Male- and female-specific variants of doublesex gene products have different roles to play towards regulation of Sex combs reduced expression and sex comb morphogenesis in Drosophila

Sexually dimorphic characters have two-fold complexities in pattern formation as they have to get input from both somatic sex determination as well as the positional determining regulators. Sex comb development in Drosophila requires functions of the somatic sex-determining gene doublesex and the homeotic gene Sex combs reduced. Attempts have not been made to decipher the role of dsx in imparting sexually dimorphic expression of SCR and the differential function of sex-specific variants of dsx products in sex comb development. Our results in this study indicate that male-like pattern of SCR expression is independent of dsx function, and dsx ^F must be responsible for bringing about dimorphism in SCR expression, whereas dsx ^M function is required with Scr for the morphogenesis of sex comb.     

Integrating multi-platform genomic data using hierarchical Bayesian relevance vector machines

Background

Recent advances in genome technologies and the subsequent collection of genomic information at various molecular resolutions hold promise to accelerate the discovery of new therapeutic targets. A critical step in achieving these goals is to develop efficient clinical prediction models that integrate these diverse sources of high-throughput data. This step is challenging due to the presence of high-dimensionality and complex interactions in the data. For predicting relevant clinical outcomes, we propose a flexible statistical machine learning approach that acknowledges and models the interaction between platform-specific measurements through nonlinear kernel machines and borrows information within and between platforms through a hierarchical Bayesian framework. Our model has parameters with direct interpretations in terms of the effects of platforms and data interactions within and across platforms. The parameter estimation algorithm in our model uses a computationally efficient variational Bayes approach that scales well to large high-throughput datasets.

Results

We apply our methods of integrating gene/mRNA expression and microRNA profiles for predicting patient survival times to The Cancer Genome Atlas (TCGA) based glioblastoma multiforme (GBM) dataset. In terms of prediction accuracy, we show that our non-linear and interaction-based integrative methods perform better than linear alternatives and non-integrative methods that do not account for interactions between the platforms. We also find several prognostic mRNAs and microRNAs that are related to tumor invasion and are known to drive tumor metastasis and severe inflammatory response in GBM. In addition, our analysis reveals several interesting mRNA and microRNA interactions that have known implications in the etiology of GBM.

Conclusions

Our approach gains its flexibility and power by modeling the non-linear interaction structures between and within the platforms. Our framework is a useful tool for biomedical researchers, since clinical prediction using multi-platform genomic information is an important step towards personalized treatment of many cancers. We have a freely available software at: http://odin.mdacc.tmc.edu/~vbaladan.

     

Acute outcome of treating patients admitted with electrical storm in a tertiary care centre

Background

Electrical storm (ES) is a life threatening emergency. There is little data available regarding acute outcome of ES.

Aims

The study aimed to analyze the acute outcome of ES, various treatment modalities used, and the factors associated with mortality.

Methods

This is a retrospective observational study involving patients admitted with ES at our centre between 1/1/2007 and 31/12/2013.

Results

41 patients (mean age 54.61 ± 12.41 years; 86.7% males; mean ejection fraction (EF) 44.51 ± 16.48%) underwent treatment for ES. Hypokalemia (14.63%) and acute coronary syndrome (ACS) (14.63%) were the commonest identifiable triggers. Only 9 (21.95%) patients already had an ICD implanted. Apart from antiarrhythmic drugs (100%), deep sedation (87.8%), mechanical ventilation (24.39%) and neuraxial modulation using left sympathetic cardiac denervation (21.95%) were the common treatment modalities used. Thirty-three (80.49%) patients could be discharged after a mean duration of 14.2 ± 2.31 days. Eight (19.5%) patients died in hospital. The mortality was significantly higher in those with EF < 35% compared to those with a higher EF (8 (42.11% vs 0 (0%), p = 0.03)). There was no significant difference in mortality between those with versus without a structural heart disease (8 (21.1% vs 0 (0%), p = 0.32)). Comparison of mortality an ACS with ES versus ES of other aetiologies (3 (50%) vs 5 (14.29) %, p = 0.076)) showed a trend towards significance.

Conclusion

With comprehensive treatment, there is reasonable acute survival rate of ES. Hypokalemia and ACS are the commonest triggers of ES. Patients with low EF and ACS have higher mortality.     

Proteomic characterization and functional analysis of outer membrane vesicles of Francisella novicida suggests possible role in virulence and use as a vaccine

We have isolated and characterized outer membrane vesicles (OMVs) from Francisella. Transport of effector molecules through secretion systems is a major mechanism by which Francisella tularensis alters the extracellular proteome and interacts with the host during infection. Outer membrane vesicles produced by Francisella were examined using TEM and AFM and found to be 43-125 nm in size, representing another potential mechanism for altering the extracellular environment. A proteomic analysis (LC-MS/MS) of OMVs from F. novicida and F. philomiragia identified 416 (F. novicida) and 238 (F. philomiragia) different proteins, demonstrating that OMVs are an important contributor to the extracellular proteome. Many of the identified OMV proteins have a demonstrated role in Francisella pathogenesis. Biochemical assays demonstrated that Francisella OMVs possess acid phosphatase and hemolytic activities that may affect host cells during infection, and are cytotoxic toward murine macrophages in cell culture. OMVs have been previously used as a human vaccine against Neisseria meningitidis . We hypothesized that Francisella OMVs could be useful as a novel Francisella vaccine. Vaccinated BALB/C mice challenged with up to 50 LD50 of Francisella showed statistically significant protection when compared to control mice. In the context of these new findings, we discuss the relevance of OMVs in Francisella pathogenesis as well as their potential use as a vaccine.     

Relax with CouchDB--into the non-relational DBMS era of bioinformatics

With the proliferation of high-throughput technologies, genome-level data analysis has become common in molecular biology. Bioinformaticians are developing extensive resources to annotate and mine biological features from high-throughput data. The underlying database management systems for most bioinformatics software are based on a relational model. Modern non-relational databases offer an alternative that has flexibility, scalability, and a non-rigid design schema. Moreover, with an accelerated development pace, non-relational databases like CouchDB can be ideal tools to construct bioinformatics utilities. We describe CouchDB by presenting three new bioinformatics resources: (a) geneSmash, which collates data from bioinformatics resources and provides automated gene-centric annotations, (b) drugBase, a database of drug-target interactions with a web interface powered by geneSmash, and (c) HapMap-CN, which provides a web interface to query copy number variations from three SNP-chip HapMap datasets. In addition to the web sites, all three systems can be accessed programmatically via web services.     

Neo-clerodane diterpenoids and phenylethanoid glycosides from Teucrium chamaedrys L

A neo-clerodane type diterpenoid, 12(S)-15,16-epoxy-19-hydroxy-neo-cleroda-13(16),14-dien-18,6alpha:20,12-diolide, and two phenylethanoid glycosides, teucrioside-3(IIII)-O-methylether and teucrioside-3(IIII),4(IIII)-O-dimethylether were isolated from the aerial parts of Teucrium chamaedrys. Their structures were identified on the basis of extensive NMR spectra, LC-ESIMS analysis, and molecular modeling studies.     

Bayesian methods for expression-based integration of various types of genomics data

We propose methods to integrate data across several genomic platforms using a hierarchical Bayesian analysis framework that incorporates the biological relationships among the platforms to identify genes whose expression is related to clinical outcomes in cancer. This integrated approach combines information across all platforms, leading to increased statistical power in finding these predictive genes, and further provides mechanistic information about the manner in which the gene affects the outcome. We demonstrate the advantages of the shrinkage estimation used by this approach through a simulation, and finally, we apply our method to a Glioblastoma Multiforme dataset and identify several genes potentially associated with the patients’ survival. We find 12 positive prognostic markers associated with nine genes and 13 negative prognostic markers associated with nine genes.     

Retroviral transfer of the p16INK4a cDNA inhibits C6 glioma formation in Wistar rats

BACKGROUND: The p16INK4A gene product halts cell proliferation by preventing phosphorylation of the Rb protein. The p16INK4a gene is often deleted in human glioblastoma multiforme, contributing to unchecked Rb phosphorylation and rapid cell division. We show here that transduction of the human p16INK4a cDNA using the pCL retroviral system is an efficient means of stopping the proliferation of the rat-derrived glioma cell line, C6, both in tissue culture and in an animal model. C6 cells were transduced with pCL retrovirus encoding the p16INK4a, p53, or Rb genes. These cells were analyzed by a colony formation assay. Expression of p16INK4a was confirmed by immunohistochemistry and Western blot analysis. The altered morphology of the p16-expressing cells was further characterized by the senescence-associated beta-galactosidase assay. C6 cells infected ex vivo were implanted by stereotaxic injection in order to assess tumor formation. RESULTS: The p16INK4a gene arrested C6 cells more efficiently than either p53 or Rb. Continued studies with the p16INK4a gene revealed that a large portion of infected cells expressed the p16INK4a protein and the morphology of these cells was altered. The enlarged, flat, and bi-polar shape indicated a senescence-like state, confirmed by the senescence-associated beta-galactosidase assay. The animal model revealed that cells infected with the pCLp16 virus did not form tumors. CONCLUSION: Our results show that retrovirus mediated transfer of p16INK4a halts glioma formation in a rat model. These results corroborate the idea that retrovirus-mediated transfer of the p16INK4a gene may be an effective means to arrest human glioma and glioblastoma.