Nucleolar-nucleoplasmic shuttling of TARG1 and its control by DNA damage-induced poly-ADP-ribosylation and by nucleolar transcription

Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors. TARG1 localized to transcriptionally active nucleoli, which occurred independently of ADP-ribose binding. TARG1 shuttled continuously between nucleoli and nucleoplasm. In response to DNA damage, which activates ARTD1/2 (PARP1/2) and promotes synthesis of poly-ADP-ribose chains, TARG1 re-localized to the nucleoplasm. This was dependent on the ability of TARG1 to bind to poly-ADP-ribose. These findings are consistent with the observed ability of TARG1 to competitively interact with RNA and PAR chains. We propose a nucleolar role of TARG1 in ribosome assembly or quality control that is stalled when TARG1 is re-located to sites of DNA damage

Environmental Factors Influence Language Development in Children with Autism Spectrum Disorders

International audienc

Multicenter evaluation of dynamic three-dimensional magnetic resonance myocardial perfusion imaging for the detection of coronary artery disease defined by fractional flow reserve

BACKGROUND First-pass myocardial perfusion cardiovascular magnetic resonance (CMR) imaging yields high diagnostic accuracy for the detection of coronary artery disease (CAD). However, standard 2D multislice CMR perfusion techniques provide only limited cardiac coverage, and hence considerable assumptions are required to assess myocardial ischemic burden. The aim of this prospective study was to assess the diagnostic performance of 3D myocardial perfusion CMR to detect functionally relevant CAD with fractional flow reserve (FFR) as a reference standard in a multicenter setting. METHODS AND RESULTS A total of 155 patients with suspected CAD listed for coronary angiography with FFR were prospectively enrolled from 5 European centers. 3D perfusion CMR was acquired on 3T MR systems from a single vendor under adenosine stress and at rest. All CMR perfusion analyses were performed in a central laboratory and blinded to all clinical data. One hundred fifty patients were successfully examined (mean age 62.9±10 years, 45 female). The prevalence of CAD defined by FFR (<0.8) was 56.7% (85 of 150 patients). The sensitivity and specificity of 3D perfusion CMR were 84.7% and 90.8% relative to the FFR reference. Comparison to quantitative coronary angiography (≥50%) yielded a prevalence of 65.3%, sensitivity and specificity of 76.5% and 94.2%, respectively. CONCLUSIONS In this multicenter study, 3D myocardial perfusion CMR proved highly diagnostic for the detection of significant CAD as defined by FFR

TCT-216 Predictors Of Patient-Oriented And Device-Oriented Outcomes Among Patients Undergoing Primary Percutaneous Coronary Intervention

Background: Treatment of STEMI has considerably evolved over the past 2 decades. However, predictors of adverse events after STEMI are mostly based on early studies without consistent use of reperfusion therapy, P2Y12 inhibitors, and drug-eluting stent implantation. We aimed to identify predictors of adverse events among patients with ST-elevation myocardial infarction (STEMI) undergoing contemporary primary percutaneous coronary intervention (PCI). Methods: Individual data of 2655 patients from 2 primary PCI trials (EXAMINATION, N=1504; COMFORTABLE-AMI, N=1161) with identical endpoint definition and event adjudication were pooled. Predictors of patient-oriented (death or reinfarction) and device-oriented (definite stent thrombosis [ST] and target-lesion revascularization [TLR]) outcomes at 1 year were identified by multivariable Cox regressions analysis. Results: Killip class III/IV was the strongest predictor of death or reinfarction (OR5.11, 95%CI2.48-10.52), ST (OR7.74, 95%CI2.87-20.93), and any TLR (OR2.88, 95%CI1.17-7.06). Impaired LVEF (OR4.77, 95%CI2.10-10.82), final TIMI flow 0-2 (OR1.93, 95%CI1.05-3.54), hypertension (OR1.69, 95%CI1.11-2.59), age (OR1.68, 95%CI1.41-2.01), and peak CK (OR1.25, 95%CI1.02-1.54) were independent predictors of death or reinfarction. Allocation to treatment with DES was an independent predictor of a lower risk of ST (OR0.35, 95%CI0.16-0.74) and any TLR (OR0.34, 95%CI0.21-0.54). Conclusions: Killip class remains the strongest predictor of death or reinfarction among STEMI patients undergoing primary PCI. Noteworthy, DES use independently predicts a lower risk of TLR and definite ST

I kappa B Kinase alpha/beta Control Biliary Homeostasis and Hepatocarcinogenesis in Mice by Phosphorylating the Cell-Death Mediator Receptor-Interacting Protein Kinase 1

The I?B-Kinase (IKK) complex-consisting of the catalytic subunits, IKK? and IKK?, as well as the regulatory subunit, NEMO-mediates activation of the nuclear factor ?B (NF-?B) pathway, but previous studies suggested the existence of NF-?B-independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell death is a crucial factor in the progression of liver diseases, and receptor-interacting kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell-death pathways and inflammation. We hypothesized that RIPKs might be unrecognized targets of the catalytic IKK-complex subunits, thereby regulating hepatocarcinogenesis and cholestasis. In this present study, mice with specific genetic inhibition of catalytic IKK activity in liver parenchymal cells (LPCs; IKK?/?(LPC-KO) ) were intercrossed with RIPK1(LPC-KO) or RIPK3(-/-) mice to examine whether RIPK1 or RIPK3 might be downstream targets of IKKs. Moreover, we performed in vivo phospho-proteome analyses and in vitro kinase assays, mass spectrometry, and mutagenesis experiments. These analyses revealed that IKK? and IKK?-in addition to their known function in NF-?B activation-directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKK?/?-dependent RIPK1 phosphorylation in LPCs inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development, but promoting biliary cell paucity and lethal cholestasis.IKK-complex subunits transmit a previously unrecognized signal through RIPK1, which is fundamental for the long-term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer. (Hepatology 2016;64:1217-1231).? 2016 by the American Association for the Study of Liver Diseases