Comparison of Whole Blood and Peripheral Blood Mononuclear Cell Gene Expression for Evaluation of the Perioperative Inflammatory Response in Patients with Advanced Heart Failure

Background: Heart failure (HF) prevalence is increasing in the United States. Mechanical Circulatory Support (MCS) therapy is an option for Advanced HF (AdHF) patients. Perioperatively, multiorgan dysfunction (MOD) is linked to the effects of device implantation, augmented by preexisting HF. Early recognition of MOD allows for better diagnosis, treatment, and risk prediction. Gene expression profiling (GEP) was used to evaluate clinical phenotypes of peripheral blood mononuclear cells (PBMC) transcriptomes obtained from patients’ blood samples. Whole blood (WB) samples are clinically more feasible, but their performance in comparison to PBMC samples has not been determined. Methods: We collected blood samples from 31 HF patients (57¡15 years old) undergoing cardiothoracic surgery and 7 healthy age-matched controls, between 2010 and 2011, at a single institution. WB and PBMC samples were collected at a single timepoint postoperatively (median day 8 postoperatively) (25–75% IQR 7–14 days) and subjected to Illumina single color Human BeadChip HT12 v4 whole genome expression array analysis. The Sequential Organ Failure Assessment (SOFA) score was used to characterize the severity of MOD into low (# 4 points), intermediate (5–11), and high ($ 12) risk categories correlating with GEP. Results: Results indicate that the direction of change in GEP of individuals with MOD as compared to controls is similar when determined from PBMC versus WB. The main enriched terms by Gene Ontology (GO) analysis included those involved in the inflammatory response, apoptosis, and other stress response related pathways. The data revealed 35 significant GO categories and 26 pathways overlapping between PBMC and WB. Additionally, class prediction using machine learning tools demonstrated that the subset of significant genes shared by PBMC and WB are sufficient to train as a predictor separating the SOFA groups. Conclusion: GEP analysis of WB has the potential to become a clinical tool for immune-monitoring in patients with MO

Efficient Coding and Statistically Optimal Weighting of Covariance among Acoustic Attributes in Novel Sounds

To the extent that sensorineural systems are efficient, redundancy should be extracted to optimize transmission of information, but perceptual evidence for this has been limited. Stilp and colleagues recently reported efficient coding of robust correlation (r = .97) among complex acoustic attributes (attack/decay, spectral shape) in novel sounds. Discrimination of sounds orthogonal to the correlation was initially inferior but later comparable to that of sounds obeying the correlation. These effects were attenuated for less-correlated stimuli (r = .54) for reasons that are unclear. Here, statistical properties of correlation among acoustic attributes essential for perceptual organization are investigated. Overall, simple strength of the principal correlation is inadequate to predict listener performance. Initial superiority of discrimination for statistically consistent sound pairs was relatively insensitive to decreased physical acoustic/psychoacoustic range of evidence supporting the correlation, and to more frequent presentations of the same orthogonal test pairs. However, increased range supporting an orthogonal dimension has substantial effects upon perceptual organization. Connectionist simulations and Eigenvalues from closed-form calculations of principal components analysis (PCA) reveal that perceptual organization is near-optimally weighted to shared versus unshared covariance in experienced sound distributions. Implications of reduced perceptual dimensionality for speech perception and plausible neural substrates are discussed

Identification of Extracellular Segments by Mass Spectrometry Improves Topology Prediction of Transmembrane Proteins

Transmembrane proteins play crucial role in signaling, ion transport, nutrient uptake, as well as in maintaining the dynamic equilibrium between the internal and external environment of cells. Despite their important biological functions and abundance, less than 2% of all determined structures are transmembrane proteins. Given the persisting technical difficulties associated with high resolution structure determination of transmembrane proteins, additional methods, including computational and experimental techniques remain vital in promoting our understanding of their topologies, 3D structures, functions and interactions. Here we report a method for the high-throughput determination of extracellular segments of transmembrane proteins based on the identification of surface labeled and biotin captured peptide fragments by LC/MS/MS. We show that reliable identification of extracellular protein segments increases the accuracy and reliability of existing topology prediction algorithms. Using the experimental topology data as constraints, our improved prediction tool provides accurate and reliable topology models for hundreds of human transmembrane proteins

An exploration into the impact of exposure to community violence and hope on children's perceptions of well-being: a South African perspective

The study aims to explore the relationship between exposure to community violence, hope, and well-being. More specifically, the study aims to ascertain whether hope is a stronger predictor of well-being than exposure to violence. Stratified random sampling was used to select a sample of 566 adolescents aged 14–17 years, from both high violence and low violence areas in Cape Town, South Africa. A questionnaire consisting of Snyder’s Children’s Hope Scale, the Recent Exposure to Violence Scale and the KIDSCREEN-52 was used. Data analysis techniques included descriptive statistics, correlations, and multiple regression. A positive, significant relationship was found between children’s hope and their well-being. Although exposure to community violence was found to be significantly correlated with wellbeing, the relationship was negligible.While exposure to community violence and hope were found to be significant predictors of well-being, hope emerged as a stronger predictor of child well-being than exposure to community violence.Department of HE and Training approved lis

Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL

Introduction It is postulated that breast cancer stem cells (bCSCs) mediate disease recurrence and drive formation of distant metastases - the principal cause of mortality in breast cancer patients. Therapeutic targeting of bCSCs however, is hampered by their heterogeneity and resistance to existing therapeutics. In order to identify strategies to selectively remove bCSCs from breast cancers, irrespective of their clinical subtype, we sought an apoptosis mechanism that would target bCSCs yet would not kill normal cells. Suppression of the apoptosis inhibitor cellular FLICE-Like Inhibitory Protein (c-FLIP) partially sensitizes breast cancer cells to the anti-cancer agent Tumour Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL). Here we demonstrate in breast cancer cell lines that bCSCs are exquisitely sensitive to the de-repression of this pro-apoptotic pathway, resulting in a dramatic reduction in experimental metastases and the loss of bCSC self-renewal. Methods Suppression c-FLIP was performed by siRNA (FLIPi) in four breast cancer cell lines and by conditional gene-knockout in murine mammary glands. Sensitivity of these cells to TRAIL was determined by complementary cell apoptosis assays, including a novel heterotypic cell assay, while tumour-initiating potential of cancer stem cell subpopulations was determined by mammosphere cultures, aldefluor assay and in vivo transplantation. Results Genetic suppression of c-FLIP resulted in the partial sensitization of TRAIL-resistant cancer lines to the pro-apoptotic effects of TRAIL, irrespective of their cellular phenotype, yet normal mammary epithelial cells remained refractory to killing. While 10%-30% of the cancer cell populations remained viable after TRAIL/FLIPi treatment, subsequent mammosphere and aldefluor assays demonstrated that this pro-apoptotic stimulus selectively targeted the functional bCSC pool, eliminating stem cell renewal. This culminated in an 80% reduction in primary tumours and a 98% reduction in metastases following transplantation. The recurrence of residual tumour initiating capacity was consistent with the observation that post-treated adherent cultures re-acquired bCSC-like properties in vitro. Importantly however this recurrent bCSC activity was attenuated following repeated TRAIL/FLIPi treatment. Conclusions We describe an apoptotic mechanism that selectively and repeatedly removes bCSC activity from breast cancer cell lines and suggest that a combined TRAIL/FLIPi therapy could prevent metastatic disease progression in a broad range of breast cancer subtypes. [PROVISIONAL

Association of warfarin dose with genes involved in its action and metabolism

We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C9*2 and/or *3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00439-006-0260-8 and is accessible for authorized users

Facultative polyandry and the role of infant-carrying in wild saddle-back tamarins ( Saguinus fuscicollis )

Wild saddle-back tamarins ( Saguinus fuscicollis ) in southeastern Peru have a variable mating system that can differ both between territories at any one time and within territories over time. Groups are usually monogamous or cooperatively polyandrous, but are occasionally even polygynous. This study addressed the following questions: why does this population contain both monogamous and polyandrous groups simultaneously? What factors determine whether specific groups are monogamous or polyandrous? The data from this study population tentatively support the hypothesis that adults should mate monogramously only if they have nonreproductive helpers (usually older offspring) to help rear infants. Without helpers, the reproductive success of both males and females is hypothesized to be higher, on average, if they mate polyandrously than if they mate monogamously. The proposed benefits of polyandry to males and females differ quantitatively, but in both cases benefits stem from the help that males provide in rearing young. The following results support this hypothesis. (1) Lone pairs were never seen to attempt breeding, and calculations suggest that the costs of lactation and infant-carrying are too great for lone pairs to have a high probability of being able to raise twin offspring (the normal litter size). (2) Polyandrous males and nonreproductive offspring contributed substantially to infant care, particularly infant-carrying (fig. 2). (3) Adult males carried infants approximately twice as often as did lactating females, presumably because of the combined costs of (a) lactation (Fig. 3) and (b) infant-carrying (Fig. 4). The proximate causes of cooperative polyandry in S. fuscicollis appear to be different from those responsible in several bird species, showing that cooperative polyandry is a complex phenomenon.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46876/1/265_2004_Article_BF00572631.pd