2,185 research outputs found
Targeting GATA4 for cardiac repair
Various strategies have been applied to replace the loss of cardiomyocytes in order to restore reduced cardiac function and prevent the progression of heart disease. Intensive research efforts in the field of cellular reprogramming and cell transplantation may eventually lead to efficient in vivo applications for the treatment of cardiac injuries, representing a novel treatment strategy for regenerative medicine. Modulation of cardiac transcription factor (TF) networks by chemical entities represents another viable option for therapeutic interventions. Comprehensive screening projects have revealed a number of molecular entities acting on molecular pathways highly critical for cellular lineage commitment and differentiation, including compounds targeting Wnt- and transforming growth factor beta (TGF beta)-signaling. Furthermore, previous studies have demonstrated that GATA4 and NKX2-5 are essential TFs in gene regulation of cardiac development and hypertrophy. For example, both of these TFs are required to fully activate mechanical stretch-responsive genes such as atrial natriuretic peptide and brain natriuretic peptide (BNP). We have previously reported that the compound 3i-1000 efficiently inhibited the synergy of the GATA4-NKX2-5 interaction. Cellular effects of 3i-1000 have been further characterized in a number of confirmatory in vitro bioassays, including rat cardiac myocytes and animal models of ischemic injury and angiotensin II-induced pressure overload, suggesting the potential for small molecule-induced cardioprotection.Peer reviewe
Balancing the dilution and oddity effects: Decisions depend on body size
Background Grouping behaviour, common across the animal kingdom, is known to reduce an individual's risk of predation; particularly through dilution of individual risk and predator confusion (predator inability to single out an individual for attack). Theory predicts greater risk of predation to individuals more conspicuous to predators by difference in appearance from the group (the ‘oddity’ effect). Thus, animals should choose group mates close in appearance to themselves (eg. similar size), whilst also choosing a large group. Methodology and Principal Findings We used the Trinidadian guppy (Poecilia reticulata), a well known model species of group-living freshwater fish, in a series of binary choice trials investigating the outcome of conflict between preferences for large and phenotypically matched groups along a predation risk gradient. We found body-size dependent differences in the resultant social decisions. Large fish preferred shoaling with size-matched individuals, while small fish demonstrated no preference. There was a trend towards reduced preferences for the matched shoal under increased predation risk. Small fish were more active than large fish, moving between shoals more frequently. Activity levels increased as predation risk decreased. We found no effect of unmatched shoal size on preferences or activity. Conclusions and Significance Our results suggest that predation risk and individual body size act together to influence shoaling decisions. Oddity was more important for large than small fish, reducing in importance at higher predation risks. Dilution was potentially of limited importance at these shoal sizes. Activity levels may relate to how much sampling of each shoal was needed by the test fish during decision making. Predation pressure may select for better decision makers to survive to larger size, or that older, larger fish have learned to make shoaling decisions more efficiently, and this, combined with their size relative to shoal-mates, and attractiveness as prey items influences shoaling decisions
Amelioration of bleomycin-induced lung fibrosis in hamsters by dietary supplementation with taurine and niacin: biochemical mechanisms.
Interstitial pulmonary fibrosis induced by intratracheal instillation of bleomycin (BL) involves an excess production of reactive oxygen species, unavailability of adequate levels of NAD and ATP to repair the injured pulmonary epithelium, and an overexuberant lung collagen reactivity followed by deposition of highly cross-linked mature collagen fibrils resistant to enzymatic degradation. In the present study, we have demonstrated that dietary supplementation with taurine and niacin offered almost complete protection against the lung fibrosis in a multidose BL hamster model. The mechanisms for the protective effect of taurine and niacin are multifaceted. These include the ability of taurine to scavenge HOCl and stabilize the biomembrane; niacin's ability to replenish the BL-induced depletion of NAD and ATP; and the combined effect of taurine and niacin to suppress all aspects of BL-induced increases in the lung collagen reactivity, a hallmark of interstitial pulmonary fibrosis. It was concluded from the data presented at this Conference that the combined treatment with taurine and niacin, which offers a multipronged approach, will have great therapeutic potential in the intervention of the development of chemically induced interstitial lung fibrosis in animals and humans
Effects of Supersymmetric Threshold Corrections on High-Scale Flavor Textures
Integration of superpartners out of the spectrum induces potentially large
contributions to Yukawa couplings. These corrections, the supersymmetric
threshold corrections, therefore influence the CKM matrix prediction in a
non-trivial way. We study effects of threshold corrections on high-scale flavor
structures specified at the gauge coupling unification scale in supersymmetry.
In our analysis, we first consider high-scale Yukawa textures which qualify
phenomenologically viable at tree level, and find that they get completely
disqualified after incorporating the threshold corrections. Next, we consider
Yukawa couplings, such as those with five texture zeroes, which are incapable
of explaining flavor-changing proceses. Incorporation of threshold corrections,
however, makes them phenomenologically viable textures. Therefore,
supersymmetric threshold corrections are found to leave observable impact on
Yukawa couplings of quarks, and any confrontation of high-scale textures with
experiments at the weak scale must take into account such corrections.Comment: 25 pages, submitted to JHE
Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation
The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi
Network Archaeology: Uncovering Ancient Networks from Present-day Interactions
Often questions arise about old or extinct networks. What proteins interacted
in a long-extinct ancestor species of yeast? Who were the central players in
the Last.fm social network 3 years ago? Our ability to answer such questions
has been limited by the unavailability of past versions of networks. To
overcome these limitations, we propose several algorithms for reconstructing a
network's history of growth given only the network as it exists today and a
generative model by which the network is believed to have evolved. Our
likelihood-based method finds a probable previous state of the network by
reversing the forward growth model. This approach retains node identities so
that the history of individual nodes can be tracked. We apply these algorithms
to uncover older, non-extant biological and social networks believed to have
grown via several models, including duplication-mutation with complementarity,
forest fire, and preferential attachment. Through experiments on both synthetic
and real-world data, we find that our algorithms can estimate node arrival
times, identify anchor nodes from which new nodes copy links, and can reveal
significant features of networks that have long since disappeared.Comment: 16 pages, 10 figure
Earth science: Redox state of early magmas
International audienceA study of cerium in zircon minerals has allowed an assessment of the redox conditions that prevailed when Earth's earliest magmas formed. The results suggest that the mantle became oxidized sooner than had been though
Coupled changes between the H-Print biomarker and delta N-15 indicates a variable sea ice carbon contribution to the diet of Cumberland Sound beluga whales
Sample Size under Inverse Negative Binomial Group Testing for Accuracy in Parameter Estimation
Background:The group testing method has been proposed for the detection and estimation of genetically modified plants (adventitious presence of unwanted transgenic plants, AP). For binary response variables (presence or absence), group testing is efficient when the prevalence is low, so that estimation, detection, and sample size methods have been developed under the binomial model. However, when the event is rare (low prevalence
Methodology/Principal Findings: This research proposes three sample size procedures (two computational and one analytic) for estimating prevalence using group testing under inverse (negative) binomial sampling. These methods provide the required number of positive pools (rm), given a pool size (k), for estimating the proportion of AP plants using the Dorfman model and inverse (negative) binomial sampling. We give real and simulated examples to show how to apply these methods and the proposed sample-size formula. The Monte Carlo method was used to study the coverage and level of assurance achieved by the proposed sample sizes. An R program to create other scenarios is given in Appendix S2.
Conclusions: The three methods ensure precision in the estimated proportion of AP because they guarantee that the width (W) of the confidence interval (CI) will be equal to, or narrower than, the desired width (v), with a probability of c. With the Monte Carlo study we found that the computational Wald procedure (method 2) produces the more precise sample size (with coverage and assurance levels very close to nominal values) and that the samples size based on the Clopper-Pearson CI (method 1) is conservative (overestimates the sample size); the analytic Wald sample size method we developed (method 3) sometimes underestimated the optimum number of pools
Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesity
There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th) and 95(th) percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th) percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50) = 0.0103). This finding was not confirmed in the trios (p(GSEA,50) = 0.5991), but in KORA (p(GSEA,50) = 0.0398). The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50) = 0.1052, p(MAGENTA,75) = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes
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