Regularizing Face Verification Nets For Pain Intensity Regression

Limited labeled data are available for the research of estimating facial expression intensities. For instance, the ability to train deep networks for automated pain assessment is limited by small datasets with labels of patient-reported pain intensities. Fortunately, fine-tuning from a data-extensive pre-trained domain, such as face verification, can alleviate this problem. In this paper, we propose a network that fine-tunes a state-of-the-art face verification network using a regularized regression loss and additional data with expression labels. In this way, the expression intensity regression task can benefit from the rich feature representations trained on a huge amount of data for face verification. The proposed regularized deep regressor is applied to estimate the pain expression intensity and verified on the widely-used UNBC-McMaster Shoulder-Pain dataset, achieving the state-of-the-art performance. A weighted evaluation metric is also proposed to address the imbalance issue of different pain intensities.Comment: 5 pages, 3 figure; Camera-ready version to appear at IEEE ICIP 201

Resistance to cardiomyocyte hypertrophy in ae3-/- mice, deficient in the AE3 Cl-/HCO3- exchanger

Background: Cardiac hypertrophy is central to the etiology of heart failure. Understanding the molecular pathways promoting cardiac hypertrophy may identify new targets for therapeutic intervention. Sodium-proton exchanger (NHE1) activity and expression levels in the heart are elevated in many models of hypertrophy through protein kinase C (PKC)/MAPK/ERK/p90RSK pathway stimulation. Sustained NHE1 activity, however, requires an acid-loading pathway. Evidence suggests that the Cl-/HCO3- exchanger, AE3, provides this acid load. Here we explored the role of AE3 in the hypertrophic growth cascade of cardiomyocytes.Methods: AE3-deficient (ae3-/-) mice were compared to wildtype (WT) littermates to examine the role of AE3 protein in the development of cardiomyocyte hypertrophy. Mouse hearts were assessed by echocardiography. As well, responses of cultured cardiomyocytes to hypertrophic stimuli were measured. pH regulation capacity of ae3-/- and WT cardiomyocytes was assessed in cultured cells loaded with the pH-sensitive dye, BCECF-AM.Results: ae3-/- mice were indistinguishable from wild type (WT) mice in terms of cardiovascular performance. Stimulation of ae3-/- cardiomyocytes with hypertrophic agonists did not increase cardiac growth or reactivate the fetal gene program. ae3-/- mice are thus protected from pro-hypertrophic stimulation. Steady state intracellular pH (pHi) in ae3-/- cardiomyocytes was not significantly different from WT, but the rate of recovery of pHi from imposed alkalosis was significantly slower in ae3-/- cardiomyocytes.Conclusions: These data reveal the importance of AE3-mediated Cl-/HCO3- exchange in cardiovascular pH regulation and the development of cardiomyocyte hypertrophy. Pharmacological antagonism of AE3 is an attractive approach in the treatment of cardiac hypertrophy.Centro de Investigaciones Cardiovasculare

ISOpureR: an R implementation of a computational purification algorithm of mixed tumour profiles

Background Tumour samples containing distinct sub-populations of cancer and normal cells present challenges in the development of reproducible biomarkers, as these biomarkers are based on bulk signals from mixed tumour profiles. ISOpure is the only mRNA computational purification method to date that does not require a paired tumour-normal sample, provides a personalized cancer profile for each patient, and has been tested on clinical data. Replacing mixed tumour profiles with ISOpure-preprocessed cancer profiles led to better prognostic gene signatures for lung and prostate cancer. Results To simplify the integration of ISOpure into standard R-based bioinformatics analysis pipelines, the algorithm has been implemented as an R package. The ISOpureR package performs analogously to the original code in estimating the fraction of cancer cells and the patient cancer mRNA abundance profile from tumour samples in four cancer datasets. Conclusions The ISOpureR package estimates the fraction of cancer cells and personalized patient cancer mRNA abundance profile from a mixed tumour profile. This open-source R implementation enables integration into existing computational pipelines, as well as easy testing, modification and extension of the model.Prostate Cancer CanadaMovember Foundation (Grant RS2014-01

Chemical and Synthetic Genetic Array Analysis Identifies Genes that Suppress Xylose Utilization and Fermentation in Saccharomyces cerevisiae

Though highly efficient at fermenting hexose sugars, Saccharomyces cerevisiae has limited ability to ferment five-carbon sugars. As a significant portion of sugars found in cellulosic biomass is the five-carbon sugar xylose, S. cerevisiae must be engineered to metabolize pentose sugars, commonly by the addition of exogenous genes from xylose fermenting fungi. However, these recombinant strains grow poorly on xylose and require further improvement through rational engineering or evolutionary adaptation. To identify unknown genes that contribute to improved xylose fermentation in these recombinant S. cerevisiae, we performed genome-wide synthetic interaction screens to identify deletion mutants that impact xylose utilization of strains expressing the xylose isomerase gene XYLA from Piromyces sp. E2 alone or with an additional copy of the endogenous xylulokinase gene XKS1. We also screened the deletion mutant array to identify mutants whose growth is affected by xylose. Our genetic network reveals that more than 80 nonessential genes from a diverse range of cellular processes impact xylose utilization. Surprisingly, we identified four genes, ALP1, ISC1, RPL20B, and BUD21, that when individually deleted improved xylose utilization of both S. cerevisiae S288C and CEN.PK strains. We further characterized BUD21 deletion mutant cells in batch fermentations and found that they produce ethanol even the absence of exogenous XYLA. We have demonstrated that the ability of laboratory strains of S. cerevisiae to utilize xylose as a sole carbon source is suppressed, which implies that S. cerevisiae may not require the addition of exogenous genes for efficient xylose fermentation

PERT: A Method for Expression Deconvolution of Human Blood Samples from Varied Microenvironmental and Developmental Conditions

The cellular composition of heterogeneous samples can be predicted using an expression deconvolution algorithm to decompose their gene expression profiles based on pre-defined, reference gene expression profiles of the constituent populations in these samples. However, the expression profiles of the actual constituent populations are often perturbed from those of the reference profiles due to gene expression changes in cells associated with microenvironmental or developmental effects. Existing deconvolution algorithms do not account for these changes and give incorrect results when benchmarked against those measured by well-established flow cytometry, even after batch correction was applied. We introduce PERT, a new probabilistic expression deconvolution method that detects and accounts for a shared, multiplicative perturbation in the reference profiles when performing expression deconvolution. We applied PERT and three other state-of-the-art expression deconvolution methods to predict cell frequencies within heterogeneous human blood samples that were collected under several conditions (uncultured mono-nucleated and lineage-depleted cells, and culture-derived lineage-depleted cells). Only PERT's predicted proportions of the constituent populations matched those assigned by flow cytometry. Genes associated with cell cycle processes were highly enriched among those with the largest predicted expression changes between the cultured and uncultured conditions. We anticipate that PERT will be widely applicable to expression deconvolution strategies that use profiles from reference populations that vary from the corresponding constituent populations in cellular state but not cellular phenotypic identity

Resistance to cardiomyocyte hypertrophy in ae3-/- mice, deficient in the AE3 Cl-/HCO3- exchanger

Background: Cardiac hypertrophy is central to the etiology of heart failure. Understanding the molecular pathways promoting cardiac hypertrophy may identify new targets for therapeutic intervention. Sodium-proton exchanger (NHE1) activity and expression levels in the heart are elevated in many models of hypertrophy through protein kinase C (PKC)/MAPK/ERK/p90RSK pathway stimulation. Sustained NHE1 activity, however, requires an acid-loading pathway. Evidence suggests that the Cl-/HCO3- exchanger, AE3, provides this acid load. Here we explored the role of AE3 in the hypertrophic growth cascade of cardiomyocytes.Methods: AE3-deficient (ae3-/-) mice were compared to wildtype (WT) littermates to examine the role of AE3 protein in the development of cardiomyocyte hypertrophy. Mouse hearts were assessed by echocardiography. As well, responses of cultured cardiomyocytes to hypertrophic stimuli were measured. pH regulation capacity of ae3-/- and WT cardiomyocytes was assessed in cultured cells loaded with the pH-sensitive dye, BCECF-AM.Results: ae3-/- mice were indistinguishable from wild type (WT) mice in terms of cardiovascular performance. Stimulation of ae3-/- cardiomyocytes with hypertrophic agonists did not increase cardiac growth or reactivate the fetal gene program. ae3-/- mice are thus protected from pro-hypertrophic stimulation. Steady state intracellular pH (pHi) in ae3-/- cardiomyocytes was not significantly different from WT, but the rate of recovery of pHi from imposed alkalosis was significantly slower in ae3-/- cardiomyocytes.Conclusions: These data reveal the importance of AE3-mediated Cl-/HCO3- exchange in cardiovascular pH regulation and the development of cardiomyocyte hypertrophy. Pharmacological antagonism of AE3 is an attractive approach in the treatment of cardiac hypertrophy.Centro de Investigaciones Cardiovasculare

Tumor Necrosis Factor-α Antagonism Improves Vasodilation During Hyperinsulinemia in Metabolic Syndrome

OBJECTIVE—Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-α. We assessed the effects of TNF-α neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome

EFFICACY AND SAFETY OF EPTACOG BETA (RECOMBINANT HUMAN FVIIA) ACCORDING TO AGE IN PERSONS WITH HAEMOPHILIA A/B WITH INHIBITORS UNDERGOING SURGICAL PROCEDURES

Introduction: Eptacog beta (CEVENFACTA®) is a new rFVIIa approved by the EMA for the treatment of bleeding events and prevention of bleeding during surgery in persons with haemophilia A/B with inhibitors (PwHABI) aged ≥12 years (y). Methods: PERSEPT 3 was a Phase 3 (NCT02020369) trial of eptacog beta in PwHABI who required surgical procedures. Eptacog beta was administered at an initial dose of 200μg/kg or 75μg/kg for major or minor procedures respectively. This was followed by 75μg/kg for ≥5 (major procedures) or ≥2 (minor procedures) days. Haemostatic efficacy was assessed using a 4-point scale during the intra and postoperative care period (primary efficacy endpoint was determined by the investigator at the study centre 48±4h after the last dose of eptacog beta, based on the totality of the assessments performed on the patient (pt) at each timepoint). This post-hoc analysis compared the efficacy and safety of eptacog beta by age (pts aged \u3c12 vs ≥12y). Results: Twelve pts were included (\u3c12y: n=5, 1 major and 4 minor procedures; ≥12y: n=7, 5 major and 2 minor procedures). The primary endpoint success proportion was 100% (95% CI: 39.8-100) in pts aged \u3c12y (4 successes, 1 missing) and 71.4% (95% CI: 29.0-96.3) in pts aged ≥12y (5 successes; 2 failures). The intraoperative success proportion was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 59.0-100) for pts aged ≥12y (7 successes). The success proportion 24h post-procedure was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 47.8-100) for pts aged ≥12y (5 successes; 2 missing). Two pts discontinued treatment (1 aged \u3c12y withdrew consent; 1 aged ≥12y due to an adverse event (AE): postprocedural hematoma). One pt experienced 2 serious AEs leading to death, both were considered unrelated to the treatment. No allergic or thrombotic events occurred; no neutralising antibodies were detected. Antifibrinolytics were used concomitantly with eptacog beta in 4 patients without any safety concerns. Discussion/Conclusion: This post-hoc subgroup analysis shows that eptacog beta is effective and well-tolerated in perioperative care irrespective of patient age (\u3c12 vs ≥12y), supporting the use of eptacog beta for bleed management (prevention and treatment) in major and minor surgical procedures in all PwHABI

Receptor selectivity between the G proteins Gα12 and Gα13 is defined by a single leucine-to-isoleucine variation

Despite recent advances in structural definition of GPCR–G protein complexes, the basis of receptor selectivity between G proteins remains unclear. The Gα12 and Gα13 subtypes together form the least studied group of heterotrimeric G proteins. G protein–coupled receptor 35 (GPR35) has been suggested to couple efficiently to Gα13 but weakly to Gα12. Using combinations of cells genome-edited to not express G proteins and bioluminescence resonance energy transfer–based sensors, we confirmed marked selectivity of GPR35 for Gα13. Incorporating Gα12/Gα13 chimeras and individual residue swap mutations into these sensors defined that selectivity between Gα13 and Gα12 was imbued largely by a single leucine-to-isoleucine variation at position G.H5.23. Indeed, leucine could not be substituted by other amino acids in Gα13 without almost complete loss of GPR35 coupling. The critical importance of leucine at G.H5.23 for GPR35–G protein interaction was further demonstrated by introduction of this leucine into Gαq, resulting in the gain of coupling to GPR35. These studies demonstrate that Gα13 is markedly the most effective G protein for interaction with GPR35 and that selection between Gα13 and Gα12 is dictated largely by a single conservative amino acid variation.—Mackenzie, A. E., Quon, T., Lin, L.-C., Hauser, A. S., Jenkins, L., Inoue, A., Tobin, A. B., Gloriam, D. E., Hudson, B. D., Milligan, G. Receptor selectivity between the G proteins Gα12 and Gα13 is defined by a single leucine-to-isoleucine variation

Conservation of core gene expression in vertebrate tissues

Abstract Background Vertebrates share the same general body plan and organs, possess related sets of genes, and rely on similar physiological mechanisms, yet show great diversity in morphology, habitat and behavior. Alteration of gene regulation is thought to be a major mechanism in phenotypic variation and evolution, but relatively little is known about the broad patterns of conservation in gene expression in non-mammalian vertebrates. Results We measured expression of all known and predicted genes across twenty tissues in chicken, frog and pufferfish. By combining the results with human and mouse data and considering only ten common tissues, we have found evidence of conserved expression for more than a third of unique orthologous genes. We find that, on average, transcription factor gene expression is neither more nor less conserved than that of other genes. Strikingly, conservation of expression correlates poorly with the amount of conserved nonexonic sequence, even using a sequence alignment technique that accounts for non-collinearity in conserved elements. Many genes show conserved human/fish expression despite having almost no nonexonic conserved primary sequence. Conclusions There are clearly strong evolutionary constraints on tissue-specific gene expression. A major challenge will be to understand the precise mechanisms by which many gene expression patterns remain similar despite extensive cis-regulatory restructuring