Non-Coding Keratin Variants Associate with Liver Fibrosis Progression in Patients with Hemochromatosis

Background: Keratins 8 and 18 (K8/K18) are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with endstage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. Methods: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene) mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCRamplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previouslygenerated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. Results: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2%) and non-coding heterozygous variants in 6 additional patients (3.7%). Two novel K8 variants (Q169E/R275W) were found. K8 R341H was the most common amino-acid altering variant (4 patients), and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. I

Measurement of the Negative Muon Anomalous Magnetic Moment to 0.7 ppm

The anomalous magnetic moment of the negative muon has been measured to a precision of 0.7 parts per million (ppm) at the Brookhaven Alternating Gradient Synchrotron. This result is based on data collected in 2001, and is over an order of magnitude more precise than the previous measurement of the negative muon. The result a_mu= 11 659 214(8)(3) \times 10^{-10} (0.7 ppm), where the first uncertainty is statistical and the second is sytematic, is consistend with previous measurements of the anomaly for the positive and negative muon. The average for the muon anomaly a_{mu}(exp) = 11 659 208(6) \times 10^{-10} (0.5ppm).Comment: 4 pages, 4 figures, submitted to Physical Review Letters, revised to reflect referee comments. Text further revised to reflect additional referee comments and a corrected Fig. 3 replaces the older versio

SCIAMACHY Level 1 data: calibration concept and in-flight calibration

The calibration of SCIAMACHY was thoroughly checked since the instrument was launched on-board ENVISAT in February 2002. While SCIAMACHY's functional performance is excellent since launch, a number of technical difficulties have appeared, that required adjustments to the calibration. The problems can be separated into three types: (1) Those caused by the instrument and/or platform environment. Among these are the high water content in the satellite structure and/or MLI layer. This results in the deposition of ice on the detectors in channels 7 and 8 which seriously affects the retrievals in the IR, mostly because of the continuous change of the slit function caused by scattering of the light through the ice layer. Additionally a light leak in channel 7 severely hampers any retrieval from this channel. (2) Problems due to errors in the on-ground calibration and/or data processing affecting for example the radiometric calibration. A new approach based on a mixture of onground and in-flight data is shortly described here. (3) Problems caused by principal limitations of the calibration concept, e.g. the possible appearance of spectral structures after the polarisation correction due to unavoidable errors in the determination of atmospheric polarisation. In this paper we give a complete overview of the calibration and problems that still have to be solved. We will also give an indication of the effect of calibration problems on retrievals where possible. Since the operational processing chain is currently being updated and no newly processed data are available at this point in time, for some calibration issues only a rough estimate of the effect on Level 2 products can be given. However, it is the intention of this paper to serve as a future reference for detailed studies into specific calibration issues

SCIAMACHY Level 1 data: calibration concept and in-flight calibration

The calibration of SCIAMACHY was thoroughly checked since the instrument was launched on-board ENVISAT in February 2002. While SCIAMACHY's functional performance is excellent since launch, a number of technical difficulties have appeared, that required adjustments to the calibration. The problems can be separated into three types: (1) Those caused by the instrument and/or platform environment. Among these are the high water content in the satellite structure and/or MLI layer. This results in the deposition of ice on the detectors in channels 7 and 8 which seriously affects the retrievals in the IR, mostly because of the continuous change of the slit function caused by scattering of the light through the ice layer. Additionally a light leak in channel 7 severely hampers any retrieval from this channel. (2) Problems due to errors in the on-ground calibration and/or data processing affecting for example the radiometric calibration. A new approach based on a mixture of on-ground and in-flight data is shortly described here. (3) Problems caused by principal limitations of the calibration concept, e.g. the possible appearance of spectral structures after the polarisation correction due to unavoidable errors in the determination of atmospheric polarisation. In this paper we give a complete overview of the calibration and problems that still have to be solved. We will also give an indication of the effect of calibration problems on retrievals where possible. Since the operational processing chain is currently being updated and no newly processed data are available at this point in time, for some calibration issues only a rough estimate of the effect on Level 2 products can be given. However, it is the intention of this paper to serve as a future reference for detailed studies into specific calibration issues

Open Problems on Central Simple Algebras

We provide a survey of past research and a list of open problems regarding central simple algebras and the Brauer group over a field, intended both for experts and for beginners.Comment: v2 has some small revisions to the text. Some items are re-numbered, compared to v

Intermediate filament cytoskeleton of the liver in health and disease

Intermediate filaments (IFs) represent the largest cytoskeletal gene family comprising ~70 genes expressed in tissue specific manner. In addition to scaffolding function, they form complex signaling platforms and interact with various kinases, adaptor, and apoptotic proteins. IFs are established cytoprotectants and IF variants are associated with >30 human diseases. Furthermore, IF-containing inclusion bodies are characteristic features of several neurodegenerative, muscular, and other disorders. Acidic (type I) and basic keratins (type II) build obligatory type I and type II heteropolymers and are expressed in epithelial cells. Adult hepatocytes contain K8 and K18 as their only cytoplasmic IF pair, whereas cholangiocytes express K7 and K19 in addition. K8/K18-deficient animals exhibit a marked susceptibility to various toxic agents and Fas-induced apoptosis. In humans, K8/K18 variants predispose to development of end-stage liver disease and acute liver failure (ALF). K8/K18 variants also associate with development of liver fibrosis in patients with chronic hepatitis C. Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated K8/K18, chaperones and sequestosome1/p62 (p62) as their major constituents. MDBs are found in various liver diseases including alcoholic and non-alcoholic steatohepatitis and can be formed in mice by feeding hepatotoxic substances griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDBs also arise in cell culture after transfection with K8/K18, ubiquitin, and p62. Major factors that determine MDB formation in vivo are the type of stress (with oxidative stress as a major player), the extent of stress-induced protein misfolding and resulting chaperone, proteasome and autophagy overload, keratin 8 excess, transglutaminase activation with transamidation of keratin 8 and p62 upregulation

Constraints from Solar and Reactor Neutrinos on Unparticle Long-Range Forces

We have investigated the impact of long-range forces induced by unparticle operators of scalar, vector and tensor nature coupled to fermions in the interpretation of solar neutrinos and KamLAND data. If the unparticle couplings to the neutrinos are mildly non-universal, such long-range forces will not factorize out in the neutrino flavour evolution. As a consequence large deviations from the observed standard matter-induced oscillation pattern for solar neutrinos would be generated. In this case, severe limits can be set on the infrared fix point scale, Lambda_u, and the new physics scale, M, as a function of the ultraviolet (d_UV) and anomalous (d) dimension of the unparticle operator. For a scalar unparticle, for instance, assuming the non-universality of the lepton couplings to unparticles to be of the order of a few per mil we find that, for d_UV=3 and d=1.1, M is constrained to be M > O(10^9) TeV (M > O(10^10) TeV) if Lambda_u= 1 TeV (10 TeV). For given values of Lambda_u and d, the corresponding bounds on M for vector [tensor] unparticles are approximately 100 [3/Sqrt(Lambda_u/TeV)] times those for the scalar case. Conversely, these results can be translated into severe constraints on universality violation of the fermion couplings to unparticle operators with scales which can be accessible at future colliders.Comment: 13 pages, 3 figures. Minor changes due to precision in numerical factors and correction in figure labels. References added. Conclusions remain unchange

The effect of the timing of exposure to Campylobacter jejuni on the gut microbiome and inflammatory responses of broiler chickens

Background Campylobacters are an unwelcome member of the poultry gut microbiota in terms of food safety. The objective of this study was to compare the microbiota, inflammatory responses, and zootechnical parameters of broiler chickens not exposed to Campylobacter jejuni with those exposed either early at 6 days old or at the age commercial broiler chicken flocks are frequently observed to become colonized at 20 days old. Results Birds infected with Campylobacter at 20 days became cecal colonized within 2 days of exposure, whereas birds infected at 6 days of age did not show complete colonization of the sample cohort until 9 days post-infection. All birds sampled thereafter were colonized until the end of the study at 35 days (mean 6.1 log10 CFU per g of cecal contents). The cecal microbiota of birds infected with Campylobacter were significantly different to age-matched non-infected controls at 2 days post-infection but generally the composition of the cecal microbiota were more affected by bird age as the time post infection increased. The effects of Campylobacter colonization on the cecal microbiota were associated with reductions in the relative abundance of OTUs within the taxonomic family Lactobacillaceae and the Clostridium cluster XIVa. Specific members of the Lachnospiraceae and Ruminococcaceae families exhibit transient shifts in microbial community populations dependent upon the age at which the birds become colonized by C. jejuni. Analysis of ileal and cecal chemokine/cytokine gene expression revealed increases in IL-6, IL-17A and Il-17F consistent with a Th17 response but the persistence of the response was dependent on the stage/time of C. jejuni colonization that coincide with significant reductions in the abundance of Clostridium cluster XIVa. Conclusions This study combines microbiome data, cytokine/chemokine gene expression with intestinal villus and crypt measurements to compare chickens colonized early or late in the rearing cycle to provide insights into the process and outcomes of Campylobacter colonization. Early colonization results in a transient growth rate reduction and pro-inflammatory response but persistent modification of the cecal microbiota. Late colonization produces pro-inflammatory responses with changes in the cecal microbiota that will endure in market ready chickens