespread and important technique of reproductive medicine. When the technique was first used, it was considered ethically controversial. This is the first study conducted of adult IVF-offspring in order to learn about their ethical opinions and personal attitudes towards this medical technology. Methods: We recruited the participants from the first cases of in vitro fertilisation in Germany at the Gynaecological Clinic of the University Hospital Erlangen. Our qualitative interview study consisted of in-depth, face-to-face interviews with 16 adults who had been conceived by IVF. Our data was analysed with methods of Grounded Theory. Results: For these adults, the most important factor influencing their personal attitudes towards IVF was the knowledge that they were deeply wanted children. The artificiality of their conception seemed irrelevant for their ethical opinion. All participants mentioned that it was important for them to be informed about the circumstances of their conception by their parents. Conclusions: IVF seems to be a medical technique which, although it affects intimate aspects of human existence, can be integrated into the lives of the affected persons without any great difficulties. The findings suggest that parents should inform their children about their fertilisation at an early age and as part of a process over time, not only on a single occasion. Physicians should advise IVF-parents accordingly.