Biomedical subjects

Hans-Michael Müller

Publications and source records attributed to Hans-Michael Müller.

10 recordsLinked to original sources

PubMed2006

WormBase: new content and better access.

WormBase (http://wormbase.org), a model organism database for Caenorhabditis elegans and other related nematodes, continues to evolve and expand. Over the past year WormBase has added new data on C.elegans, including data on classical genetics, cell biology and functional genomics; expanded the annotation of closely related nematodes with a new genome browser for Caenorhabditis remanei; and deployed new hardware for stronger performance. Several existing datasets including phenotype descriptions and RNAi experiments have seen a large increase in new content. New datasets such as the C.remanei draft assembly and annotations, the Vancouver Fosmid library and TEC-RED 5' end sites are now available as well. Access to and searching WormBase has become more dependable and flexible via multiple mirror sites and indexing through Google.

Animals↗

PubMed2006

Automatic document classification of biological literature.

BACKGROUND: Document classification is a wide-spread problem with many applications, from organizing search engine snippets to spam filtering. We previously described Textpresso, a text-mining system for biological literature, which marks up full text according to a shallow ontology that includes terms of biological interest. This project investigates document classification in the context of biological literature, making use of the Textpresso markup of a corpus of Caenorhabditis elegans literature. RESULTS: We present a two-step text categorization algorithm to classify a corpus of C. elegans papers. Our classification method first uses a support vector machine-trained classifier, followed by a novel, phrase-based clustering algorithm. This clustering step autonomously creates cluster labels that are descriptive and understandable by humans. This clustering engine performed better on a standard test-set (Reuters 21578) compared to previously published results (F-value of 0.55 vs. 0.49), while producing cluster descriptions that appear more useful. A web interface allows researchers to quickly navigate through the hierarchy and look for documents that belong to a specific concept. CONCLUSION: We have demonstrated a simple method to classify biological documents that embodies an improvement over current methods. While the classification results are currently optimized for Caenorhabditis elegans papers by human-created rules, the classification engine can be adapted to different types of documents. We have demonstrated this by presenting a web interface that allows researchers to quickly navigate through the hierarchy and look for documents that belong to a specific concept.

Abstracting and Indexing↗

PubMed2006

WormBase: better software, richer content.

WormBase (http://wormbase.org), the public database for genomics and biology of Caenorhabditis elegans, has been restructured for stronger performance and expanded for richer biological content. Performance was improved by accelerating the loading of central data pages such as the omnibus Gene page, by rationalizing internal data structures and software for greater portability, and by making the Genome Browser highly customizable in how it views and exports genomic subsequences. Arbitrarily complex, user-specified queries are now possible through Textpresso (for all available literature) and through WormMart (for most genomic data). Biological content was enriched by reconciling all available cDNA and expressed sequence tag data with gene predictions, clarifying single nucleotide polymorphism and RNAi sites, and summarizing known functions for most genes studied in this organism.

Animals↗

PubMed2006

A genetic module regulates the melanization response of Anopheles to Plasmodium.

Two modes of refractoriness to Plasmodium, ookinete lysis and melanization, are known in the malaria vector, Anopheles gambiae. Melanization, a potent insect immune response, is manifested in a genetically selected refractory strain and in susceptible mosquitoes that are depleted of specific C-type lectins (CTLs). Here we use a systematic in vivo RNA interference-mediated reverse genetic screen and other recent results to define a melanization-regulating genetic module or network. It encompasses at least 14 genes, including those that encode five Easter-like clip domain serine proteases and four Masquerade-like serine protease homologues of the mosquito CLIPB and CLIPA subfamilies respectively. We show that several but not all CLIPB genes promote Plasmodium melanization, exhibiting partial functional overlap and synergy. We also report that several CLIPA genes have contrasting roles: CLIPA8 is essential for parasite melanization, while three other CLIPAs are novel synergistic inhibitors of this response. Importantly, the roles of certain CLIPAs and CLIPBs are strain specific, indicating that this network may differ between strains. Finally, we provide evidence that in susceptible mosquitoes melanization induced by knockdown of either CTL4 or CLIPA2/CLIPA5 directly kills ookinetes, in contrast to refractory mosquitoes where it merely disposes of dead parasites.

Animals↗

PubMed2005

The roles of two clip domain serine proteases in innate immune responses of the malaria vector Anopheles gambiae.

The malaria vector Anopheles gambiae is capable of multiple immune responses against Plasmodium ookinetes. Accumulating evidence in several insect species suggests the involvement of serine protease cascades in the initiation and coordination of immune responses. We report molecular and reverse genetic characterization of two mosquito clip domain serine proteases, CLIPB14 and CLIPB15, which share structural similarity to proteases involved in prophenoloxidase activation in other insects. Both CLIPs are expressed in mosquito hemocytes and are transcriptionally induced by bacterial and Plasmodium challenges. Functional studies applying RNA interference revealed that both CLIPs are involved in the killing of Plasmodium ookinetes in Anopheles. Studies on parasite melanization demonstrated an additional role for CLIPB14 in the prophenoloxidase cascade. We further report that both CLIPs participate in defense toward Gram-negative bacteria. Our findings strongly suggest that clip domain serine proteases serve multiple functions and play distinctive roles in several immune pathways of A. gambiae.

Amino Acid Sequence↗

PubMed2004

Textpresso: an ontology-based information retrieval and extraction system for biological literature.

We have developed Textpresso, a new text-mining system for scientific literature whose capabilities go far beyond those of a simple keyword search engine. Textpresso's two major elements are a collection of the full text of scientific articles split into individual sentences, and the implementation of categories of terms for which a database of articles and individual sentences can be searched. The categories are classes of biological concepts (e.g., gene, allele, cell or cell group, phenotype, etc.) and classes that relate two objects (e.g., association, regulation, etc.) or describe one (e.g., biological process, etc.). Together they form a catalog of types of objects and concepts called an ontology. After this ontology is populated with terms, the whole corpus of articles and abstracts is marked up to identify terms of these categories. The current ontology comprises 33 categories of terms. A search engine enables the user to search for one or a combination of these tags and/or keywords within a sentence or document, and as the ontology allows word meaning to be queried, it is possible to formulate semantic queries. Full text access increases recall of biological data types from 45% to 95%. Extraction of particular biological facts, such as gene-gene interactions, can be accelerated significantly by ontologies, with Textpresso automatically performing nearly as well as expert curators to identify sentences; in searches for two uniquely named genes and an interaction term, the ontology confers a 3-fold increase of search efficiency. Textpresso currently focuses on Caenorhabditis elegans literature, with 3,800 full text articles and 16,000 abstracts. The lexicon of the ontology contains 14,500 entries, each of which includes all versions of a specific word or phrase, and it includes all categories of the Gene Ontology database. Textpresso is a useful curation tool, as well as search engine for researchers, and can readily be extended to other organism-specific corpora of text. Textpresso can be accessed at http://www.textpresso.org or via WormBase at http://www.wormbase.org.

Abstracting and Indexing↗

PubMed2004

Genome annotation by high-throughput 5' RNA end determination.

Complete gene identification and annotation, including alternative transcripts, remains a challenge in understanding genome organization. Such annotation can be achieved by a combination of computational analysis and experimental confirmation. Here, we describe a high-throughput technique, trans-spliced exon coupled RNA end determination (TEC-RED), that identifies 5' ends of expressed genes in nematodes. TEC-RED can distinguish coding regions from regulatory regions and identify genes as well as their alternative transcripts that have different 5' ends. Application of TEC-RED to approximately 10% of the Caenorhabditis elegans genome yielded tags 75% of which experimentally verified predicted 5'-RNA ends and 25% of which provided previously unknown information about 5'-RNA ends, including the identification of 99 previously unknown genes and 32 previously unknown operons. This technique will be applicable in any organisms that have a trans-splicing reaction from spliced leader RNA. We also describe an efficient sequential method for concatenating short sequence tags for any serial analysis of gene expression-like techniques.

Animals↗

PubMed2003

Quantitative measurement of carotid intima-media roughness--effect of age and manifest coronary artery disease.

UNLABELLED: Atherosclerotic changes of the common carotid artery (CCA) may appear like irregularities of the intima-media thickness (abbreviated as IM roughness) in B-mode ultrasound. The purposes of the present study were to investigate whether the CCA IM roughness changes with age and differs between individuals presumed to be healthy and patients with coronary artery disease (CAD). METHODS AND RESULTS: Based on a new automatic identification (AI) program, the segmental intima-media thickness (IMT) and IM roughness of the CCA far wall were measured in B-mode images of 15 younger and 22 older volunteers presumed to be healthy, and 46 patients with known CAD. The mean and maximum CCA IMT were lowest in the young group (0.55+/-0.05; 0.65+/-0.06 mm), higher in the older group (0.77+/-0.16; 0.87+/-0.18 mm) and highest in CAD patients (0.88+/-0.18; 1.01+/-0.27 mm) (P<0.01 among all groups). The CCA IM roughness was greatest by far in the CAD patients (0.075+/-0.02 mm; P<0.01 vs. both groups) and increased only slightly with age (younger: 0.035+/-0.008 mm; older: 0.040+/-0.014 mm; P<0.05). Areas under the curve (AUC) of receiver-operating characteristic curves (ROC) predicting patients with CAD were higher for the CCA IM roughness (0.80) than for the mean (0.66) and maximum IMT (0.71). CONCLUSIONS: It is suggested that the CCA IM roughness increases with age, and helps to discriminate between individuals presumed to be healthy and patients with manifest CAD better than the CCA mean and maximum IMT.

Adult↗

PubMed2003

Thioredoxin reductase from the malaria mosquito Anopheles gambiae.

The mosquito, Anopheles gambiae, is an important vector of Plasmodium falciparum malaria. Full genome analysis revealed that, as in Drosophila melanogaster, the enzyme glutathione reductase is absent in A. gambiae and functionally substituted by the thioredoxin system. The key enzyme of this system is thioredoxin reductase-1, a homodimeric FAD-containing protein of 55.3 kDa per subunit, which catalyses the reaction NADPH + H+ + thioredoxin disulfide-->NADP+ + thioredoxin dithiol. The A. gambiae trxr gene is located on chromosome X as a single copy; it represents three splice variants coding for two cytosolic and one mitochondrial variant. The predominant isoform, A. gambiae thioredoxin reductase-1, was recombinantly expressed in Escherichia coli and functionally compared with the wild-type enzyme isolated in a final yield of 1.4 U.ml(-1) of packed insect cells. In redox titrations, the substrate A. gambiae thioredoxin-1 (Km=8.5 microm, kcat=15.4 s(-1) at pH 7.4 and 25 degrees C) was unable to oxidize NADPH-reduced A. gambiae thioredoxin reductase-1 to the fully oxidized state. This indicates that, in contrast to other disulfide reductases, A. gambiae thioredoxin reductase-1 oscillates during catalysis between the four-electron reduced state and a two-electron reduced state. The thioredoxin reductases of the malaria system were compared. A. gambiae thioredoxin reductase-1 shares 52% and 45% sequence identity with its orthologues from humans and P. falciparum, respectively. A major difference among the three enzymes is the structure of the C-terminal redox centre, reflected in the varying resistance of catalytic intermediates to autoxidation. The relevant sequences of this centre are Thr-Cys-Cys-SerOH in A. gambiae thioredoxin reductase, Gly-Cys-selenocysteine-GlyOH in human thioredoxin reductase, and Cys-X-X-X-X-Cys-GlyOH in the P. falciparum enzyme. These differences offer an interesting approach to the design of species-specific inhibitors. Notably, A. gambiae thioredoxin reductase-1 is not a selenoenzyme but instead contains a highly unusual redox-active Cys-Cys sequence.

Amino Acid Sequence↗

PubMed2002

Immunity-related genes and gene families in Anopheles gambiae.

We have identified 242 Anopheles gambiae genes from 18 gene families implicated in innate immunity and have detected marked diversification relative to Drosophila melanogaster. Immune-related gene families involved in recognition, signal modulation, and effector systems show a marked deficit of orthologs and excessive gene expansions, possibly reflecting selection pressures from different pathogens encountered in these insects' very different life-styles. In contrast, the multifunctional Toll signal transduction pathway is substantially conserved, presumably because of counterselection for developmental stability. Representative expression profiles confirm that sequence diversification is accompanied by specific responses to different immune challenges. Alternative RNA splicing may also contribute to expansion of the immune repertoire.

Alternative Splicing↗