Autoimmune Hepatitis: Clinical Review with Insights into the Purinergic Mechanism of Disease

Abstract Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women. The clinicopathological picture is characterized by symptoms associated with both systemic inflammation and hepatic dysfunction, and with increased serum aminotransferases, elevated IgG, autoantibodies, and interface hepatitis on liver biopsy. AIH usually results in liver injury as a consequence of chronic hepatitis and cirrhosis. However, rarely, patients may present with fulminant liver failure. Early diagnosis is important in all instances because the disease can be highly responsive to immunosuppressive therapeutic options. Left untreated, the disease is associated with high morbidity and mortality. Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults. We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance. We focus on regulatory T cell impairments as a consequence of changes in CD39 ectonucleotidase expression and altered purinergic signaling. Further understanding of hepatic tolerance may aid in the development of specific and well-tolerated therapies for AIH

Thermodynamic aspects of the grain boundary segregation in Cu (Bi) alloys

AbstractÐThe grain boundary segregation of Bi in dilute polycrystalline Cu±Bi alloys was systematically studied as a function of temperature and composition. The temperature dependencies of the Gibbsian excess of Bi at the grain boundaries exhibited discontinuous changes at the temperatures close to, but dierent from the bulk solidus temperatures. The observed segregational phase transition was interpreted in terms of prewetting model.

Vibrational spectroscopy in the electron microscope

Vibrational spectroscopies using infrared radiation In the past two decades, the performance of electron microscopes has been greatly improved by the introduction of multipole-based aberration correction technology Because of recent progress, we are now able to answer the question in the positive. The progress has taken place on three principal fronts: (1) the energy resolution of EELS carried out in the electron microscope has been improved to around 10 meV; (2) the EELS-STEM instrument has been optimized so that the electron probe incident on the sample contains a current sufficient to perform EELS experiments even when the energy width of the probe is ,10 meV and its size ,1 nm; and (3) the tail of the intense zero loss peak (ZLP) in the EELS spectrum has been reduced so that it does not obscure the vibrational features of interest. The innovations responsible for the progress are (1) a monochromator of a new design 17 , which is able to reach an energy resolution comparable to the highest resolution attained previously The observation of vibrational peaks due to hydrogen in TiH 2 and in the epoxy resin is especially interesting. In TiH 2 , hydrogen is mobile and bound only weakly, which results in the relatively low (for hydrogen) vibrational energy of 147 meV. In epoxy resin, hydrogen is mostly bound to carbon, and 360 meV (2,900 cm 21 ) is a typical C-H stretch vibrational energy 1-3 . Up to now, hydrogen has been essentially invisible in electron microscopes, its presence typically inferred from the modified electron distribution due to the electron it contributes to the sample's electron density distribution. Its unambiguous detection by vibrational spectroscopy promises to provide a general technique for hydrogen Macmillan Publishers Limited. All rights reserved ©2014 detection in the many hydrogen-containing materials studied by electron microscopy. Another attractive prospect involves analysing the types of covalent hydrogen bonding present in microscopic amounts of matter, with H-C, H-N, H-O and other types of hydrogen bonds giving distinct vibrational frequencies 1-3 . The width of the vibrational peaks shown in The vibrational signal was obtained by subtracting the background under the peak at 138 meV in all the spectra, which were similar to the spectrum shown in Aloof beams losing energy to delocalized electronic excitations (such as surface plasmons) have been studied extensively in low-loss EELS The spatial resolution obtainable with the aloof signal is comparable to that of tip-enhanced optical spectroscopy 7 , without needing to have a sharp tip in the vicinity of the examined structure. Because the interaction distance for the signal can be much larger than the diameter o

Worldwide variations in artificial skyglow

Despite constituting a widespread and significant environmental change, understanding of artificial nighttime skyglow is extremely limited. Until now, published monitoring studies have been local or regional in scope, and typically of short duration. In this first major international compilation of monitoring data we answer several key questions about skyglow properties. Skyglow is observed to vary over four orders of magnitude, a range hundreds of times larger than was the case before artificial light. Nearly all of the study sites were polluted by artificial light. A non-linear relationship is observed between the sky brightness on clear and overcast nights, with a change in behavior near the rural to urban landuse transition. Overcast skies ranged from a third darker to almost 18 times brighter than clear. Clear sky radiances estimated by the World Atlas of Artificial Night Sky Brightness were found to be overestimated by ,25%; our dataset will play an important role in the calibration and ground truthing of future skyglow models. Most of the brightly lit sites darkened as the night progressed, typically by ,5% per hour. The great variation in skyglow radiance observed from site-to-site and with changing meteorological conditions underlines the need for a long-term international monitoring program

Human contribution to more- intense precipitation extremes

Extremes of weather and climate can have devastating effects on human society and the environment Owing to the high spatial variability of precipitation and the sparseness of the observing network in many regions, estimates of area means of extreme precipitation may be uncertain; for example, for regions where the distribution of individual stations does not adequately sample the spatial variability of extreme values across the region. In order to reduce the effects of this source of uncertainty on area means, and to improve representativeness and inter-comparability, we standardized values at each grid-point before estimating large area averages by mapping extreme precipitation amounts onto a zero-toone scale In order to consider long-term changes in extreme precipitation, we calculate non-overlapping five-year mean PI anomaly time series for 1955-99 and append a four-year mean for 1951-54. The time evolution of five-year mean PI anomalies averaged over Northern Hemisphere land (using the locations plotted i

Predicting evolutionary patterns of mammalian teeth from development. Nature 449: 427–432

One motivation in the study of development is the discovery of mechanisms that may guide evolutionary change. Here we report how development governs relative size and number of cheek teeth, or molars, in the mouse. We constructed an inhibitory cascade model by experimentally uncovering the activator-inhibitor logic of sequential tooth development. The inhibitory cascade acts as a ratchet that determines molar size differences along the jaw, one effect being that the second molar always makes up one-third of total molar area. By using a macroevolutionary test, we demonstrate the success of the model in predicting dentition patterns found among murine rodent species with various diets, thereby providing an example of ecologically driven evolution along a developmentally favoured trajectory. In general, our work demonstrates how to construct and test developmental rules with evolutionary predictability in natural systems. A recurring promise of evolutionary developmental biology is the discovery of the mechanisms and rules that govern the production of the phenotypic variation available for natural selection The mammalian dentition is a classic system in which developmental mechanisms have been used to explain variation in shape and size Inhibitory dynamics of molar initiatio

LETTER OPEN Genome-wide signatures of convergent evolution in echolocating mammals

Evolution is typically thought to proceed through divergence of genes, proteins and ultimately phenotypes Echolocation is a complex phenotypic trait that has evolved independently in bats and whales, and which involves the production, reception and auditory processing of ultrasonic pulses for obstacle avoidance, orientation and hunting 21 . Here, using the evolution of echolocation as a model of phenotypic convergence, we investigated the extent to which parallel changes have occurred across the genome during the independent evolution of echolocation in bats and cetaceans. We undertook genome sequencing of four divergent bat species, including both echolocating and non-echolocating forms. From the proposed suborder Yinpterochiroptera we sequenced the greater horseshoe bat Rhinolophus ferrumequinum and the greater false vampire bat Megaderma lyra, which exhibit 'constant frequency' (CF) and 'frequency modulated' (FM) echolocation, respectively (for details of calls, see refs 15, 22). From this suborder we also sequenced the nonecholocating straw-coloured fruit bat Eidolon helvum, to which we added published draft genome data from a second non-echolocating fruit bat, the large flying fox Pteropus vampyrus. From the second suborder, Yangochiroptera, we sequenced the CF echolocating Parnell's moustached bat Pteronotus parnellii, and added published data from the FM echolocating little brown bat Myotis lucifugus. For each of our four focal bat species, we generated paired-end short read sequence data on a Hi-Seq 2000 platform (Illumina), assembled the raw reads de novo into contigs using CLC bio, and then built scaffolds in SOAPdenovo (see Methods for details). Short-read data have been deposited into the Short Read Archive under accession numbers SRR924356, SRR924359, SRR924361 and SRR924427. We conducted homology-based gene prediction and identified 20,424 genes for R. ferrumequinum, 20,043 for M. lyra, 20,455 for E. helvum and 20,357 for P. parnellii. Screening for single-copy (1-to-1) orthologous protein-coding nuclear genes conserved across eutherian mammals identified 7,612 genes present in each of our four draft genomes (see Methods for details). To build a mammal-wide alignment of orthologous coding gene sequences (CDSs) we retrieved the CDS of each locus from 18 published mammal genomes from Ensembl (http://www.ensembl.org/, release 63), covering a broad taxonomic range and including M. lucifugus and P. vampyrus (see Methods) as well as the echolocating common bottlenose dolphin Tursiops truncatus. Individual gene data sets were built and aligned in frame as codons with all ambiguous sites and codons removed (see Methods). To avoid potential errors that could arise either during sequencing or data assembly, which could adversely affect phylogenetic and molecular evolution analyses, we focused on all identified genes that, after clean up, contained no missing data or gaps in any of the newly sequenced bats. In total we generated alignments for 2,326 CDSs, each spanning at least 450 base pairs, and containing a minimum of six bat species (2% of alignments had missing data from P. vampyrus due to its lower coverage) as well as the bottlenose dolphin and the following five other mammals: dog Canis familiaris, horse Equus caballus, cow Bos taurus, mouse Mus musculus and human Homo sapiens. To detect genome-wide sequence convergence between echolocating lineages, we built an analytical pipeline based on maximum likelihood (ML) phylogenetic reconstructio

Hydrogen bonding at the water surface revealed by isotopic dilution spectroscopy. Nature 474

The air-water interface is perhaps the most common liquid interface. It covers more than 70 per cent of the Earth's surface and strongly affects atmospheric, aerosol and environmental chemistry. The airwater interface has also attracted much interest as a model system that allows rigorous tests of theory, with one fundamental question being just how thin it is. Theoretical studies have suggested a surprisingly short 'healing length' of about 3 ångströms (1 Å 5 0.1 nm), with the bulk-phase properties of water recovered within the top few monolayers The vibrational spectroscopy of aqueous interfaces has progressed significantly in recent years with the development of surface-selective spectroscopic techniques The intramolecular and intermolecular vibrational coupling between the OH transition dipoles of the same molecule or between neighbours affect the spectral lineshapes of the water OH-stretch band We overcome these challenges by using the heterodyne-detected SFG technique 10 , which uses interference of the signal with a reference beam to (1) amplify the SFG signal, considerably enhancing the sensitivity, (2) make it linear with the number of chromophores, an

Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486

Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone 13 and MAP3K1 10 , we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATPcompetitive AKT small-molecule inhibitor. Breast cancers are classified according to gene-expression subtypes: luminal A, luminal B, Her2-enriched (Her2 is also known as ERBB2), and basal-like 14 . Luminal subtypes are associated with expression of oestrogen and progesterone receptors and differentiated luminal epithelial cell markers. The subtypes differ in genomic complexity, key genetic alterations and clinical prognosis In total, whole-exome sequencing was performed on 103 tumour/ normal pairs, 54 from Mexico and 49 from Vietnam, targeting 189,980 exons comprising 33 megabases (Mb) of the genome and with a median of 85.1% of targeted bases covered at least 30-fold across the sample set. This analysis revealed a total of 4,985 candidate somatic substitutions (see https://confluence.broadinstitute.org/display/CGATools/MuTect for methods and data sets) and insertions/deletions (indels, see https:// confluence.broadinstitute.org/display/CGATools/Indelocator for methods) in the target protein-coding regions and the adjacent splice sites, ranging from 14 to 307 putative events in individual samples (Supplementar