Jonsson T.,University of Iceland |
Stefansson H.,University of Iceland |
Steinberg S.,University of Iceland |
Jonsdottir I.,University of Iceland |
And 24 more authors.
New England Journal of Medicine | Year: 2013
Background: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Methods: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. Results: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10-10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10-12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P = 0.003). Conclusions: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.) Copyright © 2012 Massachusetts Medical Society.
Muller S.,University of Frankfurt am Main |
Muller S.,GenXPro GmbH |
Muller S.,Institute of Computer Science |
Rycak L.,GenXPro GmbH |
And 4 more authors.
Bioinformatics | Year: 2013
Summary: Small RNA deep sequencing is widely used to characterize non-coding RNAs (ncRNAs) differentially expressed between two conditions, e.g. healthy and diseased individuals and to reveal insights into molecular mechanisms underlying condition-specific phenotypic traits. The ncRNAome is composed of a multitude of RNAs, such as transfer RNA, small nucleolar RNA and microRNA (miRNA), to name few. Here we present omiRas, a Web server for the annotation, comparison and visualization of interaction networks of ncRNAs derived from next-generation sequencing experiments of two different conditions. The Web tool allows the user to submit raw sequencing data and results are presented as: (i) static annotation results including length distribution, mapping statistics, alignments and quantification tables for each library as well as lists of differentially expressed ncRNAs between conditions and (ii) an interactive network visualization of user-selected miRNAs and their target genes based on the combination of several miRNA-mRNA interaction databases. Availability and Implementation: The omiRas Web server is implemented in Python, PostgreSQL, R and can be accessed at: http://tools.genxpro.net/omiras/. Contact: firstname.lastname@example.org Supplementary Information: Supplementary data are available at Bioinformatics online. © The Author 2013. Published by Oxford University Press.
News Article | November 12, 2016
University of Tübingen researchers have developed new inhibitors which act on a special enzyme known as the Janus kinase 3 (JAK3). Janus kinases carry out important intracellular functions in many organs -- for instance, activating key signal pathways in the systems which form new blood cells. But mutations in Janus kinase genes can cause alterations in these processes, leading to a number of blood and immune diseases. Because many cytokines use Janus kinases to carry their signals during inflammation, these molecules also play a major role in inflammatory autoimmune disorders such as rheumatoid arthritis and psoriasis. If researchers can inhibit the function of Janus kinases, they may be able to find better treatments for a number of diseases. The researchers have published their findings in the latest edition of Cell Chemical Biology. "For ten years, medicine has been looking for the right inhibitors to control the effect of JAK3," says Stefan Laufer, Professor of Pharmaceutical Chemistry at the University of Tübingen. "Because JAK3 has such an isolated role in the immune system, we believe that inhibiting it will lead to a suppression of immune responses which could be used to treat autoimmune disorders like psoriasis and rheumatoid arthritis. All the agents which are currently available -- and have been approved as medication in some countries -- inhibit several Janus kinases at the same time." That may be the cause of undesirable side effects observed in patients treated with JAK inhibitors. The JAK inhibitors developed in Tübingen exploit small differences in the amino acid sequences of the four types of Janus kinases. They bond with a cysteine amino acid which only occurs in JAK3 -- thereby blocking this enzyme but not the other Janus kinases. "There are more than 500 kinases in the human body; and many of them are essential building-blocks of life," Laufer explains. "So it is of vital importance that a JAK inhibitor has a very selective effect." The promising properties of the new inhibitors saw them registered in the Structural Genomics Consortium's Chemical Probe program. The Structural Genomics Consortium is a global network of research universities and pharmaceutical companies which focuses on research into genetically-determined disorders and communicates findings to researchers around the world. An important contribution has been made to it by Professor Stefan Knapp of the University of Frankfurt am Main. The Consortium also has long had ties with the University of North Carolina in Chapel Hill, one of Tübingen's partner universities in the US. "Making our inhibitors available could take basic research and the understanding of JAK signal pathways and their role in guiding the immune system a big step further in the future," Laufer says.
Haeussinger F.B.,University of Tübingen |
Heinzel S.,University of Tübingen |
Heinzel S.,University of Würzburg |
Heinzel S.,German Center for Neurodegenerative Diseases |
And 5 more authors.
PLoS ONE | Year: 2011
Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age: (25.0 ± 2.8) years), we characterized the individual distribution of tissue-specific NIR-light absorption underneath 24 prefrontal fNIRS channels. We, thereby, investigated the impact of scalp-cortex distance (SCD), frontal sinus volume as well as sulcal morphology on gray matter volumes (V gray) traversed by NIR-light, i.e. anatomy-dependent fNIRS sensitivity. The NIR-light absorption between optodes was distributed describing a rotational ellipsoid with a mean penetration depth of (23.6 ± 0.7)mm considering the deepest 5% of light. Of the detected photon packages scalp and bone absorbed (96.4 ± 9.7)% and V gray absorbed (3.1 ± 1.8)% of the energy. The mean V gray volume (1.1 ± 0.4)cm 3 was negatively correlated (r= -.76) with the SCD and frontal sinus volume (r= -.57) and was reduced by 41.5% in subjects with relatively large compared to small frontal sinus. Head circumference was significantly positively correlated with the mean SCD (r=.46) and the traversed frontal sinus volume (r=.43). Sulcal morphology had no significant impact on V gray. Our findings suggest to consider individual SCD and frontal sinus volume as anatomical factors impacting fNIRS sensitivity. Head circumference may represent a practical measure to partly control for these sources of error variance. © 2011 Haeussinger et al.
Rodel F.,University of Frankfurt Am Main |
Sprenger T.,University of Gottingen |
Kaina B.,University Medical Center Mainz |
Liersch T.,University of Frankfurt Am Main |
And 3 more authors.
Current Medicinal Chemistry | Year: 2012
Evasion from apoptotic cell death is reported to be a pivotal mechanism by which tumor cells acquire resistance to therapeutic treatment. Targeting the apoptotic pathways may constitute a promising strategy to counteract therapy resistance and to re-sensitize cancer cells. Expression of survivin, the smallest and structurally unique member of the inhibitor of apoptosis protein (IAP) family, has been shown to be associated with poor clinical outcome, more aggressive clinicopathologic features and resistance to both, conventional chemo and radiation therapy. Moreover, survivin detection in cancer tissue, in circulating tumor cells and in patient's serum has prognostic and predictive relevance and may display a prerequisite for marker based molecular therapies. Indeed, due to its universal over expression in malignant tissue, and its prominent role at disparate networks of cellular division, intracellular signaling, apoptosis and adaption to unfavorable surroundings, survivin has been shown to be a suitable target for a targeted therapy. The applicability of survivindriven strategies in clinical practice is currently under investigation as the first survivin antagonists (small molecule inhibitors, antisense oligonucleotides and immunotherapy) successfully entered phase I/II trials. Taken together, these data provide a rationale for the implementation of both, survivin as a molecular diagnostic tool and survivin targeted therapies, within future clinical practice. © 2012 Bentham Science Publishers.
Neumann K.,University of Frankfurt am Main |
Stephens D.,University of Cardiff
Folia Phoniatrica et Logopaedica | Year: 2011
Objective: To develop a clear and meaningful set of definitions of types of hearing impairment. Method: A critical analysis was made of previous definitions together with a consideration of current knowledge of functions and dysfunctions of the auditory system. Results and Conclusions: A coherent set of definitions compatible with the contemporary understanding of auditory disorders and their perceptual effects is proposed. Copyright © 2010 S. Karger AG, Basel.
Reichert S.,University of Frankfurt Am Main |
Reinboldt V.,University of Frankfurt Am Main |
Hehlgans S.,University of Frankfurt Am Main |
Efferth T.,University of Mainz |
And 2 more authors.
Radiotherapy and Oncology | Year: 2012
Background and purpose: Novel strategies to overcome an irradiation resistant phenotype may help to increase therapeutic efficacy in glioblastoma multiforme. The present study aimed to elucidate radiation sensitizing properties of artesunate, a semi synthetic derivate of artemisinin and to assess factors involved in this effect. Materials and methods: LN229 and U87MG cells were treated with various concentrations of artesunate and radiation response was determined by a colony forming assay. Cell numbers, apoptosis induction, cell cycle distribution, and DNA repair following combined modality treatment were monitored by MTT-, caspase 3/7 assay, cytofluorometry, and γ-H2AX foci formation. Expression of survivin, survivin-GFP fusion protein, XIAP, cellular (c)IAP1 and cIAP2 was monitored by Western immunoblotting. Results: Treatment of glioma cells with artesunate and irradiation resulted in an increased apoptotic fraction, pronounced G2/M arrest and increased DNA damage as demonstrated by an elevated amount of γ-H2AX foci/nucleus. Incubation with artesunate lowers survivin expression in a time and dose-dependent manner, whereas expression of XIAP, cIAP1 and cIAP2 was not affected. In clonogenic assays, treatment with artesunate revealed a significantly reduced surviving fraction, whereas stable over expression of a survivin-GFP protein reversed artesunate-mediated radiosensitization. Conclusion: Artesunate selectively down regulates survivin that contributes to a radio-sensitization of glioma cells by an increased induction of apoptosis, cell cycle arrest, and a hampered DNA damage response. © 2012 Elsevier Ireland Ltd. All rights reserved.
Reichert S.,University of Frankfurt Am Main |
Rodel C.,University of Frankfurt Am Main |
Mirsch J.,University of Frankfurt Am Main |
Harter P.N.,Goethe University Frankfurt |
And 4 more authors.
Radiotherapy and Oncology | Year: 2011
Background and purpose: Gliomas display prime examples of ionizing radiation (IR) resistant tumors. The IAP Survivin is reported to be critically involved in radiation resistance by anti-apoptotic and by caspase-independent mechanisms. The present study aimed to elucidate an interrelationship between Survivin's cellular localization and DNA damage repair in glioma cells. Material and methods: Cellular distribution and nuclear complex formation were assayed by immunoblotting, immunofluorescence staining and co-immunoprecipitation of Survivin bound proteins in LN229 glioblastoma cells. Apoptosis induction, survival and DNA repair following IR were assayed by means of caspase3/7 activity, clonogenic assay, γ-H2AX/53BP1 foci formation, single cell gel electrophoresis assay, and DNA-PKcs kinase assay in the presence of Survivin siRNA or over expression of Survivin-GFP. Results: Following irradiation, we observed a nuclear accumulation and a direct interrelationship between Survivin, MDC1, γ-H2AX, 53BP1 and DNA-PKcs, which was confirmed by immunofluorescence co-localization. Survivin downregulation by siRNA resulted in an increased apoptotic fraction, decreased clonogenic survival and increased DNA-damage, as demonstrated by higher amount of DNA breaks and an increased amount of γ-H2AX/53BP1 foci post irradiation. Furthermore, we detected in Survivin-depleted LN229 cells a hampered S2056 (auto)phosphorylation and a significantly decreased DNA-PKcs kinase activity. Conclusion: Nuclear accumulation of Survivin and interaction with components of the DNA-double-strand break (DSB) repair machinery indicates Survivin to regulate DSB damage repair that leads to a significant improvement of survival of LN229 glioblastoma cells. © 2011 Elsevier Ireland Ltd. All rights reserved.
Haueisen H.,University of Frankfurt am Main
Quintessence international (Berlin, Germany : 1985) | Year: 2013
A vertical root fracture (VRF) is a frustrating complication that may occur following root canal treatment, and in almost every case leads to the extraction of the affected tooth. This type of fracture is usually diagnosed by secondary symptoms that develop some time after primary treatment, often when prosthodontic restoration has already been completed. The fracture line itself is often not directly visible, and therefore clinical and radiographic signs and symptoms indicate the diagnosis indirectly. Knowledge of the condition and pathogenesis of VRF is required in order to avoid hopeless trials of periodontal and/or endodontic therapy. Several etiologic factors are discussed that make teeth susceptible to VRF, such as the loss of substance due to restorative and endodontic therapy and stress factors associated with root canal debridement, and filling.
Stockburger C.,University of Frankfurt am Main |
Kurz C.,University of Frankfurt am Main |
Koch K.A.,University of Frankfurt am Main |
Eckert S.H.,University of Frankfurt am Main |
And 2 more authors.
Biochemical Society Transactions | Year: 2013
The metabolic enhancer piracetam is used in many countries to treat cognitive impairment in aging, brain injuries, as well as dementia such as AD (Alzheimer's disease). As a specific feature of piracetam, beneficial effects are usually associated with mitochondrial dysfunction. In previous studies we were able to show that piracetam enhanced ATP production, mitochondrial membrane potential as well as neurite outgrowth in cell and animal models for aging and AD. To investigate further the effects of piracetam on mitochondrial function, especially mitochondrial fission and fusion events, we decided to assess mitochondrial morphology. Human neuroblastoma cells were treated with the drug under normal conditions and under conditions imitating aging and the occurrence of ROS (reactive oxygen species) as well as in stably transfected cells with the human wild-type APP (amyloid precursor protein) gene. This AD model is characterized by expressing only 2-fold more human Aβ (amyloid β-peptide) compared with control cells and therefore representing very early stages of AD when Aβ levels gradually increase over decades. Interestingly, these cells exhibit an impaired mitochondrial function and morphology under baseline conditions. Piracetam is able to restore this impairment and shifts mitochondrial morphology back to elongated forms, whereas there is no effect in control cells. After addition of a complex I inhibitor, mitochondrial morphology is distinctly shifted to punctate forms in both cell lines. Under these conditions piracetam is able to ameliorate morphology in cells suffering from the mild Aβ load, as well as mitochondrial dynamics in control cells. ©2013 Biochemical Society.