Center for Integrative Bioinformatics Vienna

Vienna, Austria

Center for Integrative Bioinformatics Vienna

Vienna, Austria
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PubMed | Leibniz Institute for Natural Product Research and Infection Biology, Friedrich - Schiller University of Jena, Center for Integrative Bioinformatics Vienna and University of Gottingen
Type: Journal Article | Journal: FEMS microbiology ecology | Year: 2015

The genome sequence of Tricholoma vaccinum was obtained to predict its secretome in order to elucidate communication of T. vaccinum with its host tree spruce (Picea abies) in interkingdom signaling. The most prominent protein domains within the 206 predicted secreted proteins belong to energy and nutrition (52%), cell wall degradation (19%) and mycorrhiza establishment (9%). Additionally, we found small secreted proteins that show typical features of effectors potentially involved in host communication. From the secretome, 22 proteins could be identified, two of which showed higher protein abundances after spruce root exudate exposure, while five were downregulated in this treatment. The changes in T. vaccinum protein excretion with first recognition of the partner were used to identify small secreted proteins with the potential to act as effectors in the mutually beneficial symbiosis. Our observations support the hypothesis of a complex communication network including a cocktail of communication molecules induced long before physical contact of the partners.


Foerster A.M.,Gregor Mendel Institute of Molecular Plant Biology | Dinh H.Q.,Gregor Mendel Institute of Molecular Plant Biology | Dinh H.Q.,Center for Integrative Bioinformatics Vienna | Sedman L.,Gregor Mendel Institute of Molecular Plant Biology | And 2 more authors.
PLoS Genetics | Year: 2011

Analogous to genetically distinct alleles, epialleles represent heritable states of different gene expression from sequence-identical genes. Alleles and epialleles both contribute to phenotypic heterogeneity. While alleles originate from mutation and recombination, the source of epialleles is less well understood. We analyze active and inactive epialleles that were found at a transgenic insert with a selectable marker gene in Arabidopsis. Both converse expression states are stably transmitted to progeny. The silent epiallele was previously shown to change its state upon loss-of-function of trans-acting regulators and drug treatments. We analyzed the composition of the epialleles, their chromatin features, their nuclear localization, transcripts, and homologous small RNA. After mutagenesis by T-DNA transformation of plants carrying the silent epiallele, we found new active alleles. These switches were associated with different, larger or smaller, and non-overlapping deletions or rearrangements in the 3′ regions of the epiallele. These cis-mutations caused different degrees of gene expression stability depending on the nature of the sequence alteration, the consequences for transcription and transcripts, and the resulting chromatin organization upstream. This illustrates a tight dependence of epigenetic regulation on local structures and indicates that sequence alterations can cause epigenetic changes at some distance in regions not directly affected by the mutation. Similar effects may also be involved in gene expression and chromatin changes in the vicinity of transposon insertions or excisions, recombination events, or DNA repair processes and could contribute to the origin of new epialleles. © 2011 Foerster et al.


Bracher A.,Medical University of Vienna | Cardona A.S.,Medical University of Vienna | Tauber S.,Medical University of Vienna | Tauber S.,Center for Integrative Bioinformatics Vienna | And 7 more authors.
Journal of Investigative Dermatology | Year: 2013

Alterations in epidermal growth factor (EGF) expression are known to be of prognostic relevance in human melanoma, but EGF-mediated effects on melanoma have not been extensively studied. As lymph node metastasis usually represents the first major step in melanoma progression, we were trying to identify a potential role of primary tumor-derived EGF in the mediation of melanoma lymph node metastases. Stable EGF knockdown (EGFkd) in EGF-high (M24met) and EGF-low (A375) expressing melanoma cells was generated. Only in EGF-high melanoma cells, EGFkd led to a significant reduction of lymph node metastasis and primary tumor lymphangiogenesis in vivo, as well as impairment of tumor cell migration in vitro. Moreover, EGF-induced sprouting of lymphatic but not of blood endothelial cells was abolished using supernatants of M24met EGFkd cells. In addition, M24met EGFkd tumors showed reduced vascular endothelial growth factor-C (VEGF-C) expression levels. Similarly, in human primary melanomas, a direct correlation between EGF/VEGF-C and EGF/Prox-1 expression levels was found. Finally, melanoma patients with lymph node micrometastases undergoing sentinel node biopsy were found to have significantly elevated EGF serum levels as compared with sentinel lymph node-negative patients. Our data indicate that tumor-derived EGF is important in mediating melanoma lymph node metastasis. © 2013 The Society for Investigative Dermatology.


Gurley K.A.,Howard Hughes Medical Institute | Gurley K.A.,University of Pittsburgh | Elliott S.A.,Howard Hughes Medical Institute | Simakov O.,EMBL Heidelberg | And 4 more authors.
Developmental Biology | Year: 2010

Regeneration is widespread throughout the animal kingdom, but our molecular understanding of this process in adult animals remains poorly understood. Wnt/β-catenin signaling plays crucial roles throughout animal life from early development to adulthood. In intact and regenerating planarians, the regulation of Wnt/β-catenin signaling functions to maintain and specify anterior/posterior (A/P) identity. Here, we explore the expression kinetics and RNAi phenotypes for secreted members of the Wnt signaling pathway in the planarian Schmidtea mediterranea. Smed-wnt and sFRP expression during regeneration is surprisingly dynamic and reveals fundamental aspects of planarian biology that have been previously unappreciated. We show that after amputation, a wounding response precedes rapid re-organization of the A/P axis. Furthermore, cells throughout the body plan can mount this response and reassess their new A/P location in the complete absence of stem cells. While initial stages of the amputation response are stem cell independent, tissue remodeling and the integration of a new A/P address with anatomy are stem cell dependent. We also show that WNT5 functions in a reciprocal manner with SLIT to pattern the planarian mediolateral axis, while WNT11-2 patterns the posterior midline. Moreover, we perform an extensive phylogenetic analysis on the Smed-wnt genes using a method that combines and integrates both sequence and structural alignments, enabling us to place all nine genes into Wnt subfamilies for the first time. © 2010 Elsevier Inc.


News Article | November 4, 2016
Site: phys.org

It is estimated that in Germany alone around 150,000 people fall ill with sepsis every year; despite medical advances, between 30 and 50 percent of the patients still die of the consequences (see box). One of the reasons for the high mortality rate: the diagnosis often comes too late for the lifesaving therapy with antibiotics that only combat the specific causative pathogen. In general the sepsis pathogens are detected by means of so-called blood cultures in which the pathogenic organism from blood samples of the patients are cultivated in the laboratory. Here, two to five days pass before the pathogens have multiplied and a result is available. Due to rapid progress in nucleic acid analysis, the currently available high-throughput technologies (NGS, Next-Generation Sequencing) make it possible to sequence the complete genome of organisms within just a few hours and to check them against known gene sequences (see box). On the basis of these technologies researchers at the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB have developed an alternative diagnostic platform for sepsis. This enables them to identify bacteria, fungi or viruses directly by means of a sequence analysis of their DNA – without having to cultivate the pathogens beforehand in the laboratory. In a clinical study that the researchers carried out in cooperation with Heidelberg University Hospital, they have now validated their diagnostic method with blood samples from sepsis patients. Here, they identified the infectious microorganisms by means of the high-throughput sequencing of DNA circulating freely in the blood (CNAPS, Circulating Nucleic Acids in Plasma and Serum). "With our next-generation sequencing diagnostic method we were able to determine within just 24 hours which pathogens the patients were infected with," Dr. Kai Sohn, head of the "Functional Genomics" working group at Fraunhofer IGB, explains. "As a result of the direct sequencing of the DNA of a blood sample, the time-consuming step of cultivating the microorganisms in the lab is no longer necessary. In this way we can also identify those pathogens that are more difficult to grow under laboratory conditions," says Dr. Sohn. A further advantage: If the samples contain not only the DNA of bacteria, but also that of viruses or fungi, these are sequenced, analyzed and identified as well. "For example, in our study we were able to identify a viral pathogen as the cause of a patient's illness. Yet the patient's blood culture showed a negative result because here only bacteria can be detected," the scientist explains. The method provides both qualitative and quantitative results at the same time. "With our technology, we can recognize on the basis of the number of genome fragments which pathogens have greatly multiplied in the patient and which are already responding to the therapy," Dr. Sohn points out. This permits the physician to immediately implement further targeted therapeutic measures instead of allowing valuable time to pass employing incorrect medication. Over 99 percent of the DNA freely circulating in the blood plasma is of human origin – thus identifying the sepsis pathogens resembles the proverbial search for a needle in a haystack. The researchers therefore use special software programs to compare the sequenced fragments with a genome database into which they have entered publicly available DNA sequences of bacteria, fungi and viruses. However, not every microorganism that is identified is necessarily also the cause of the sepsis. One of the greatest challenges in the evaluation of the sequencing data is therefore to assess whether the finding differs from the statistically expected result. In order to be able to answer this decisive question, Philip Stevens, the bioinformatics specialist in the team, developed a special algorithm in his doctoral thesis at the Center for Integrative Bioinformatics Vienna (CIBIV) and the Institute of Interfacial Process Engineering and Plasma Technology (IGVP) of the University of Stuttgart. The centerpiece of the diagnostic method, for which a patent is pending, compares the sequencing results with sequenced fragments from the blood of healthy test persons. "In this way the algorithm provides us with a score with which we can assess the significance of the data and can exclude the microbial "background noise", i.e. harmless bacteria of our skin or intestinal flora, as diagnostically relevant pathogens," Stevens explains. The clinical study showed that the computed diagnoses correlated closely with those of the blood culture. The resistance of bacteria to commonly used antibiotics such as methicillin, vancomycin or tetracycline is acquired via corresponding resistance genes. Therefore high-throughput sequencing makes it possible, in the same analysis, to identify both the biological species of the pathogen and its resistance genes. This also helps the physician treating the patient to set in motion a targeted therapy. In order to further shorten the time from sample to final diagnosis, the scientists are examining how the method can be transferred to more recently developed sequencing platforms. With nanopore-based sequencing, for example, which is currently in the test phase, DNA can be sequenced in an even shorter time than previously. Thus in future the specific diagnosis of infections would be possible within a period of six to eight hours. For 2017 the Fraunhofer scientists are planning to carry out a multicenter validation study together with leading clinical partners. Explore further: UTI testing technology cuts screening time to four hours More information: Silke Grumaz et al. Next-generation sequencing diagnostics of bacteremia in septic patients, Genome Medicine (2016). DOI: 10.1186/s13073-016-0326-8


News Article | November 6, 2016
Site: www.sciencedaily.com

Microbial pathogens can be diagnosed unambiguously and within just 24 hours by means of high-throughput sequencing of their genetic makeup and special bioinformatics evaluation algorithms. Fraunhofer researchers have validated this in a clinical study with sepsis patients. The researchers present the NGS diagnosis platform at Medica in Düsseldorf from November 14-17, 2016. It is estimated that in Germany alone around 150,000 people fall ill with sepsis every year; despite medical advances, between 30 and 50 percent of the patients still die of the consequences (see box). One of the reasons for the high mortality rate: the diagnosis often comes too late for the lifesaving therapy with antibiotics that only combat the specific causative pathogen. In general the sepsis pathogens are detected by means of so-called blood cultures in which the pathogenic organism from blood samples of the patients are cultivated in the laboratory. Here, two to five days pass before the pathogens have multiplied and a result is available. Due to rapid progress in nucleic acid analysis, the currently available high-throughput technologies (NGS, Next-Generation Sequencing) make it possible to sequence the complete genome of organisms within just a few hours and to check them against known gene sequences (see box). On the basis of these technologies researchers at the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB have developed an alternative diagnostic platform for sepsis. This enables them to identify bacteria, fungi or viruses directly by means of a sequence analysis of their DNA -- without having to cultivate the pathogens beforehand in the laboratory. In a clinical study that the researchers carried out in cooperation with Heidelberg University Hospital, they have now validated their diagnostic method with blood samples from sepsis patients. Here, they identified the infectious microorganisms by means of the high-throughput sequencing of DNA circulating freely in the blood (CNAPS, Circulating Nucleic Acids in Plasma and Serum). "With our next-generation sequencing diagnostic method we were able to determine within just 24 hours which pathogens the patients were infected with," Dr. Kai Sohn, head of the "Functional Genomics" working group at Fraunhofer IGB, explains. "As a result of the direct sequencing of the DNA of a blood sample, the time-consuming step of cultivating the microorganisms in the lab is no longer necessary. In this way we can also identify those pathogens that are more difficult to grow under laboratory conditions," says Dr. Sohn. A further advantage: If the samples contain not only the DNA of bacteria, but also that of viruses or fungi, these are sequenced, analyzed and identified as well. "For example, in our study we were able to identify a viral pathogen as the cause of a patient's illness. Yet the patient's blood culture showed a negative result because here only bacteria can be detected," the scientist explains. The method provides both qualitative and quantitative results at the same time. "With our technology, we can recognize on the basis of the number of genome fragments which pathogens have greatly multiplied in the patient and which are already responding to the therapy," Dr. Sohn points out. This permits the physician to immediately implement further targeted therapeutic measures instead of allowing valuable time to pass employing incorrect medication. Over 99 percent of the DNA freely circulating in the blood plasma is of human origin -- thus identifying the sepsis pathogens resembles the proverbial search for a needle in a haystack. The researchers therefore use special software programs to compare the sequenced fragments with a genome database into which they have entered publicly available DNA sequences of bacteria, fungi and viruses. However, not every microorganism that is identified is necessarily also the cause of the sepsis. One of the greatest challenges in the evaluation of the sequencing data is therefore to assess whether the finding differs from the statistically expected result. In order to be able to answer this decisive question, Philip Stevens, the bioinformatics specialist in the team, developed a special algorithm in his doctoral thesis at the Center for Integrative Bioinformatics Vienna (CIBIV) and the Institute of Interfacial Process Engineering and Plasma Technology (IGVP) of the University of Stuttgart. The centerpiece of the diagnostic method, for which a patent is pending, compares the sequencing results with sequenced fragments from the blood of healthy test persons. "In this way the algorithm provides us with a score with which we can assess the significance of the data and can exclude the microbial "background noise," i.e. harmless bacteria of our skin or intestinal flora, as diagnostically relevant pathogens," Stevens explains. The clinical study showed that the computed diagnoses correlated closely with those of the blood culture. The resistance of bacteria to commonly used antibiotics such as methicillin, vancomycin or tetracycline is acquired via corresponding resistance genes. Therefore high-throughput sequencing makes it possible, in the same analysis, to identify both the biological species of the pathogen and its resistance genes. This also helps the physician treating the patient to set in motion a targeted therapy. In order to further shorten the time from sample to final diagnosis, the scientists are examining how the method can be transferred to more recently developed sequencing platforms. With nanopore-based sequencing, for example, which is currently in the test phase, DNA can be sequenced in an even shorter time than previously. Thus in future the specific diagnosis of infections would be possible within a period of six to eight hours. For 2017 the Fraunhofer scientists are planning to carry out a multicenter validation study together with leading clinical partners. Fraunhofer IGB presents sepsis diagnostics by means of next-generation sequencing at Medica in Düsseldorf from November 14-17, 2016 at the Fraunhofer joint stand.


Loidl J.,University of Vienna | Lukaszewicz A.,University of Vienna | Howard-Till R.A.,University of Vienna | Koestler T.,Center for Integrative Bioinformatics Vienna
Journal of Cell Science | Year: 2012

In order to form crossovers and to undergo reductional segregation during meiosis, homologous chromosomes must pair. In Tetrahymena, meiotic prophase nuclei elongate immensely, and, within the elongated nucleus, chromosomes are arranged with telomeres assembled at one pole and centromeres at the opposite pole. This organisation is an exaggerated form of the bouquet, a meiotic chromosome arrangement that is widely conserved among eukaryotes. We show that centromere function is crucial for the formation of Tetrahymena's stretched bouquet and, thereby, for homologue pairing. This finding adds to previous reports of the importance of centromeres in chromosome pairing in budding yeast and in Drosophila. Tetrahymena's bouquet is an ataxia telangiectasia- and RAD3-related (ATR)-dependent meiotic DNA damage response that is triggered by meiotic DNA double-strand breaks (DSBs), suggesting that the bouquet is needed for DSB repair. However, in the present study we show that although homologous pairing is impeded in the absence of the bouquet, DSB repair takes place nevertheless. Moreover, recombinational DSB repair, as monitored by bromodeoxyuridine incorporation, takes place only after exit from the bouquet stage. Therefore, we conclude that the bouquet is not required for DSB repair per se, but may be necessary for the alignment of homologous loci in order to promote homologous crossovers over alternative repair pathways. © 2012. Published by The Company of Biologists Ltd.


Lorenz R.,University of Vienna | Lorenz R.,The Interdisciplinary Center | Luntzer D.,University of Vienna | Hofacker I.L.,University of Vienna | And 4 more authors.
Bioinformatics | Year: 2015

Summary: Chemical mapping experiments allow for nucleotide resolution assessment of RNA structure. We demonstrate that different strategies of integrating probing data with thermodynamics-based RNA secondary structure prediction algorithms can be implemented by means of soft constraints. This amounts to incorporating suitable pseudo-energies into the standard energy model for RNA secondary structures. As a showcase application for this new feature of the ViennaRNA Package we compare three distinct, previously published strategies to utilize SHAPE reactivities for structure prediction. The new tool is benchmarked on a set of RNAs with known reference structure. Availability and implementation: The capability for SHAPE directed RNA folding is part of the upcoming release of the ViennaRNA Package 2.2, for which a preliminary release is already freely available at http://www.tbi.univie.ac.at/RNA. © 2015 The Author 2015. Published by Oxford University Press.


Koestler T.,University of Vienna | Koestler T.,Medical University of Vienna | Koestler T.,Center for Integrative Bioinformatics Vienna | Haeseler A.V.,University of Vienna | And 5 more authors.
Molecular Biology and Evolution | Year: 2012

Simulating the change of protein sequences over time in a biologically realistic way is fundamental for a broad range of studies with a focus on evolution. It is, thus, problematic that typically simulators evolve individual sites of a sequence identically and independently. More realistic simulations are possible; however, they are often prohibited by limited knowledge concerning site-specific evolutionary constraints or functional dependencies between amino acids. As a consequence, a protein's functional and structural characteristics are rapidly lost in the course of simulated evolution. Here, we present REvolver (www.cibiv.at/software/revolver), a program that simulates protein sequence alteration such that evolutionarily stable sequence characteristics, like functional domains, are maintained. For this purpose, REvolver recruits profile hidden Markov models (pHMMs) for parameterizing site-specific models of sequence evolution in an automated fashion. pHMMs derived from alignments of homologous proteins or protein domains capture information regarding which sequence sites remained conserved over time and where in a sequence insertions or deletions are more likely to occur. Thus, they describe constraints on the evolutionary process acting on these sequences. To demonstrate the performance of REvolver as well as its applicability in large-scale simulation studies, we evolved the entire human proteome up to 1.5 expected substitutions per site. Simultaneously, we analyzed the preservation of Pfam and SMART domains in the simulated sequences over time. REvolver preserved 92 of the Pfam domains originally present in the human sequences. This value drops to 15 when traditional models of amino acid sequence evolution are used. Thus, REvolver represents a significant advance toward a realistic simulation of protein sequence evolution on a proteome-wide scale. Further, REvolver facilitates the simulation of a protein family with a user-defined domain architecture at the root. © 2012 The Author(s).


Coccia E.,University of L'Aquila | Chernomor O.,University of L'Aquila | Chernomor O.,Center for Integrative Bioinformatics Vienna | Barborini M.,University of L'Aquila | And 2 more authors.
Journal of Chemical Theory and Computation | Year: 2012

We used Quantum Monte Carlo (QMC) methods to study the polarizability and the quadrupole moment of the ethyne molecule using the Jastrow-Antisymmetrised Geminal Power (JAGP) wave function, a compact and strongly correlated variational ansatz. The compactness of the functional form and the full optimization of all its variational parameters, including linear and exponential coefficients in atomic orbitals, allow us to observe a fast convergence of the electrical properties with the size of the atomic and Jastrow basis sets. Both variational results on isotropic polarizability and quadrupole moment based on Gaussian type and Slater type basis sets are very close to the Lattice Regularized Diffusion Monte Carlo values and in very good agreement with experimental data and with other quantum chemistry calculations. We also study the electronic density along the C - C and C-H bonds by introducing a generalization for molecular systems of the small-variance improved estimator of the electronic density proposed by Assaraf et al. (Assaraf, R.; Caffarel, M.; Scemama, A. Phys. Rev. E, 2007, 75, 035701). © 2012 American Chemical Society.

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