Mixed action computations on fine dynamical lattices

We report on our first experiences in simulating Neuberger valence fermions on CLS $N_f=2$ configurations with light sea quark masses and small lattice spacings. Valence quark masses are considered that allow to explore the matching to (partially quenched) chiral perturbation theory both in the $\epsilon$- and $p$-regimes. The setup is discussed, and first results are presented for spectral observables.Comment: 7 pages. Presented at the XXVII International Symposium on Lattice Field Theory, July 26-31, 2009, Peking University, Beijing, Chin

Determination of the ΔS=1\Delta S = 1 weak Hamiltonian in the SU(4) chiral limit through topological zero-mode wave functions

A new method to determine the low-energy couplings of the $\Delta S=1$ weak Hamiltonian is presented. It relies on a matching of the topological poles in $1/m^2$ of three-point correlators of two pseudoscalar densities and a four-fermion operator, measured in lattice QCD, to the same observables computed in the $\epsilon$-regime of chiral perturbation theory. We test this method in a theory with a light charm quark, i.e. with an SU(4) flavour symmetry. Quenched numerical measurements are performed in a 2 fm box, and chiral perturbation theory predictions are worked out up to next-to-leading order. The matching of the two sides allows to determine the weak low-energy couplings in the SU(4) limit. We compare the results with a previous determination, based on three-point correlators containing two left-handed currents, and discuss the merits and drawbacks of the two procedures.Comment: 38 pages, 9 figure

Weak low-energy couplings from topological zero-mode wavefunctions

We discuss a new method to determine the low-energy couplings of the $\Delta S=1$ weak Hamiltonian in the $\epsilon$-regime. It relies on a matching of the topological poles in $1/m^2$ of three-point functions of two pseudoscalar densities and a four-fermion operator computed in lattice QCD, to the same observables in the Chiral Effective Theory. We present the results of a NLO computation in chiral perturbation theory of these correlation functions together with some preliminary numerical results.Comment: 7 pages. Contribution to Lattice 200

On the determination of low-energy constants for ΔS=1\Delta S=1 transitions

We present our preliminary results for three-point correlation functions involving the operators entering the $\Delta{S}=1$ effective Hamiltonian with an active charm quark, obtained using overlap fermions in the quenched approximation. This is the first computation carried out for valence quark masses small enough so as to permit a matching to Quenched Chiral Perturbation Theory in the $\epsilon$-regime. The commonly observed large statistical fluctuations are tamed by means of low-mode averaging techniques, combined with restrictions to individual topological sectors. We also discuss the matching of the resulting hadronic matrix elements to the effective low-energy constants for $\Delta{S}=1$ transitions. This involves (a) finite-volume corrections which can be evaluated at NLO in Quenched Chiral Perturbation Theory, and (b) the short-distance renormalization of the relevant four-quark operators in discretizations based on the overlap operator. We discuss perturbative estimates for the renormalization factors and possible strategies for their non-perturbative evaluation. Our results can be used to isolate the long-distance contributions to the $\Delta I=1/2$ rule, coming from physics effects around the intrinsic QCD scale.Comment: 11 pages, 2 figures, talks presented at Lattice 2005 (Weak matrix elements

When the most potent combination of antibiotics selects for the greatest bacterial load: the Smile-Frown transition

Final published PDF version of article deposited in accordance with SHERPA RoMEO guidelinesConventional wisdom holds that the best way to treat infection with antibiotics is to ‘hit early and hit hard’. A favoured strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal? We combine mathematical modelling, evolution experiments, whole genome sequencing and genetic manipulation of a resistance mechanism to demonstrate that deploying synergistic antibiotics can, in practice, be the worst strategy if bacterial clearance is not achieved after the first treatment phase. As treatment proceeds, it is only to be expected that the strength of antibiotic synergy will diminish as the frequency of drug-resistant bacteria increases. Indeed, antibiotic efficacy decays exponentially in our five-day evolution experiments. However, as the theory of competitive release predicts, drug-resistant bacteria replicate fastest when their drug-susceptible competitors are eliminated by overly-aggressive treatment. Here, synergy exerts such strong selection for resistance that an antagonism consistently emerges by day 1 and the initially most aggressive treatment produces the greatest bacterial load, a fortiori greater than if just one drug were given. Whole genome sequencing reveals that such rapid evolution is the result of the amplification of a genomic region containing four drug-resistance mechanisms, including the acrAB efflux operon. When this operon is deleted in genetically manipulated mutants and the evolution experiment repeated, antagonism fails to emerge in five days and antibiotic synergy is maintained for longer. We therefore conclude that unless super-inhibitory doses are achieved and maintained until the pathogen is successfully cleared, synergistic antibiotics can have the opposite effect to that intended by helping to increase pathogen load where, and when, the drugs are found at sub-inhibitory concentrations

Perinatal asphyxia: CNS development and deficits with delayed onset

Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. The primary insult relates to the duration of the period lacking oxygenation, leading to death if not re-established. Re-oxygenation leads to a secondary insult, related to a cascade of biochemical events required for restoring proper function. Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated to mental and neurological diseases with delayed clinical onset, by mechanisms not yet clarified. In the experimental scenario, the effects observed long after perinatal asphyxia have been explained by over expression of sentinel proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1), competing for NAD+ during re-oxygenation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. Asphyxia induces transcriptional activation of proinflammatory factors, in tandem with PARP-1 overactivation, and pharmacologically induced PARP-1 inhibition also down-regulates the expression of proinflammatory cytokines. Nicotinamide has been proposed as a suitable PARP-1 inhibitor. Its effect has been studied in an experimental model of global hypoxia in rats. In that model, the insult is induced by immersing rat foetuses into a water bath for various periods of time. Following asphyxia, the pups are delivered, treated, and nursed by surrogate dams, pending further experiments. Nicotinamide rapidly distributes into the brain following systemic administration, reaching steady state concentrations sufficient to inhibit PARP-1 activity for several hours, preventing several of the long-term consequences of perinatal asphyxia, supporting the idea that it constitutes a lead for exploring compounds with similar or better pharmacological profiles

TGF-beta(2)- and H2O2-Induced Biological Changes in Optic Nerve Head Astrocytes Are Reduced by the Antioxidant Alpha-Lipoic Acid

Background/Aims: The goal of the present study was to determine whether transforming growth factor-beta(2) (TGF-beta(2))- and oxidative stress-induced cellular changes in cultured human optic nerve head (ONH) astrocytes could be reduced by pretreatment with the antioxidant alpha-lipoic acid (LA). Methods: Cultured ONH astrocytes were treated with 1.0 ng/ml TGF-beta(2) for 24 h or 200 mu M hydrogen peroxide (H2O2) for 1 h. Lipid peroxidation was measured by a decrease in cis-pari-naric acid fluorescence. Additionally, cells were pretreated with different concentrations of LA before TGF-beta 2 or H2O2 exposure. Expressions of the heat shock protein (Hsp) alpha B-crystallin and Hsp27, the extracellular matrix (ECM) component fibronectin and the ECM-modulating protein connective tissue growth factor (CTGF) were examined with immunohistochemistry and real-time PCR analysis. Results: Both TGF-beta(2) and H2O2 increased lipid peroxidation. Treatment of astrocytes with TGF-beta(2) and H2O2 upregulated the expression of alpha B-crystallin, Hsp27, fibronectin and CTGF. Pretreatment with different concentrations of LA reduced the TGF-beta(2)- and H2O2-stimulated gene expressions. Conclusion: We showed that TGF-beta(2)- and H2O2-stimulated gene expressions could be prevented by pretreatment with the antioxidant LA in cultured human ONH astrocytes. Therefore, it is tempting to speculate that the use of antioxidants could have protective effects in glaucomatous optic neuropathy. Copyright (C) 2012 S. Karger AG, Base

New multisite observations of Delta Scuti stars V624 Tauri and HD 23194

The preliminary results of STEPHI 2006 campaign are reported.Comment: To be published in Communications in Asteroseismolgy: Special Issu

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

Validity of ultrasonography and measures of adult shoulder function and reliability of ultrasonography in detecting shoulder synovitis in patients with rheumatoid arthritis using magnetic resonance imaging as a gold standard

Objective. To assess the intra- and interobserver reproducibility of musculoskeletal ultrasonography (US) in detecting in.ammatory shoulder changes in patients with rheumatoid arthritis, and to determine the agreement between US and the Shoulder Pain and Disability Index (SPADI) and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, using magnetic resonance imaging (MRI) as a gold standard. Methods. Eleven rheumatologists investigated 10 patients in 2 rounds independently and blindly of each other by US. US results were compared with shoulder function tests and MRI. Results. The positive and negative predictive values (NPVs) for axillary recess synovitis (ARS) were 0.88 and 0.43, respectively, for posterior recess synovitis (PRS) were 0.36 and 0.97, respectively, for subacromial/subdeltoid bursitis (SASB) were 0.85 and 0.28, respectively, and the NPV for biceps tenosynovitis (BT) was 1.00. The intraobserver kappa was 0.62 for ARS, 0.59 for PRS, 0.51 for BT, and 0.70 for SASB. The intraobserver kappa for power Doppler US (PDUS) signal was 0.91 for PRS, 0.77 for ARS, 0.94 for SASB, and 0.53 for BT. The interobserver maximum kappa was 0.46 for BT, 0.95 for ARS, 0.52 for PRS, and 0.61 for SASB. The interobserver reliability of PDUS was 1.0 for PRS, 0.1 for ARS, 0.5 for BT, and 1.0 for SASB. P values for the SPADI and DASH versus cuff tear on US were 0.02 and 0.01, respectively; all other relationships were not significant. Conclusion. Overall agreements between gray-scale US and MRI regarding synovitis of the shoulder varied considerably, but excellent results were seen for PDUS. Measures of shoulder function have a poor relationship with US and MRI. Improved standardization of US scanning technique could further reliability of shoulder US. © 2010, American College of Rheumatology