Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells

<p>Abstract</p> <p>Background</p> <p>Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress.</p> <p>Results</p> <p>Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm²) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1.</p> <p>Conclusion</p> <p>Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.</p

1HMAS NMR Study of Partial Oxidation of Methane to Syngas over Rh/ SiO2 Catalyst

The adsorption of H-2 at low temperature (773 K) and partial oxidation of methane (POM) to syngas at low (773 K) and high (973 K) temperatures over SiO2 and Rh/SiO2 were investigated by H-1 MAS NMR. When H-2 was adsorbed on the catalyst, four forms of hydrogen species were formed, i.e., the reversible and mobile hydrogen species (H-aM, delta = - 100 similar to - 120), the irreversible and immobile hydrogen species (H-beta, delta = - 100 similar to - 120), the hydrogen species named "hydrogen fog" or "hydrogen cloud" (H-beta, delta = 0 similar to 100), and the spill-over hydrogen species (H-sp, delta = 3.0). When Km and/or Hp spilled over to SiO2 and weakly adsorbed on bridged oxygen near Rh particles, the HP species was formed - It was proposed that the bridged oxygen could be activated and extracted from the SiO2 framework, forming the active oxygen species of OH - for POM. Once spilled over back to Rh particles, the OH - species reacted with CH, forming the CHxO species with 6 = 5 similar to 7. Gas phase O-2 participated in the further oxidation of CHxO to CO2 or replenished the oxygen vacancies in SiO2 left by the extraction of bridged oxygen. At the higher temperature, O-2 preferentially functioned to replenish the oxygen vacancies and this resulted in the POM reaction occurring by the surface mechanism

Pairing symmetry and properties of iron-based high temperature superconductors

Pairing symmetry is important to indentify the pairing mechanism. The analysis becomes particularly timely and important for the newly discovered iron-based multi-orbital superconductors. From group theory point of view we classified all pairing matrices (in the orbital space) that carry irreducible representations of the system. The quasiparticle gap falls into three categories: full, nodal and gapless. The nodal-gap states show conventional Volovik effect even for on-site pairing. The gapless states are odd in orbital space, have a negative superfluid density and are therefore unstable. In connection to experiments we proposed possible pairing states and implications for the pairing mechanism.Comment: 4 pages, 1 table, 2 figures, polished versio

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

Association Between Acute Kidney Injury and Long-Term Mortality in Patients With Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study

Background: Though acute kidney injury (AKI) in the context of aneurysmal subarachnoid hemorrhage (aSAH) worsens short-term outcomes, its impact on long-term survival is unknown. Aim: We aimed to evaluate the association between long-term mortality and AKI during hospitalization for aSAH. Methods: This was a retrospective study of patients who survived \u3e12 months after aSAH. All patients were evaluated at West China Hospital, Sichuan University, between December 2013 and June 2019. The minimum follow-up time was over 1 year. the maximum follow-up time was about 7.3 years. AKI was defined by the KDIGO (The Kidney Disease Improving Global Outcomes) guidelines, which stratifies patients into three stages of severity. The primary outcome was long-term mortality, which was analyzed with Kaplan-Meier curves and Cox proportional hazards models. Results: During this study period, 238 (9.2%) patients had AKI among 2,592 patients with aSAH. We confirmed that AKI during care for aSAH significantly increased long-term mortality (median 4.3 years of follow-up) and that risk increased with the severity of the kidney failure, with an adjusted hazard ratio (HR) of 2.08 (95% CI 1.49-2.89) for stage 1 AKI, 2.15 (95% CI 1.05-4.43) for stage 2 AKI, and 2.66 (95% CI 1.08-6.53) for stage 3 AKI compared with patients without AKI. Among patients with an AKI episode, those with renal recovery still had increased long-term mortality (HR 1.96; 95% CI 1.40-2.74) compared with patients without AKI but had better long-term outcomes than those without renal recovery (HR 0.51, 95% CI 0.27-0.97). Conclusions: Among 12-month survivors of aSAH, AKI during their initial hospitalization for aSAH was associated with increased long-term mortality, even for patients who had normal renal function at the time of hospital discharge. Longer, multidisciplinary post-discharge follow-up may be warranted for these patients

RPRD1A and RPRD1B Are Human RNA Polymerase II C-Terminal Domain Scaffolds for Ser5 Dephosphorylation

The RNA polymerase II (RNAPII) carboxyl-terminal domain (CTD) heptapeptide repeats (Y1-S2-P3-T4-S5-P6-S7) undergo dynamic phosphorylation and dephosphorylation during the transcription cycle to recruit factors that regulate transcription, RNA processing and chromatin modification. We show here that RPRD1A and RPRD1B form homodimers and heterodimers through their coiled-coil domains and interact preferentially via CTD interaction domains (CIDs) with CTD repeats phosphorylated at S2 and S7. Our high resolution crystal structures of the RPRD1A, RPRD1B and RPRD2 CIDs, alone and in complex with CTD phosphoisoforms, elucidate the molecular basis of CTD recognition. In an interesting example of cross-talk between different CTD modifications, our data also indicate that RPRD1A and RPRD1B associate directly with RPAP2 phosphatase and, by interacting with CTD repeats where phospho-S2 and/or phospho-S7 bracket a phospho-S5 residue, serve as CTD scaffolds to coordinate the dephosphorylation of phospho-S5 by RPAP2

Nuclear spin pair coherence in diamond for atomic scale magnetometry

The nitrogen-vacancy (NV) centre, as a promising candidate solid state system of quantum information processing, its electron spin coherence is influenced by the magnetic field fluctuations due to the local environment. In pure diamonds, the environment consists of hundreds of C-13 nuclear spins randomly spreading in several nanometers range forming a spin bath. Controlling and prolonging the electron spin coherence under the influence of spin bath are challenging tasks for the quantum information processing. On the other hand, for a given bath distribution, many of its characters are encoded in the electron spin coherence. So it is natural to ask the question: is it possible to 'decode' the electron spin coherence, and extract the information about the bath structures? Here we show that, among hundreds of C-13 bath spins, there exist strong coupling clusters, which give rise to the millisecond oscillations of the electron spin coherence. By analyzing these oscillation features, the key properties of the coherent nuclear spin clusters, such as positions, orientations, and coupling strengths, could be uniquely identified. This addressability of the few-nuclear-spin cluster extends the feasibility of using the nuclear spins in diamond as qubits in quantum computing. Furthermore, it provides a novel prototype of single-electron spin based, high-resolution and ultra-sensitive detector for the chemical and biological applications.Comment: 15 pages, 4 figures, Nature Nanotechnology (2011

Case report: Incomplete penetrance of autosomal dominant myotonia congenita caused by a rare CLCN1 variant c.1667T>A (p.I556N) in a Malaysian family

Myotonia congenita (MC) is a rare neuromuscular disease caused by mutations within the CLCN1 gene encoding skeletal muscle chloride channels. MC is characterized by delayed muscle relaxation during contraction, resulting in muscle stiffness. There is a lack of MC case reports and data on the prevalence among Malaysians. We report a clinical case of a 50-year-old woman presents with muscle stiffness and cramp episodes that started in early childhood. She had difficulty initiating muscle movement and presented with transient muscle weakness after rest, which usually improved after repeated contraction (warm-up phenomenon). She was diagnosed with MC after myotonic discharge on electromyography (EMG). Her brother had similar symptoms; however, no additional family members showed MC symptoms. Serum creatine kinase levels were elevated in both the proband and her brother with 447 U/L and 228 U/L recorded, respectively. Genetic analysis by whole-exome sequencing (WES) revealed a previously reported pathogenic CLCN1 gene variant c.1667T&gt;A (p.I556N). Genetic screening of all family members revealed that the same variant was observed in the children of both the proband and her brother; however, the children did not present with either clinical or electrophysiological MC symptoms. The multiplex ligation-dependent probe amplification (MLPA) analysis conducted identified neither exon deletion nor duplication in CLCN1. In conclusion, this report describes the first case of MC in Malaysia in which incomplete penetrance observed in this family is caused by a known pathogenic CLCN1 variant

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom