Large-scale inference and graph theoretical analysis of gene-regulatory networks in B. stubtilis

We present the methods and results of a two-stage modeling process that generates candidate gene-regulatory networks of the bacterium B. subtilis from experimentally obtained, yet mathematically underdetermined microchip array data. By employing a computational, linear correlative procedure to generate these networks, and by analyzing the networks from a graph theoretical perspective, we are able to verify the biological viability of our inferred networks, and we demonstrate that our networks' graph theoretical properties are remarkably similar to those of other biological systems. In addition, by comparing our inferred networks to those of a previous, noisier implementation of the linear inference process [17], we are able to identify trends in graph theoretical behavior that occur both in our networks as well as in their perturbed counterparts. These commonalities in behavior at multiple levels of complexity allow us to ascertain the level of complexity to which our process is robust to noise.Comment: 22 pages, 4 figures, accepted for publication in Physica A (2006

The role of Neurochemicals, Stress Hormones and Immune System in the Positive Feedback Loops between Diabetes, Obesity and Depression

Type 2 diabetes mellitus (T2DM) and depression are significant public health and socioeconomic issues. They commonly co-occur, with T2DM occurring in 11.3% of the US population, while depression has a prevalence of about 9%, with higher rates among youths. Approximately 31% of patients with T2DM suffer from depressive symptoms, with 11.4% having major depressive disorders, which is twice as high as the prevalence of depression in patients without T2DM. Additionally, over 80% of people with T2DM are overweight or obese. This review describes how T2DM and depression can enhance one another, using the same molecular pathways, by synergistically altering the brain’s structure and function and reducing the reward obtained from eating. In this article, we reviewed the evidence that eating, especially high-caloric foods, stimulates the limbic system, initiating Reward Deficiency Syndrome. Analogous to other addictive behaviors, neurochemical changes in those with depression and/or T2DM are thought to cause individuals to increase their food intake to obtain the same reward leading to binge eating, weight gain and obesity. Treating the symptoms of T2DM, such as lowering HbA1c, without addressing the underlying pathways has little chance of eliminating the disease. Targeting the immune system, stress circuit, melatonin, and other alterations may be more effective

Geneshot: search engine for ranking genes from arbitrary text queries

The frequency by which genes are studied correlates with the prior knowledge accumulated about them. This leads to an imbalance in research attention where some genes are highly investigated while others are ignored. Geneshot is a search engine developed to illuminate this gap and to promote attention to the under-studied genome. Through a simple web interface, Geneshot enables researchers to enter arbitrary search terms, to receive ranked lists of genes relevant to the search terms. Returned ranked gene lists contain genes that were previously published in association with the search terms, as well as genes predicted to be associated with the terms based on data integration from multiple sources. The search results are presented with interactive visualizations. To predict gene function, Geneshot utilizes gene–gene similarity matrices from processed RNA-seq data, or from gene–gene co-occurrence data obtained from multiple sources. In addition, Geneshot can be used to analyze the novelty of gene sets and augment gene sets with additional relevant genes. The Geneshot web-server and API are freely and openly available from https://amp.pharm.mssm.edu/geneshot

Expression of HIV transgene aggravates kidney injury in diabetic mice

With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy has decreased. Currently, HIV-infected patients live much longer and often suffer from comorbidities such as diabetes mellitus. Recent epidemiological studies suggest that concurrent HIV infection and diabetes mellitus may have a synergistic effect on the incidence of chronic kidney disease. To address this, we determined whether HIV-1 transgene expression accelerates diabetic kidney injury using a diabetic HIV-1 transgenic (Tg26) murine model. Diabetes was initially induced with low-dose streptozotocin in both Tg26 and wild-type mice on a C57BL/6 background, which is resistant to classic HIV-associated nephropathy. Although diabetic nephropathy is minimally observed on the C57BL/6 background, diabetic Tg26 mice exhibited a significant increase in glomerular injury compared with nondiabetic Tg26 mice and diabetic wild-type mice. Validation of microarray gene expression analysis from isolated glomeruli showed a significant upregulation of proinflammatory pathways in diabetic Tg26 mice. Thus, our study found that expression of HIV-1 genes aggravates diabetic kidney disease

Structural characterization of the Get4/Get5 complex and its interaction with Get3

The recently elucidated Get proteins are responsible for the targeted delivery of the majority of tail-anchored (TA) proteins to the endoplasmic reticulum. Get4 and Get5 have been identified in the early steps of the pathway mediating TA substrate delivery to the cytoplasmic targeting factor Get3. Here we report a crystal structure of Get4 and an N-terminal fragment of Get5 from Saccharomyces cerevisae. We show Get4 and Get5 (Get4/5) form an intimate complex that exists as a dimer (two copies of Get4/5) mediated by the C-terminus of Get5. We further demonstrate that Get3 specifically binds to a conserved surface on Get4 in a nucleotide dependent manner. This work provides further evidence for a model in which Get4/5 operates upstream of Get3 and mediates the specific delivery of a TA substrate

Distinct Contribution of the HtrA Protease and PDZ Domains to Its Function in Stress Resilience and Virulence of Bacillus anthracis

Anthrax is a lethal disease caused by the Gram-positive spore-producing bacterium Bacillus anthracis. We previously demonstrated that disruption of htrA gene, encoding the chaperone/protease HtrABA (High Temperature Requirement A of B. anthracis) results in significant virulence attenuation, despite unaffected ability of ΔhtrA strains (in which the htrA gene was deleted) to synthesize the key anthrax virulence factors: the exotoxins and capsule. B. anthracis ΔhtrA strains exhibited increased sensitivity to stress regimens as well as silencing of the secreted starvation-associated Neutral Protease A (NprA) and down-modulation of the bacterial S-layer. The virulence attenuation associated with disruption of the htrA gene was suggested to reflect the susceptibility of ΔhtrA mutated strains to stress insults encountered in the host indicating that HtrABA represents an important B. anthracis pathogenesis determinant. As all HtrA serine proteases, HtrABA exhibits a protease catalytic domain and a PDZ domain. In the present study we interrogated the relative impact of the proteolytic activity (mediated by the protease domain) and the PDZ domain (presumably necessary for the chaperone activity and/or interaction with substrates) on manifestation of phenotypic characteristics mediated by HtrABA. By inspecting the phenotype exhibited by ΔhtrA strains trans-complemented with either a wild-type, truncated (ΔPDZ), or non-proteolytic form (mutated in the catalytic serine residue) of HtrABA, as well as strains exhibiting modified chromosomal alleles, it is shown that (i) the proteolytic activity of HtrABA is essential for its N-terminal autolysis and subsequent release into the extracellular milieu, while the PDZ domain was dispensable for this process, (ii) the PDZ domain appeared to be dispensable for most of the functions related to stress resilience as well as involvement of HtrABA in assembly of the bacterial S-layer, (iii) conversely, the proteolytic activity but not the PDZ domain, appeared to be dispensable for the role of HtrABA in mediating up-regulation of the extracellular protease NprA under starvation stress, and finally (iv) in a murine model of anthrax, the HtrABA PDZ domain, was dispensable for manifestation of B. anthracis virulence. The unexpected dispensability of the PDZ domain may represent a unique characteristic of HtrABA amongst bacterial serine proteases of the HtrA family