Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

Contains fulltext : 175039.pdf (publisher's version ) (Open Access)BACKGROUND: Age-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits. METHODS: For each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression. RESULTS: Of the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27-20.69%) and 16 of them were found to be significantly associated with AMD (Q-values < 0.01, p values from < 1.0 x 10-16 to 1.9 x 10-3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values < 0.01, p values from 1.1 x 10-7 to 3.0 x 10-4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis. CONCLUSIONS: We demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common

Design and construction of new central and forward muon counters for CDF II

New scintillation counters have been designed and constructed for the CDF upgrade in order to complete the muon coverage of the central CDF detector, and to extend this coverage to larger pseudorapidity. A novel light collection technique using wavelength shifting fibers, together with high quality polystyrene-based scintillator resulted in compact counters with good and stable light collection efficiency over lengths extending up to 320 cm. Their design and construction is described and results of their initial performance are reported.Comment: 20 pages, 15 figure

Pulse Shape Discrimination Techniques in Scintillating CsI(Tl) Crystals

There are recent interests with CsI(Tl) scintillating crystals for Dark Matter experiments. The key merit is the capability to differentiate nuclear recoil (nr) signatures from the background $\beta / \gamma$-events due to ambient radioactivity on the basis of their different pulse shapes. One of the major experimental challenges is to perform such pulse shape analysis in the statistics-limited domain where the light output is close to the detection threshold. Using data derived from measurements with low energy $\gamma$'s and nuclear recoils due to neutron elastic scatterings, it was verified that the pulse shapes between $\beta / \gamma$-events are different. Several methods of pulse shape discrimination are studied, and their relative merits are compared. Full digitization of the pulse shapes is crucial to achieve good discrimination. Advanced software techniques with mean time, neural network and likelihood ratios give rise to satisfactory performance, and are superior to the conventional Double Charge method commonly applied at higher energies. Pulse shape discrimination becomes effective starting at a light yield of about 20 photo-electrons. This corresponds to a detection threshold of about 5 keV electron-equivalence energy, or 40$-$50 keV recoil kinetic energy, in realistic experiments.Comment: 20 pages, 7 figure

Measurement of the Intrinsic Radiopurity of Cs-137/U-235/U-238/Th-232 in CsI(Tl) Crystal Scintillators

The inorganic crystal scintillator CsI(Tl) has been used for low energy neutrino and Dark Matter experiments, where the intrinsic radiopurity is an issue of major importance. Low-background data were taken with a CsI(Tl) crystal array at the Kuo-Sheng Reactor Neutrino Laboratory. The pulse shape discrimination capabilities of the crystal, as well as the temporal and spatial correlations of the events, provide powerful means of measuring the intrinsic radiopurity of Cs-137 as well as the U-235, U-238 and Th-232 series. The event selection algorithms are described, with which the decay half-lives of Po-218, Po-214, Rn-220, Po-216 and Po-212 were derived. The measurements of the contamination levels, their concentration gradients with the crystal growth axis, and the uniformity among different crystal samples, are reported. The radiopurity in the U-238 and Th-232 series are comparable to those of the best reported in other crystal scintillators. Significant improvements in measurement sensitivities were achieved, similar to those from dedicated massive liquid scintillator detector. This analysis also provides in situ measurements of the detector performance parameters, such as spatial resolution, quenching factors, and data acquisition dead time.Comment: 28 pages, 12 figure

Precise Critical Exponents for the Basic Contact Process

We calculated some of the critical exponents of the directed percolation universality class through exact numerical diagonalisations of the master operator of the one-dimensional basic contact process. Perusal of the power method together with finite-size scaling allowed us to achieve a high degree of accuracy in our estimates with relatively little computational effort. A simple reasoning leading to the appropriate choice of the microscopic time scale for time-dependent simulations of Markov chains within the so called quantum chain formulation is discussed. Our approach is applicable to any stochastic process with a finite number of absorbing states.Comment: LaTeX 2.09, 9 pages, 1 figur

Human papillomavirus gene expression is controlled by host cell splicing factors

Human papillomaviruses (HPV) infect stratified epithelia and cause a variety of lesions ranging from benign warts to invasive tumours. The virus life cycle is tightly linked to differentiation of the keratinocyte it infects: papillomaviruses modulate host gene expression to ensure efficient virus replication. For example, the viral transcription factor E2 can directly upregulate, in an epithelial differentiation-dependent manner, cellular SR (serine/arginine-rich) splicing factors that control constitutive and alternative splicing. Changes in alternative splicing and the mechanisms controlling this for viral mRNAs have been a subject to intense exploration. However, to date experiments have only been carried out in model systems because the genetic systems suitable for studying alternative splicing of viral RNAs in the context of the virus life cycle are relatively recent and technically challenging. Now using these life cycle-supporting systems, our laboratory has identified SR proteins as important players in differentiation-dependent regulation of HPV gene expression. Better understanding of the role of cellular factors in regulating the virus life cycle is needed as it may help development of novel diagnostic approaches and antiviral therapies in the future

On consensus biomarker selection

<p>Abstract</p> <p>Background</p> <p>Recent development of mass spectrometry technology enabled the analysis of complex peptide mixtures. A lot of effort is currently devoted to the identification of biomarkers in human body fluids like serum or plasma, based on which new diagnostic tests for different diseases could be constructed. Various biomarker selection procedures have been exploited in recent studies. It has been noted that they often lead to different biomarker lists and as a consequence, the patient classification may also vary.</p> <p>Results</p> <p>Here we propose a new approach to the biomarker selection problem: to apply several competing feature ranking procedures and compute a consensus list of features based on their outcomes. We validate our methods on two proteomic datasets for the diagnosis of ovarian and prostate cancer.</p> <p>Conclusion</p> <p>The proposed methodology can improve the classification results and at the same time provide a unified biomarker list for further biological examinations and interpretation.</p

Approximation Techniques for Stochastic Analysis of Biological Systems

There has been an increasing demand for formal methods in the design process of safety-critical synthetic genetic circuits. Probabilistic model checking techniques have demonstrated significant potential in analyzing the intrinsic probabilistic behaviors of complex genetic circuit designs. However, its inability to scale limits its applicability in practice. This chapter addresses the scalability problem by presenting a state-space approximation method to remove unlikely states resulting in a reduced, finite state representation of the infinite-state continuous-time Markov chain that is amenable to probabilistic model checking. The proposed method is evaluated on a design of a genetic toggle switch. Comparisons with another state-of-art tool demonstrates both accuracy and efficiency of the presented method

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration : A Randomized Phase 2 Trial

Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

Historical roots of gauge invariance

Gauge invariance is the basis of the modern theory of electroweak and strong interactions (the so called Standard Model). The roots of gauge invariance go back to the year 1820 when electromagnetism was discovered and the first electrodynamic theory was proposed. Subsequent developments led to the discovery that different forms of the vector potential result in the same observable forces. The partial arbitrariness of the vector potential A brought forth various restrictions on it. div A = 0 was proposed by J. C. Maxwell; 4-div A = 0 was proposed L. V. Lorenz in the middle of 1860's . In most of the modern texts the latter condition is attributed to H. A. Lorentz, who half a century later was one of the key figures in the final formulation of classical electrodynamics. In 1926 a relativistic quantum-mechanical equation for charged spinless particles was formulated by E. Schrodinger, O. Klein, and V. Fock. The latter discovered that this equation is invariant with respect to multiplication of the wave function by a phase factor exp(ieX/hc) with the accompanying additions to the scalar potential of -dX/cdt and to the vector potential of grad X. In 1929 H. Weyl proclaimed this invariance as a general principle and called it Eichinvarianz in German and gauge invariance in English. The present era of non-abelian gauge theories started in 1954 with the paper by C. N. Yang and R. L. Mills.Comment: final-final, 34 pages, 1 figure, 106 references (one added with footnote since v.2); to appear in July 2001 Rev. Mod. Phy