Finding disease similarity based on implicit semantic similarity

AbstractGenomics has contributed to a growing collection of gene–function and gene–disease annotations that can be exploited by informatics to study similarity between diseases. This can yield insight into disease etiology, reveal common pathophysiology and/or suggest treatment that can be appropriated from one disease to another. Estimating disease similarity solely on the basis of shared genes can be misleading as variable combinations of genes may be associated with similar diseases, especially for complex diseases. This deficiency can be potentially overcome by looking for common biological processes rather than only explicit gene matches between diseases. The use of semantic similarity between biological processes to estimate disease similarity could enhance the identification and characterization of disease similarity. We present functions to measure similarity between terms in an ontology, and between entities annotated with terms drawn from the ontology, based on both co-occurrence and information content. The similarity measure is shown to outperform other measures used to detect similarity. A manually curated dataset with known disease similarities was used as a benchmark to compare the estimation of disease similarity based on gene-based and Gene Ontology (GO) process-based comparisons. The detection of disease similarity based on semantic similarity between GO Processes (Recall=55%, Precision=60%) performed better than using exact matches between GO Processes (Recall=29%, Precision=58%) or gene overlap (Recall=88% and Precision=16%). The GO-Process based disease similarity scores on an external test set show statistically significant Pearson correlation (0.73) with numeric scores provided by medical residents. GO-Processes associated with similar diseases were found to be significantly regulated in gene expression microarray datasets of related diseases

Ontology-based methods for disease similarity estimation and drug repositioning

Title from PDF of title page, viewed on October 2, 2012Dissertation advisor: Deendayal DinakarpandianVitaIncludes bibliographic references (p. 174-181)Thesis (Ph.D.)--School of Computing and Engineering and Dept. of Mathematics and Statistics. University of Missouri--Kansas City, 2012Human genome sequencing and new biological data generation techniques have provided an opportunity to uncover mechanisms in human disease. Using gene-disease data, recent research has increasingly shown that many seemingly dissimilar diseases have similar/common molecular mechanisms. Understanding similarity between diseases aids in early disease diagnosis and development of new drugs. The growing collection of gene-function and gene-disease data has instituted a need for formal knowledge representation in order to extract information. Ontologies have been successfully applied to represent such knowledge, and data mining techniques have been applied on them to extract information. Informatics methods can be used with ontologies to find similarity between diseases which can yield insight into how they are caused. This can lead to therapies which can actually cure diseases rather than merely treating symptoms. Estimating disease similarity solely on the basis of shared genes can be misleading as variable combinations of genes may be associated with similar diseases, especially for complex diseases. This deficiency can be potentially overcome by looking for common or similar biological processes rather than only explicit gene matches between diseases. The use of semantic similarity between biological processes to estimate disease similarity could enhance the identification and characterization of disease similarity besides indentifying novel biological processes involved in the diseases. Also, if diseases have similar molecular mechanisms, then drugs that are currently being used could potentially be used against diseases beyond their original indication. This can greatly benefit patients with diseases that do not have adequate therapies especially people with rare diseases. This can also drastically reduce healthcare costs as development of new drugs is far more expensive than re-using existing ones. In this research we present functions to measure similarity between terms in an ontology, and between entities annotated with terms drawn from the ontology, based on both co-occurrence and information content. The new similarity measure is shown to outperform existing methods using biological pathways. The similarity measure is then used to estimate similarity among diseases using the biological processes involved in them and is evaluated using a manually curated and external datasets with known disease similarities. Further, we use ontologies to encode diseases, drugs and biological processes and demonstrate a method that uses a network-based algorithm to combine biological data about diseases with drug information to find new uses for existing drugs. The effectiveness of the method is demonstrated by comparing the predicted new disease-drug pairs with existing drug-related clinical trials.Introduction and motivation -- Ontologies in biomedical domain -- Methods to compute ontological similarity -- Proposed approach for ontological term similarity -- Augmentation of vocabulary and annotation in ontologies -- Estimation of disease similarity -- Use of ontologies for drug repositioning -- Future directions-perspective from pharmaceutical industry -- Appendix 1. Table for the ontological similarity scores -- Appendix 2. Test set of 200 records for evaluating mapping of disease text to Disease Ontology -- Appendix 3. Curated set of disease similarities used as the benchmark set -- Appendix 4. F-scores for different combinations of Score-Pvalues and GO-Process-Pvalues for PSB estimates of disease similarity -- Appendix 5. Test set formed from opinions of medical residents http://rxinformatics.umn.edu/SemanticRelatednessResources.html -- Appendix 6. Drug repositioning candidate

Surgical Anatomy of Acetabulum and Biomechanics

Both column acetabular fractures are challenging articular injuries. Majority of them are treated operatively. The concept of “secondary congruence” was introduced by Letournel. Despite this, biomechanical data on secondary congruence indicate that nonoperative treatment leads to an increase in peak pressures in the supra-acetabular region with the potential risk of developing posttraumatic degenerative osteoarthritis. Operative management is therefore justified. A cohort of 10 patients having both column (anterior and posterior) acetabular fractures managed using bicolumnar plating between Jan 2016 and Dec 2017 were enrolled in the study and were analyzed during follow-up period. Eighty percent of the patients had excellent to good result. Average postoperative score was 85.7. Assessment was done using Modified Harris Hip score

Sex-dimorphic gene expression and ineffective dosage compensation of Z-linked genes in gastrulating chicken embryos

<p>Abstract</p> <p>Background</p> <p>Considerable progress has been made in our understanding of sex determination and dosage compensation mechanisms in model organisms such as <it>C. elegans</it>, <it>Drosophila </it>and <it>M. musculus</it>. Strikingly, the mechanism involved in sex determination and dosage compensation are very different among these three model organisms. Birds present yet another situation where the heterogametic sex is the female. Sex determination is still poorly understood in birds and few key determinants have so far been identified. In contrast to most other species, dosage compensation of bird sex chromosomal genes appears rather ineffective.</p> <p>Results</p> <p>By comparing microarrays from microdissected primitive streak from single chicken embryos, we identified a large number of genes differentially expressed between male and female embryos at a very early stage (Hamburger and Hamilton stage 4), long before any sexual differentiation occurs. Most of these genes are located on the Z chromosome, which indicates that dosage compensation is ineffective in early chicken embryos. Gene ontology analyses, using an enhanced annotation tool for Affymetrix probesets of the chicken genome developed in our laboratory (called Manteia), show that among these male-biased genes found on the Z chromosome, more than 20 genes play a role in sex differentiation.</p> <p>Conclusions</p> <p>These results corroborate previous studies demonstrating the rather inefficient dosage compensation for Z chromosome in birds and show that this sexual dimorphism in gene regulation is observed long before the onset of sexual differentiation. These data also suggest a potential role of non-compensated Z-linked genes in somatic sex differentiation in birds.</p

An Intelligent Online System for Enhanced Recruitment of Patients for Clinical Research

Computational Infrastructure and Informatics Poster SessionThe recruitment and retention of subjects for clinical research has been identified as one of the bottlenecks in the development of new drugs and treatments by the healthcare industry. The Kansas City Area Life Sciences Institute has been instrumental in bringing together the Midwest Psychiatric Research Group and researchers from the School of Computing and Engineering at the University of Missouri-Kansas City to address this important problem. The resulting academic-corporate partnership has been funded by a 2-year Small Business Innovation Research Grant of $518,298 awarded by the National Institute of Mental Health at the National Institutes of Health. The project is based on developing and employing a novel internet-based system to enhance the voluntary enrollment of research subjects for studies conducted by Clinical Research Organizations. This will proactively engage patients and their caregivers who desire to be informed about clinical trials that might be relevant for their specific diagnoses, disease states and other characteristics. An important goal of the project is to facilitate accurate matches between the requirements of a clinical research study and the profile of research volunteers. To achieve this, state of the art knowledge representation and search techniques are being employed. Phase I of the project is focused on the development of a system for recruitment for clinical research trials on “Generalized Anxiety Disorder,” with eventual expansion to the inclusion of volunteers for studies on other mental health disorders

Comprehensive mutations analyses of FTO (fat mass and obesity-associated gene) and their effects on FTO’s substrate binding implicated in obesity

An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity (FTO) gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the FTO gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the FTO gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders

Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses.

The central amygdala (CeA) is a key structure at the limbic-motor interface regulating stress responses and emotional learning. Endocannabinoid (eCB) signaling is heavily implicated in the regulation of stress-response physiology and emotional learning processes; however, the role of eCBs in the modulation of synaptic efficacy in the CeA is not well understood. Here we describe the subcellular localization of CB1 cannabinoid receptors and eCB synthetic machinery at glutamatergic synapses in the CeA and find that CeA neurons exhibit multiple mechanistically and temporally distinct modes of postsynaptic eCB mobilization. These data identify a prominent role for eCBs in the modulation of excitatory drive to CeA neurons and provide insight into the mechanisms by which eCB signaling and exogenous cannabinoids could regulate stress responses and emotional learning

Versuche uber Immunisierung von dem Konjunktivalsack aus mit Berucksichtigung des Einflusses der Ultraviolettbestrahlung auf den Immunisierungsvorgang

1) In Vorversuchen hat der Verfasser eingehend einerseits den direkten Einfluss der Ultraviolettstrahlen auf die beabsichtigte Antigene, ihre Suspensions-bzw. Losungs-medien so wie auf die in Immunserum anwesenden Antikorper festgestellt, anderseits die lokale und allgemeine Einwirkung auf den Tierkorper der U. V. Bestrahlung des Kaninchenauges sichergestellt. Im allgemeinen hat die U. V. Bestrahlung auf lebende Bakterien verschiedener Rassen bakterizide Wirkung entfaltet. Die Wirkungskraft war bei verschiedenen Bakterienarten, in verschiedenen Suspensionsmedien und je nach der Bestrahlungsweise verschieden. Auf das Auge selbst hat die U. V. Bestrahlung, vorausgesetzt, dass sie zweck-massig durchgefuhrt wird, keinen ublen Einfluss. Die Keime des Konjunktivalsackes nehmen als Folge der Bestrahlung an ihrer Zahl ab. Als allgemeiner Einfluss auf den Tierkorper kann der Aufstieg der Korpertem-peratur nach der Bestrahlung und die Korpergewichtzunahme erwahnt werden. Uber-massiges Bestrahlen fuhrt zur Gewichtsabnahme. Im Gegenteil zu der Wirkung im immuisierten Korper verliert das direkt bestr-ahlte Immunserum an seinem Antikorpergehalt. 2) Durch Agglutinationsproben wurde der Immunisierungsvorgang verfolgt und die Moglichkeit der Immunisierung vom Konjumktivalsack aus festgestellt. Es kamen die folgenden Bakterien in Frage; B. typhi B. prodigiosus, Staphylokokken, Gonoko-kken, Pneumokokken, V. Metschnikoffi. Als Aufschwemmungsmedium der bakteriellen Antigene wurde Kochsalzlosung, Dionin-, NaHCO3-, und verdunnte HCl- losung gebraucht. Diese Immunisierungsversuche wurden teilweise mit, teilweise ohne U. V. Bestrahlung durchgefuhrt, wodurch die Tatsache festgestellt wurde, dass die Bestr-ahlung auf die Agglutininbildung einen gunstigen Einfluss ausubt. 3) Ahnlich wie mit den verschiedenen Bakterien wurden auch Immunisierungs-versuche mit Diphterietoxin angestellt. Es ist zwar gelungen im Blute der auf die in Frage stehende Weise behandelten Versuchstiere das spezifische Antitoxin nachzuweisen, aber es lag kein Beweis a