A Curated Database of miRNA Mediated Feed-Forward Loops Involving MYC as Master Regulator

BACKGROUND: The MYC transcription factors are known to be involved in the biology of many human cancer types. But little is known about the Myc/microRNAs cooperation in the regulation of genes at the transcriptional and post-transcriptional level. METHODOLOGY/PRINCIPAL FINDINGS: Employing independent databases with experimentally validated data, we identified several mixed microRNA/Transcription Factor Feed-Forward Loops regulated by Myc and characterized completely by experimentally supported regulatory interactions, in human. We then studied the statistical and functional properties of these circuits and discussed in more detail a few interesting examples involving E2F1, PTEN, RB1 and VEGF. CONCLUSIONS/SIGNIFICANCE: We have assembled and characterized a catalogue of human mixed Transcription Factor/microRNA Feed-Forward Loops, having Myc as master regulator and completely defined by experimentally verified regulatory interactions

Interpretation of In Vitro Concentration-Response Data for Risk Assessment and Regulatory Decision-making: Report from the 2022 IWGT Quantitative Analysis Expert Working Group Meeting.

Quantitative risk assessments of chemicals are routinely performed using in vivo data from rodents; however, there is growing recognition that non-animal approaches can be human-relevant alternatives. There is an urgent need to build confidence in non-animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk assessors to prepare for this paradigm shift in toxicity assessment, standardization and consensus on in vitro testing strategies and data interpretation will need to be established. To address this issue, an Expert Working Group (EWG) of the 8th International Workshop on Genotoxicity Testing (IWGT) evaluated the utility of quantitative in vitro genotoxicity concentration-response data for risk assessment. The EWG first evaluated available in vitro methodologies and then examined the variability and maximal response of in vitro tests to estimate biologically relevant values for the critical effect sizes considered adverse or unacceptable. Next, the EWG reviewed the approaches and computational models employed to provide human-relevant dose context to in vitro data. Lastly, the EWG evaluated risk assessment applications for which in vitro data are ready for use and applications where further work is required. The EWG concluded that in vitro genotoxicity concentration-response data can be interpreted in a risk assessment context. However, prior to routine use in regulatory settings, further research will be required to address the remaining uncertainties and limitations. This article is protected by copyright. All rights reserved

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Utility of Cardiac Magnetic Resonance to assess association between admission hyperglycemia and myocardial damage in patients with reperfused ST-Segment Elevation Myocardial Infarction

International audienceAbstract: Aims: to investigate the association between admission hyperglycemia and myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI) using Cardiac Magnetic Resonance (CMR). Methods: We analyzed 113 patients with STEMI treated with successful primary percutaneous coronary intervention. Admission hyperglycemia was defined as a glucose level >= 7.8 mmol/l. Contrast-enhanced CMR was performed between 3 and 7 days after reperfusion to evaluate left ventricular function and perfusion data after injection of gadolinium-DTPA. First-pass images (FP), providing assessment of microvascular obstruction and Late Gadolinium Enhanced images (DE), reflecting the extent of infarction, were investigated and the extent of transmural tissue damage was determined by visual scores. Results: Patients with a supramedian FP and DE scores more frequently had left anterior descending culprit artery (p = 0.02 and < 0.001), multivessel disease (p = 0.02 for both) and hyperglycemia (p < 0.001). Moreover, they were characterized by higher levels of HbA(1c) (p = 0.01 and 0.04), peak plasma Creatine Kinase (p < 0.001), left ventricular end-systolic volume (p = 0.005 and < 0.001), and lower left ventricular ejection fraction (p = 0.001 and < 0.001). In a multivariate model, admission hyperglycemia remains independently associated with increased FP and DE scores. Conclusion: Our results show the existence of a strong relationship between glucose metabolism impairment and myocardial damage in patients with STEMI. Further studies are needed to show if aggressive glucose control improves myocardial perfusion, which could be assessed using CMR

Hip abduction weakness in elite junior footballers is common but easy to correct quickly: a prospective sports team cohort based study

Background: Hip abduction weakness has never been documented on a population basis as a common finding in a healthy group of athletes and would not normally be found in an elite adolescent athlete. This study aimed to show that hip abduction weakness not only occurs in this group but also is common and easy to correct with an unsupervised home based program. Methods: A prospective sports team cohort based study was performed with thirty elite adolescent under-17 Australian Rules Footballers in the Australian Institute of Sport/Australian Football League Under-17 training academy. The players had their hip abduction performance assessed and were then instructed in a hip abduction muscle training exercise. This was performed on a daily basis for two months and then they were reassessed.Results: The results showed 14 of 28 athletes who completed the protocol had marked weakness or a side-to-side difference of more than 25% at baseline. Two months later ten players recorded an improvement of ≥ 80% in their recorded scores. The mean muscle performance on the right side improved from 151 Newton (N) to 202 N (p<0.001) while on the left, the recorded results improved from 158 N to 223 N (p<0.001). Conclusions: The baseline values show widespread profound deficiencies in hip abduction performance not previously reported. Very large performance increases can be achieved, unsupervised, in a short period of time to potentially allow large clinically significant gains. This assessment should be an integral part of preparticipation screening and assessed in those with lower limb injuries. This particular exercise should be used clinically and more research is needed to determine its injury prevention and performance enhancement implications

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.

Study of CP violation in Dalitz-plot analyses of B0 --> K+K-KS, B+ --> K+K-K+, and B+ --> KSKSK+

We perform amplitude analyses of the decays $B^0 \to K^+K^-K^0_S$, $B^+ \rightarrow K^+K^-K^+$, and $B^+ \to K^0_S K^0_S K^+$, and measure CP-violating parameters and partial branching fractions. The results are based on a data sample of approximately $470\times 10^6$ $B\bar{B}$ decays, collected with the BABAR detector at the PEP-II asymmetric-energy $B$ factory at the SLAC National Accelerator Laboratory. For $B^+ \to K^+K^-K^+$, we find a direct CP asymmetry in $B^+ \to \phi(1020)K^+$ of $A_{CP}= (12.8\pm 4.4 \pm 1.3)$, which differs from zero by $2.8 \sigma$. For $B^0 \to K^+K^-K^0_S$, we measure the CP-violating phase $\beta_{\rm eff} (\phi(1020)K^0_S) = (21\pm 6 \pm 2)^\circ$. For $B^+ \to K^0_S K^0_S K^+$, we measure an overall direct CP asymmetry of $A_{CP} = (4 ^{+4}_{-5} \pm 2)$. We also perform an angular-moment analysis of the three channels, and determine that the $f_X(1500)$ state can be described well by the sum of the resonances $f_0(1500)$, $f_2^{\prime}(1525)$, and $f_0(1710)$.Comment: 35 pages, 68 postscript figures. v3 - minor modifications to agree with published versio

Measurement of the W+W−W^+W^- Production Cross Section and Search for Anomalous WWγWW\gamma and WWZWWZ Couplings in ppˉp \bar p Collisions at s=1.96\sqrt{s} = 1.96 TeV

This Letter describes the current most precise measurement of the $W$ boson pair production cross section and most sensitive test of anomalous $WW\gamma$ and $WWZ$ couplings in $p \bar p$ collisions at a center-of-mass energy of 1.96 TeV. The $WW$ candidates are reconstructed from decays containing two charged leptons and two neutrinos, where the charged leptons are either electrons or muons. Using data collected by the CDF II detector from 3.6 fb$^{-1}$ of integrated luminosity, a total of 654 candidate events are observed with an expected background contribution of $320 \pm 47$ events. The measured total cross section is $\sigma (p \bar p \to W^+ W^- + X) = 12.1 \pm 0.9 \textrm{(stat)} ^{+1.6}_{-1.4} \textrm{(syst)}$ pb, which is in good agreement with the standard model prediction. The same data sample is used to place constraints on anomalous $WW\gamma$ and $WWZ$ couplings.Comment: submitted to Phys. Rev. Let

Stat3 and c-Myc Genome-Wide Promoter Occupancy in Embryonic Stem Cells

Embryonic stem (ES) cell pluripotency is regulated in part by transcription factor (TF) pathways that maintain self-renewal and inhibit differentiation. Stat3 and c-Myc TFs are essential for maintaining mouse ES cell self-renewal. c-Myc, together with Oct4, Sox2, and Klf4, is a reprogramming factor. While previous studies have investigated core transcriptional circuitry in ES cells, other TF pathways that promote ES cell pluripotency have yet to be investigated. Therefore, to further understand ES cell transcriptional networks, we used genome-wide chromatin immunoprecipitation and microarray analysis (ChIP-chip) to map Stat3 and c-Myc binding targets in ES cells. Our results show that Stat3 and c-Myc occupy a significant number of genes whose expression is highly enriched in ES cells. By comparing Stat3 and c-Myc target genes with gene expression data from undifferentiated ES cells and embryoid bodies (EBs), we found that Stat3 binds active and inactive genes in ES cells, while c-Myc binds predominantly active genes. Moreover, the transcriptional states of Stat3 and c-Myc targets are correlated with co-occupancy of pluripotency-related TFs, polycomb group proteins, and active and repressive histone modifications. We also provide evidence that Stat3 targets are differentially expressed in ES cells following removal of LIF, where culture of ES cells in the absence of LIF resulted in downregulation of Stat3 target genes enriched in ES cells, and upregulation of lineage specific Stat3 target genes. Altogether, we reveal transcriptional targets of two key pluripotency-related genes in ES cells – Stat3 and c-Myc, thus providing further insight into the ES cell transcriptional network