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Laufs A.,Heinrich Group | Livingstone R.,Heinrich Group | Nowotny B.,Heinrich Group | Nowotny P.,Heinrich Group | And 6 more authors.
Magnetic Resonance in Medicine | Year: 2014

Purpose The aims of this study were (i) to establish a robust and fast method to quantify hepatocellular phosphorus compounds in molar concentration on a 3T clinical scanner, (ii) to evaluate its reproducibility, and (iii) to test its feasibility for a use in large cohort studies. Method Proton-decoupled 31P magnetic resonance spectroscopy of liver 31P compounds were acquired on 85 healthy subjects employing image selected in-vivo spectroscopy localization in 13 min of acquisition at 3T. Absolute quantification was achieved using an external reference and double-matching phantoms (inorganic phosphates and adenosine triphosphate (ATP) solutions). Reproducibility of the method was also examined. Results This method showed a high intra- and interday as well as inter- and intraobserver reproducibility (r > 0.98; P < 0.001), with a high signal to noise ratio (SNR) (i.e., mean SNR of γ-ATP: 16). The mean liver concentrations of 85 healthy subjects were assessed to be 1.99 ± 0.51 and 2.74 ± 0.55 mmol/l of wet tissue volume for Pi and γ-ATP, respectively. Conclusion This method reliably quantified molar concentrations of liver 31P compounds on 85 subjects with a short total examination time (25 min) on a 3T clinical scanner. Thus, the current method can be readily utilized for a clinical study, such as a large cohort study. © 2013 Wiley Periodicals, Inc.

Kersting A.R.,University of Munster | Kersting A.R.,Heinrich Group | Mizrachi E.,University of Pretoria | Bornberg-Bauer E.,University of Munster | Myburg A.A.,University of Pretoria
New Phytologist | Year: 2015

Eucalyptus is a pivotal genus within the rosid order Myrtales with distinct geographic history and adaptations. Comparative analysis of protein domain evolution in the newly sequenced Eucalyptus grandis genome and other rosid lineages sheds light on the adaptive mechanisms integral to the success of this genus of woody perennials. We reconstructed the ancestral domain content to elucidate the gain, loss and expansion of protein domains and domain arrangements in Eucalyptus in the context of rosid phylogeny. We used functional gene ontology (GO) annotation of genes to investigate the possible biological and evolutionary consequences of protein domain expansion. We found that protein modulation within the angiosperms occurred primarily on the level of expansion of certain domains and arrangements. Using RNA-Seq data from E. grandis, we showed that domain expansions have contributed to tissue-specific expression of tandemly duplicated genes. Our results indicate that tandem duplication of genes, a key feature of the Eucalyptus genome, has played an important role in the expansion of domains, particularly in proteins related to the specialization of reproduction and biotic and abiotic interactions affecting root and floral biology, and that tissue-specific expression of proteins with expanded domains has facilitated subfunctionalization in domain families. © 2014 New Phytologist Trust.

Van Rahden V.A.,University of Hamburg | Fernandez-Vizarra E.,Mitochondrial Biology Unit | Alawi M.,University of Hamburg | Alawi M.,Heinrich Group | And 5 more authors.
American Journal of Human Genetics | Year: 2015

Microphthalmia with linear skin defects (MLS) syndrome is an X-linked male-lethal disorder also known as MIDAS (microphthalmia, dermal aplasia, and sclerocornea). Additional clinical features include neurological and cardiac abnormalities. MLS syndrome is genetically heterogeneous given that heterozygous mutations in HCCS or COX7B have been identified in MLS-affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with MLS syndrome carry a mutation in either HCCS or COX7B. The majority of MLS-affected females have severe skewing of X chromosome inactivation, suggesting that mutations in HCCS, COX7B, and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in NDUFB11 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. NDUFB11 encodes one of 30 poorly characterized supernumerary subunits of NADH:ubiquinone oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated NDUFB11 knockdown in HeLa cells, we demonstrate that NDUFB11 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that X-linked genetic defects leading to the complete inactivation of complex I, III, or IV underlie MLS syndrome. Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of mitochondrial diseases associated with neurocutaneous manifestations. © 2015 The American Society of Human Genetics.

Eggert D.,Heinrich Group | Eggert D.,University of Hamburg | Naumann M.,University of Hamburg | Reimer R.,Heinrich Group | Voigt C.A.,University of Hamburg
Scientific Reports | Year: 2014

Successful defence of plants against colonisation by fungal pathogens depends on the ability to prevent initial penetration of the plant cell wall. Here we report that the pathogen-induced (1,3)-β-glucan cell wall polymer callose, which is deposited at sites of attempted penetration, directly interacts with the most prominent cell wall polymer, the (1,4)-β-glucan cellulose, to form a three-dimensional network at sites of attempted fungal penetration. Localisation microscopy, a super-resolution microscopy technique based on the precise localisation of single fluorescent molecules, facilitated discrimination between single polymer fibrils in this network. Overexpression of the pathogen-induced callose synthase PMR4 in the model plant Arabidopsis thaliana not only enlarged focal callose deposition and polymer network formation but also resulted in the exposition of a callose layer on the surface of the pre-existing cellulosic cell wall facing the invading pathogen. The importance of this previously unknown polymeric defence network is to prevent cell wall hydrolysis and penetration by the fungus. We anticipate our study to promote nanoscale analysis of plant-microbe interactions with a special focus on polymer rearrangements in and at the cell wall. Moreover, the general applicability of localisation microscopy in visualising polymers beyond plant research will help elucidate their biological function in complex networks.

Gunther T.,Heinrich Group | Schreiner S.,Heinrich Pette Institute | Dobner T.,Heinrich Pette Institute | Tessmer U.,Heinrich Group | Grundhoff A.,Heinrich Group
PLoS Pathogens | Year: 2014

We have previously demonstrated that acquisition of intricate patterns of activating (H3K4me3, H3K9/K14ac) and repressive (H3K27me3) histone modifications is a hallmark of KSHV latency establishment. The precise molecular mechanisms that shape the latent histone modification landscape, however, remain unknown. Promyelocytic leukemia nuclear bodies (PML-NB), also called nuclear domain 10 (ND10), have emerged as mediators of innate immune responses that can limit viral gene expression via chromatin based mechanisms. Consequently, although ND10 functions thus far have been almost exclusively investigated in models of productive herpesvirus infection, it has been proposed that they also may contribute to the establishment of viral latency. Here, we report the first systematic study of the role of ND10 during KSHV latency establishment, and link alterations in the subcellular distribution of ND10 components to a temporal analysis of histone modification acquisition and host cell gene expression during the early infection phase. Our study demonstrates that KSHV infection results in a transient interferon response that leads to induction of the ND10 components PML and Sp100, but that repression by ND10 bodies is unlikely to contribute to KSHV latency establishment. Instead, we uncover an unexpected role for soluble Sp100 protein, which is efficiently and permanently relocalized from nucleoplasmic and chromatin-associated fractions into the insoluble matrix. We show that LANA expression is sufficient to induce Sp100 relocalization, likely via mediating SUMOylation of Sp100. Furthermore, we demonstrate that depletion of soluble Sp100 occurs precisely when repressive H3K27me3 marks first accumulate on viral genomes, and that knock-down of Sp100 (but not PML or Daxx) facilitates H3K27me3 acquisition. Collectively, our data support a model in which non-ND10 resident Sp100 acts as a negative regulator of polycomb repressive complex-2 (PRC2) recruitment, and suggest that KSHV may actively escape ND10 silencing mechanisms to promote establishment of latent chromatin. © 2014 Günther et al.

Huttenrauch M.,University Hospital Freiburg | Baches S.,Heinrich Group | Gerth J.,University Hospital Freiburg | Gerth J.,University of Bonn | And 3 more authors.
Journal of Alzheimer's Disease | Year: 2015

The deposition of amyloid-β (Aβ) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). In the case of sporadic AD, an imbalance in Aβ in production and clearance seems to be the reason for an enhanced Aβ accumulation. Besides a systematic clearance through the blood-brain barrier, Aβ is cleared from the brain by Aβ-degrading enzymes. The metalloprotease neprilysin (NEP) is an important Aβ-degrading enzyme as shown by numerous in vitro, in vivo and reverse genetics studies. 5XFAD mice represent an early-onset AD mouse model which develops plaque pathology starting with 2 months of age in addition to robust behavioral deficits at later time points. By crossing 5XFAD mice with homozygous NEP-knock-out mice (NEP-/-), we show that hemizygous NEP deficiency aggravates the behavioral and neuropathological phenotype of 5XFAD mice. We found that 5XFAD mice per se showed strongly decreased NEP expression levels compared to wildtype mice, which was aggravated by NEP reduction. 5XFAD/NEP+/- mice demonstrated impairment in spatial working memory and increased astrocytosis in all studied brain areas, in addition to an overall increased level of soluble Aβ42 as well as region-specific increases in extracellular Aβ deposition. Surprisingly, in young mice, a more abundant cortical Aβ plaque pathology was observed in 5XFAD compared to 5XFAD/NEP+/- mice. Additionally, young 5XFAD/NEP+/- as well as hemi- and homozygous NEP knockout mice showed elevated levels of endothelin-converting enzyme 1 (ECE1), suggesting a mutual regulation of ECE1 and NEP at young ages. The present data indicate that NEP mainly degrades soluble Aβ peptides, which confirms previous observations. Increased ECE1 levels correlated well with the strongly reduced extracellular plaque load in young 5XFAD/NEP+/- mice and might suggest a reciprocal effect between ECE and NEP activities in Aβ degradation. © 2015 - IOS Press and the authors. All rights reserved.

Bulic B.,Research Group Chemical Biology of Neurodegenerative Diseases | Ness J.,Heinrich Group | Hahn S.,Heinrich Group | Rennhack A.,Research Group Chemical Biology of Neurodegenerative Diseases | And 2 more authors.
Current Neuropharmacology | Year: 2011

Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Aβ peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs. © 2011 Bentham Science Publishers.

Liebner S.,Heinrich Group | Plate K.,Heinrich Group
Journal of Angiogenesis Research | Year: 2010

Vascularization of the vertebrate brain takes place during embryonic development from a preformed perineural vascular plexus. As a consequence of the intimate contact with neuroectodermal cells the vessels, which are entering the brain exclusively via sprouting angiogenesis, acquire and maintain unique barrier properties known as the blood-brain barrier (BBB). The endothelial BBB depends upon the close association of endothelial cells with pericytes, astrocytes, neurons and microglia, which are summarized in the term neuro-vascular unit. Although it is known since decades that the CNS tissue provides the cues for BBB induction and differentiation in endothelial cells, the molecular mechanism remained obscure. Only recently, the canonical Wnt/-catenin pathway and the Wnt7a/7b growth factors have been implicated in brain angiogenesis on the one hand and in BBB induction on the other. This breakthrough in understanding the differentiation of the brain vasculature prompted us to review these findings embedded in the emerging concepts of Wnt signaling in the vasculature. In particular, interactions with other pathways that are crucial for vascular development such as VEGF, Notch, angiopoietins and Sonic hedgehog are discussed. Finally, we considered the potential role of the Wnt pathway in vascular brain pathologies in which BBB function is hampered, as for example in glioma, stroke and Alzheimer's disease. © 2010 Liebner and Plate; licensee BioMed Central Ltd.

Liebmann J.,Heinrich Group | Born M.,Philips | Kolb-Bachofen V.,Heinrich Group
Journal of Investigative Dermatology | Year: 2010

Sunlight influences the physiology of the human skin in beneficial as well as harmful ways, as has been shown for UV light. However, little is known about the effects of other wavelengths of solar irradiation. In this study we irradiated human keratinocytes and skin-derived endothelial cells with light-emitting-diode devices of distinct wavelengths to study the effects on cell physiology. We found that light at wavelengths of 632-940 nm has no effect, but irradiation with blue light at 412-426 nm exerts toxic effects at high fluences. Light at 453 nm is nontoxic up to a fluence of 500 J/cm 2. At nontoxic fluences, blue light reduces proliferation dose dependently by up to 50%, which is attributable to differentiation induction as shown by an increase of differentiation markers. Experiments with BSA demonstrate that blue-light irradiation up to 453 nm photolytically generates nitric oxide (NO) from nitrosated proteins, which is known to initiate differentiation in skin cells. Our data provide evidence for a molecular mechanism by which blue light may be effective in treating hyperproliferative skin conditions by reducing proliferation due to the induction of differentiation. We observed a photolytic release of NO from nitrosated proteins, indicating that they are light acceptors and signal transducers up to a wavelength of 453 nm. © 2010 The Society for Investigative Dermatology.

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