Thyrotropin receptor blocking antibodies

Autoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be done either via competitive-binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity. Historically bioassays for anti-TSHR-Ab were research tools and were used to study the pathophysiology of Graves\u27 disease and Hashimoto\u27s thyroiditis. In the past, bioassays for anti-TSHR-Abs were laborious and time-consuming and varied widely in performance from laboratory to laboratory. Recent advances in the development of cell-based assays, including the application of molecular engineering, have led to significant improvements that have enabled bioassays to be employed routinely in clinical laboratories. The prevalence and functional significance of TSHR blocking autoantibodies (TBAb) in autoimmune hypothyroidism has been less well investigated compared to TSHR stimulating Ab. There is an increasing body of data, however, that demonstrate the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with AITD. In the present review, we summarize the different methods used to measure TBAb, and discuss their prevalence and clinical relevance

The Varicella-Zoster virus origin-binding protein can substitute for the herpes simplex virus origin-binding protein in a transient origin-dependent DNA replication assay in insect cells

AbstractWe isolated two recombinant baculoviruses each of which expresses a varicella-zoster virus (VZV) homolog of one ofthe seven herpes simplex virus type 1 (HSV-1) genes required for DNA replication. We performed transient origin-dependent DNA replication assays in insect cells in which we substituted a baculovirus which expresses a VZV protein for a baculovirus which expresses its HSV homolog. VZV gene 51 protein was found to be able to support origin-dependent DNA synthesis when it was substituted for UL9, the HSV-1 origin-binding protein (01313). This occurred whether an HSV-1 or a VZV origin-containing plasmid was used in the assay. These results suggest that VZV gene 51 protein is able to interact with the HSV replication machinery, and in light of the extensive structural divergence of these proteins, it suggests that initiation of VZV and HSV-1 DNA synthesis may involve a limited number of interactions between the OBP and other replication factors. Substitution of infected-cell protein 8 (ICP8), the major single-stranded DNA-binding protein of HSV-1, with VZV gene 29 protein, however, did not result in amplification of plasmids containing either an HSV-1 or a VZV origin. In the absence of ICP8, addition of both VZV gene 51 protein and gene 29 protein was also negative for origin-dependent replication whether or not UL9 was present. Although demonstration that our baculovirus-expressed VZV gene 29 protein is functional for DNA replication will await development of a VZV replication system, our results suggest that VZV gene 29 protein is unable to interact functionally with one or more of the HSV replication proteins. This approach should contribute to efforts to define the interactions among the alphaherpesvirus DNA replication proteins

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile range from 4.2 × 10−9 to 4.1 × 10−8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome

The Proterozoic Vazante hypogene zinc silicate district, Minas Gerais, Brazil: a review of the ore system applied to mineral exploration

The Proterozoic Vazante zinc silicate district in Minas Gerais, Brazil, hosts world-class hypogene willemite deposits in dolomitic rocks interbedded with siliciclastic rocks deposited in subtidal to supratidal environments. Willemite ore bodies are structurally controlled along regional NE-trending structures which are interpreted as being active during the Neoproterozoic Brasiliano orogeny. The hydrothermal alteration is characterized by an early stage of Fe-dolomite, which replaced the host dolomitic rocks, followed by precipitation of minor sphalerite and then hematite and willemite. Elements commonly enriched in the zinc ore include As, Ba, Be, Bi, Cd, Co, Fe, Ge, In, Mo, Ni, Sb, Se, U, V and W. Mineralogical, fluid inclusion and isotopic data indicates that mixing of S-poor metalliferous saline fluids with meteoric water favored the formation of willemite ore. Carbonaceous phyllites from the underlying thick siliciclastic sequence show evidence of early enrichment in zinc (and ore-related metals) and remobilization, respectively, prior to and during the Brasiliano orogenic event. This unit is interpreted as a possible source of ore-related elements. It is proposed that during the Brasiliano orogeny, hot (T > 170 degrees C) saline fluids (>15 wt % eq. NaCl) leached metals from siliciclastic source rocks and precipitated willemite ore in the overlying dolomitic sequence along structures that favored mixing with oxidizing meteoric water

Calibration and Characterization of the IceCube Photomultiplier Tube

Over 5,000 PMTs are being deployed at the South Pole to compose the IceCube neutrino observatory. Many are placed deep in the ice to detect Cherenkov light emitted by the products of high-energy neutrino interactions, and others are frozen into tanks on the surface to detect particles from atmospheric cosmic ray showers. IceCube is using the 10-inch diameter R7081-02 made by Hamamatsu Photonics. This paper describes the laboratory characterization and calibration of these PMTs before deployment. PMTs were illuminated with pulses ranging from single photons to saturation level. Parameterizations are given for the single photoelectron charge spectrum and the saturation behavior. Time resolution, late pulses and afterpulses are characterized. Because the PMTs are relatively large, the cathode sensitivity uniformity was measured. The absolute photon detection efficiency was calibrated using Rayleigh-scattered photons from a nitrogen laser. Measured characteristics are discussed in the context of their relevance to IceCube event reconstruction and simulation efforts.Comment: 40 pages, 12 figure

Search for Relativistic Magnetic Monopoles with IceCube

We present the first results in the search for relativistic magnetic monopoles with the IceCube detector, a subsurface neutrino telescope located in the South Polar ice cap containing a volume of 1 km$^{3}$. This analysis searches data taken on the partially completed detector during 2007 when roughly 0.2 km$^{3}$ of ice was instrumented. The lack of candidate events leads to an upper limit on the flux of relativistic magnetic monopoles of \Phi_{\mathrm{90%C.L.}}\sim 3\e{-18}\fluxunits for $\beta\geq0.8$. This is a factor of 4 improvement over the previous best experimental flux limits up to a Lorentz boost $\gamma$ below $10^{7}$. This result is then interpreted for a wide range of mass and kinetic energy values.Comment: 11 pages, 11 figures. v2 is minor text edits, no changes to resul

Lateral Distribution of Muons in IceCube Cosmic Ray Events

In cosmic ray air showers, the muon lateral separation from the center of the shower is a measure of the transverse momentum that the muon parent acquired in the cosmic ray interaction. IceCube has observed cosmic ray interactions that produce muons laterally separated by up to 400 m from the shower core, a factor of 6 larger distance than previous measurements. These muons originate in high pT (> 2 GeV/c) interactions from the incident cosmic ray, or high-energy secondary interactions. The separation distribution shows a transition to a power law at large values, indicating the presence of a hard pT component that can be described by perturbative quantum chromodynamics. However, the rates and the zenith angle distributions of these events are not well reproduced with the cosmic ray models tested here, even those that include charm interactions. This discrepancy may be explained by a larger fraction of kaons and charmed particles than is currently incorporated in the simulations

The IceCube Neutrino Observatory Part VI: Ice Properties, Reconstruction and Future Developments

Papers on ice properties, reconstruction and future developments submitted to the 33nd International Cosmic Ray Conference (Rio de Janeiro 2013) by the IceCube Collaboration.Comment: 28 pages, 38 figures; Papers submitted to the 33nd International Cosmic Ray Conference, Rio de Janeiro 2013; version 2 corrects errors in the author lis

All-particle cosmic ray energy spectrum measured with 26 IceTop stations

We report on a measurement of the cosmic ray energy spectrum with the IceTop air shower array, the surface component of the IceCube Neutrino Observatory at the South Pole. The data used in this analysis were taken between June and October, 2007, with 26 surface stations operational at that time, corresponding to about one third of the final array. The fiducial area used in this analysis was 0.122 km^2. The analysis investigated the energy spectrum from 1 to 100 PeV measured for three different zenith angle ranges between 0{\deg} and 46{\deg}. Because of the isotropy of cosmic rays in this energy range the spectra from all zenith angle intervals have to agree. The cosmic-ray energy spectrum was determined under different assumptions on the primary mass composition. Good agreement of spectra in the three zenith angle ranges was found for the assumption of pure proton and a simple two-component model. For zenith angles {\theta} < 30{\deg}, where the mass dependence is smallest, the knee in the cosmic ray energy spectrum was observed between 3.5 and 4.32 PeV, depending on composition assumption. Spectral indices above the knee range from -3.08 to -3.11 depending on primary mass composition assumption. Moreover, an indication of a flattening of the spectrum above 22 PeV were observed.Comment: 38 pages, 17 figure