Co-occurrence based meta-analysis of scientific texts: retrieving biological relationships between genes.

MOTIVATION: The advent of high-throughput experiments in molecular biology creates a need for methods to efficiently extract and use information for large numbers of genes. Recently, the associative concept space (ACS) has been developed for the representation of information extracted from biomedical literature. The ACS is a Euclidean space in which thesaurus concepts are positioned and the distances between concepts indicates their relatedness. The ACS uses co-occurrence of concepts as a source of information. In this paper we evaluate how well the system can retrieve functionally related genes and we compare its performance with a simple gene co-occurrence method. RESULTS: To assess the performance of the ACS we composed a test set of five groups of functionally related genes. With the ACS good scores were obtained for four of the five groups. When compared to the gene co-occurrence method, the ACS is capable of revealing more functional biological relations and can achieve results with less literature available per gene. Hierarchical clustering was performed on the ACS output, as a potential aid to users, and was found to provide useful clusters. Our results suggest that the algorithm can be of value for researchers studying large numbers of genes. AVAILABILITY: The ACS program is available upon request from the authors.

Distribution of information in biomedical abstracts and full-text publications.

MOTIVATION: Full-text documents potentially hold more information than their abstracts, but require more resources for processing. We investigated the added value of full text over abstracts in terms of information content and occurrences of gene symbol--gene name combinations that can resolve gene-symbol ambiguity. RESULTS: We analyzed a set of 3902 biomedical full-text articles. Different keyword measures indicate that information density is highest in abstracts, but that the information coverage in full texts is much greater than in abstracts. Analysis of five different standard sections of articles shows that the highest information coverage is located in the results section. Still, 30-40% of the information mentioned in each section is unique to that section. Only 30% of the gene symbols in the abstract are accompanied by their corresponding names, and a further 8% of the gene names are found in the full text. In the full text, only 18% of the gene symbols are accompanied by their gene names.

Evaluation of the stability and efficacy of rhGM-CSF as a topical agent in a gel formulation.

OBJECTIVE: It has been reported that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), applied as a solution or an emulsion, improves wound healing. In order to confirm these data, the wound-healing efficacy of this growth factor was studied in a murine model. METHOD: In this double-blind randomised study, murine excisional wounds were treated with either sterilised rhGM-CSF gel (10 micrograms/cm2) or a sterilised placebo gel (control group). rhGM-CSF was applied at dosages of 10 micrograms/cm2/day to wounds until complete closure occurred. RESULTS: rhGM-CSF stability in gel formulation was excellent during the first week but decreased thereafter. Full wound healing occurred within 9.7 days (mean time) in the intervention group compared with 10 days in the control group. This difference was not statistically significant. Histological evaluation of the healed wounds indicated that there was a similar percentage of neutrophils in the cellular infiltrate in both groups. CONCLUSION: rhGM-CSF sterile gel had an excellent safety profile and was easy to use, but did not significantly accelerate the healing rate in this model.

Facilitating networks of information.

In this paper we describe an approach to respond to a request for information with the identification and location of the appropriate person as a source of information for answering the question. The expertise of a person is characterized using a weighted profile that has been derived from a series of documents describing the expert's activities. Having these profiles, requests for information can be matched with these profiles. The best matches correspond with the people that are experts for providing information on the request.

Chimpanzees and supporting models in the study of malaria pre-erythrocytic stages.

Chimpanzees are being used in the study of immune response to Plasmodium falciparum malaria pre-erythrocytic stages (MPES). Responses induced by immunisation with recombinant/synthetic antigens and by irradiated sporozoites are being evaluated in a model system that is phylogenetically close to humans and that is amenable to limited manipulation not possible in humans. The value of chimpanzees for the in-depth study of immunological mechanisms at work in MPES-induced protection are discussed. A total number of 7 chimpanzees have been used to evaluate the immune response to recombinant antigens, and 5 have been challenged with large numbers of sporozoites, followed by surgical liver-wedge resection, in order to generate infected liver tissue for histological and immunological studies. As a complementary model, SCID mice carrying live, transplanted human and primate hepatocytes have been inoculated with sporozoites and infection of transplanted cells has been monitored by histological and immunological methods. In ongoing experiments chimpanzees are being immunised with MPES-derived lipopeptides that have been shown to overcome MHC restriction in mice, and with irradiated sporozoites.

Chimpanzees and supporting models in the study of malaria pre-erythrocytic stages

Chimpanzees are being used in the study of immune response to Plasmodium falciparum malaria pre-erythrocytic stages (MPES). Responses induced by immunisation with recombinant/synthetic antigens and by irradiated sporozoites are being evaluated in a model system that is phylogenetically close to humans and that is amenable to limited manipulation not possible in humans. The value of chimpanzees for the in-depth study of immunological mechanisms at work in MPES-induced protection are discussed. A total number of 7 chimpanzees have been used to evaluate the immune response to recombinant antigens, and 5 have been challenged with large numbers of sporozoites, followed by surgical liver-wedge resection, in order to generate infected liver tissue for histological and immunological studies. As a complementary model, SCID mice carrying live, transplanted human and primate hepatocytes have been inoculated with sporozoites and infection of transplanted cells has been monitored by histological and immunological methods. In ongoing experiments chimpanzees are being immunised with MPES-derived lipopeptides that have been shown to overcome MHC restriction in mice, and with irradiated sporozoites.

Flow cytometric screening of blood samples for malaria parasites.

An automated method for the detection and estimation of malaria parasites in blood samples using flow cytometry is presented. In a single-step procedure 50 microliters of blood sample was collected in 1 ml of lysis solution containing formaldehyde, causing red blood cells to lyse while parasites and white blood cells are preserved. Thus prepared, samples could be transported and remained stored in lysis solution until flow cytometric analysis was performed. The cells were stained for DNA with the fluorescent dye Hoechst 33258 and subsequently analyzed by a FACStar flow cytometer. Parasites and white blood cells were distinguished and counted based on blue Hoechst fluorescence and forward scattering. Since red blood cells were lysed, parasite numbers were given related to the number of white blood cells similar to what is done in microscopic examination of thick blood smears. In dilution experiments with animal and human material, parasite counts by flow cytometry correlated very well with the theoretically calculated numbers (regression coefficients of > 0.94). In human material parasitemias of approximately 0.005% were detected. In a pilot study, 700 samples were collected in Thailand and screened by microscopic examination of thick smears and by flow cytometry; 29 were found positive by combining both methods, 2 were missed by flow cytometry, and 20 were missed by microscopists in the field. After microscopic reexamination in the central laboratory, 15 of these 20 were found positive, 5 remained unconfirmed.

Plasmodium berghei: in vivo generation and selection of karyotype mutants and non-gametocyte producer mutants.

We previously reported that karyotype and gametocyte-producer mutants spontaneously arose during in vivo asexual multiplication of Plasmodium berghei. Here we studied the rate of selection of these mutants in vivo. Gametocyte production and karyotype pattern were established at regular intervals during prolonged periods of asexual multiplication of clone 8417 of P. berghei. We found that karyotype mutants and mutants which do not produce gametocytes can replace the original high-producer parasites of clone 8417 within several weeks. The time at which mutants became predominant in the population in different experiments, however, differed greatly. Mutants with intermediate or low gametocyte production were not found. In experimentally mixed infections, containing parasites from two clones from different strains (clone 8417 of the ANKA strain; clone 1 of the K173 strain), high-producer parasites of clone 8417 were overgrown by parasites of the nonproducer clone. Nonproducer mutants from the originally high-producer clone 8417, however, were able to coexist with parasites of the nonproducer clone. These results demonstrate that in our experiments nonproducer parasites had a strong selective advantage during asexual multiplication compared to high producers. All karyotype mutants which became predominant in our experiments were nonproducers. In two experiments a change in karyotype coincided with the loss of gametocyte production which may suggest a causal relationship between these events.

Chromosome translocation in Plasmodium berghei.

We describe a chromosome translocation in a karyotype mutant of the rodent malarial parasite Plasmodium berghei. In this mutant (named EP) a small chromosome (chromosome 7), which has exhibited a size range between 0.9 and 1.4 Mb in other clones of P. berghei, is translocated to chromosome 13 or 14 with a size of about 3 Mb. By comparison of Apa-I restriction fragments of the chromosomes from mutant EP and from a reference clone (named HP) of P. berghei, we found evidence for a junction of subtelomeric chromosome 7 sequences and internal chromosome 13/14 sequences. In addition, a new chromosome of 1.4 Mb (named EP7) is present in mutant EP, which is (mainly) composed of sequences of chromosome 13/14. EP7 contains one telomeric region derived from chromosome 13/14. We found evidence that internal sequences of chromosome 13/14 are joined to telomeric sequences in the other telomeric region of EP7. The karyotype of mutant EP was stable during asexual and sexual multiplication and we found no indications for phenotypic changes.

Contact cw-Nd:YAG laser cyclophotocoagulation for treatment of refractory glaucoma.

Contact cw-Nd:YAG laser transscleral cyclophotocoagulation was performed on 42 patients (44 eyes) with glaucoma who were not responding to medical treatment or had failure of prior surgical procedures. No selection was made as to the type of glaucoma (congenital, primary, secondary due to trauma or inflammation). We applied between 16 and 60 exposures 0.5-2 mm posterior to the limbus. Prior to cyclophotocoagulation the mean intraocular pressure (IOP) was 40.4 mm Hg (+/- 8.0). As a result of the treatment, the mean IOP was lowered to 21.1 mm Hg (+/- 5.2). In eyes with congenital, neovascular, and inflammatory glaucoma, a therapeutic effect could only be achieved by repeated coagulations. The patients were followed for a mean of 4.8 months (3-7 months). One eye developed a transient choroidal detachment. In two eyes, iris hemorrhages were noted. Contact cyclophotocoagulation is generally well tolerated. Randomized studies are to be carried out to confirm whether cyclophotocoagulation is an effective tool in the treatment of glaucoma. Until then, cyclophotocoagulation should be restricted to cases not responding to conventional therapy.

Deletion, insertion and translocation of DNA sequences contribute to chromosome size polymorphism in Plasmodium berghei.

Extensive chromosome size polymorphism arises in Plasmodium berghei during in vivo mitotic multiplication. Size differences between homologous chromosomes mainly involve rearrangements in the subtelomeric regions while internal chromosomal regions are more conserved. Size differences are almost exclusively due to differences in the copy number of a 2.3 kb subtelomeric repeat unit. Not only deletion of 2.3 kb repeats occurs, but addition of new copies of this repeat sometimes results in the formation of enlarged chromosomes. Even chromosomes which originally lack 2.3 kb repeats, can acquire these during mitotic multiplication. In one karyotype mutant, 2.3 kb repeats were inserted within one of the original telomeres of chromosome 4, creating an internal stretch of telomeric repeats. Chromosome translocation can contribute to chromosome size polymorphism as well. We found a karyotype mutant in which chromosome 7 with a size of about 1.4 Mb is translocated to chromosome 13/14 with a size of about 3 Mb, resulting in a rearranged chromosome, which was shown to contain a junction between internal DNA sequences of chromosome 13/14 and subtelomeric 2.3 kb repeats of chromosome 7. In this mutant a new chromosome of 1.4 Mb is present which consists of part of chromosome 13/14.

The complete sequence of a Plasmodium malariae SSUrRNA gene and its comparison to other plasmodial SSUrRNA genes.

A gene encoding the small subunit rRNA (SSUrRNA) has been isolated from the human parasite, Plasmodium malariae. The gene has been sequenced. It contains conserved and variable regions which conform to patterns established for other eukaryotic SSUrRNA genes. Comparisons with other SSUrRNA genes from Plasmodium species reveal regions unique to P. malariae which could be used in specific diagnostic probes for this organism, and provide evidence that the gene is of the type expressed during asexual growth. In addition the '5.8S' gene has been cloned from P. malariae. The gene has been sequenced. It contains bases universally conserved in '5.8S' genes but there is considerable divergence between the P. malariae sequence and that of the P. falciparum gene.