Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103

Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimerâ €™ s disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD). Using an in vitro model we demonstrate that this downregulation is due to to Aβ-plaque formation and tau hyper-phosphorylation. Transcriptomics revealed a neuroprotective role for both orexins and QRFP. Finally we provide conclusive evidence using BRET and FRET that OXRs and GPR103 form functional hetero-dimers to exert their effects involving activation of ERK 1/2. Pharmacological intervention directed at the orexigenic system may prove to be an attractive avenue towards the discovery of novel therapeutics for diseases such as AD and improving neuroprotective signalling pathways

Saccharopolyspora ghardaiensis sp. nov., an extremely halophilic actinomycete isolated from Algerian Saharan soil

A novel halophilic actinomycete, strain designated H53T, was isolated from a Saharan soil sample collected from Chaâbet Ntissa, Béni-isguen, Ghardaïa (South of Algeria) and was characterized taxonomically by means of polyphasic approach. Optimal growth was found to occur at 30–35 °C, pH 6–7 and in the presence of 15–25% (w/v) NaCl. The strain was observed to produce abundant aerial mycelium, which formed long chains of rod-shaped spores at maturity, and well developed and fragmented substrate mycelium. The cell wall was determined to contain meso-diaminopimelic acid; the diagnostic whole-cell sugars were arabinose and galactose. The predominant menaquinones were found to be MK-9(H4) and MK-9(H6). The predominant cellular fatty acids were determined to be iso- and anteiso-C17:0, iso-C15:0, and cis9 iso-C17:1. The diagnostic phospholipid detected was phosphatidylcholine. The morphological and chemotaxonomic characteristics of the strain were consistent with those of members of the genus Saccharopolyspora. Phylogenetic analyses on the basis of the 16S ribosomal RNA (rRNA) gene sequence showed that this strain formed a distinct phyletic line within the radiation of the genus Saccharopolyspora. The 16S rRNA sequence similarities between strain H53T and other members of the genus Saccharopolyspora ranged from 92.1 to 94.3%. The DNA G+C content of strain H53T was 72.6%. The genotypic and phenotypic data showed that the strain H53T represents a novel species of the genus Saccharopolyspora, for which the name Saccharopolyspora ghardaiensis sp. nov. is proposed, with the type strain H53T (=DSM 45606T=CCUG 63370T=CECT 8304T)

Gaia Early Data Release 3: Summary of the contents and survey properties

ABSTRACT: Context. We present the early installment of the third Gaia data release, Gaia EDR3, consisting of astrometry and photometry for 1.8 billion sources brighter than magnitude 21, complemented with the list of radial velocities from Gaia DR2. Aims. A summary of the contents of Gaia EDR3 is presented, accompanied by a discussion on the differences with respect to Gaia DR2 and an overview of the main limitations which are present in the survey. Recommendations are made on the responsible use of Gaia EDR3 results. Methods. The raw data collected with the Gaia instruments during the first 34 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium and turned into this early third data release, which represents a major advance with respect to Gaia DR2 in terms of astrometric and photometric precision, accuracy, and homogeneity. Results. Gaia EDR3 contains celestial positions and the apparent brightness in G for approximately 1.8 billion sources. For 1.5 billion of those sources, parallaxes, proper motions, and the (GBP ? GRP) colour are also available. The passbands for G, GBP, and GRP are provided as part of the release. For ease of use, the 7 million radial velocities from Gaia DR2 are included in this release, after the removal of a small number of spurious values. New radial velocities will appear as part of Gaia DR3. Finally, Gaia EDR3 represents an updated materialisation of the celestial reference frame (CRF) in the optical, the Gaia-CRF3, which is based solely on extragalactic sources. The creation of the source list for Gaia EDR3 includes enhancements that make it more robust with respect to high proper motion stars, and the disturbing effects of spurious and partially resolved sources. The source list is largely the same as that for Gaia DR2, but it does feature new sources and there are some notable changes. The source list will not change for Gaia DR3. Conclusions. Gaia EDR3 represents a significant advance over Gaia DR2, with parallax precisions increased by 30 per cent, proper motion precisions increased by a factor of 2, and the systematic errors in the astrometry suppressed by 30-40% for the parallaxes and by a factor ~2.5 for the proper motions. The photometry also features increased precision, but above all much better homogeneity across colour, magnitude, and celestial position. A single passband for G, GBP, and GRP is valid over the entire magnitude and colour range, with no systematics above the 1% levelThe Gaia mission and data processing have financially been supported by ; the Spanish Ministry of Economy (MINECO/FEDER, UE) through grants ESP2016-80079-C2-1-R, ESP2016-80079-C2-2-R, RTI2018-095076-B-C21, RTI2018-095076-B-C22, BES-2016-078499, and BES-2017-083126 and the Juan de la Cierva formación 2015 grant FJCI-2015-2671, the Spanish Ministry of Education, Culture, and Sports through grant FPU16/03827, the Spanish Ministry of Science and Innovation (MICINN) through grant AYA2017-89841P for project “Estudio de las propiedades de los fósiles estelares en el entorno del Grupo Local” and through grant TIN2015-65316-P for project “Computación de Altas Prestaciones VII

Gaia Data Release 3: Mapping the asymmetric disc of the Milky Way

With the most recent Gaia data release the number of sources with complete 6D phase space information (position and velocity) has increased to well over 33 million stars, while stellar astrophysical parameters are provided for more than 470 million sources, in addition to the identification of over 11 million variable stars. Using the astrophysical parameters and variability classifications provided in Gaia DR3, we select various stellar populations to explore and identify non-axisymmetric features in the disc of the Milky Way in both configuration and velocity space. Using more about 580 thousand sources identified as hot OB stars, together with 988 known open clusters younger than 100 million years, we map the spiral structure associated with star formation 4-5 kpc from the Sun. We select over 2800 Classical Cepheids younger than 200 million years, which show spiral features extending as far as 10 kpc from the Sun in the outer disc. We also identify more than 8.7 million sources on the red giant branch (RGB), of which 5.7 million have line-of-sight velocities, allowing the velocity field of the Milky Way to be mapped as far as 8 kpc from the Sun, including the inner disc. The spiral structure revealed by the young populations is consistent with recent results using Gaia EDR3 astrometry and source lists based on near infrared photometry, showing the Local (Orion) arm to be at least 8 kpc long, and an outer arm consistent with what is seen in HI surveys, which seems to be a continuation of the Perseus arm into the third quadrant. Meanwhile, the subset of RGB stars with velocities clearly reveals the large scale kinematic signature of the bar in the inner disc, as well as evidence of streaming motions in the outer disc that might be associated with spiral arms or bar resonances. (abridged

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe