Effects of BRCA2 deficiency on telomere recombination in non-ALT and ALT cells

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2011 Sapir et al.Background: Recent studies suggest that BRCA2 affects telomere maintenance. Interestingly, anti cancer treatments that involve BRCA2 and telomerase individually are currently being explored. In the light of the above recent studies their combinatorial targeting may be justified in the development of future treatments. In order to investigate effects of BRCA2 that can be explored for this combinatorial targeting we focused on the analysis of recombination rates at telomeres by monitoring T-SCEs (Telomere Sister Chromatid Exchanges). Results: We observed a significant increase in T-SCE frequencies in four BRCA2 defective human cell lines thus suggesting that BRCA2 suppresses recombination at telomeres. To test this hypothesis further we analyzed T-SCE frequencies in a set of Chinese hamster cell lines with or without functional BRCA2. Our results indicate that introduction of functional BRCA2 normalizes frequencies of T-SCEs thus supporting the notion that BRCA2 suppresses recombination at telomeres. Given that ALT (Alternative Lengthening of Telomeres) positive cells maintain telomeres by recombination we investigated the effect of BRCA2 depletion in these cells. Our results show that this depletion causes a dramatic reduction in T-SCE frequencies in ALT positive cells, but not in non-ALT cells. Conclusion: BRCA2 suppresses recombination at telomeres in cells that maintain them by conventional mechanisms. Furthermore, BRCA2 depletion in ALT positive cells reduces high levels of T-SCEs normally found in these cells. Our results could be potentially important for refining telomerase-based anti-cancer therapies.This work is supported in part by grants from European Commission RISC-RAD contract FI6RCT2003-508842 and British Counci

On threshold resummation beyond leading 1-x order

We check against exact finite order three-loop results for the non-singlet F_2 and F_3 structure functions the validity of a class of momentum space ansaetze for threshold resummation at the next-to-leading order in 1-x, which generalize results previously obtained in the large-\beta_0 limit. We find that the ansaetze do not work exactly, pointing towards an obstruction to threshold resummation at this order, but still yield correct results at the leading logarithmic level for each color structures, as well as at the next-to-next-to-leading logarithmic level for the specific C_F^3 color factor. A universality of the leading logarithm contributions to the physical evolution kernels of F_2 and F_3 at the next-to-leading order in 1-x is observed.Comment: v1:18 pages; v2: 26 pages, expanded version with new results for the F_3 structure function and added references; v3: more concise sections 3 and 4, improved discussion in section 5, added references, to be published in JHE

Polymorphisms in ARMS2/HTRA1 and complement genes and age-related macular degeneration in India: findings from the INDEYE study.

PURPOSE: Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India. METHODS: Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1-3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center. RESULTS: Of 3569 participants, 53.2% had no signs of amd, 45.6% had features of early amd, and 1.2% had late amd. CFH (RS1061170), C2 (RS547154), OR CFB (RS438999) was not associated with early or late AMD. In the ARMS2 locus, RS10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13-1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15-2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02-1.23; P = 0.02); rs10490923 was not associated with early or late AMD. CONCLUSIONS: Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India

Retinal Changes in Transgenic Mouse Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, the most common form of dementia. AD is characterised by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) in the brain, in association with neuronal loss and synaptic failure, causing cognitive deficits. Accurate and early diagnosis is currently unavailable in lifespan, hampering early intervention of potential new treatments. Visual deficits have been well documented in AD patients, and the pathological changes identified in the brain are also believed to be found in the retina, an integral part of the central nervous system. Retinal changes can be detected by real-time non-invasive imaging, due to the transparent nature of the ocular media, potentially allowing an earlier diagnosis as well as monitoring disease progression and treatment outcome. Animal models are essential for AD research, and this review has a focus on retinal changes in various transgenic AD mouse models with retinal imaging and immunohistochemical analysis as well as therapeutic effects in those models. We also discuss the limitations of transgenic AD models in clinical translations

Analytical Method Development and Validation of Iron, Arsenic, Cadmium, Mercury and Lead Content in Sunset Yellow by Inductively Coupled Plasma Mass Spectrometry (Icp-Ms)

A method for determining the iron, arsenic, cadmium, mercury, and lead content in Sunset Yellow by ICP-MS was developed, verified, and implemented for routine ICP-MS analysis. Inductively coupled plasma mass spectrometry (ICP-MS) is a good instrument for determining the basic composition of numerous substances. Iron, arsenic, cadmium, mercury, and lead metal as defined in USP (233) linearity, method precision, accuracy, robustness, and ruggedness factors were taken into account and analysed for method validation in this work. The recovery rates of iron, arsenic, cadmium, mercury, and lead metals ranged between 92.0% and 101.4%. The detection limits of all elements investigated demonstrated the procedure's suitability for routine analyses. To summarize, the provided analytical processes can be used to measure the mass fractions of iron, arsenic, cadmium, mercury, and lead components in Sunset Yellow samples

Detailed electronic structure studies on superconducting MgB2_2 and related compounds

In order to understand the unexpected superconducting behavior of MgB$_2$ compound we have made electronic structure calculations for MgB$_2$ and closely related systems. Our calculated Debye temperature from the elastic properties indicate that the average phonon frequency is very large in MgB$_2$ compared with other superconducting intermetallics and the exceptionally high $T_c$ in this material can be explained through BCS mechanism only if phonon softening occurs or the phonon modes are highly anisotropic. We identified a doubly-degenerate quasi-two dimensional key-energy band in the vicinity of $E_{F}$ along $\Gamma$-A direction of BZ which play an important role in deciding the superconducting behavior of this material. Based on this result, we have searched for similar kinds of electronic feature in a series of isoelectronic compounds such as BeB$_2$, CaB$_2$, SrB$_2$, LiBC and MgB$_2$C$_2$ and found that MgB$_2$C$_2$ is one potential material from the superconductivity point of view. There are contradictory experimental results regarding the anisotropy in the elastic properties of MgB$_2$ ranging from isotropic, moderately anisotropic to highly anisotropic. In order to settle this issue we have calculated the single crystal elastic constants for MgB$_2$ by the accurate full-potential method and derived the directional dependent linear compressibility, Young's modulus, shear modulus and relevant elastic properties. We have observed large anisotropy in the elastic properties. Our calculated polarized optical dielectric tensor shows highly anisotropic behavior even though it possesses isotropic transport property. MgB$_2$ possesses a mixed bonding character and this has been verified from density of states, charge density and crystal orbital Hamiltonian population analyses

NLO Corrections to lepton pair production beyond the Standard Model at hadron colliders

We consider lepton pair production at a hadron collider in a class of effective theories with the relevant operators being four-fermion contact interaction. Despite the nonrenormalizable nature of the interaction, we explicitly demonstrate that calculating QCD corrections is both possible and meaningful. Calculating the corrections for various differential distributions, we show that these can be substantial and significantly different from those within the SM. Furthermore, the corrections have a very distinctive flavour dependence. And finally, the scale dependence of the cross sections are greatly reduced once the NLO corrections are taken into account.Comment: 23 pages, 14 figures, few typos corrected, written in JHEP styl

Finite top quark mass effects in NNLO Higgs boson production at LHC

We present next-to-next-to-leading order corrections to the inclusive production of the Higgs bosons at the CERN Large Hadron Collider (LHC) including finite top quark mass effects. Expanding our analytic results for the partonic cross section around the soft limit we find agreement with a very recent publication by Harlander and Ozeren \cite{Harlander:2009mq}.Comment: 15 page