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Chromatin remodeling, particularly histone acetylation, plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. We hypothesized that curcumin, a natural polyphenolic compound abundant in the spice turmeric and a known suppressor of histone acetylation, would suppress cardiac hypertrophy through the disruption of p300 histone acetyltransferase-dependent (p300-HAT--dependent) transcriptional activation. We tested this hypothesis using primary cultured rat cardiac myocytes and fibroblasts as well as two well-established mouse models of cardiac hypertrophy. Curcumin blocked phenylephrin-induced (PE-induced) cardiac hypertrophy in vitro in a dose-dependent manner. Furthermore, curcumin both prevented and reversed mouse cardiac hypertrophy induced by aortic banding (AB) and PE infusion, as assessed by heart weight/BW and lung weight/BW ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that curcumin abrogated histone acetylation, GATA4 acetylation, and DNA-binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced inflammation and fibrosis through disrupting p300-HAT--dependent signaling pathways. Our results indicate that curcumin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-HAT activity and downstream GATA4, NF-[kappa]B, and TGF-[beta]-Smad signaling pathways., Introduction Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to increased workload, characterized by an increase in the size of individual cardiac myocytes and whole-organ enlargement. Although [...]

The proton decay of 53Com(3174.1 keV; 19/2−) was investigated via the fragmentation of a 58Ni primary beam. The proton-decay energy was determined with an improved precision to be 1558(8) keV. With this new result and the mass of 53Com, the 52Fe mass excess was derived to be −48330(8) keV, which is in good agreement with the AME12 value. A new recommended value of −48331.6(49) keV is given.

Jinping Underground lab for Nuclear Astrophysics (JUNA) will take the advantage of the ultralow background in Jinping underground lab, high current accelerator based on an ECR source and highly sensitive detector to study directly a number of crucial reactions to the hydrostatic stellar evolution for the first time at their relevant stellar energies. In its first phase, JUNA aims at the direct measurements of 25Mg(p,γ)26Al, 19F(p,α)16O, 13C(α,n)16O and 12C(α,γ)16O. The experimental setup, which include the accelerator system with high stability and high intensity, the detector system, and the shielding material with low background, will be established during the above research. The current progress of JUNA will be given.

Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers., Author(s): Liyong Zhang [1, 2, 5]; Michael S Anglesio [3, 5]; Maureen O'Sullivan [3]; Fan Zhang [3]; Ge Yang [2]; Renu Sarao [1, 2]; Mai P Nghiem [1, 2]; Shane [...]

Molecularly imprinted polymers (MIPs) in bead form were prepared by seed swelling and suspension polymerization with trimethylolpropane trimethacrylate (TRIM) as crosslinker arid tyrosine as template. The appearance of the beads [...]

Author(s): Michael A. Crackower [1, 2, 3]; Renu Sarao [1, 4, 5]; Gavin Y. Oudit [3, 5, 6, 7]; Chana Yagil [8]; Ivona Kozieradzki [1, 4]; Sam E. Scanga [9]; [...]

Background: Aicardi-Goutières syndrome (AGS) is a severe infant or juvenile-onset autoimmune disease characterized by inflammatory encephalopathy with an elevated type 1 interferon-stimulated gene (ISG) expression signature in the brain. Mutations in seven different protein-coding genes, all linked to DNA/RNA metabolism or sensing, have been identified in AGS patients, but none of them has been demonstrated to activate the IFN pathway in the brain of an animal. The molecular mechanism of inflammatory encephalopathy in AGS has not been well defined. Adenosine Deaminase Acting on RNA 1 (ADAR1) is one of the AGS-associated genes. It carries out A-to-I RNA editing that converts adenosine to inosine at double-stranded RNA regions. Whether an AGS-associated mutation in ADAR1 activates the IFN pathway and causes autoimmune pathogenesis in the brain is yet to be determined.Methods: Mutations in the ADAR1 gene found in AGS patients were introduced into the mouse genome via CRISPR/Cas9 technology. Molecular activities of the specific p.K999N mutation were investigated by measuring the RNA editing levels in brain mRNA substrates of ADAR1 through RNA sequencing analysis. IFN pathway activation in the brain was assessed by measuring ISG expression at the mRNA and protein level through real-time RT-PCR and Luminex assays, respectively. The locations in the brain and neural cell types that express ISGs were determined by RNA in situ hybridization (ISH). Potential AGS-related brain morphologic changes were assessed with immunohistological analysis. Von Kossa and Luxol Fast Blue staining was performed on brain tissue to assess calcification and myelin, respectively.Results: Mice bearing the ADAR1 p.K999N were viable though smaller than wild type sibs. RNA sequencing analysis of neuron-specific RNA substrates revealed altered RNA editing activities of the mutant ADAR1 protein. Mutant mice exhibited dramatically elevated levels of multiple ISGs within the brain. RNA ISH of brain sections showed selective activation of ISG expression in neurons and microglia in a patchy pattern. ISG-15 mRNA was upregulated in ADAR1 mutant brain neurons whereas CXCL10 mRNA was elevated in adjacent astroglia. No calcification or gliosis was detected in the mutant brain.Conclusions: We demonstrated that an AGS-associated mutation in ADAR1, specifically the p.K999N mutation, activates the IFN pathway in the mouse brain. The ADAR1 p.K999N mutant mouse replicates aspects of the brain interferonopathy of AGS. Neurons and microglia express different ISGs. Basal ganglia calcification and leukodystrophy seen in AGS patients were not observed in K999N mutant mice, indicating that development of the full clinical phenotype may need an additional stimulus besides AGS mutations. This mutant mouse presents a robust tool for the investigation of AGS and neuroinflammatory diseases including the modeling of potential "second hits" that enable severe phenotypes of clinically variable diseases. [ABSTRACT FROM AUTHOR]

Nine fluorine targets of various types were developed for the 19F(p , α)16O experiment to be performed at the Jinping Underground Nuclear Astrophysics Experiment (JUNA), China. Two targets were produced by evaporating CaF 2 on Ta backings: one was produced by sputtering MgF 2 on the Cr+Fe backings, and six were produced by implanting 20–80 keV 19F ions into pure Fe and Cu backings. Thin Cr protective layers were covered over these targets. We assessed each target's stability by monitoring the γ -ray yields of the 19F(p , α γ)16O reaction over the well-known 340 keV resonance. Our results indicate that the traditional evaporated and sputtered targets exhibit 0.6%–6% deterioration (or 19F material loss) per Coulomb, while the implanted targets exhibit relatively small deterioration due to the proton beam bombardment. For the optimum target #8, the 19F target material loss is only approximately 0.05% per Coulomb proton beam bombardment, and such target is much more stable than the traditional targets. The fluorine depth distribution of the implanted target #8 was precisely analyzed by the atom probe tomography (APT) technique. The obtained depth distribution can well reproduce the experimental γ -ray yield curve. Furthermore, as test experiment, the 19F(p , α γ)16O cross section was measured with the implanted target #8 in a center-of-mass energy region of E c.m. = 174–358 keV, which is consistent with the previous results. In conclusion, traditional fluorine targets produced with the evaporation and sputtering techniques are not suitable for the high-current experiment even with a protective layer. For the upcoming high-current JUNA experiment, this work offers an optimum target scheme: first, implanting 19F ions into the pure Fe backings with an implantation energy of 40 keV, and then sputtering a 50 nm thick Cr layer to further prevent the fluorine material loss. [ABSTRACT FROM AUTHOR]

Background: Cerebral ischemia-reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated.Methods: We retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization.Results: The baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2-3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood-brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments.Conclusions: Ac2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT. [ABSTRACT FROM AUTHOR]