Many genomes have been sequenced to high-quality draft status using Sanger capillary electrophoresis and/or newer short-read sequence data and whole genome assembly techniques. However, even the best ...draft genomes contain gaps and other imperfections due to limitations in the input data and the techniques used to build draft assemblies. Sequencing biases, repetitive genomic features, genomic polymorphism, and other complicating factors all come together to make some regions difficult or impossible to assemble. Traditionally, draft genomes were upgraded to "phase 3 finished" status using time-consuming and expensive Sanger-based manual finishing processes. For more facile assembly and automated finishing of draft genomes, we present here an automated approach to finishing using long-reads from the Pacific Biosciences RS (PacBio) platform. Our algorithm and associated software tool, PBJelly, (publicly available at https://sourceforge.net/projects/pb-jelly/) automates the finishing process using long sequence reads in a reference-guided assembly process. PBJelly also provides "lift-over" co-ordinate tables to easily port existing annotations to the upgraded assembly. Using PBJelly and long PacBio reads, we upgraded the draft genome sequences of a simulated Drosophila melanogaster, the version 2 draft Drosophila pseudoobscura, an assembly of the Assemblathon 2.0 budgerigar dataset, and a preliminary assembly of the Sooty mangabey. With 24× mapped coverage of PacBio long-reads, we addressed 99% of gaps and were able to close 69% and improve 12% of all gaps in D. pseudoobscura. With 4× mapped coverage of PacBio long-reads we saw reads address 63% of gaps in our budgerigar assembly, of which 32% were closed and 63% improved. With 6.8× mapped coverage of mangabey PacBio long-reads we addressed 97% of gaps and closed 66% of addressed gaps and improved 19%. The accuracy of gap closure was validated by comparison to Sanger sequencing on gaps from the original D. pseudoobscura draft assembly and shown to be dependent on initial reference quality.
We analyze 494 main sequence turnoff and subgiant stars from the AMBRE:HARPS survey. These stars have accurate astrometric information from Gaia DR1, providing reliable age estimates with relative ...uncertainties of ±1 or 2 Gyr and allowing precise orbital determinations. The sample is split based on chemistry into a low-Mg/Fe sequence, which are often identified as thin disk stellar populations, and high-Mg/Fe sequence, which are often associated with thick disk stellar populations. We find that the high-Mg/Fe chemical sequence has extended star formation for several Gyr and is coeval with the oldest stars of the low-Mg/Fe chemical sequence: both the low- and high-Mg/Fe sequences were forming stars at the same time. We find that the high-Mg/Fe stellar populations are only vertically extended for the oldest, most-metal poor and highest Mg/Fe stars. When comparing vertical velocity dispersion for the low- and high-Mg/Fe sequences, the high-Mg/Fe sequence has lower vertical velocity dispersion than the low-Mg/Fe sequence for stars of similar age. This means that identifying either group as thin or thick disk based on chemistry is misleading. The stars belonging to the high-Mg/Fe sequence have perigalacticons that originate in the inner disk, while the perigalacticons of stars on the low-Mg/Fe sequence are generally around the solar neighborhood. From the orbital properties of the stars, the high-Mg/Fe and low-Mg/Fe sequences are most likely a reflection of the chemical enrichment history of the inner and outer disk populations, respectively; radial mixing causes both populations to be observed in situ at the solar position. Based on these results, we emphasize that it is important to be clear in defining what populations are being referenced when using the terms thin and thick disk, and that ideally the term thick disk should be reserved for purely geometric definitions to avoid confusion and be consistent with definitions in external galaxies.
Analysing population genomic data from killer whale ecotypes, which we estimate have globally radiated within less than 250,000 years, we show that genetic structuring including the segregation of ...potentially functional alleles is associated with socially inherited ecological niche. Reconstruction of ancestral demographic history revealed bottlenecks during founder events, likely promoting ecological divergence and genetic drift resulting in a wide range of genome-wide differentiation between pairs of allopatric and sympatric ecotypes. Functional enrichment analyses provided evidence for regional genomic divergence associated with habitat, dietary preferences and post-zygotic reproductive isolation. Our findings are consistent with expansion of small founder groups into novel niches by an initial plastic behavioural response, perpetuated by social learning imposing an altered natural selection regime. The study constitutes an important step towards an understanding of the complex interaction between demographic history, culture, ecological adaptation and evolution at the genomic level.
The fourth version of the Community Climate System Model (CCSM4) was recently completed and released to the climate community. This paper describes developments to all CCSM components, and documents ...fully coupled preindustrial control runs compared to the previous version, CCSM3. Using the standard atmosphere and land resolution of 1° results in the sea surface temperature biases in the major upwelling regions being comparable to the 1.4°-resolution CCSM3. Two changes to the deep convection scheme in the atmosphere component result in CCSM4 producing El Niño–Southern Oscillation variability with a much more realistic frequency distribution than in CCSM3, although the amplitude is too large compared to observations. These changes also improve the Madden–Julian oscillation and the frequency distribution of tropical precipitation. A new overflow parameterization in the ocean component leads to an improved simulation of the Gulf Stream path and the North Atlantic Ocean meridional overturning circulation. Changes to the CCSM4 land component lead to a much improved annual cycle of water storage, especially in the tropics. The CCSM4 sea ice component uses much more realistic albedos than CCSM3, and for several reasons the Arctic sea ice concentration is improved in CCSM4. An ensemble of twentieth-century simulations produces a good match to the observed September Arctic sea ice extent from 1979 to 2005. The CCSM4 ensemble mean increase in globally averaged surface temperature between 1850 and 2005 is larger than the observed increase by about 0.4°C. This is consistent with the fact that CCSM4 does not include a representation of the indirect effects of aerosols, although other factors may come into play. The CCSM4 still has significant biases, such as the mean precipitation distribution in the tropical Pacific Ocean, too much low cloud in the Arctic, and the latitudinal distributions of shortwave and longwave cloud forcings.
Chemosensory-related gene (CRG) families have been studied extensively in insects, but their evolutionary history across the Arthropoda had remained relatively unexplored. Here, we address current ...hypotheses and prior conclusions on CRG family evolution using a more comprehensive data set. In particular, odorant receptors were hypothesized to have proliferated during terrestrial colonization by insects (hexapods), but their association with other pancrustacean clades and with independent terrestrial colonizations in other arthropod subphyla have been unclear. We also examine hypotheses on which arthropod CRG family is most ancient. Thus, we reconstructed phylogenies of CRGs, including those from new arthropod genomes and transcriptomes, and mapped CRG gains and losses across arthropod lineages. Our analysis was strengthened by including crustaceans, especially copepods, which reside outside the hexapod/branchiopod clade within the subphylum Pancrustacea. We generated the first high-resolution genome sequence of the copepod Eurytemora affinis and annotated its CRGs. We found odorant receptors and odorant binding proteins present only in hexapods (insects) and absent from all other arthropod lineages, indicating that they are not universal adaptations to land. Gustatory receptors likely represent the oldest chemosensory receptors among CRGs, dating back to the Placozoa. We also clarified and confirmed the evolutionary history of antennal ionotropic receptors across the Arthropoda. All antennal ionotropic receptors in E. affinis were expressed more highly in males than in females, suggestive of an association with male mate-recognition behavior. This study is the most comprehensive comparative analysis to date of CRG family evolution across the largest and most speciose metazoan phylum Arthropoda.
Summary Background In pancreatic ductal adenocarcinoma, the CCL2–CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. ...This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). Methods We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m2 , irinotecan 180 mg/m2 , leucovorin 400 mg/m2 , and bolus fluorouracil 400 mg/m2 , followed by 2400 mg/m2 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01413022. Results Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5–89·0) in the FOLFIRINOX alone group and 77·0 days (70·0–90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. Interpretation CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. Funding Washington University–Pfizer Biomedical Collaborative.
Abstract The transcription of genes that support memory processes are likely to be impacted by the normal aging process. Because Arc is necessary for memory consolidation and enduring synaptic ...plasticity, we examined Arc transcription within the aged hippocampus. Here, we report that Arc transcription is reduced within the aged hippocampus compared to the adult hippocampus during both “off line” periods of rest, and following spatial behavior. This reduction is observed within ensembles of CA1 “place cells”, which make less mRNA per cell, and in the dentate gyrus (DG) where fewer granule cells are activated by behavior. In addition, we present data suggesting that aberrant changes in methylation of the Arc gene may be responsible for age-related decreases in Arc transcription within CA1 and the DG. Given that Arc is necessary for normal memory function, these subregion-specific epigenetic and transcriptional changes may result in less efficient memory storage and retrieval during aging.
Assemblies of β-amyloid (Aβ) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by β-secretase (BACE1) ...and γ-secretase. The generation of Aβ is coupled to neuronal activity, but the molecular basis is unknown. Here, we report that the immediate early gene
Arc is required for activity-dependent generation of Aβ. Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both Hebbian and non-Hebbian forms of plasticity. The Arc-endosome also traffics APP and BACE1, and Arc physically associates with presenilin1 (PS1) to regulate γ-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces Aβ load in a transgenic mouse model of AD. In concert with the finding that patients with AD can express anomalously high levels of Arc, we hypothesize that Arc participates in the pathogenesis of AD.
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► Arc is required for activity-dependent generation of Aβ ► Arc directly binds to Presenilin1 to regulate γ-secretase trafficking ► Genetic deletion of Arc reduces Aβ load in a mouse model of AD ► Arc level is increased in medial frontal cortex of patients with AD
The trafficking pathway that enables synaptic plasticity brings together the Aβ precursor proteins and its processing enzyme.
Abstract
We study the chemical evolution of the thick and thin discs of the Galaxy by comparing detailed chemical evolution models with recent data from the Archéologie avec Matisse Basée sur les ...aRchives de l'ESO project. The data suggest that the stars in the thick and thin discs form two distinct sequences with the thick disc stars showing higher α/Fe ratios. We adopt two different approaches to model the evolution of thick and thin discs. In particular, we adopt (i) a two-infall approach where the thick disc forms fast and before the thin disc and by means of a fast gas accretion episode, whereas the thin disc forms by means of a second accretion episode on a longer time-scale; (ii) a parallel approach, where the two discs form in parallel but at different rates. By comparing our model results with the observed Mg/Fe versus Fe/H and the metallicity distribution functions in the two Galactic components, we conclude that the parallel approach can account for a group of α-enhanced metal-rich stars present in the data, whereas the two-infall approach cannot explain these stars unless they are the result of stellar migration. In both approaches, the thick disc has formed on a time-scale of accretion of 0.1 Gyr, whereas the thin disc formed on a time-scale of 7 Gyr in the solar region. In the two-infall approach, a gap in star formation between the thick and thin disc formation of several hundreds of Myr should be present, at variance with the parallel approach where no gap is present.
Context. The chemical evolution of lithium in the Milky Way represents a major problem in modern astrophysics. Indeed, lithium is, on the one hand, easily destroyed in stellar interiors, and, on the ...other hand, produced at some specific stellar evolutionary stages that are still not well constrained. Aims. The goal of this paper is to investigate the lithium stellar content of Milky Way stars in order to put constraints on the lithium chemical enrichment in our Galaxy, in particular in both the thin and thick discs. Methods. Thanks to high-resolution spectra from the ESO archive and high quality atmospheric parameters, we were able to build a massive and homogeneous catalogue of lithium abundances for 7300 stars derived with an automatic method coupling, a synthetic spectra grid, and a Gauss-Newton algorithm. We validated these lithium abundances with literature values, including those of the Gaia benchmark stars. Results. In terms of lithium galactic evolution, we show that the interstellar lithium abundance increases with metallicity by 1 dex from M/H = −1 dex to + 0.0 dex. Moreover, we find that this lithium ISM abundance decreases by about 0.5 dex at super-solar metalllicity. Based on a chemical separation, we also observed that the stellar lithium content in the thick disc increases rather slightly with metallicity, while the thin disc shows a steeper increase. The lithium abundance distribution of α-rich, metal-rich stars has a peak at ALi ~ 3 dex. Conclusions. We conclude that the thick disc stars suffered of a low lithium chemical enrichment, showing lithium abundances rather close to the Spite plateau while the thin disc stars clearly show an increasing lithium chemical enrichment with the metallicity, probably thanks to the contribution of low-mass stars.
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