α1-Antitrypsin Polymerizes in Alveolar Macrophages of Smokers With and Without α1-Antitrypsin Deficiency

BACKGROUND: The deficiency of α1-antitrypsin (AAT) is secondary to misfolding and polymerization of the abnormal Z-AAT in liver cells and is associated with lung emphysema. Alveolar macrophages (AM) produce AAT, however it is not known if Z-AAT can polymerize in AM, further decreasing lung AAT and promoting lung inflammation. AIMS: To investigate if AAT polymerizes in human AM and to study the possible relation between polymerization and degree of lung inflammation. METHODS: Immunohistochemical analysis with 2C1 monoclonal antibody specific for polymerized AAT was performed in sections of: 9 lungs from individuals with AAT deficiency (AATD) and severe COPD, 35 smokers with normal AAT levels of which 24 with severe COPD and 11 without COPD, and 13 non-smokers. AM positive for AAT polymers were counted and expressed as percentage of total AM in lung. RESULTS: AAT polymerization was detected in [27(4-67)%] of AM from individuals with AATD but also in AM from smokers with normal AAT with [24(0-70)%] and without [24(0-60)%] COPD, but not in AM from non-smokers [0(0-1.5)%] (p<0.0001). The percentage of AM with polymerized AAT correlated with pack-years smoked (r=0.53,p=0.0001), FEV1/FVC (r=-0.41,p=0.005), Small Airways Disease (r=0.44,p=0.004), number of CD8+T-cells and neutrophils in alveolar walls (r=0.51,p=0.002; r=0.31,p=0.05 respectively). CONCLUSIONS: Polymerization of AAT in alveolar macrophages occurs in lungs of individuals with AATD but also in smokers with normal AAT levels with or without COPD. Our findings highlight the similarities in the pathophysiology of COPD in individuals with and without AATD, adding a potentially important step to the mechanism of COPD

Turnip yellow mosaic virus in Chinese cabbage in Spain: Commercial seed transmission and molecular characterization

[EN] Seed transmission of Turnip yellow mosaic virus (TYMV, genus Tymovirus) was evaluated in the whole seeds and seedlings that emerged from three commercial Chinese cabbage (Brassica pekinensis) seed batches. Seedlings in the cotyledon stage and adult plants were assayed for TYMV by DAS-ELISA and confirmed by RT-PCR. The proportion of whole seeds infected with TYMV was at least 0.15 %. The seeds of the three seed batches were grown in Petri dishes, and surveyed in the cotyledon stage in trays that contained a peat:sand mixture grown in greenhouses or growth chambers, which were analysed in the cotyledon and adult stages. The seed-to-seedling transmission rate ranged from 2.5 % to 2.9 % in two different seed batches (lot-08 and lot-09, respectively). Spanish isolates derived from turnip (Sp-03) and Chinese cabbage (Sp-09 and Sp-13), collected in 2003, 2009 and 2013 in two different Spanish regions, were molecularly characterised by analysing the partial nucleotide sequences of three TYMV genome regions: partial RNA-dependent RNA polymerase (RdRp), methyltransferase (MTR) and coat protein (CP) genes. Phylogenetic analyses showed that the CP gene represented two different groups: TYMV-1 and TYMV-2. The first was subdivided into three subclades: European, Australian and Japanese. Spanish isolate Sp-03 clustered together with European TYMV group, whereas Sp-09 and Sp-13 grouped with the Japanese TYMV group, and all differed from group TYMV-2. The sequences of the three different genomic regions examined clustered into the same groups. The results suggested that Spanish isolates grouped according to the original hosts from which they were isolated. 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The use of a multiple-transfer method in plant virus transmission studies: some statistical points arising in the analysis of results. Annals of Applied Biology, 48, 75–83.Hayden, C. M., Mackenzie, A. M., & Gibbs, A. J. (1998a). Virion protein sequence variation among Australian isolates of turnip yellow mosaic tymovirus. Archives of Virology, 143, 191–201.Hayden, C. M., Mackenzie, A. M., Skotnicki, M. L., & Gibbs, A. (1998b). Turnip yellow mosaic virus isolates with experimentally produced recombinant virion proteins. Journal of General Virology, 79, 395–403.Hein, A. (1984). Transmission of Turnip yellow mosaic virus through seed of Camelina sativa gold of pleasure. Journal of Plant Diseases and Protection, 91, 549–551.Herrera-Vásquez, J. A., Córdoba-Sellés, M. C., Cebrián, M. C., Alfaro-Fernández, A., & Jordá, C. (2009). Seed transmission of Melon necrotic spot virus and efficacy of seed-disinfection treatments. Plant Pathology, 58, 436–452.Hull, R. (2002). Matthews’ plant virology (4a ed.1001 pp). San Diego: Academic Press.Johansen, E., Edwards, M. C., & Hampton, R. O. (1994). Seed transmission of viruses: current perspectives. Annual Review of Phytopathology, 32, 363–386.Kirino, N., Inoue, K., Tanina, K., Yamazaki, Y., & Ohki, S. T. (2008). Turnip yellow mosaic virus isolated from Chinese cabbage in Japan. Journal of General Plant Pathology, 74, 331–334.Markham, R., & Smith, K. S. (1949). Studies on the virus of turnip yellow mosaic. Parasitology, 39, 330–342.Mathews, R. E. F. (1980). Turnip yellow mosaic virus, CMI/AAB Descriptions of plant virus No. 230 (No. 2 revised). Kew: Commonwealth Mycology Institute/Association of Applied Biologists.Mitchell, E. J., & Bond, J. M. (2005). Variation in the coat protein sequence of British isolates of Turnip yellow mosaic virus and comparison with previously published isolates. Archives of Virology, 150, 2347–2355.Pagán, I., Fraile, A., Fernández-Fueyo, E., Montes, N., Alonso-Blanco, C., & García-Arenal, F. (2010). Arabidopsis thaliana as a model for the study of plant-virus co-evolution. Philosophical Transations of the Royal Society Biological Sciences, 365, 1983–1995.Paul, H. L., Gibbs, A., & Wittman-Liebold, B. (1980). The relationships of certain Tymoviruses assessed from the amino acid composition of their coat proteins. Intervirology, 13, 99–109.Pelikanova, J. (1990). Garlic mustard a spontaneous host of TYMV. Ochrana Rostlin, 26, 17–22.Procházková, Z. (1980). Host range and symptom differences between isolates of Turnip mosaic virus obtained from Sisymbrium loeselii. Biologia Plantarum, 22, 341–347.Rimmer, S. R., Shtattuck, V. I., & Buchwaldt, L. (2007). Compendium of brassica diseases (1ª Edición ed.p. 117). USA: APS press.Rot, M. E., & Jelkman, W. (2001). Characterization and detection of several filamentous viruses of cherry: Adaptation of an alternative cloning method (DOP-PCR), and modification of an RNA extraction protocol. European Journal of Plant Pathology, 107, 411–420.Sabanadzovic, S., Abou-Ghanem, N., Castellano, M. A., Digiaero, M., & Martelli, G. P. (2000). Grapevine fleck virus-like in Vitis. Archives of Virology, 145, 553–565.Špack, J., & Kubelková, D. (2000). Serological variability among European isolates of Radish mosaic virus. Plant Pathology, 49, 295–301.Špack, J., Kubelková, D., & Hnilicka, E. (1993). Seed transmission of Turnip yellow mosaic virus in winter turnip and winter oilseed rapes. Annals of Applied Biology, 123, 33–35.Stobbs, L. W., Cerkauskas, R. F., Lowery, T., & VanDriel, L. (1998). Occurrence of Turnip yellow mosaic virus on oriental cruciferours vegetables in Southern Ontario, Canada. Plant Disease, 82, 351.Tamura, K., Peterson, D., Peterson, N., Stecher, G., Nei, M., & Kumar, S. (2011). 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Relationship between Gene Body DNA Methylation and Intragenic H3K9me3 and H3K36me3 Chromatin Marks

To elucidate the relationship between intragenic DNA methylation and chromatin marks, we performed epigenetic profiling of chromosome 19 in human bronchial epithelial cells (HBEC) and in the colorectal cancer cell line HCT116 as well as its counterpart with double knockout of DNMT1 and DNMT3B (HCT116-DKO). Analysis of H3K36me3 profiles indicated that this intragenic mark of active genes is associated with two categories of genes: (i) genes with low CpG density and H3K9me3 in the gene body or (ii) genes with high CpG density and DNA methylation in the gene body. We observed that a combination of low CpG density in gene bodies together with H3K9me3 and H3K36me3 occupancy is a specific epigenetic feature of zinc finger (ZNF) genes, which comprise 90% of all genes carrying both histone marks on chromosome 19. For genes with high intragenic CpG density, transcription and H3K36me3 occupancy were not changed in conditions of partial or intensive loss of DNA methylation in gene bodies. siRNA knockdown of SETD2, the major histone methyltransferase responsible for production of H3K36me3, did not reduce DNA methylation in gene bodies. Our study suggests that the H3K36me3 and DNA methylation marks in gene bodies are established largely independently of each other and points to similar functional roles of intragenic DNA methylation and intragenic H3K9me3 for CpG-rich and CpG-poor genes, respectively

Brain Structural Networks Associated with Intelligence and Visuomotor Ability

Increasing evidence indicates that multiple structures in the brain are associated with intelligence and cognitive function at the network level. The association between the grey matter (GM) structural network and intelligence and cognition is not well understood. We applied a multivariate approach to identify the pattern of GM and link the structural network to intelligence and cognitive functions. Structural magnetic resonance imaging was acquired from 92 healthy individuals. Source-based morphometry analysis was applied to the imaging data to extract GM structural covariance. We assessed the intelligence, verbal fluency, processing speed, and executive functioning of the participants and further investigated the correlations of the GM structural networks with intelligence and cognitive functions. Six GM structural networks were identified. The cerebello-parietal component and the frontal component were significantly associated with intelligence. The parietal and frontal regions were each distinctively associated with intelligence by maintaining structural networks with the cerebellum and the temporal region, respectively. The cerebellar component was associated with visuomotor ability. Our results support the parieto-frontal integration theory of intelligence by demonstrating how each core region for intelligence works in concert with other regions. In addition, we revealed how the cerebellum is associated with intelligence and cognitive functions

Association between TCF7L2 gene polymorphisms and susceptibility to Type 2 Diabetes Mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Transcription factor 7-like 2 (<it>TCF7L2</it>) has been shown to be associated with type 2 diabetes mellitus (T2MD) in multiple ethnic groups in the past two years, but, contradictory results were reported for Chinese and Pima Indian populations. The authors then performed a large meta-analysis of 36 studies examining the association of type 2 diabetes mellitus (T2DM) with polymorphisms in the <it>TCF7L2 </it>gene in various ethnicities, containing rs7903146 C-to-T (IVS3C>T), rs7901695 T-to-C (IVS3T>C), a rs12255372 G-to-T (IVS4G>T), and rs11196205 G-to-C (IVS4G>C) polymorphisms and to evaluate the size of gene effect and the possible genetic mode of action.</p> <p>Methods</p> <p>Literature-based searching was conducted to collect data and three methods, that is, fixed-effects, random-effects and Bayesian multivariate mete-analysis, were performed to pool the odds ratio (<it>OR</it>). Publication bias and study-between heterogeneity were also examined.</p> <p>Results</p> <p>The studies included 35,843 cases of T2DM and 39,123 controls, using mainly primary data. For T2DM and IVS3C>T polymorphism, the Bayesian <it>OR </it>for TT homozygotes and TC heterozygotes versus CC homozygote was 1.968 (95% credible interval (<it>CrI</it>): 1.790, 2.157), 1.406 (95% <it>CrI</it>: 1.341, 1.476), respectively, and the population attributable risk (PAR) for the TT/TC genotypes of this variant is 16.9% for overall. For T2DM and IVS4G>T polymorphism, TT homozygotes and TG heterozygotes versus GG homozygote was 1.885 (95%<it>CrI</it>: 1.698, 2.088), 1.360 (95% <it>CrI</it>: 1.291, 1.433), respectively. Four <it>OR</it>s among these two polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and the main source of heterogeneity was ethnic differences. Data also showed significant associations between T2DM and the other two polymorphisms, but with low heterogeneity (<it>P </it>> 0.10). Pooled <it>OR</it>s fit a codominant, multiplicative genetic model for all the four polymorphisms of <it>TCF7L2 </it>gene, and this model was also confirmed in different ethnic populations when stratification of IVS3C>T and IVS4G>T polymorphisms except for Africans, where a dominant, additive genetic mode is suggested for IVS3C>T polymorphism.</p> <p>Conclusion</p> <p>This meta-analysis demonstrates that four variants of <it>TCF7L2 </it>gene are all associated with T2DM, and indicates a multiplicative genetic model for all the four polymorphisms, as well as suggests the <it>TCF7L2 </it>gene involved in near 1/5 of all T2MD. Potential gene-gene and gene-environmental interactions by which common variants in the <it>TCF7L2 </it>gene influence the risk of T2MD need further exploration.</p

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The DUNE Far Detector Interim Design Report, Volume 3: Dual-Phase Module

The DUNE IDR describes the proposed physics program and technical designs of the DUNE far detector modules in preparation for the full TDR to be published in 2019. It is intended as an intermediate milestone on the path to a full TDR, justifying the technical choices that flow down from the high-level physics goals through requirements at all levels of the Project. These design choices will enable the DUNE experiment to make the ground-breaking discoveries that will help to answer fundamental physics questions. Volume 3 describes the dual-phase module's subsystems, the technical coordination required for its design, construction, installation, and integration, and its organizational structure

The DUNE Far Detector Interim Design Report, Volume 2: Single-Phase Module

The DUNE IDR describes the proposed physics program and technical designs of the DUNE far detector modules in preparation for the full TDR to be published in 2019. It is intended as an intermediate milestone on the path to a full TDR, justifying the technical choices that flow down from the high-level physics goals through requirements at all levels of the Project. These design choices will enable the DUNE experiment to make the ground-breaking discoveries that will help to answer fundamental physics questions. Volume 2 describes the single-phase module's subsystems, the technical coordination required for its design, construction, installation, and integration, and its organizational structure