Biomedical subjects

Andreas Wagner

Publications and source records attributed to Andreas Wagner.

At least 19 recordsLinked to original sources

PubMed2004

Molecular evolution in the yeast transcriptional regulation network.

We analyze the structure of the yeast transcriptional regulation network, as revealed by chromatin immunoprecipitation experiments, and characterize the molecular evolution of both its transcriptional regulators and their target (regulated) genes. We test the hypothesis that highly connected genes are more important to the function of gene networks. Three lines of evidence-the rate of molecular evolution of network genes, the rate at which network genes undergo gene duplication, and the effects of synthetic null mutation in network genes-provide no strong support for this hypothesis. In addition, we ask how network genes diverge in their transcriptional regulation after duplication. Both loss (subfunctionalization) and gain (neofunctionalization) of transcription factor binding play a role in this divergence, which is often rapid. On the one hand, gene duplicates experience a net loss in the number of transcription factors binding to them, indicating the importance of losing transcription factor binding sites after gene duplication. On the other hand, the number of transcription factors that bind to highly diverged duplicates is significantly greater than would be expected if loss of binding played the only role in the divergence of duplicate genes.

Binding Sites↗

PubMed2004

A fast algorithm for determining the best combination of local alignments to a query sequence.

BACKGROUND: Existing sequence alignment algorithms assume that similarities between DNA or amino acid sequences are linearly ordered. That is, stretches of similar nucleotides or amino acids are in the same order in both sequences. Recombination perturbs this order. An algorithm that can reconstruct sequence similarity despite rearrangement would be helpful for reconstructing the evolutionary history of recombined sequences. RESULTS: We propose a graph-based algorithm for combining multiple local alignments to a query sequence into the single combination of alignments that either covers the maximal portion of the query or results in the single highest alignment score to the query. This algorithm can help study the process of genome rearrangement, improve functional gene annotation, and reconstruct the evolutionary history of recombined proteins. The algorithm takes O(n2) time, where n is the number of local alignments considered. CONCLUSIONS: We discuss two example applications of the algorithm. The algorithm is able to provide useful reconstructions of the metazoan mitochondrial genome. It is also able to increase the percentage of a query sequence's amino acid residues for which similar stretches of amino acids can be found in sequence databases.

Algorithms↗

PubMed2004

Enriching for direct regulatory targets in perturbed gene-expression profiles.

Here we build on a previously proposed algorithm to infer direct regulatory relationships using gene-expression profiles from cells in which individual genes are deleted or overexpressed. The updated algorithm can process networks containing feedback loops, incorporate positive and negative regulatory relationships during network reconstruction, and utilize data from double mutants to resolve ambiguous regulatory relationships. When applied to experimental data the reconstruction procedure preferentially retains direct transcription factor-target relationships.

Algorithms↗

PubMed2004

A statistical framework for combining and interpreting proteomic datasets.

MOTIVATION: To identify accurately protein function on a proteome-wide scale requires integrating data within and between high-throughput experiments. High-throughput proteomic datasets often have high rates of errors and thus yield incomplete and contradictory information. In this study, we develop a simple statistical framework using Bayes' law to interpret such data and combine information from different high-throughput experiments. In order to illustrate our approach we apply it to two protein complex purification datasets. RESULTS: Our approach shows how to use high-throughput data to calculate accurately the probability that two proteins are part of the same complex. Importantly, our approach does not need a reference set of verified protein interactions to determine false positive and false negative error rates of protein association. We also demonstrate how to combine information from two separate protein purification datasets into a combined dataset that has greater coverage and accuracy than either dataset alone. In addition, we also provide a technique for estimating the total number of proteins which can be detected using a particular experimental technique. AVAILABILITY: A suite of simple programs to accomplish some of the above tasks is available at www.unm.edu/~compbio/software/DatasetAssess

Algorithms↗

PubMed2004

Duplicate genes and robustness to transient gene knock-downs in Caenorhabditis elegans.

We examine robustness to mutations in the nematode worm Caenorhabditis elegans and the role of single-copy and duplicate genes in it. We do so by integrating complete genome sequence and microarray gene expression data with results from a genome-scale study using RNA interference (RNAi) to temporarily eliminate the functions of more than 16000 worm genes. We found that 89% of single-copy and 96% of duplicate genes show no detectable phenotypic effect in an RNAi knock-down experiment. We find that mutational robustness is greatest for closely related gene duplicates, large gene families and similarly expressed genes. We discuss the different causes of mutational robustness in single-copy and duplicate genes, as well as its evolutionary origin.

Animals↗

PubMed2004

Molecular evolution in large genetic networks: does connectivity equal constraint?

Genetic networks show a broad-tailed distribution of the number of interaction partners per protein, which is consistent with a power-law. It has been proposed that such broad-tailed distributions are observed because they confer robustness against mutations to the network. We evaluate this hypothesis for two genetic networks, that of the E. coli core intermediary metabolism and that of the yeast protein-interaction network. Specifically, we test the hypothesis through one of its key predictions: highly connected proteins should be more important to the cell and, thus, subject to more severe selective and evolutionary constraints. We find, however, that no correlation between highly connected proteins and evolutionary rate exists in the E. coli metabolic network and that there is only a weak correlation in the yeast protein-interaction network. Furthermore, we show that the observed correlation is function-specific within the protein-interaction network: only genes involved in the cell cycle and transcription show significant correlations. Our work sheds light on conflicting results by previous researchers by comparing data from multiple types of protein-interaction datasets and by using a closely related species as a reference taxon. The finding that highly connected proteins can tolerate just as many amino acid substitutions as other proteins leads us to conclude that power-laws in cellular networks do not reflect selection for mutational robustness.

Energy Metabolism↗

PubMed2004

X-ray detection of structural orientation in human articular cartilage.

OBJECTIVE: To determine the feasibility of detecting the structural orientation in cartilage with Diffraction Enhanced X-Ray Imaging. DESIGN: Human tali and femoral head specimens were Diffraction Enhanced X-Ray Imaged (DEI) at the SYRMEP beamline at Elettra at various energy levels to detect the architectural arrangement of collagen within cartilage. DEI utilizes a monochromatic and highly collimated beam, with an analyzer crystal that selectively weights out photons according to the angle they have been deviated with respect to the original direction. This provides images of very high contrast, and with the rejection of X-ray scatter. RESULTS: DEI allowed the visualization of articular cartilage and a structural orientation, resembling arcades, within. CONCLUSION: Our diffraction enhanced images represent the first radiographic detection of the structural orientation in cartilage. Our data are in line with previous studies on the structural organization of joint cartilage. They confirm the model of a vaulting system of collagen fiber bundles interrupted by proteoglycan aggregates.

Cartilage, Articular↗

PubMed2004

Reconstructing pathways in large genetic networks from genetic perturbations.

I present an algorithm that determines the longest path between every gene pair in an arbitrarily large genetic network from large scale gene perturbation data. The algorithm's computational complexity is O(nk(2)), where n is the number of genes in the network and k is the average number of genes affected by a genetic perturbation. The algorithm is able to distinguish a large fraction of direct regulatory interactions from indirect interactions, even if the accuracy of its input data is substantially compromised.

Algorithms↗

PubMed2003

Risk management in biological evolution.

I present a framework to study the evolution of traits that allow an organism to survive life-threatening but rare risks. Specifically, I am concerned with risks so rare that any one individual in a population may not experience the risk-causing event in its lifetime. A theory of rare risk management is virtually absent in evolutionary biology, although it is well developed in economics. This is surprising because of the great influence economics had on evolutionary biology, and because biology is full of examples for evolved risk management traits. They include the ability of bacteria to sporulate, of pathogens to survive antibiotic treatment, of temperate bacteriophages to enter a lytic life cycle, as well as traits that allow higher organisms to survive rare environmental disasters, such as sporadic wildfires and irregular flooding. I make predictions about the sustenance of risk management traits under two scenarios, one where the catastrophic events cause individual deaths, and another one where catastrophic events cause population extinction. A well-developed theory of risk management will not only predict the distribution of risk management traits, but may also serve other purposes, such as to reconstruct the spectrum of environments that an organism encountered in its evolutionary history from the record stored in its genome's memory.

Adaptation, Physiological↗

PubMed2003

Does selection mold molecular networks?

The dissection of molecular networks vital to cellular life can provide important hints about optimal network design principles. However, these hints can become conclusive only if one can determine that natural selection has molded a network's structure. I illustrate the importance of thorough studies of network evolution with two recent examples, one from genome-scale networks, the other from small transcriptional regulation circuits.

Animals↗

PubMed2003

Induction of cytotoxic T-cell responses against the oncofetal antigen-immature laminin receptor for the treatment of hematologic malignancies.

The oncofetal antigen immature laminin receptor protein (OFA-iLRP) is a highly conserved protein that is preferentially expressed in fetal tissues and in many types of cancer, including hematopoietic malignancies, whereas OFA-iLRP is not detectable on healthy differentiated adult cells. To investigate whether OFA-iLRP-specific cytotoxic T lymphocytes (CTLs) are capable of killing OFA-iLRP-expressing hematologic targets, CTLs were generated from healthy HLA-A*0201-positive volunteers by incubating T cells with autologous dendritic cells (DCs) transfected with OFA-iLRP RNA. OFA-iLRP-specific CTLs lysed HLA-A2+ OFA-iLRP+ tumor cells, including several lymphoma and leukemia cell lines, as well as fresh leukemic targets from patients with acute myeloid leukemia (AML) and chronic lymphatic leukemia (CLL), indicating that OFA-iLRP-derived peptides are naturally processed and presented by hematologic tumors. Healthy OFA-iLRP-negative target cells (CD14+ monocytes, activated B cells, DCs, bone marrow cells) were not attacked by OFA-iLRP-specific CTLs. Furthermore, in an established murine B-cell lymphoma model (A20), treatment with syngeneic DCs transfected with OFA-iLRP-coding RNA resulted in powerful antitumor effects in a significant portion of mice. For the first time, these data show that OFA-iLRP can be used as a target for T-cell-based immunotherapeutic strategies against hematologic malignancies.

Animals↗

PubMed2003

Generation of cytotoxic responses in mice and human individuals against hematological malignancies using survivin-RNA-transfected dendritic cells.

Survivin is a member of the inhibitors of apoptosis family and is overexpressed in many types of human cancers, making it an attractive target for T cell-based immunotherapeutic strategies. Recently, HLA-A2-binding peptides derived from the survivin protein were identified as capable of inducing specific T cell responses in cancer patients. Here we demonstrate that human survivin-specific CTLs generated from PBMC by stimulation with autologous dendritic cells transfected with survivin-RNA were cytotoxic for a range of hemopoietic malignant cell lines and primary tumor cells isolated from patients with acute myeloid leukemia. We also show that vaccination of mice with survivin-RNA-transfected dendritic cells leads to long term resistance to challenge by a survivin-expressing lymphoma, demonstrating the potential of survivin as a tumor rejection Ag. Our data provide evidence for the use of survivin as a target structure for immunotherapeutic strategies against hematological neoplasms.

Animals↗

PubMed2003

How the global structure of protein interaction networks evolves.

Two processes can influence the evolution of protein interaction networks: addition and elimination of interactions between proteins, and gene duplications increasing the number of proteins and interactions. The rates of these processes can be estimated from available Saccharomyces cerevisiae genome data and are sufficiently high to affect network structure on short time-scales. For instance, more than 100 interactions may be added to the yeast network every million years, a fraction of which adds previously unconnected proteins to the network. Highly connected proteins show a greater rate of interaction turnover than proteins with few interactions. From these observations one can explain (without natural selection on global network structure) the evolutionary sustenance of the most prominent network feature, the distribution of the frequency P(d) of proteins with d neighbours, which is broad-tailed and consistent with a power law, that is: P(d) proportional, variant d (-gamma).

Evolution, Molecular↗

PubMed2003

[Radiochemotherapy with gemcitabine and cisplatin in pancreatic cancer -- feasible and effective].

BACKGROUND: Concomitant radiotherapy and chemotherapy with gemcitabine appears to be a promising tool for the treatment of pancreatic cancer since gemcitabine -- applied as single or combination therapy -- proved to have better efficacy in pancreatic cancer than 5-FU containing schemes and furthermore offers radiosensitizing potential. In the present paper our pilot data of concomitant and sequential chemoradiation with gemcitabine and cisplatin are presented. PATIENTS AND METHODS: A total of 57 patients (f/m 23/34) with pancreatic cancer was treated, of whom 33 patients had irresectable tumors, 19 patients following resection (R1 and/or pN+) and five patients with local recurrent disease. Radiotherapy was delivered in 25 fractions up to a total dose of 45.0 Gy specified according to ICRU reference point (50 patients, 1.8 Gy/fraction) respectively 50.0 Gy to gross tumor volume (seven patients; 45.0 Gy in locoregional lymphatic pathways; 2.0/1.8 Gy/fraction). Concomitant with radiotherapy cisplatin (30 mg/m(2)) and gemcitabine (300 mg/m(2)) were applied on days 1, 8, 22 and 29. After simultaneous chemoradiation two sequential cycles gemcitabine and cisplatin (1000 mg/m(2) and 50 mg/m(2) d 1, 15) were applied. RESULTS: With a median follow-up of 8.2 months the median survival time was 14.8 months (irresectable patients: 10.3 months, postoperative patients, 15.1 months). Within 33 irresectable patients 19 and four partial and complete remissions, respectively, were observed. In 14 patients a secondary resection was possible. Using leveled antiemetics with ondansetron and dexamethasone no gastrointestinal toxicities grade III or IV were observed. Hematologic toxicities were the most grave side effects (leukocytopenia III/IV in 29/five patients and thrombocytopenia III/IV in 21/eight patients), however with minor clinical relevancy (one neutropenic infection, one thrombopenic epistaxis). CONCLUSION: The presented treatment scheme using concomitant and sequential gemcitabine and cisplatin with radiation is feasible with justifiable side effects. To evaluate the promising remission and survival rates, randomized trials of neoadjuvant and primary chemoradiation are started.

Adult↗

PubMed2003

First metatarsophalangeal joint replacement: the method of choice for end-stage hallux rigidus?

Replacement of the first metatarsophalangeal (MTP) joint remains critical because of complex biomechanical conditions and implant fixation. After a 3-year follow-up, most patients who experienced an MTP joint replacement were extremely satisfied with the outcome. Plantar pressure distribution revealed a marked improvement. Nevertheless, recovery of MTP dorsiflexion was limited and joint stability worsened. Radiologically, one-third of the prostheses showed radiolucent lines as a sign of implant loosening. MTP replacement offers distinct advantages in the treatment of end-stage hallux rigidus, but requires further research on implant design and osseous fixation.

Adult↗

PubMed2003

[Effects of a computer-assisted system for nursing care documentation on quality and quantity of nursing care documentation].

The University Hospital in Heidelberg has been gathering experience with the computer based nursing documentationsystem PIK since 1998. Its introduction on four pilotwards was systematically evaluated in an intervention study, gaining data to acceptance issues as well as to the quality of nursing documentation, as the nursing process is often not documented in an appropriate manner. Data to quantity and quality of nursing documentation before and after the intervention was gathered by means of a quality checklist, which was developed on the basis of an intensive literature review. To measure a difference in the quality of nursing documentation 20 documents from each of the four wards were assessed at the three assigned points of time by two nursing experts. The assessors stated a significant improvement in documentation quality due to the increase in formal completeness when documenting the nursing process. The content of the documentation as well as the individualization of the nursing care plan still need to be improved.

Attitude to Computers↗

PubMed2003

Convergent evolution of gene circuits.

Convergent evolution is a potent indicator of optimal design. We show here that convergent evolution occurs in genetic networks. Specifically, we show that multiple types of transcriptional regulation circuitry in Escherichia coli and the yeast Saccharomyces cerevisiae have evolved independently and not by duplication of one or a few ancestral circuits.

Escherichia coli↗

PubMed2003

Induction of antitumour immunity using survivin peptide-pulsed dendritic cells in a murine lymphoma model.

Survivin is overexpressed in several types of haematological malignancies making it an attractive target for therapeutic cytotoxic T-lymphocyte responses. Here, we identify two peptide epitopes derived from the murine survivin protein and demonstrate that Balb/c mice treated with syngeneic dendritic cells pulsed with the survivin epitopes were able to reject an otherwise lethal tumour inoculation of the A20 lymphoma. For the first time, these data provide evidence for the use of survivin peptide epitopes in T cell-based immunotherapeutic concepts against a B-cell lymphoma in vivo.

Animals↗