Renormalization Constants of Quark Operators for the Non-Perturbatively Improved Wilson Action

We present the results of an extensive lattice calculation of the renormalization constants of bilinear and four-quark operators for the non-perturbatively O(a)-improved Wilson action. The results are obtained in the quenched approximation at four values of the lattice coupling by using the non-perturbative RI/MOM renormalization method. Several sources of systematic uncertainties, including discretization errors and final volume effects, are examined. The contribution of the Goldstone pole, which in some cases may affect the extrapolation of the renormalization constants to the chiral limit, is non-perturbatively subtracted. The scale independent renormalization constants of bilinear quark operators have been also computed by using the lattice chiral Ward identities approach and compared with those obtained with the RI-MOM method. For those renormalization constants the non-perturbative estimates of which have been already presented in the literature we find an agreement which is typically at the level of 1%.Comment: 36 pages, 13 figures. Minor changes in the text and in one figure. Accepted for publication on JHE

Clinical and biochemical improvements in a patient with MNGIE following enzyme replacement.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive metabolic disorder caused by a deficiency of thymidine phosphorylase (TP, EC2.4.2.4) due to mutations in the nuclear gene TYMP. TP deficiency leads to plasma and tissue accumulations of thymidine and deoxyuridine which generate imbalances within the mitochondrial nucleotide pools, ultimately leading to mitochondrial dysfunction.1 MNGIE is characterized clinically by leukoencephalopathy, external ophthalmoplegia, peripheral polyneuropathy, cachexia, and enteric neuromyopathy manifesting as gastrointestinal dysmotility. The condition is relentlessly progressive, with patients usually dying from a combination of nutritional and neuromuscular failure at an average age of 37 years.2 Allogeneic hematopoietic stem cell transplantation (AHSCT) offers a permanent cure. Clinical and biochemical improvements following AHSCT have been reported but it carries a high mortality risk and is limited by matched donor availability.3 A consensus proposal for standardizing AHSCT recommends treatment of patients without irreversible end-stage disease and with an optimally matched donor; a majority of patients are ineligible and thus there is a critical requirement for an alternative treatment

Pinwheel patterns and powder diffraction

Pinwheel patterns and their higher dimensional generalisations display continuous circular or spherical symmetries in spite of being perfectly ordered. The same symmetries show up in the corresponding diffraction images. Interestingly, they also arise from amorphous systems, and also from regular crystals when investigated by powder diffraction. We present first steps and results towards a general frame to investigate such systems, with emphasis on statistical properties that are helpful to understand and compare the diffraction images. We concentrate on properties that are accessible via an alternative substitution rule for the pinwheel tiling, based on two different prototiles. Due to striking similarities, we compare our results with the toy model for the powder diffraction of the square lattice.Comment: 7 pages, 4 figure

Collabor8: (Re-) Engaging female secondary cohorts in STEM subjects

Demand for skilled professionals in science, technology, engineering and mathematics (STEM) is projected to increase significantly with 75% of the fastest growing occupations requiring STEM skills (Australian Industry Group, 2013). Yet, over the past 20 years, Australia has seen significant decline in the number of secondary students - particularly girls - electing to study science and advanced mathematics (Office of Chief Scientist, 2014). A 2014 national STEM strategy from the Office of the Chief Scientist recommended support for `high levels of participation and success in STEM [education] for all Australians, including women, Indigenous students and students from disadvantaged and marginalised backgrounds’. Recent research builds on previous work (e.g. Fine et al, 2010; Lyons et al, 2012; Sikora, 2012; Mills et al, 2010). Zecharia et al identify three key factors found to be influencing young women’s participation in STEM subjects: 1. Relevance of STEM to sense of identity and future aspirations. 2. Perceived actual and relative ability in STEM subjects. 3. ‘Science capital’ - or experience of STEM, including formal and informal exposure to STEM subjects and careers through the curriculum, schooling, media, culture, family and personal connections’ (Zecharia et al., 2014 p.9). This paper introduces Collabor8, an engineering and IT outreach program for junior female students from high schools serving low socio-economic communities. Collabor8 will test the relative importance of Zecharia et al’s three key factors for participants’ interest in STEM; intention to select STEM subjects in senior high school and tertiary study, and evaluate the chosen outreach model

Poor Outcome in a Mitochondrial Neurogastrointestinal Encephalomyopathy Patient with a Novel TYMP Mutation: The Need for Early Diagnosis.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped TP therapy) and newer, promising therapies are expected in the near future. However, successful treatment is strictly related to early diagnosis. We report on an incomplete MNGIE phenotype in a young man harboring the novel heterozygote c.199 C>T (Q67X) mutation in exon 2, and the previously reported c.866 A>C (E289A) mutation in exon 7 in TYMP. The correct diagnosis was achieved many years after the onset of symptoms and unfortunately, the patient died soon after diagnosis because of multiorgan failure due to severe malnutrition and cachexia before any therapeutic option could be tried. To date, early diagnosis is essential to ensure that patients have the opportunity to be treated. MNGIE should be suspected in all patients who present with both gastrointestinal and nervous system involvement, even if the classical complete phenotype is lacking

Quantification of Plasma and Urine Thymidine and 2'-Deoxyuridine by LC-MS/MS for the Pharmacodynamic Evaluation of Erythrocyte Encapsulated Thymidine Phosphorylase in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disorder caused by mutations in TYMP, leading to a deficiency in thymidine phosphorylase and a subsequent systemic accumulation of thymidine and 2'-deoxyuridine. Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is under clinical development as an enzyme replacement therapy for MNGIE. Bioanalytical methods were developed according to regulatory guidelines for the quantification of thymidine and 2'-deoxyuridine in plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for supporting the pharmacodynamic evaluation of EE-TP. Samples were deproteinized with 5% perchloric acid (v/v) and the supernatants analyzed using a Hypercarb column (30 × 2.1 mm, 3 µm), with mobile phases of 0.1% formic acid in methanol and 0.1% formic acid in deionized water. Detection was conducted using an ion-spray interface running in positive mode. Isotopically labelled thymidine and 2'-deoxyuridine were used as internal standards. Calibration curves for both metabolites showed linearity (r > 0.99) in the concentration ranges of 10-10,000 ng/mL for plasma, and 1-50 µg/mL for urine, with method analytical performances within the acceptable criteria for quality control samples. The plasma method was successfully applied to the diagnosis of two patients with MNGIE and the quantification of plasma metabolites in three patients treated with EE-TP

Predominance of weakly cytotoxic, T-betLowEomesNeg CD8+ T-cells in human gastrointestinal mucosa: implications for HIV infection.

The gastrointestinal mucosa is an important site of HIV acquisition, viral replication, and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8+ T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8+ T-cells compared with their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared with those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8+ T-cells compared with blood, and in vitro neutralization of TGF-β partially restored perforin expression in gut CD8+ T-cells. These findings suggest that rectal CD8+ T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues