HLA association with the susceptibility to anti-synthetase syndrome

Objective: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions: Our results support the association of the HLA complex with the susceptibility to ASSD

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

Anaerobic digestion and gasification of seaweed

The potential of algal biomass as a source of liquid and gaseous biofuels is a highly topical theme, with over 70 years of sometimes intensive research and considerable financial investment. A wide range of unit operations can be combined to produce algal biofuel, but as yet there is no successful commercial system producing such biofuel. This suggests that there are major technical and engineering difficulties to be resolved before economically viable algal biofuel production can be achieved. Both gasification and anaerobic digestion have been suggested as promising methods for exploiting bioenergy from biomass, and two major projects have been funded in the UK on the gasification and anaerobic digestion of seaweed, MacroBioCrude and SeaGas. This chapter discusses the use of gasification and anaerobic digestion of seaweed for the production of biofuel

Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.Peer reviewe

Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

Bounds on the density of sources of ultra-high energy cosmic rays from the Pierre Auger Observatory

We derive lower bounds on the density of sources of ultra-high energy cosmic rays from the lack of significant clustering in the arrival directions of the highest energy events detected at the Pierre Auger Observatory. The density of uniformly distributed sources of equal intrinsic intensity was found to be larger than similar to (0.06 – 5) x 10(-4) Mpc(-3) at 95% CL, depending on the magnitude of the magnetic defections. Similar bounds, in the range (0.2 – 7) x 10(-4) Mpc(-3), were obtained for sources following the local matter distribution.We are very grateful to the following agencies and organizations for financial support,: Comision Nacional de Energia Atomica, Fundacion Antorchas, Gobierno De La, Provincia de Ailendoza. Municipalidad de Malargile. INDM floldings and Valle Las Lenas, in gratitude for their continuing cooperation over land access. Argentina; the Australian Research Council; Conselho Nacional de Desenvolvimento Cientifico e 'Tecnologico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundacdo de Amparo a Pesquisa do Est ado de Rio de Janeiro (FAP HRJ), Fundacdo de Amparo Pesquisa do Estado de Sdo Paulo (FAPESP), Ministerio de Ciencia e Tecnologia (IVICT), Brazil; AVCR AVOZ10100502 and AVOZ10100522, GAAV KJB100100904, AISMT-CR LA08016, LG11044, 1VIEB111003, MSAI0021620859, LA08015, TACR TA01010517 and GA U.K. 119810, Czech Republic; Centre de Calcul I-N2P3/CNRS, Centre National de la -Recherche Scientifique ((1 NRS), Conseil Regional Ile-de-France, f)epartement, Physique Nuclealre et Corpusculaire (I N( Departement Sciences de l'Univers (SDU-INSU/CNRS), France; Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DITG), Finanzministerium Baden-Wurttemberg, flelmholtz-Gemeinschaft Deutscher Forschungszentren Ministerium fur Wissenschaft und Forschung, Nordrhein-Westfalen, Ministerimn fur Wissenschaft, Forschung und Kunst, Baden-WUrttemberg, Germany; Istituto Nazion ale di Fisica Nucleare (INFN), Ministero dell'Istruzione, delhLniversita e della Ricerca (MIUR), Italy: Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico; Ministerie van Onden s Cultuur on NVetenschap Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), Stichting voor Rmdamenteel Onderzoek der Materie (FOM), Netherlands; Ministry of Science and Higher Education, Grant Nos. N N202 200239 and N N202 207238, Poland; Portuguese national funds and FEDER funds within COMPETE - Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia, Portugal; Romanian Authority for Scientific Research ANCS, CNDI-UEFISETD1 partnership projects nr.20/2012 and nr.194/2012, project nr.1 /ASPERA2/20I2 ERA-NET and PN-IIRU-PD-2011-3-0145-17, Romania; Ministry for Higher Education, Science, and 'Technology, Slovenian Research Agency, Slovenia; Comunidad de Madrid, FEDER funds, Ministerio de Ciencia e Innovacion and Consolider-Ingenio 2010 (( PAN), X unta de Galicia Spain; Science and Technology Facilities Council, United kingdom; Department of Luergy, Contract Nos. DE-ACO2-07(11-111359, DE-FR02-04E1(41300, DE-FG02-99E1(41107, National Science Foundation, Grant No. 0450696, The Grainger Foundation U.S.A.; NAFOSTED, Vietnam; Marie Curie-IRSES/HPLANET, European Particle Physics Latin American Network, European Union 7th Frarneworlc Program. Grant No. IIRSES-2009-GA-246806; and UNESCO.Peer reviewe

Identifying clouds over the Pierre Auger Observatory using infrared satellite data

We describe a new method of identifying night-time clouds over the Pierre Auger Observatory using infrared data from the Imager instruments on the GOES-12 and GOES-13 satellites. We compare cloud. identifications resulting from our method to those obtained by the Central Laser Facility of the Auger Observatory. Using our new method we can now develop cloud probability maps for the 3000 km(2) of the Pierre Auger Observatory twice per hour with a spatial resolution of similar to 2.4 km by similar to 5.5 km. Our method could also be applied to monitor cloud cover for other ground-based observatories and for space-based observatories. (C) 2013 Elsevier B.V. All rights reserved.The successful installation, commissioning, and operation of the Pierre Auger Observatory would not have been possible without the strong commitment and effort from the technical and adminis- trative staff in Malargüe. We are very grateful to the following agencies and organiza- tions for financial support: Comisión Nacional de Energía Atómica, Fundación Antorchas, Gobierno De La Provincia de Mendoza, Municipalidad de Malargüe, NDM Holdings and Valle Las Leñas, in gratitude for their continuing cooperation over land access, Argentina; the Australian Research Council; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundação de Amparo à Pesquisa do Estado de Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Ministério de Ciência e Tecnolo- gia (MCT), Brazil; AVCR AV0Z10100502 and AV0Z10100522, GAAV KJB100100904, MSMT-CR LA08016, LG11044, MEB111003, MSM0021620859, LA08015, TACR TA01010517 and GA UK 119810, Czech Republic; Centre de Calcul IN2P3/CNRS, Centre Na- tional de la Recherche Scientifique (CNRS), Conseil Régional Ile-de- France, Département Physique Nucléaire et Corpusculaire (PNC- IN2P3/CNRS), Département Sciences de l’Univers (SDU-INSU/ CNRS), France; Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Finanzministeri- um Baden-Württemberg, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen, Ministerium für Wissenschaft, Forschung und Kunst, Baden-Württemberg, Germany; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), Italy; Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico; Ministerie van Ond- erwijs, Cultuur en Wetenschap, Nederlandse Organisatie voor Wet- enschappelijk Onderzoek (NWO), Stichting voor Fundamenteel Onderzoek der Materie (FOM), Netherlands; Ministry of Science and Higher Education, Grant Nos. N N202 200239 and N N202 207238, Poland; Portuguese national funds and FEDER funds with- in COMPETE - Programa Operacional Factores de Competitividade through Fundação para a Ciência e a Tecnologia, Portugal; Roma- nian Authority for Scientific Research ANCS, CNDI-UEFISCDI part- nership projects nr.20/2012 and nr.194/2012, project nr.1/ ASPERA2/2012 ERA-NET and PN-II-RU-PD-2011-3-0145-17, Roma- nia; Ministry for Higher Education, Science, and Technology, Slove- nian Research Agency, Slovenia; Comunidad de Madrid, FEDER funds, Ministerio de Ciencia e Innovación and Consolider-Ingenio 2010 (CPAN), Xunta de Galicia, Spain; The Leverhulme Foundation, Science and Technology Facilities Council, United Kingdom; Department of Energy, Contract Nos. DE-AC02-07CH11359, DE- FR02-04ER41300, DE-FG02-99ER41107, National Science Founda- tion, Grant No. 0450696, The Grainger Foundation USA; NAFO- STED, Vietnam; Marie Curie-IRSES/EPLANET, European Particle Physics Latin American Network, European Union 7th Framework Program, Grant No. PIRSES-2009-GA-246806; and UNESCO. We would like to thank the former Michigan Tech students: Nathan Kelley-Hoskins, Kyle Luck and Arin Nelson for their impor- tant contribution to the development of this paper. We would like to thank NOAA for the GOES satellite data that we freely down- loaded from their website. Also, we would like to mention in these acknowledgments Dr. Steve Ackerman and Dr. Tony Schreiner for very valuable conversationsPeer reviewe

Biology of moderately halophilic aerobic bacteria

The moderately halophilic heterotrophic aerobic bacteria form a diverse group of microorganisms. The property of halophilism is widespread within the bacterial domain. Bacterial halophiles are abundant in environments such as salt lakes, saline soils, and salted food products. Most species keep their intracellular ionic concentrations at low levels while synthesizing or accumulating organic solutes to provide osmotic equilibrium of the cytoplasm with the surrounding medium. Complex mechanisms of adjustment of the intracellular environments and the properties of the cytoplasmic membrane enable rapid adaptation to changes in the salt concentration of the environment. Approaches to the study of genetic processes have recently been developed for several moderate halophiles, opening the way toward an understanding of haloadaptation at the molecular level. The new information obtained is also expected to contribute to the development of novel biotechnological uses for these organisms