The Implicitome: A Resource for Rationalizing Gene-Disease Associations

High-throughput experimental methods such as medical sequencing and genome-wide association studies (GWAS) identify increasingly large numbers of potential relations between genetic variants and diseases. Both biological complexity (millions of potential gene-disease associations) and the accelerating rate of data production necessitate computational approaches to prioritize and rationalize potential gene-disease relations. Here, we use concept profile technology to expose from the biomedical literature both explicitly stated gene-disease relations (the explicitome) and a much larger set of implied gene-disease associations (the implicitome). Implicit relations are largely unknown to, or are even unintended by the original authors, but they vastly extend the reach of existing biomedical knowledge for identification and interpretation of gene-disease associations. The implicitome can be used in conjunction with experimental data resources to rationalize both known and novel associations. We demonstrate the usefulness of the implicitome by rationalizing known and novel gene-disease associations, including those from GWAS. To facilitate the re-use of implicit gene-disease associations, we publish our data in compliance with FAIR Data Publishing recommendations [https://www.force11.org/group/fairgroup] using nanopublications. An online tool (http://knowledge.bio) is available to explore established and potential gene-disease associations in the context of other biomedical relations.     

Removal Risks in Swedish Friesian Dairy Cows According to Parity,Stage of Lactation,and Occurrence of Clinical Mastitis

The removal risk of Swedish Friesian dairy cows was analysed. The risk of removal increased with parity, and first parity cows were removed earlier in lactation than cows of higher parities. A positive report of clinical mastitis increased the risk of removal, both in the month of developing mastitis and during subsequent part of lactation. The consequences of different removal pattern for epidemiologic analyses of observational studies are discussed.     

Tramped Teats – Clinical Mastitis Disease Complex in Tied Cows. Environmental Risk Factors and Interrelationships with Other Diseases

The effects of stall length, manure system, type of bedding and calving disorders on incidence rates of tramped teats, udder injuries, and clinical mastitis in Swedish Red and White tied cows, as well as interrelationships between these 3 disorders were investigated. Data used consisted of 370 herds, for a total of 45,133 cow records. Cows in herds with liquid manure system were at hihger risk of udder injuries and mastitis than in herds with solid system. Lower risk of both udder injuries and mastitis was found for cows in herds with short stall size (< 180 cm) compared to herds with stalls of 205–219 cm length. It was suggested that other factors, such as slipperiness of the stall floor and presence and type of feeding barrier, must be considered when the effect of stall characteristics on tramped teats is investigated. In farms with solid manure system cut straw or sawdust bedding increased the risk of tramped teats and mastitis relative to uncut straw. Parity and calving disorders were important risk factors for udder health and their effect was greater in herds with liquid manure system. Tramped teats and udder injuries were the most serious risk factors for clinical mastitis.     

Plasmodium berghei: gametocyte production, DNA content, and chromosome-size polymorphisms during asexual multiplication in vivo

In this study the DNA content and the karyotype of clones of Plasmodium berghei, which differed in the capability to produce gametocytes, were determined. The DNA content per haploid genome was established by cytofluorometric methods after staining of the haploid merozoites with DNA-specific fluorescent dyes. Field inversion gel electrophoresis was used to establish the number and size of the chromosomes. Parasites of a high gametocyte producer clone (original HP) and a low producer clone (original LP) contained 13 to 14 chromosomes in the size range of 0.5-3.8 megabase. In four independent experiments parasites of the original HP clone were maintained in mice and were mechanically transmitted for prolonged periods of time (up to 90 weeks). During the transmission period the capability to produce gametocytes decreased in all four lines. After mosquito transmission of parasites from these low producer lines, the gametocyte production returned to the level of the original HP clone. The total DNA content per haploid genome of low producer parasites was not significantly different from that of HP parasites. During prolonged periods of asexual multiplication of the HP clone in vivo, changes in the relative size of several chromosomes were detected. Mosquito transmission of the original HP clone did not result in a change of the karyotype. However, novel karyotypes were readily observed after mosquito transmission of parasites of the low producer lines. The decrease of the capability to produce gametocytes did not necessarily involve detectable changes in DNA content or in karyotype.     

Detection of different developmental stages of malaria parasites by non-radioactive DNAin situ hybridization

Summary A highly sensitive non-radioactive DNAin situ hybridization procedure is described that enables detection and unequivocal identification of various developmental stages of human and rodent malaria parasites. Using biotinylated species-specific DNA probes, erythrocytic parasites can be specifically stained in blood smears. Similarly exoerythrocytic stages can be visualized in cell culture and in sections of paraffin-embedded liver. In blood smears, the hybridization procedure provides a rapid detection of (low) parasitemia and species-determination for experienced microscopists at 100 to 400x magnification. Moreover, the procedure can be applied even after previous Giemsa staining of the preparation, enabling revision of patient smears which were difficult to read after routine Giemsa staining.     

Assignment of protein function and discovery of novel nucleolar proteins based on automatic analysis of MEDLINE

Attribution of the most probable functions to proteins identified by proteomics is a significant challenge that requires extensive literature analysis. We have developed a system for automated prediction of implicit and explicit biologically meaningful functions for a proteomics study of the nucleolus. This approach uses a set of vocabulary terms to map and integrate the information from the entire MEDLINE database. Based on a combination of cross-species sequence homology searches and the corresponding literature, our approach facilitated the direct association between sequence data and information from biological texts describing function. Comparison of our automated functional assignment to manual annotation demonstrated our method to be highly effective. To establish the sensitivity, we defined the functional subtleties within a family containing a highly conserved sequence. Clustering of the DEAD-box protein family of RNA helicases confirmed that these proteins shared similar morphology although functional subfamilies were accurately identified by our approach. We visualized the nucleolar proteome in terms of protein functions using multi-dimensional scaling, showing functional associations between nucleolar proteins that were not previously realized. Finally, by clustering the functional properties of the established nucleolar proteins, we predicted novel nucleolar proteins. Subsequently, nonproteomics studies confirmed the predictions of previously unidentified nucleolar proteins.