Division IX: Optical and Infrared Techniques Sterken, Christiaan; Hearnshaw, John B.; Cullum, Martin ...
Proceedings of the International Astronomical Union,
12/2005, Letnik:
1, Številka:
T26A
Journal Article
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This document introduces the reports by the Commissions and Working Groups of Division IX.
Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some ...cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.
Cloud and aerosol data acquired by the National Research Council of Canada (NRC) Convair‐580 aircraft in, above, and below single‐layer arctic stratocumulus cloud during the Indirect and Semi‐Direct ...Aerosol Campaign (ISDAC) in April 2008 were used to test three aerosol indirect effects hypothesized to act in mixed‐phase clouds: the riming indirect effect, the glaciation indirect effect, and the thermodynamic indirect effect. The data showed a correlation of R = 0.78 between liquid drop number concentration, Nliq inside cloud and ambient aerosol number concentration NPCASP below cloud. This, combined with increasing liquid water content LWC with height above cloud base and the nearly constant vertical profile of Nliq, suggested that liquid drops nucleated from aerosol at cloud base. No evidence of a riming indirect effect was observed, but a strong correlation of R = 0.69 between ice crystal number concentration Ni and NPCASP above cloud was noted. Increases in ice nuclei (IN) concentration with NPCASP above cloud for 2 flight dates combined with the subadiabatic LWC profiles suggest possible mixing of IN from cloud top consistent with the glaciation indirect effect. The lower Nice and lower effective radius rel for the more polluted ISDAC cases compared to data collected in cleaner single‐layer stratocumulus conditions during the Mixed‐Phase Arctic Cloud Experiment is consistent with the operation of the thermodynamic indirect effect. However, more data in a wider variety of meteorological and surface conditions, with greater variations in aerosol forcing, are required to identify the dominant aerosol forcing mechanisms in mixed‐phase arctic clouds.
Key Points
In entrainment from above arctic clouds may enhance ice crystal concentration
No strong evidence for a riming indirect effect was found
Thermodynamic indirect effect is consistent with ISDAC and M‐PACE
NASA's Navigator Program comprises a suite of interrelated missions that will discover and characterize planetary systems and Earth-like planets around nearby stars. The missions are designed to ...build on each other's success, each providing an essential step forward toward the goal of discovering habitable planets and life. The missions in the Navigator Program and their relation to each other are described in this paper. Moreover, the Program is described in the wider context of international efforts in the broadening field of extrasolar planet research. Science priorities and research opportunities related to the Navigator Program are also described
Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for ...lineage tracing
. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.
The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans
. Comparative analyses can shed light on the diversity of mutagenesis across species, and on ...long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans
, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.
The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (
= 1914 microbiopsies), ...whole-exome (
= 655), and whole-genome (
= 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.
Planetary rovers can use onboard data analysis to adapt their measurement plan on the fly, improving the science value of data collected between commands from Earth. This paper describes the ...implementation of an adaptive sampling algorithm used by PIXL, the X-ray fluorescence spectrometer of the Mars 2020 Perseverance rover. PIXL is deployed using the rover arm to measure X-ray spectra of rocks with a scan density of several thousand points over an area of typically 5 x 7 mm. The adaptive sampling algorithm is programmed to recognize points of interest and to increase the signal-to-noise ratio at those locations by performing longer integrations. Two approaches are used to formulate the sampling rules based on past quantification data: 1) Expressions that isolate particular regions within a ternary compositional diagram, and 2) Machine learning rules that threshold for a high weight percent of particular compounds. The design of the rulesets are outlined and the performance of the algorithm is quantified using measurements from the surface of Mars. To our knowledge, PIXL's adaptive sampling represents the first autonomous decision-making based on real-time compositional analysis by a spacecraft on the surface of another planet.
Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and ...disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.
Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we ...studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B-expressing macrophages, offering a potential therapeutic target.
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•Single-cell and spatial sequencing reveals key features of renal cell carcinoma (RCC)•Intra-tumoral heterogeneity of CD8+ clonotypes dwarfs that from somatic mutations•RCC cells showing epithelial-mesenchymal transition (EMT) enrich at tumor edges•Macrophages expressing IL1B correlate with EMT and could have therapeutic importance
Li et al. use single-cell and spatial sequencing to examine the cellular features of kidney tumors and classify cancer cells according to function. They find a more invasive phenotype at the interface separating tumor with normal kidney, which appears to be driven by IL-1β signaling in macrophages.
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