Tellipsoid: Exploiting inter-gene correlation for improved detection of differential gene expression

Motivation: Algorithms for differential analysis of microarray data are vital to modern biomedical research. Their accuracy strongly depends on effective treatment of inter-gene correlation. Correlation is ordinarily accounted for in terms of its effect on significance cut-offs. In this paper it is shown that correlation can, in fact, be exploited {to share information across tests}, which, in turn, can increase statistical power. Results: Vastly and demonstrably improved differential analysis approaches are the result of combining identifiability (the fact that in most microarray data sets, a large proportion of genes can be identified a priori as non-differential) with optimization criteria that incorporate correlation. As a special case, we develop a method which builds upon the widely used two-sample t-statistic based approach and uses the Mahalanobis distance as an optimality criterion. Results on the prostate cancer data of Singh et al. (2002) suggest that the proposed method outperforms all published approaches in terms of statistical power. Availability: The proposed algorithm is implemented in MATLAB and in R. The software, called Tellipsoid, and relevant data sets are available at http://www.egr.msu.edu/~desaikeyComment: 19 pages, Submitted to Bioinformatic

The role of hRev7, the accessory subunit of hPolζ, in translesion synthesis past DNA damage induced by benzo[a]pyrene diol epoxide (BPDE)

<p>Abstract</p> <p>Background</p> <p>DNA polymerase zeta (Polζ) is a specialized DNA polymerase that, unlike classical replicative polymerases, is capable of replicating past DNA lesions, i.e. of performing translesion synthesis (TLS). The catalytic subunit of hPolζ, hRev3, has been shown to play a critical role in DNA damage-induced mutagenesis in human cells, but less is known about the role of hRev7, the accessory subunit of hPolζ, in such mutagenesis. To address this question, we recently generated human fibroblasts with very significantly reduced levels of hRev7 protein and demonstrated that hRev7 is required to protect cells from ultraviolet_{(254 nm)}(UV) radiation-induced cytotoxicity and mutagenesis (McNally et al., DNA Repair 7 (2008) 597-604). The goal of the present study was to determine whether hRev7 is similarly involved in the tolerance of DNA damage induced by benzo[a]pyrene diol epoxide (BPDE), the reactive form of the widespread environmental carcinogen benzo[a]pyrene.</p> <p>Methods</p> <p>To determine whether hRev7 also plays a role in protecting human cells from the cytotoxicity and mutagenesis induced by benzo[a]pyrene diol epoxide (BPDE), cell strains with reduced hRev7 were compared to their parental strain and a vector control strain for the effect of BPDE on cell survival, induction of mutations, and the ability to progress through the cell cycle.</p> <p>Results</p> <p>The results show that cell strains with reduced hRev7 are more sensitive to the cytotoxic effect of BPDE than the control strains, and progress through S-phase at a slower rate than the control cells following BPDE treatment, indicating that hRev7, and likely hPolζ, is required for efficient bypass of BPDE-induced DNA lesions. However, neither the frequency nor kinds of mutations induced by BPDE in cells with reduced hRev7 differ significantly from those induced in the control strains, suggesting that hPolζ is not essential for inserting nucleotides opposite BPDE-induced DNA damage.</p> <p>Conclusions</p> <p>Taken together, our results which show that hRev7 is required for TLS past BPDE-induced DNA lesions but that it is not essential for inserting nucleotides opposite such lesions suggest a role for hPolζ in the extension step of translesion synthesis.</p

Identification of a selective G1-phase benzimidazolone inhibitor by a senescence-targeted virtual screen using artificial neural networks

Cellular senescence is a barrier to tumorigenesis in normal cells and tumour cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. 147 virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase (SA-β-gal) assays. Among the found hits a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced SA-β-gal activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1 and CDC25C. Additionally, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long term treatments. Preliminary structure-activity and structure clustering analyses are reported and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells

The Effects of Accentuated Eccentric Loading on Barbell and Trap Bar Countermovement Jumps

This study examined effects of accentuated eccentric loading (AEL) on barbell and trap bar loaded countermovement jumps (LCMJ). Twenty-one subjects (16 male, 5 female; Age: 23.5 ± 1.8 years; Body mass: 81.4 ± 10.6 kg; Height: 176.9 ± 7.2 cm; Training age: 7.1 ± 2.6 years) participated in this study. Upon establishing one repetition maximum and baseline jumping conditions, three experimental loading sessions were completed in random order. Barbell and trap bar LCMJ were performed with a spectrum of fixed loads from 20-50 kg during control conditions and with additional AEL loads of 10, 20, or 30 kg for experimental conditions. According to coefficients of variation

Facing Aggression: Cues Differ for Female versus Male Faces

The facial width-to-height ratio (face ratio), is a sexually dimorphic metric associated with actual aggression in men and with observers’ judgements of aggression in male faces. Here, we sought to determine if observers’ judgements of aggression were associated with the face ratio in female faces. In three studies, participants rated photographs of female and male faces on aggression, femininity, masculinity, attractiveness, and nurturing. In Studies 1 and 2, for female and male faces, judgements of aggression were associated with the face ratio even when other cues in the face related to masculinity were controlled statistically. Nevertheless, correlations between the face ratio and judgements of aggression were smaller for female than for male faces (F1,36 = 7.43, p = 0.01). In Study 1, there was no significant relationship between judgements of femininity and of aggression in female faces. In Study 2, the association between judgements of masculinity and aggression was weaker in female faces than for male faces in Study 1. The weaker association in female faces may be because aggression and masculinity are stereotypically male traits. Thus, in Study 3, observers rated faces on nurturing (a stereotypically female trait) and on femininity. Judgements of nurturing were associated with femininity (positively) and masculinity (negatively) ratings in both female and male faces. In summary, the perception of aggression differs in female versus male faces. The sex difference was not simply because aggression is a gendered construct; the relationships between masculinity/femininity and nurturing were similar for male and female faces even though nurturing is also a gendered construct. Masculinity and femininity ratings are not associated with aggression ratings nor with the face ratio for female faces. In contrast, all four variables are highly inter-correlated in male faces, likely because these cues in male faces serve as ‘‘honest signals’’

A New Adenovirus Based Vaccine Vector Expressing an Eimeria tenella Derived TLR Agonist Improves Cellular Immune Responses to an Antigenic Target

Adenoviral based vectors remain promising vaccine platforms for use against numerous pathogens, including HIV. Recent vaccine trials utilizing Adenovirus based vaccines expressing HIV antigens confirmed induction of cellular immune responses, but these responses failed to prevent HIV infections in vaccinees. This illustrates the need to develop vaccine formulations capable of generating more potent T-cell responses to HIV antigens, such as HIV-Gag, since robust immune responses to this antigen correlate with improved outcomes in long-term non-progressor HIV infected individuals.. Moreover, we show that these improved responses were dependent upon improved TLR pathway interactions.The data presented in this study illustrate the potential utility of Ad-based vectors expressing TLR agonists to improve clinical outcomes dependent upon induction of robust, antigen specific immune responses

A Detailed Observational Analysis of V1324 Sco, the Most Gamma-Ray Luminous Classical Nova to Date

It has recently been discovered that some, if not all, classical novae emit GeV gamma rays during outburst, but the mechanisms involved in the production of the gamma rays are still not well understood. We present here a comprehensive multi-wavelength dataset---from radio to X-rays---for the most gamma-ray luminous classical nova to-date, V1324 Sco. Using this dataset, we show that V1324 Sco is a canonical dusty Fe-II type nova, with a maximum ejecta velocity of 2600 km s$^{-1}$ and an ejecta mass of few $\times 10^{-5}$ M$_{\odot}$. There is also evidence for complex shock interactions, including a double-peaked radio light curve which shows high brightness temperatures at early times. To explore why V1324~Sco was so gamma-ray luminous, we present a model of the nova ejecta featuring strong internal shocks, and find that higher gamma-ray luminosities result from higher ejecta velocities and/or mass-loss rates. Comparison of V1324~Sco with other gamma-ray detected novae does not show clear signatures of either, and we conclude that a larger sample of similarly well-observed novae is needed to understand the origin and variation of gamma rays in novae.Comment: 26 pages, 13 figure

A horizon scan of priorities for coastal marine microbiome research

Research into the microbiomes of natural environments is changing the way ecologists and evolutionary biologists view the importance of microbes in ecosystem function. This is particularly relevant in ocean environments, where microbes constitute the majority of biomass and control most of the major biogeochemical cycles, including those that regulate the Earth's climate. Coastal marine environments provide goods and services that are imperative to human survival and well-being (e.g. fisheries, water purification), and emerging evidence indicates that these ecosystem services often depend on complex relationships between communities of microorganisms (the ‘microbiome’) and their hosts or environment – termed the ‘holobiont’. Understanding of coastal ecosystem function must therefore be framed under the holobiont concept, whereby macroorganisms and their associated microbiomes are considered as a synergistic ecological unit. Here we evaluated the current state of knowledge on coastal marine microbiome research and identified key questions within this growing research area. Although the list of questions is broad and ambitious, progress in the field is increasing exponentially, and the emergence of large, international collaborative networks and well-executed manipulative experiments are rapidly advancing the field of coastal marine microbiome research

Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever

<p>Abstract</p> <p>Background</p> <p>A number of RNA viruses cause viral hemorrhagic fever (VHF), in which proinflammatory mediators released from infected cells induce increased permeability of the endothelial lining of blood vessels, leading to loss of plasma volume, hypotension, multi-organ failure, shock and death. The optimal treatment of VHF should therefore include both the use of antiviral drugs to inhibit viral replication and measures to prevent or correct changes in vascular function. Although rodent models have been used to evaluate treatments for increased vascular permeability (VP) in bacterial sepsis, such studies have not been performed for VHF.</p> <p>Results</p> <p>Here, we use an established model of Pichinde virus infection of hamsters to demonstrate how changes in VP can be detected by intravenous infusion of Evans blue dye (EBD), and compare those measurements to changes in hematocrit, serum albumin concentration and serum levels of proinflammatory mediators. We show that EBD injected into sick animals in the late stage of infection is rapidly sequestered in the viscera, while in healthy animals it remains within the plasma, causing the skin to turn a marked blue color. This test could be used in live animals to detect increased VP and to assess the ability of antiviral drugs and vasoactive compounds to prevent its onset. Finally, we describe a multiplexed assay to measure levels of serum factors during the course of Pichinde arenavirus infection and demonstrate that viremia and subsequent increase in white blood cell counts precede the elaboration of inflammatory mediators, which is followed by increased VP and death.</p> <p>Conclusions</p> <p>This level of model characterization is essential to the evaluation of novel interventions designed to control the effects of virus-induced hypercytokinemia on host vascular function in VHF, which could lead to improved survival.</p

Facing Aggression: Cues Differ for Female versus Male Faces

The facial width-to-height ratio (face ratio), is a sexually dimorphic metric associated with actual aggression in men and with observers' judgements of aggression in male faces. Here, we sought to determine if observers' judgements of aggression were associated with the face ratio in female faces. In three studies, participants rated photographs of female and male faces on aggression, femininity, masculinity, attractiveness, and nurturing. In Studies 1 and 2, for female and male faces, judgements of aggression were associated with the face ratio even when other cues in the face related to masculinity were controlled statistically. Nevertheless, correlations between the face ratio and judgements of aggression were smaller for female than for male faces (F1,36 = 7.43, p = 0.01). In Study 1, there was no significant relationship between judgements of femininity and of aggression in female faces. In Study 2, the association between judgements of masculinity and aggression was weaker in female faces than for male faces in Study 1. The weaker association in female faces may be because aggression and masculinity are stereotypically male traits. Thus, in Study 3, observers rated faces on nurturing (a stereotypically female trait) and on femininity. Judgements of nurturing were associated with femininity (positively) and masculinity (negatively) ratings in both female and male faces. In summary, the perception of aggression differs in female versus male faces. The sex difference was not simply because aggression is a gendered construct; the relationships between masculinity/femininity and nurturing were similar for male and female faces even though nurturing is also a gendered construct. Masculinity and femininity ratings are not associated with aggression ratings nor with the face ratio for female faces. In contrast, all four variables are highly inter-correlated in male faces, likely because these cues in male faces serve as “honest signals”