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  • 1
    Publication Date: 2016-11-01
    Description: Histone methylation by lysine methyltransferase enzymes regulate the expression of genes implicated in lineage specificity and cellular differentiation. While it is known that Set7 catalyzes mono-methylation of histone and non-histone proteins, the functional importance of this enzyme in stem cell differentiation remains poorly understood. We show Set7 expression is increased during mouse embryonic stem cell (mESC) differentiation and is regulated by the pluripotency factors, Oct4 and Sox2. Transcriptional network analyses reveal smooth muscle (SM) associated genes are subject to Set7-mediated regulation. Furthermore, pharmacological inhibition of Set7 activity confirms this regulation. We observe Set7-mediated modification of serum response factor (SRF) and mono-methylation of histone H4 lysine 4 (H3K4me1) regulate gene expression. We conclude the broad substrate specificity of Set7 serves to control key transcriptional networks in embryonic stem cells.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 2
    Publication Date: 2014-10-15
    Description: The alternative adaptive immune system of jawless vertebrates is based on different isotypes of variable lymphocyte receptors (VLRs) that are composed of leucine-rich repeats (LRRs) and expressed by distinct B- and T-like lymphocyte lineages. VLRB is expressed by B-like cells, whereas VLRA and VLRC are expressed by two T-like lineages...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2013-09-11
    Description: Jawless vertebrates (cyclostomes) have an alternative adaptive immune system in which lymphocytes somatically diversify their variable lymphocyte receptors (VLR) through recombinatorial use of leucine-rich repeat cassettes during VLR gene assembly. Three types of these anticipatory receptors in lampreys (VLRA, VLRB, and VLRC) are expressed by separate lymphocyte lineages. However, only...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
    Publication Date: 2013-03-23
    Description: Mutations in genes in the retinal pigment epithelium (RPE) cause or contribute to debilitating ocular diseases, including Leber's congenital amaurosis (LCA). Genetic therapies, particularly adeno-associated viruses (AAVs), are a popular choice for monogenic diseases; however, the limited payload capacity of AAVs combined with the large number of retinal disease genes exceeding that capacity make the development of alternative delivery methods critical. Here, we test the ability of compacted DNA nanoparticles (NPs) containing a plasmid with a scaffold matrix attachment region (S/MAR) and vitelliform macular dystrophy 2 (VMD2) promoter to target the RPE, drive long-term, tissue-specific gene expression and mediate proof-of-principle rescue in the rpe65 –/– model of LCA. We show that the S/MAR-containing plasmid exhibited reporter gene expression levels several fold higher than plasmid or NPs without S/MARs. Importantly, this expression was highly persistent, lasting up to 2 years (last timepoint studied). We therefore selected this plasmid for testing in the rpe65 –/– mouse model and observe that NP or plasmid VMD2-hRPE65-S/MAR led to structural and functional improvements in the LCA disease phenotype. These results indicate that the non-viral delivery of hRPE65 vectors can result in persistent, therapeutically efficacious gene expression in the RPE.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 5
    Publication Date: 2012-12-06
    Description: Laurentianite, [NbO(H 2 O)] 3 (Si 2 O 7 ) 2 [Na(H 2 O) 2 ] 3 , is a new mineral discovered in siderite-dominant pods in an altered syenite at the Poudrette quarry, Mont Saint-Hilaire, Quebec. Crystals are colorless, acicular, euhedral, and elongate along [001] with average dimensions of 0.012 x 0.012 x 0.25 mm. The mineral generally occurs in loose, randomly oriented groupings (‘nests’) of crystals. Associated minerals include quartz, pyrite, franconite, rutile, lepidochrocite, and an unidentified Fe-bearing mineral. Laurentianite is transparent to translucent with a vitreous luster and is non-fluorescent under long-, medium-, and short-wave radiation. The Mohs hardness could not be measured owing to the small size of the crystals. No partings or cleavages were observed, although crystals do exhibit a splintery fracture. The calculated density is 2.464 g/cm 3 . Laurentianite is nonpleochroic and uniaxial negative, with 1.612(2) and 1.604(2). The average of 12 analyses from several crystals is: Na 2 O 8.88 (4.54–12.80), K 2 O 0.26 (0.14–0.44), CaO 0.22 (0.10–0.43), TiO 2 0.58 (0.31–0.83), Nb 2 O 5 43.64 (36.43–49.90), SiO 2 26.87 (22.81–29.07), and H 2 O (calc.) 17.93, total 98.38 wt.% on the basis of 26 anions, corresponding to [(Nb 0.99 Ti 0.01 ) 1.00 O(H 2 O)] 3 (Si 2.00 O 7 ) 2 [(Na 0.86 0.10 K 0.02 Ca 0.01 ) 0.99 (H 2 O) 2 ] 3 or, ideally, [NbO(H 2 O)] 3 (Si 2 O 7 ) 2 [Na(H 2 O) 2 ] 3 . The presence of H 2 O in laurentianite is inferred from Raman spectroscopy and results from refinement of the crystal structure. The mineral crystallizes in space group P 3 (#143) with a 9.937(1), c 7.004(1) Å, V 599.0(1) Å 3 , and Z = 1. The strongest six lines on the X-ray powder-diffraction pattern [ d in Å (I) ( hkl )] are: 8.608 (100) (010), 7.005 (19) (001), 4.312 (25) (020), 3.675 (25) (201, 021), 3.260 (31) (120, 210), and 2.870 (20) (030). The crystal structure of laurentianite, refined to R = 2.78% for 2347 reflections ( F o 〉 4 F o ) contains one Na , two Nb , and four Si sites. The two Nb sites are coordinated in distorted Nb O 5 (H 2 O) octahedra, with four equatorial bonds of typical Nb–O bond distances (~2 Å) and two highly asymmetric ones (one long, ~2.5 Å and one short, ~1.8 Å). Each site is each only partially occupied (~50%) and because of the short distance between them (~0.7 Å), they are not simultaneously occupied. A novel cation-anion coordination scheme involving the apical oxygens, Nb, and disordered H 2 O groups is developed: when one of the Nb sites is occupied, the other is vacant, resulting in one of the apical O sites being occupied by O 2– and the other by H 2 O. The opposite situation occurs when the occupancy and vacancy of the Nb sites are reversed, leading to both apical O sites having an equal, mixed (O 2– /H 2 O) composition. A minor charge understaturation at both apical O sites is remedied by each of these O sites receiving a single H-bond from one of the H 2 O groups associated with the Na cation. The crystal structure of laurentianite is based on five-membered pinwheels of composition [Nb 3 Si 2 O 17 (H 2 O) 3 ] –11 , consisting of three Nb O 5 (H 2 O) octahedra linked to two SiO 4 tetrahedra. Individual Nb–Si pinwheels are attached to form a layer composed of 18-membered rings of composition [Nb 6 Si 12 O 54 (H 2 O) 6 ] 30– perpendicular to [001]. The crystal structure is also layered along [001], with a silicate layer composed of (Si 2 O 7 ) dimers and a layer of isolated Nb O 5 (H 2 O) octahedra. Sodium atoms are positioned within the silicate layer, occupying sites that almost directly overly the Nb sites but are displaced ~ z + 1/2. Laurentianite is a late-stage mineral intergrown with lepidocrocite, both of which overgrow franconite and quartz. The mineral is believed to have precipitated from a late-stage aqueous fluid enriched in Na, Si, and Nb, possibly arising through the breakdown of franconite, sodalite, and quartz.
    Print ISSN: 0008-4476
    Topics: Geosciences
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  • 6
    Publication Date: 2012-06-01
    Description: Krásnoite is a new mineral (IMA2011-040) from the Huber open pit, Krásno ore district, Czech Republic and the Silver Coin mine, Nevada, USA. Krásnoite is the fluorophosphate analogue of perhamite. Krásnoite occurs as compact to finely crystalline aggregates, balls and rosette-like clusters up to 1 mm across. Individual crystals are platy, show a hexagonal outline and can reach 0.1 mm on edge at Krásno and 0.4 mm at Silver Coin. At both localities, krásnoite occurs very late in phosphaterich paragenetic sequences. Krásnoite crystals are partly transparent with a typically pearly lustre, but can also appear greasy (Krásno) or dull (Silver Coin). The streak is white and the hardness is 5 on the Mohs scale. Crystals are brittle, have an irregular fracture, one imperfect cleavage on {001} and are not fluorescent under SW and LW ultraviolet light. Penetration twinning ⊥ {001} is common. The density for both Krásno and Silver Coin material is 2.48(4) g cm−3, measured by the sink–float method in an aqueous solution of sodium polytungstate. The calculated density is 2.476 g cm−3 (Krásno). Krásnoite crystals are uniaxial (+), with ω = 1.548(2) and ϵ = 1.549(2) (Krásno) and ω = 1.541(1) and ϵ = 1.543(1) (Silver Coin). The simplified formula of krásnoite is: Ca3Al7.7Si3P4O23.5(OH)12.1F2·8H2O. Krásnoite is trigonal, space group P3İm1, with a = 6.9956(4), c = 20.200(2) Å, V = 856.09(9) Å3 and Z = 3. Raman and infrared spectroscopy, coupled with magic-angle spinning nuclear magnetic resonance (MAS–NMR) spectrometry, confirmed the presence of PO3F, PO4, SiO4, H2O and OH in the crystal structure of krásnoite.
    Print ISSN: 0026-461X
    Electronic ISSN: 1471-8022
    Topics: Geosciences
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  • 7
    Publication Date: 2014-06-04
    Description: If climate change outpaces the rate of adaptive evolution within a site, populations previously well adapted to local conditions may decline or disappear, and banked seeds from those populations will be unsuitable for restoring them. However, if such adaptational lag has occurred, immigrants from historically warmer climates will outperform natives...
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 8
    Publication Date: 2018-03-12
    Description: Geology is, in essence, the history of the Earth, and any history depends on dates and rates.  Geochronology supplies these. A new book, Geochronology and Thermochronology , recently published by the American Geophysical Union, presents the current state of this science including its concepts, approaches, methods, and applications. Here, the authors answer some questions about the science of geochronology and its relevance, and describe how this field has evolved. What is the role of geochronology in Earth and planetary sciences? The Earth and planetary sciences are fundamentally interwoven with the importance of time. Understanding the basic workings of our Solar System requires knowledge of the evolution of the constituent planets and their interactions. This in turn requires sequencing events far back in time, orders of magnitude beyond the scope of human history. The Paria River, a slot canyon carved by fluvial incision in northern Arizona. Geochronology and thermochronology provide key understanding of the timing and rate of uplift of the Colorado Plateau that drove incision of its rivers such as the Paria and Colorado. Credit: Peter Reiners Geochronology expressly fills this need, often providing the key to causality hypotheses linking various phenomena in the distant prehistoric past. Many basic discoveries, from the theory of plate tectonics to the antiquity of our own species, were made possible by geochronology. Such discoveries are ongoing, as geochronology plays a key role in, for example, linking major extinctions of Earth’s biota to large meteoroid impacts and massive volcanic episodes. In such cases, causality requires temporal coincidence, which is what geochronology can establish (or refute). Geochronology and the related discipline of thermochronology are also invaluable to determining the rates at which processes happen; for example, the rates at which species evolve or become extinct. Ultimately, understanding the mechanisms and rates of various modes of planetary evolution enable humankind to better anticipate future events affecting our planet and beyond. What are some examples of the application of geochronology? Want to know when the Solar System formed? Uranium-lead ages for the first mineral grains to condense from the hot gases surrounding the proto-Sun date that event at 4.5675 billion years ago. Want more resolution on this time? The 700,000-year half-life for radioactive decay of 26-aluminum to 26-magnesium can provide relative ages with precision of tens of thousands of years for events occurring close to the time of Solar System formation. Want to know when Earth’s core formed? The 9-million-year half-life for decay of 182-hafnium to 182-tungsten dates that event to within the first 30-100 million years of Solar System history, depending on the duration and mechanism of core formation. Want to know what’s the oldest mineral found on Earth? Grains of the mineral zircon from sediments in western Australia have been dated using uranium-lead to 4.37 billion years. Want to know the rate of sedimentation in a Precambrian sedimentary basin? Either zircon uranium-lead or rhenium-osmium can provide the answer, depending on the type of sediment. Want to know the rate of biological evolution? A variety of geochronologic methods now place precise absolute dates on the boundaries of the geologic time scale that historically were marked by the appearance or disappearance of certain types of fossils. Geologists Jay Quade and Kendra Murray sample volcanic ash deposits in the Atacama Desert, Chile to determine the age of sedimentary rocks bearing a record of tectonic processes in the Central Andes. Credit: Peter Reiners Want to know where the magmas erupted from volcanoes come from? Uranium-series dating tells us their sources, ascent rates, and residence times in magma chambers. Want to know the uplift or erosion rate of a terrane? Uranium-helium in apatite can date the time when a rock cooled below 60 degrees Celsius, and cosmogenic nuclides created by the impact of cosmic rays on surface materials can be used to determine the rates of removal of surface layers from rocks or sediments. What is the specific focus of thermochronology? Thermochronology is a type of geochronology based on the fact that, in some minerals, some daughter products produced by radioactive decay are not fully retained in crystals until these crystals have cooled to low temperatures. The “closure temperature” at which this full retention starts depends on the decay system (for example, uranium to lead, potassium to argon, etc.), and the type of mineral. Examples include the uranium-lead system in titanite, the potassium-argon system in biotite mica, and the uranium-helium system in apatite, which have closure temperatures of about 600, 300, and 60 degrees Celsius, respectively. If we measure ages of these minerals/systems in the same rock, we can map out the time-temperature path (thermal history) of a rock. This is useful for many applications, including understanding when and how fast rocks get to Earth’s surface by faulting or erosion during mountain-building, when metamorphism deep in the crust occurs, or when surficial events like meteorite impacts or wildfires occurred in the past. How has discipline of geochronology developed and advanced over the last century? Geochronology in its nascent years was mainly the playground of physicists using homemade instruments and methods. Today, the field is mainly populated by geoscientists using commercially available equipment and common protocols to analyze rocks and other materials. Cathodoluminescence images of zircon crystals from igneous rocks of the Cornucopia Stock in northeastern Oregon. Geochronology and thermochronology of zircon provides some of the most precise and accurate ages of Earth materials, as well as their thermal histories. Credit: Peter Reiners Progress in geochronology has evolved along several interrelated tracks in the last century. The most fundamental is conceptual, beginning with the discovery of radioactivity, which allowed sequences of events and roughly estimated times to be quantified. Remarkably, this enabled rudimentary geochronology (and actually foreshadowed thermochronology) even before the discovery of the neutron, which in turn led to the recognition of isotopes and major conceptual refinements in the field as well as analytical methods such as mass spectrometry. Another major area of progress has been technical, notably accelerated by the invention of mass spectrometers that have undergone continuous refinement in terms of stability, sensitivity, and throughput over the past half-century. These technical developments have enabled increasingly large quantities of data, of increasingly better quality from ever-smaller samples, to be obtained. A third avenue of progress, driven in part by the burgeoning data quality and volume occasioned by technical advances such as process automation, has been in data analysis and calibration. Our knowledge of radioisotopes’ half-lives is now in many cases the accuracy-limiting step in geochronology, and new measurements are ongoing to further improve this situation. Also ongoing are developments of numerical techniques for translating isotope measurements into ages and meaningful uncertainties in these ages. Measurements of diffusion parameters needed for thermochronology, and of cosmogenic production rates needed for cosmogenic nuclide dating, have dramatically strengthened these applications and are undergoing continuous refinement today. What are some of the most exciting new techniques in the field? Refinements in uranium-lead dating of zircon can date crystallization ages to better than 0.01%.  Similar precision can be obtained with modern argon-argon techniques on young volcanic rocks. The use of a number of radioactive isotopes that were present when the Solar System formed, but have half-lives much shorter than the age of the Earth, now allow precise resolution of the events that were occurring in the first five million years or so of Solar System history when the planets, including Earth, formed. While once abandoned as “leaky” geochronometers, the accumulation of helium from uranium and thorium decay has been turned into a versatile thermochronometer that can be used to measure the timing and rates of cooling of rocks to temperatures close to the Earth’s surface. The use of cosmogenic isotopes, those generated by interaction of Earth’s surface with cosmic rays, allows wide ranging applications from archeology, to paleoseismology, to studies of landscape evolution. Another technique experiencing exciting growth is dating nucleogenic neon, which forms as a by-product of uranium and thorium decay, and is opening up opportunities for dating minerals including some types of hydrothermal ores that have been difficult or impossible to date by other means. Geochronology and thermochronology are dynamic fields whose capabilities and range of applications will continue to expand for the foreseeable future. Geochronology and Thermochronology , 2017, 480pp., ISBN: 978-1-118-45585-2, list price $150 (hardcover), $100 (paperback), $80.99 (e-book) —Peter W. Reiners, University of Arizona: email: reiners@email.arizona.edu; Richard W. Carlson, Carnegie Institution for Science; Paul R. Renne, Berkeley Geochronology Center and University of California; Kari M. Cooper, University of California, Davis; Darryl E. Granger, Purdue University; Noah M. McLean, University of Kansas; and Blair Schoene, Princeton University The post The Science of Dates and Rates appeared first on Eos .
    Print ISSN: 0096-3941
    Electronic ISSN: 2324-9250
    Topics: Geosciences
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  • 9
    Publication Date: 2018-01-05
    Description: Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy ( n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples ( n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity ( P 〈 0.01) and relative abundance of bacteria of the Ruminococcaceae family ( P 〈 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
    Keywords: Immunology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2018-02-10
    Description: Cell response to matrix rigidity has been explained by the mechanical properties of the actin-talin-integrin-fibronectin clutch. Here the molecular clutch model is extended to account for cell interactions with purely viscous surfaces (i.e., without an elastic component). Supported lipid bilayers present an idealized and controllable system through which to study...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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