Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis

Copyright @ 2012 Nature Publishing GroupThis article has been made available through the Brunel Open Access Publishing Fund.Background: The objective of this study was to determine the molecular mechanism(s) responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. Methods: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double strand break (DSB) repair in cells. Quantitative-PCR (Q-PCR) established the expression levels of key DNA DSB repair proteins. Imaging flow cytometry using Annexin V-FITC was used to compare artemis expression and apoptosis in cells. Results: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Over-expression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. Conclusion: We conclude elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.This work was supported in part by The Vidal Sassoon Foundation USA. This article is made available through the Brunel Open Access Publishing Fund

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

Re-thinking global health sector efforts for HIV and tuberculosis epidemic control: promoting integration of programme activities within a strengthened health system

<p>Abstract</p> <p>Background</p> <p>The global financial crisis threatens global health, particularly exacerbating diseases of inequality, e.g. HIV/AIDS, and diseases of poverty, e.g. tuberculosis. The aim of this paper is to reconsider established practices and policies for HIV and tuberculosis epidemic control, aiming at delivering better results and value for money. This may be achieved by promoting greater integration of HIV and tuberculosis control programme activities within a strengthened health system.</p> <p>Discussion</p> <p>HIV and tuberculosis share many similarities in terms of their disease burden and the recommended stratagems for their control. HIV and tuberculosis programmes implement similar sorts of control activities, e.g. case finding and treatment, which depend for success on generic health system issues, including vital registration, drug procurement and supply, laboratory network, human resources, and financing. However, the current health system approach to HIV and tuberculosis control often involves separate specialised services. Despite some recent progress, collaboration between the programmes remains inadequate, progress in obtaining synergies has been slow, and results remain far below those needed to achieve universal access to key interventions. A fundamental re-think of the current strategic approach involves promoting integrated delivery of HIV and tuberculosis programme activities as part of strengthened general health services: epidemiological surveillance, programme monitoring and evaluation, community awareness of health-seeking behavior, risk behaviour modification, infection control, treatment scale-up (first-line treatment regimens), drug-resistance surveillance, containing and countering drug-resistance (second-line treatment regimens), research and development, global advocacy and global partnership. Health agencies should review policies and progress in HIV and tuberculosis epidemic control, learn mutual lessons for policy development and scaling up interventions, and identify ways of joint planning and joint funding of integrated delivery as part of strengthened health systems.</p> <p>Summary</p> <p>As both a danger and an opportunity, the global financial crisis may entail disaster or recovery for global health sector efforts for HIV and tuberculosis epidemic control. Review of policies and progress in control paves the way for identification of synergies between the two programmes, within strengthened health services. The silver lining in the global economic crisis could be better control of the HIV and tuberculosis epidemics, better overall health system performance and outcomes, and better value for money.</p

Evaluation and optimization of a commercial enzyme linked immunosorbent assay for detection of Chlamydophila pneumoniae IgA antibodies

<p>Abstract</p> <p>Background</p> <p>Serologic diagnosis of <it>Chlamydophila pneumoniae </it>(Cpn) infection routinely involves assays for the presence of IgG and IgM antibodies to Cpn. Although IgA antibodies to Cpn have been found to be of interest in the diagnosis of chronic infections, their significance in serological diagnosis remains unclear. The microimmunofluorescence (MIF) test is the current method for the measurement of Cpn antibodies. While commercial enzyme linked immunosorbent assays (ELISA) have been developed, they have not been fully validated. We therefore evaluated and optimized a commercial ELISA kit, the SeroCP IgA test, for the detection of Cpn IgA antibodies.</p> <p>Methods</p> <p>Serum samples from 94 patients with anti-Cpn IgG titers ≥ 256 (study group) and from 100 healthy blood donors (control group) were tested for the presence of IgA antibodies to Cpn, using our in-house MIF test and the SeroCP IgA test. Two graph receiver operating characteristic (TG-ROC) curves were created to optimize the cut off given by the manufacturer.</p> <p>Results</p> <p>The MIF and SeroCP IgA tests detected Cpn IgA antibodies in 72% and 89%, respectively, of sera from the study group, and in 9% and 35%, respectively, of sera from the control group. Using the MIF test as the reference method and the cut-off value of the ELISA test specified by the manufacturer for seropositivity and negativity, the two tests correlated in 76% of the samples, with an agreement of Ƙ = 0.54. When we applied the optimized cut-off value using TG-ROC analysis, 1.65, we observed better concordance (86%) and agreement (0.72) between the MIF and SeroCP IgA tests.</p> <p>Conclusion</p> <p>Use of TG-ROC analysis may help standardize and optimize ELISAs, which are simpler, more objective and less time consuming than the MIF test. Standardization and optimization of commercial ELISA kits may result in better performance.</p

Expanded phenotype of AARS1-related white matter disease.

Purpose Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. Methods A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. Results We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile–onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile–onset and late-onset phenotypes. Conclusion We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile–onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome

'So wide and varied': The origins and character of British information science

This paper examines some characteristics of the ‘British School’ of information science. Three main forces driving the development of the new subject in Britain are identified: the documentation movement; special libraries; and the need for better treatment of scientific and technical information. Five characteristics which, taken together, distinguish the early British approach to information science from those adopted elsewhere are identified: its subject-based nature; its broad approach to information and information science; its status as an academic subject with a strong professional remit; its involvement with, but distinction from, information technology; and its involvement with memory institutions. Lessons are drawn for the future development of the information sciences

Properties of Graphene: A Theoretical Perspective

In this review, we provide an in-depth description of the physics of monolayer and bilayer graphene from a theorist's perspective. We discuss the physical properties of graphene in an external magnetic field, reflecting the chiral nature of the quasiparticles near the Dirac point with a Landau level at zero energy. We address the unique integer quantum Hall effects, the role of electron correlations, and the recent observation of the fractional quantum Hall effect in the monolayer graphene. The quantum Hall effect in bilayer graphene is fundamentally different from that of a monolayer, reflecting the unique band structure of this system. The theory of transport in the absence of an external magnetic field is discussed in detail, along with the role of disorder studied in various theoretical models. We highlight the differences and similarities between monolayer and bilayer graphene, and focus on thermodynamic properties such as the compressibility, the plasmon spectra, the weak localization correction, quantum Hall effect, and optical properties. Confinement of electrons in graphene is nontrivial due to Klein tunneling. We review various theoretical and experimental studies of quantum confined structures made from graphene. The band structure of graphene nanoribbons and the role of the sublattice symmetry, edge geometry and the size of the nanoribbon on the electronic and magnetic properties are very active areas of research, and a detailed review of these topics is presented. Also, the effects of substrate interactions, adsorbed atoms, lattice defects and doping on the band structure of finite-sized graphene systems are discussed. We also include a brief description of graphane -- gapped material obtained from graphene by attaching hydrogen atoms to each carbon atom in the lattice.Comment: 189 pages. submitted in Advances in Physic

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration