Filtered overlap: speedup, locality, kernel non-normality and Z_A~1

We investigate the overlap operator with a UV filtered Wilson kernel. The filtering leads to a better localization of the operator even on coarse lattices and with the untuned choice $\rho=1$. Furthermore, the axial-vector renormalization constant $Z_A$ is much closer to 1, reducing the mismatch with perturbation theory. We show that all these features persist over a wide range of couplings and that the details of filtering prove immaterial. We investigate the properties of the kernel spectrum and find that the kernel non-normality is reduced. As a side effect we observe that for certain applications of the filtered overlap a speed-up factor of 2-4 can be achieved.Comment: 30 pp, 23 fig

Up, down, strange and charm quark masses with N-f=2+1+1 twisted mass lattice QCD

We present a lattice QCD calculation of the up, down, strange and charm quark masses performed using the gauge configurations produced by the European Twisted Mass Collaboration with N-f = 2 + 1 + 1 dynamical quarks, which include in the sea, besides two light mass degenerate quarks, also the strange and charm quarks with masses close to their physical values. The simulations are based on a unitary setup for the two light quarks and on a mixed action approach for the strange and charm quarks. The analysis uses data at three values of the lattice spacing and pion masses in the range 210-450 MeV, allowing for accurate continuum limit and controlled chiral extrapolation. The quark mass renormalization is carried out non-perturbatively using the RI'-MOM method. The results for the quark masses converted to the (MS) over bar scheme are: m(ud) (2 GeV) = 3.70(17) MeV, m(s)(2 GeV) = 99.6(4.3) MeV and m(c)(m(c)) = 1.348(46) GeV. We obtain also the quark mass ratios m(s)/m(ud) = 26.66(32) and m(c)/m(s) = 11.62(16). By studying the mass splitting between the neutral and charged kaons and using available lattice results for the electromagnetic contributions, we evaluate m(u)/m(d) = 0.470(56), leading to m(u) = 2.36(24) MeV and m(d) = 5.03(26) MeV

Effects of non-perturbatively improved dynamical fermions in QCD at fixed lattice spacing

We present results for the static inter-quark potential, lightest glueballs, light hadron spectrum and topological susceptibility using a non-perturbatively improved action on a $16^3\times 32$ lattice at a set of values of the bare gauge coupling and bare dynamical quark mass chosen to keep the lattice size fixed in physical units ($\sim 1.7$ fm). By comparing these measurements with a matched quenched ensemble, we study the effects due to two degenerate flavours of dynamical quarks. With the greater control over residual lattice spacing effects which these methods afford, we find some evidence of charge screening and some minor effects on the light hadron spectrum over the range of quark masses studied ($M_{PS}/M_{V}\ge0.58$). More substantial differences between quenched and unquenched simulations are observed in measurements of topological quantities.Comment: 53 pages, LaTeX/RevTeX, 16 eps figures; corrected clover action expression and various typos, no results change

Two Functionally Distinct Isoforms of TL1A (TNFSF15) Generated by Differential Ectodomain Shedding

Tumor necrosis factor–like cytokine 1A (TL1A) is expressed in endothelial cells and contributes to T-cell activation, via an extracellular fragment TL1AL72-L251, generated by ectodomain shedding. Fragments of TL1A, referred to as vascular endothelial growth inhibitor, were found to induce growth arrest and apoptosis in endothelial cells; however, the underlying mechanisms remained obscure. Here, we show that full-length TL1A is the major detectable gene product in both human umbilical vein endothelial cells and circulating endothelial progenitor cells. TL1A expression was significantly enhanced in senescent circulating endothelial progenitor cells, and knockdown of TL1A partially reverted senescence. TL1A overexpression induced premature senescence in both circulating endothelial progenitor cells and human umbilical vein endothelial cells. We also identified a novel extracellular fragment of TL1A, TL1AV84-L251, resulting from differential ectodomain shedding, which induced growth arrest and apoptosis in human umbilical vein endothelial cells. These findings suggest that TL1A is involved in the regulation of endothelial cell senescence, via a novel fragment produced by differential ectodomain shedding

Autosomal recessive cerebellar ataxias

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia

The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein

Development of the nervous system requires that timely withdrawal from the cell cycle be coupled with initiation of differentiation. Ubiquitin-mediated degradation of the N-Myc oncoprotein in neural stem/progenitor cells is thought to trigger the arrest of proliferation and begin differentiation. Here we report that the HECT-domain ubiquitin ligase Huwe1 ubiquitinates the N-Myc oncoprotein through Lys 48-mediated linkages and targets it for destruction by the proteasome. This process is physiologically implemented by embryonic stem (ES) cells differentiating along the neuronal lineage and in the mouse brain during development. Genetic and RNA interference-mediated inactivation of the Huwe1 gene impedes N-Myc degradation, prevents exit from the cell cycle by opposing the expression of Cdk inhibitors and blocks differentiation through persistent inhibition of early and late markers of neuronal differentiation. Silencing of N-myc in cells lacking Huwe1 restores neural differentiation of ES cells and rescues cell-cycle exit and differentiation of the mouse cortex, demonstrating that Huwe1 restrains proliferation and enables neuronal differentiation by mediating the degradation of N-Myc. These findings indicate that Huwe1 links destruction of N-Myc to the quiescent state that complements differentiation in the neural tissue

Myc Stimulates Cell Cycle Progression Through the Activation of Cdk1 and Phosphorylation of p27

Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of the Cdk inhibitors p15 and p21 and the degradation of p27. The Myc-p27 antagonism has been shown to be relevant in human cancer. To be degraded, p27 must be phosphorylated at Thr-187 to be recognized by Skp2, a component of the ubiquitination complex. We previously described that Myc induces Skp2 expression. Here we show that not only Cdk2 but Cdk1 phosphorylates p27 at the Thr-187. Moreover, Myc induced p27 degradation in murine fibroblasts through Cdk1 activation, which was achieved by Myc-dependent cyclin A and B induction. In the absence of Cdk2, p27 phosphorylation at Thr-187 was mainly carried out by cyclin A2-Cdk1 and cyclin B1-Cdk1. We also show that Cdk1 inhibition was enough for the synthetic lethal interaction with Myc. This result is relevant because Cdk1 is the only Cdk strictly required for cell cycle and the reported synthetic lethal interaction between Cdk1 and Myc.The work was supported by grant SAF2017-88026-R from MINECO, Spanish Government, to JL and MDD (partially funded by FEDER program from European Union). L.G.G. was recipient of FPI fellowship from Spanish Government. We are grateful Sandra Zunzunegui for technical assistance and John Sedivy and M. Dolores Delgado for helpful discussion

Replication-induced stimulation of the major late promoter of adenovirus is correlated to the binding of a factor to sequences in the first intron.

The sequence requirements for transcriptional stimulation of the adenovirus major late promoter (MLP) by the products of the early transcription unit Ela and by the replication of viral DNA were analyzed by in vitro transcription. Sequences upstream of +33 are involved in the moderate Ela-responsiveness of the MLP, while sequences between +33 and +131 are required for its major replication-induced transcriptional activation. Dnase I footprinting experiments delineate a sequence component, extending from +76 to +120, which binds protein(s) only in extracts of cells where viral DNA replication occurred. Taken together, these results suggest that the replication-dependent stimulation of the MLP is mediated by the increased binding of this protein(s)