Requirement of the FATC domain of protein kinase Tel1 for localization to DNA ends and target protein recognition

Two large phosphatidylinositol 3-kinase-related protein kinases (PIKKs), ATM and ATR, play a central role in the DNA damage response pathway. PIKKs contain a highly conserved extreme C-terminus called the FRAP-ATM-TRRAP-C-terminal (FATC) domain. In budding yeast, ATM and ATR correspond to Tel1 and Mec1, respectively. In this study, we characterized functions of the FATC domain of Tel1 by introducing substitution or truncation mutations. One substitution mutation, termed tel1-21, and a truncation mutation, called tel1- Î"C, did not significantly affect the expression level. The tel1-21 mutation impaired the cellular response to DNA damage and conferred moderate telomere maintenance defect. In contrast, the tel1-Î"C mutation behaved like a null mutation, conferring defects in both DNA damage response and telomere maintenance. Tel1-21 protein localized to DNA ends as effectively as wild-type Tel1 protein, whereas Tel1-Î"C protein failed. Introduction of a hyperactive TEL1-hy mutation suppressed the tel1-21 mutation but not the tel1-Î"C mutation. In vitro analyses revealed that both Tel1-21 and Tel1-Î"C proteins undergo efficient autophosphorylation but exhibit decreased kinase activities toward the exogenous substrate protein, Rad53. Our results show that the FATC domain of Tel1 mediates localization to DNA ends and contributes to phosphorylation of target proteins. © 2015 Ogi, Goto, Ghosh, et al

Structural phase control of (La1.48_{1.48}Nd0.40_{0.40}Sr0.12_{0.12})CuO4_4 thin films by epitaxial growth technique

Epitaxial growth of (La$_{1.48}$Nd$_{0.40}$Sr$_{0.12}$)CuO$_4$ thin films was studied by pulsed-laser deposition technique on three different substrates, SrTiO$_3$ (100), LaSrAlO$_4$ (001), and YAlO$_3$ (001). The (Nd,Sr,Ce)$_2$CuO$_4$-type structure appears at the initial growth stage on SrTiO$_3$ (100) when the film is deposited under the growth conditions optimized for (La,Sr)$_2$CuO$_4$. This (Nd,Sr,Ce)$_2$CuO$_4$-type structure can be eliminated by increasing the substrate temperature and the laser repetition frequency. Films on LaSrAlO$_4$ (001) maintain a La$_2$CuO$_4$-type structure as bulk samples, but those on YAlO$_3$ (001) show phase separation into La$_2$CuO$_4$- and Nd$_2$CuO$_4$-type structures. Such complicated results are explained in terms of the competition between lattice misfit and thermodynamic conditions. Interestingly the films with La$_2$CuO$_4$-type structure prepared on SrTiO$_3$ and LaSrAlO$_4$ show different surface structures and transport properties. The results indicate the possibility of controlling charge stripes of (La$_{1.48}$Nd$_{0.40}$Sr$_{0.12}$)CuO$_4$ as was demonstrated in (La,Ba)$_2$CuO$_4$ thin films by Sato et al. (Phys. Rev. B {\bf 62}, R799 (2000)).Comment: 5 pages, 6 EPS figure, accepted for publication in Phys. Rev.

Localized D-dimensional global k-defects

We explicitly demonstrate the existence of static global defect solutions of arbitrary dimensionality whose energy does not diverge at spatial infinity, by considering maximally symmetric solutions described by an action with non-standard kinetic terms in a D+1 dimensional Minkowski space-time. We analytically determine the defect profile both at small and large distances from the defect centre. We verify the stability of such solutions and discuss possible implications of our findings, in particular for dark matter and charge fractionalization in graphene.Comment: 6 pages, published versio

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362