Data-Mining Analysis Suggests an Epigenetic Pathogenesis for Type 2 Diabetes

The etiological origin of type 2 diabetes mellitus (T2DM) has long been controversial. The body of literature related to T2DM is vast and varied in focus, making a broad epidemiological perspective difficult, if not impossible. A data-mining approach was used to analyze all electronically available scientific literature, over 12 million Medline records, for “objects” such as genes, diseases, phenotypes, and chemical compounds linked to other objects within the T2DM literature but were not themselves within the T2DM literature. The goal of this analysis was to conduct a comprehensive survey to identify novel factors implicated in the pathology of T2DM by statistically evaluating mutually shared associations. Surprisingly, epigenetic factors were among the highest statistical scores in this analysis, strongly implicating epigenetic changes within the body as causal factors in the pathogenesis of T2DM. Further analysis implicates adipocytes as the potential tissue of origin, and cytokines or cytokine-like genes as the dysregulated factor(s) responsible for the T2DM phenotype. The analysis provides a wealth of literature supporting this hypothesis, which—if true—represents an important paradigm shift for researchers studying the pathogenesis of T2DM

Detecting strain in birefringent materials using spectral polarimetry

A method, computer program product and system for analyzing multispectral images from a plurality of regions of birefringent material, such as a polymer film, using polarized light and a corresponding polar analyzer to identify differential strain in the birefringent material. For example, the birefringement material may be low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene, polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyvinylidene chloride, polyester, nylon, or cellophane film. Optionally, the method includes generating a real-time quantitative strain map

eTBLAST: a web server to identify expert reviewers, appropriate journals and similar publications

Authors, editors and reviewers alike use the biomedical literature to identify appropriate journals in which to publish, potential reviewers for papers or grants, and collaborators (or competitors) with similar interests. Traditionally, this process has either relied upon personal expertise and knowledge or upon a somewhat unsystematic and laborious process of manually searching through the literature for trends. To help with these tasks, we report three utilities that parse and summarize the results of an abstract similarity search to find appropriate journals for publication, authors with expertise in a given field, and documents similar to a submitted query. The utilities are based upon a program, eTBLAST, designed to identify similar documents within literature databases such as (but not limited to) MEDLINE. These services are freely accessible through the Internet at http://invention.swmed.edu/etblast/etblast.shtml, where users can upload a file or paste text such as an abstract into the browser interface

sIR: siRNA Information Resource, a web-based tool for siRNA sequence design and analysis and an open access siRNA database

<p>Abstract</p> <p>Background</p> <p>RNA interference has revolutionized our ability to study the effects of altering the expression of single genes in mammalian (and other) cells through targeted knockdown of gene expression. In this report we describe a web-based computational tool, siRNA Information Resource (sIR), which consists of a new open source database that contains validation information about published siRNA sequences and also provides a user-friendly interface to design and analyze siRNA sequences against a chosen target sequence.</p> <p>Results</p> <p>The siRNA design tool described in this paper employs empirically determined rules derived from a meta-analysis of the published data; it uses a weighted scoring system that determines the optimal sequence within a target mRNA and thus aids in the rational selection of siRNA sequences. This scoring system shows a non-linear correlation with the knockdown efficiency of siRNAs. sIR provides a fast, customized BLAST output for all selected siRNA sequences against a variety of databases so that the user can verify the uniqueness of the design. We have pre-designed siRNAs for all the known human genes (24,502) in the Refseq database. These siRNAs were pre-BLASTed against the human Unigene database to estimate the target specificity and all results are available online.</p> <p>Conclusion</p> <p>Although most of the rules for this scoring system were influenced by previously published rules, the weighted scoring system provides better flexibility in designing an appropriate siRNA when compared to the un-weighted scoring system. sIR is not only a comprehensive tool used to design siRNA sequences and lookup pre-designed siRNAs, but it is also a platform where researchers can share information on siRNA design and use.</p

Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas

Genomic studies of glioma sub-types have amassed new disease specific mutations, yet these only partially explain how mutations are linked to predisposition or progression. We hypothesized that microsatellite variation could expand the understanding of glioma etiology. Furthermore, germline markers for gliomas are typically undetectable; therefore we also hypothesize that the predictability of cancer-associated microsatellite loci in germline DNA may support the current hypothesis of a glioma cell of origin. In this study, “normal” germline exome sequenced DNA from the 1000 Genomes Project (n=390) were compared with exome sequences from germlines of subjects with WHO grade II and III lower-grade glioma (LGG, n=136) and WHO grade IV glioblastoma (GBM, n=252) from The Cancer Genome Atlas to identify microsatellite loci non-randomly associated with glioma. From germline data, we identified 48 GBM-specific loci, 42 Lower-grade glioma specific loci and 29 loci that distinguish GBM from LGG (p≤ 0.01). We then attempted to distinguish WHO grade II glioma (n=67) from GBM resulting in 8 informative loci. Significantly, in all glioma grades, comparisons between tumor and matched germline sequences demonstrated no significant differences in these variants (p≥ 0.01). Therefore, these microsatellite loci are considered to be components of grade-specific signatures for glioma which distinguish germline sequences of individuals with cancer from those of individuals that are “normal”. In order to better understand the significance of these loci, we identified biological processes enriched in genes with these variants. Most strikingly, six helicase genes were enriched in the GBM cohort (p≤ 1.0 x10-3). The preservation of these glioma-specific loci could therefore serve as valuable diagnostic and therapeutic markers; especially since the heterogeneity of tumor cell populations can obscure the identification of mutations preceding a metastatic phenotype

Biomedical term mapping databases

Longer words and phrases are frequently mapped onto a shorter form such as abbreviations or acronyms for efficiency of communication. These abbreviations are pervasive in all aspects of biology and medicine and as the amount of biomedical literature grows, so does the number of abbreviations and the average number of definitions per abbreviation. Even more confusing, different authors will often abbreviate the same word/phrase differently. This ambiguity impedes our ability to retrieve information, integrate databases and mine textual databases for content. Efforts to standardize nomenclature, especially those doing so retrospectively, need to be aware of different abbreviatory mappings and spelling variations. To address this problem, there have been several efforts to develop computer algorithms to identify the mapping of terms between short and long form within a large body of literature. To date, four such algorithms have been applied to create online databases that comprehensively map biomedical terms and abbreviations within MEDLINE: ARGH (http://lethargy.swmed.edu/ARGH/argh.asp), the Stanford Biomedical Abbreviation Server (http://bionlp.stanford.edu/abbreviation/), AcroMed (http://medstract.med.tufts.edu/acro1.1/index.htm) and SaRAD (http://www.hpl.hp.com/research/idl/projects/abbrev.html). In addition to serving as useful computational tools, these databases serve as valuable references that help biologists keep up with an ever-expanding vocabulary of terms

Carbamazepine alone and in combination with doxycycline attenuates isoproterenol-induced cardiac hypertrophy

β-adrenergic signaling is involved in the development of cardiac hypertrophy (CH), justifying the use of β-blockers as a therapy to minimize and postpone the consequences of this disease. Evidence suggests that adenylate cyclase, a downstream effector of the β-adrenergic pathway, might be a therapeutic target. We examined the effects of the anti-epileptic drug carbamazepine (CBZ), an inhibitor of adenylate cyclase. In a murine cardiac hypertrophy model, carbamazepine significantly attenuates isoproteronol (ISO)-induced cardiac hypertrophy. Carbamazepine also has an effect in transverse aortic banding induced cardiac hypertrophy (TAB) (P=0.07). When carbamazepine was given in combination with the antibiotic doxycycline (DOX), which inhibits matrix metalloproteinases (MMPs), therapeutic outcome measured by heart weight-to-body weight and heart weight-to-tibia length ratios was improved compared to either drug alone. Additionally, the combination therapy resulted in an increase in the survival rate over a 56-day period compared to that of untreated mice with cardiac hypertrophy or either drug used alone. Moreover, in support of a role for carbamaze -pine as a β-adrenergic antagonist via cAMP inhibition, a lower heart rate and a lower level of the activated phosphorylated form of the cAMP Response Element-Binding (CREB) were observed in heart extracts from mice treated with carbamazepine. Gene expression analysis identified 19 genes whose expression is significantly altered in treated animals and might be responsible for the added benefit provided by the combination therapy. These results suggest that carbamazepine acts as a β-adrenergic antagonist. Carbamazepine and doxycycline are approved by the US Food and Drug Administration (FDA) as drugs that might complement medications for cardiac hypertrophy or serve as an alternative therapy to traditional β-blockers. Furthermore, these agents reproducibly impact the expression of genes that may serve as additional therapeutic targets in the management of cardiac hypertrophy

Brucella melitensis VjbR and C12-HSL regulons: contributions of the N-dodecanoyl homoserine lactone signaling molecule and LuxR homologue VjbR to gene expression

<p>Abstract</p> <p>Background</p> <p>Quorum sensing is a communication system that regulates gene expression in response to population density and often regulates virulence determinants. Deletion of the <it>luxR </it>homologue <it>vjbR </it>highly attenuates intracellular survival of <it>Brucella melitensis </it>and has been interpreted to be an indication of a role for QS in <it>Brucella </it>infection. Confirmation for such a role was suggested, but not confirmed, by the demonstrated <it>in vitro </it>synthesis of an auto-inducer (AI) by <it>Brucella </it>cultures. In an effort to further delineate the role of VjbR to virulence and survival, gene expression under the control of VjbR and AI was characterized using microarray analysis.</p> <p>Results</p> <p>Analyses of wildtype <it>B. melitensis </it>and isogenic Δ<it>vjbR </it>transciptomes, grown in the presence and absence of exogenous <it>N</it>-dodecanoyl homoserine lactone (C₁₂-HSL), revealed a temporal pattern of gene regulation with variances detected at exponential and stationary growth phases. Comparison of VjbR and C₁₂-HSL transcriptomes indicated the shared regulation of 127 genes with all but 3 genes inversely regulated, suggesting that C₁₂-HSL functions via VjbR in this case to reverse gene expression at these loci. Additional analysis using a Δ<it>vjbR </it>mutant revealed that AHL also altered gene expression in the absence of VjbR, up-regulating expression of 48 genes and a <it>luxR </it>homologue <it>blxR </it>93-fold at stationary growth phase. Gene expression alterations include previously un-described adhesins, proteases, antibiotic and toxin resistance genes, stress survival aids, transporters, membrane biogenesis genes, amino acid metabolism and transport, transcriptional regulators, energy production genes, and the previously reported <it>fliF </it>and <it>virB </it>operons.</p> <p>Conclusions</p> <p>VjbR and C₁₂-HSL regulate expression of a large and diverse number of genes. Many genes identified as virulence factors in other bacterial pathogens were found to be differently expressed, suggesting an important contribution to intracellular survival of <it>Brucella</it>. From these data, we conclude that VjbR and C₁₂-HSL contribute to virulence and survival by regulating expression of virulence mechanisms and thus controlling the ability of the bacteria to survive within the host cell. A likely scenario occurs via QS, however, operation of such a mechanism remains to be demonstrated.</p

Comparative Analyses of Transcriptional Profiles in Mouse Organs Using a Pneumonic Plague Model after Infection with Wild-Type Yersinia pestis CO92 and Its Braun Lipoprotein Mutant

We employed Murine GeneChips to delineate the global transcriptional profiles of the livers, lungs, and spleens in a mouse pneumonic plague infection model with wild-type (WT) Y. pestis CO92 and its Braun lipoprotein (Δlpp) mutant with reduced virulence. These organs showed differential transcriptional responses to infection with WT Y. pestis, but the overall host functional processes affected were similar across all three tissues. Gene expression alterations were found in inflammation, cytokine signaling, and apoptotic cell death-associated genes. Comparison of WT and Δlpp mutant-infected mice indicated significant overlap in lipopolysaccharide- (LPS-) associated gene expression, but the absence of Lpp perturbed host cell signaling at critical regulatory junctions resulting in altered immune response and possibly host cell apoptosis. We generated a putative signaling pathway including major inflammatory components that could account for the synergistic action of LPS and Lpp and provided the mechanistic basis of attenuation caused by deletion of the lpp gene from Y. pestis in a mouse model of pneumonic plague