3,616 research outputs found

    Emergence of a STAT3 mutated NK clone in LGL leukemia

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    AbstractLarge granular lymphocyte (LGL) leukemia is a chronic clonal lymphoproliferative disorder. Here, a T-LGL leukemia patient developed NK-LGL leukemia with residual leukemic T-LGL. TCRVβ usage and CDR3 sequence drifts were observed with disease progression. A STAT3 S614R mutation was identified in NK but not T-cells in the mixed leukemic stage. Multiple, non-dominant T-cell clones with distinct STAT3 mutations were present throughout. Our results suggest that T and NK-LGL leukemia may share common pathogenesis mechanisms and that STAT3 mutation alone is insufficient to bring about clonal expansion. Mutational and immunological monitoring may provide diagnostic and therapeutic significance in LGL leukemia

    Shifts in Southern Wisconsin Forest Canopy and Understory Richness, Composition, and Heterogeneity

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    We resurveyed the under- and overstory species composition of 94 upland forest stands in southern Wisconsin in 2002–2004 to assess shifts in canopy and understory richness, composition, and heterogeneity relative to the original surveys in 1949–1950. The canopy has shifted from mostly oaks (Quercus spp.) toward more mesic and shade-tolerant trees (primarily Acer spp.). Oak-dominated early-successional stands and those on coarse, nutrient-poor soils changed the most in canopy composition. Understories at most sites (80%) lost native species, with mean species density declining 25% at the 1-m2 scale and 23.1% at the 20-m2 scale. Woody species have increased 15% relative to herbaceous species in the understory despite declining in absolute abundance. Initial canopy composition, particularly the abundance of red oaks (Quercus rubra and Q. velutina), predicted understory changes better than the changes observed in the overstory. Overall rates of native species loss were greater in later-successional stands, a pattern driven by differential immigration rather than differential extirpation. However, understory species initially found in early-successional habitats declined the most, particularly remnant savanna taxa with narrow or thick leaves. These losses have yet to be offset by compensating increases in native shade-adapted species. Exotic species have proliferated in prevalence (from 13 to 76 stands) and relative abundance (from 1.2% to 8.4%), but these increases appear unrelated to the declines in native species richness and heterogeneity observed. Although canopy succession has clearly influenced shifts in understory composition and diversity, the magnitude of native species declines and failure to recruit more shade-adapted species suggest that other factors now act to limit the richness, heterogeneity, and composition of these communities

    Stability of Monomer-Dimer Piles

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    We measure how strong, localized contact adhesion between grains affects the maximum static critical angle, theta_c, of a dry sand pile. By mixing dimer grains, each consisting of two spheres that have been rigidly bonded together, with simple spherical monomer grains, we create sandpiles that contain strong localized adhesion between a given particle and at most one of its neighbors. We find that tan(theta_c) increases from 0.45 to 1.1 and the grain packing fraction, Phi, decreases from 0.58 to 0.52 as we increase the relative number fraction of dimer particles in the pile, nu_d, from 0 to 1. We attribute the increase in tan(theta_c(nu_d)) to the enhanced stability of dimers on the surface, which reduces the density of monomers that need to be accomodated in the most stable surface traps. A full characterization and geometrical stability analysis of surface traps provides a good quantitative agreement between experiment and theory over a wide range of nu_d, without any fitting parameters.Comment: 11 pages, 12 figures consisting of 21 eps files, submitted to PR

    A Leptin-regulated Circuit Controls Glucose Mobilization During Noxious Stimuli

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    Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor–expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores

    Isotope Effect in Electron-Capture Differential Cross Sections at Intermediate Energies

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    The isotope dependence in the angular distribution of electron-capture cross sections for protons and deuterons with equal velocity (E=40 keV/u) colliding with atomic hydrogen or deuterium targets is predicted theoretically and observed experimentally. A projectile-dependent effect is observed at small scattering angles. No target dependence was detected in the differential cross sections. A scaling relationship is determined which permits the prediction of differential cross sections for hydrogen-isotope projectiles

    Somatic STAT3 mutations in Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia

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    Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3, which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8(+) T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that ten of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.Peer reviewe

    Tissue-specific expression of high-voltage-activated dihydropyridine-sensitive L-type calcium channels

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    The cloning of the cDNA for the α1 subunit of L-type calcium channels revealed that at least two genes (CaCh1 and CaCh2) exist which give rise to several splice variants. The expression of mRNA for these α1 subunits and the skeletal muscle α2/δ, β and γ subunits was studied in rabbit tissues and BC3H1 cells. Nucleic-acid-hybridization studies showed that the mRNA of all subunits are expressed in skeletal muscle, brain, heart and aorta. However, the α1-, β- and γ-specific transcripts had different sizes in these tissues. Smooth muscle and heart contain different splice variants of the CaCh2 gene. The α1, β and γ mRNA are expressed together in differentiated but not in proliferating BC3H1 cells. A probe specific for the skeletal muscle α2/δ subunit did not hybridize to poly(A)-rich RNA from BC3H1 cells. These results suggest that different splice variants of the genes for the α1, β and γ subunits exist in tissues containing L-type calcium channels, and that their expression is regulated in a coordinate manner

    The Crystal Structure of CHIR-AB1: A Primordial Avian Classical Fc Receptor

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    CHIR-AB1 is a newly identified avian immunoglobulin (Ig) receptor that includes both activating and inhibitory motifs and was therefore classified as a potentially bifunctional receptor. Recently, CHIR-AB1 was shown to bind the Fc region of chicken IgY and to induce calcium mobilization via association with the common γ-chain, a subunit that transmits signals upon ligation of many different immunoreceptors. Here we describe the 1.8-Å-resolution crystal structure of the CHIR-AB1 ectodomain. The receptor ectodomain consists of a single C2-type Ig domain resembling the Ig-like domains found in mammalian Fc receptors such as FcγRs and FcαRI. Unlike these receptors and other monomeric Ig superfamily members, CHIR-AB1 crystallized as a 2-fold symmetrical homodimer that bears no resemblance to variable or constant region dimers in an antibody. Analytical ultracentrifugation demonstrated that CHIR-AB1 exists as a mixture of monomers and dimers in solution, and equilibrium gel filtration revealed a 2:1 receptor/ligand binding stoichiometry. Measurement of the 1:1 CHIR-AB1/IgY interaction affinity indicates a relatively low affinity complex, but a 2:1 CHIR-AB1/IgY interaction allows an increase in apparent affinity due to avidity effects when the receptor is tethered to a surface. Taken together, these results add to the structural understanding of Fc receptors and their functional mechanisms

    Ontogeny of synaptophysin and synaptoporin in the central nervous system

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    The expression of the synaptic vesicle antigens synaptophysin (SY) and synaptoporin (SO) was studied in the rat striatum, which contains a nearly homogeneous population of GABAergic neurons. In situ hybridization revealed high levels of SY transcripts in the striatal anlage from embryonic day (E) 14 until birth. In contrast. SO hybridization signals were low, and no immunoreactive cell bodies were detected at these stages of development. At E 14, SY-immunoreactivity was restricted to perikarya. In later prenatal stages of development SY-immunoreactivity appeared in puncta (identified as terminals containing immunostained synaptic vesicles), fibers, thick fiber bundles and ‘patches’. In postnatal and adult animals, perikarya of striatal neurons exhibited immunoreaction for SO; ultrastructurally SO antigen was found in the Golgi apparatus and in multivesicular bodies. SO-positive boutons were rare in the striatum. In the neuropil, numerous presynaptic terminals positive for SY were observed. Our data indicate that the expression of synaptic vesicle proteins in GABAergic neurons of the striatum is developmentally regulated. Whereas SY is prevalent during embryonic development, SO is the major synaptic vesicle antigen expressed postnatally by striatal neurons which project to the globus pallidus and the substantia nigra. In contrast synapses of striatal afferents (predominantly from cortex, thalamus and substantia nigra) contain SY

    Magnetic Fields in Earth-like Exoplanets and Implications for Habitability around M-dwarfs

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    We present estimations of dipolar magnetic moments for terrestrial exoplanets using the Olson & Christiansen (2006) scaling law and assuming their interior structure is similar to Earth. We find that the dipolar moment of fast rotating planets (where the Coriolis force dominates convection in the core), may amount up to ~80 times the magnetic moment of Earth, M_Earth, for at least part of the planets' lifetime. For very slow rotating planets (where the force of inertia dominates), the dipolar magnetic moment only reaches up to ~1.5 M_Earth. Applying our calculations to currently confirmed rocky exoplanets, we find that CoRoT-7b, Kepler-10b and 55 Cnc e can sustain dynamos up to ~ 18, 15 and 13 M_Earth, respectively. Our results also indicate that the magnetic moment of rocky exoplanets not only depends on their rotation rate, but also on their formation history, thermal state, age and composition, as well as the geometry of the field. These results apply to all rocky planets, but have important implications for the particular case of exoplanets in the Habitable Zone of M-dwarfs.Comment: 4 pages, 1 figure, to appear in the Origins 2011 ISSOL & IAU Meeting Conference Proceedings, Montpellier, France, July 3-8 201
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