Submillimetre Common-User Bolometer Array 2 (SCUBA-2) is an innovative 10 000 pixel bolometer camera operating at submillimetre wavelengths on the James Clerk Maxwell Telescope (JCMT). The camera has ...the capability to carry out wide-field surveys to unprecedented depths, addressing key questions relating to the origins of galaxies, stars and planets. With two imaging arrays working simultaneously in the atmospheric windows at 450 and 850 μm, the vast increase in pixel count means that SCUBA-2 maps the sky 100-150 times faster than the previous SCUBA instrument. In this paper, we present an overview of the instrument, discuss the physical characteristics of the superconducting detector arrays, outline the observing modes and data acquisition, and present the early performance figures on the telescope. We also showcase the capabilities of the instrument via some early examples of the science SCUBA-2 that have already been undertaken. In 2012 February, SCUBA-2 began a series of unique legacy surveys for the JCMT community. These surveys will take 2.5 yr and the results are already providing complementary data to the shorter wavelength, shallower, larger area surveys from Herschel. The SCUBA-2 surveys will also provide a wealth of information for further study with new facilities such as ALMA, and future telescopes such as CCAT and SPICA.
We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation ...influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.
Abstract
Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural ...understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
Modified clay minerals on Mars
Sedimentary rocks exposed in Gale crater on Mars contain extensive clay minerals. Bristow
et al.
analyzed drill samples collected by the Curiosity rover as it climbed ...up sedimentary layers in the crater. They found evidence of past reactions with liquid water and sulfate brines, which could have percolated through the clay from an overlying sulfate deposit. Similar sulfate deposits are widespread across the planet and represent some of the last sedimentary rocks to form before the planet lost its surface liquid water, so the results inform our understanding of the geologic processes that occurred as Mars dried out.
Science, abg5449, this issue p.
198
Clay minerals examined by the Curiosity rover contain evidence of reactions with sulfate brines as Mars dried out.
Mars’ sedimentary rock record preserves information on geological (and potential astrobiological) processes that occurred on the planet billions of years ago. The
Curiosity
rover is exploring the lower reaches of Mount Sharp, in Gale crater on Mars. A traverse from Vera Rubin ridge to Glen Torridon has allowed
Curiosity
to examine a lateral transect of rock strata laid down in a martian lake ~3.5 billion years ago. We report spatial differences in the mineralogy of time-equivalent sedimentary rocks <400 meters apart. These differences indicate localized infiltration of silica-poor brines, generated during deposition of overlying magnesium sulfate–bearing strata. We propose that destabilization of silicate minerals driven by silica-poor brines (rarely observed on Earth) was widespread on ancient Mars, because sulfate deposits are globally distributed.
Curiosity investigated active eolian sands near linear dunes during Phase 2 of the Bagnold Dunes campaign in Gale crater, Mars. Ogunquit Beach, a sample scooped from a large‐ripple trough within the ...Mount Desert Island ripple field and delivered to the Chemistry and Mineralogy (CheMin) X‐ray diffraction instrument, is dominated by basaltic igneous minerals and X‐ray amorphous materials. CheMin mineralogy of the Gobabeb sample acquired at a large‐ripple crest on the Namib barchan dune during Phase 1 is similar to Ogunquit Beach. Ogunquit Beach, however, contains more plagioclase and Gobabeb contains more olivine. Compact Reconnaissance Imaging Spectrometer for Mars (CRISM)‐based estimates of mineralogy at the optical surface of Namib Dune and Mount Desert Island demonstrate that surface sands are enriched in olivine and depleted in plagioclase over Mount Desert Island relative to Namib Dune. Differences between CheMin‐derived and CRISM‐derived mineralogies suggest sorting by grain size on bedform to dune field scales. Crystal chemistry from CheMin suggests contributions from multiple igneous sources and the local bedrock.
Plain Language Summary
Remote sensing data from orbit indicate that wind‐blown sands in the Bagnold Dune Field in Gale crater, Mars, are sorted by their composition. The Mars Science Laboratory Curiosity rover studied the Bagnold Dune Field at two locations to investigate the chemical and mineral composition of the sands and why they are sorted across the dune field. Data from Curiosity show distinct differences between the minerals in the upwind portion of the dune field compared to the downwind portion, but these differences are not the same as those observed from orbit. The scale and location of the sampling by Curiosity compared to orbiters explains the discrepancy between the two techniques. Results from both techniques suggest subtle differences in mineralogy within a single dune and across the dune field that can be explained by sorting from wind and contribution from the erosion of local bedrock.
Key Points
The mineralogy of active eolian sands were measured by the Curiosity rover at two locations in the Bagnold Dune Field in Gale crater, Mars
X‐ray diffraction data from the CheMin instrument of two sand samples indicate differences in plagioclase and olivine abundances
The mineralogy derived from CheMin and CRISM can be used in concert to characterize sediment sorting and sources across the Bagnold Dunes
Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to ...lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
Vera Rubin ridge (VRR) is an erosion-resistant feature on the northwestern slope of Mount Sharp in Gale crater, Mars, and orbital visible/short-wave infrared measurements indicate it contains ...red-colored hematite. The Mars Science Laboratory Curiosity rover performed an extensive campaign on VRR to study its mineralogy, geochemistry, and sedimentology to determine the depositional and diagenetic history of the ridge and constrain the processes by which the hematite could have formed. X-ray diffraction (XRD) data from the CheMin instrument of four samples drilled on and below VRR demonstrate differences in iron, phyllosilicate, and sulfate mineralogy and hematite grain size. Hematite is common across the ridge, and its detection in a gray-colored outcrop suggested localized regions with coarse-grained hematite, which commonly forms from warm fluids. Broad XRD peaks for hematite in one sample below VRR and the abundance of FeOT in the amorphous component suggest the presence of nano-crystalline hematite and amorphous Fe oxides/oxyhydroxides. Well-crystalline akaganeite and jarosite are present in two samples drilled from VRR, indicating at least limited alteration by acid-saline fluids. Collapsed nontronite is present below VRR, but samples from VRR contain phyllosilicate with d(001) = 9.6 Å, possibly from ferripyrophyllite or an acid-altered smectite. The most likely cementing agents creating the ridge are hematite and opaline silica. We hypothesize late diagenesis can explain much of the mineralogical variation on the ridge, where multiple fluid episodes with variable pH, salinity, and temperature altered the rocks, causing the precipitation and crystallization of phases that are not otherwise in equilibrium.
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking ...nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite
, namely tyrosine RS (
YRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.
Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the ...efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT.
In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34).
Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 4% in the vaccine consistency lot group, and 29 5% in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 33% of 657 vs 181 33% of 554; risk difference 0·2%, 95% CI −5·1 to 5·5) and serious vaccine-related adverse events (five 1% vs five 1%; risk difference 0·1%, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 29% vs 36 7%; risk difference 22·6%, 95% CI 18·5–26·6; p<0·0001).
This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated.
Merck & Co., Inc.
Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to ...bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling.
Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants.
We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed.
We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6– and IL-11–dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane–proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome.
Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.
Display omitted
PDF
