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  • Wiley-Blackwell  (125,848)
  • International Union of Crystallography (IUCr)  (13,105)
  • 2015-2019  (2,569)
  • 1990-1994  (73,232)
  • 1970-1974  (35,299)
  • 1965-1969  (27,853)
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  • 1
    facet.materialart.
    Unknown
    International Union of Crystallography (IUCr)
    In: IUCrJ
    Publication Date: 2018-12-19
    Description: The defect structure of γ-Al2O3 derived from boehmite was investigated using a combination of selected-area electron diffraction (SAED) and powder X-ray diffraction (XRD). Both methods confirmed a strong dependence of the diffraction line broadening on the diffraction indices known from literature. The analysis of the SAED patterns revealed that the dominant structure defects in the spinel-type γ-Al2O3 are antiphase boundaries located on the lattice planes (00l), which produce the sublattice shifts {{1}\over{4}}\langle 10{\overline 1}\rangle. Quantitative information about the defect structure of γ-Al2O3 was obtained from the powder XRD patterns. This includes mainly the size of γ-Al2O3 crystallites and the density of planar defects. The correlation between the density of the planar defects and the presence of structural vacancies, which maintain the stoichiometry of the spinel-type γ-Al2O3, is discussed. A computer routine running on a fast graphical processing unit was written for simulation of the XRD patterns. This routine calculates the atomic positions for a given kind and density of planar defect, and simulates the diffracted intensities with the aid of the Debye scattering equation.
    Keywords: γ-aluminamicrostructure defectsantiphase boundariesrotational boundariesselected-area electron diffractionpowder X-ray diffractionDebye equationanisotropic broadening
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 2
    Publication Date: 2018-11-19
    Description: β-Propeller proteins form one of the largest families of protein structures, with a pseudo-symmetrical fold made up of subdomains called blades. They are not only abundant but are also involved in a wide variety of cellular processes, often by acting as a platform for the assembly of protein complexes. WD40 proteins are a subfamily of propeller proteins with no intrinsic enzymatic activity, but their stable, modular architecture and versatile surface have allowed evolution to adapt them to many vital roles. By computationally reverse-engineering the duplication, fusion and diversification events in the evolutionary history of a WD40 protein, a perfectly symmetrical homologue called Tako8 was made. If two or four blades of Tako8 are expressed as single polypeptides, they do not self-assemble to complete the eight-bladed architecture, which may be owing to the closely spaced negative charges inside the ring. A different computational approach was employed to redesign Tako8 to create Ika8, a fourfold-symmetrical protein in which neighbouring blades carry compensating charges. Ika2 and Ika4, carrying two or four blades per subunit, respectively, were found to assemble spontaneously into a complete eight-bladed ring in solution. These artificial eight-bladed rings may find applications in bionanotechnology and as models to study the folding and evolution of WD40 proteins.
    Keywords: bioinformaticsprotein structurecomputational modellingmolecular simulationstructural biologyWD40 proteinsβ-propeller proteins
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 3
    Publication Date: 2018-12-08
    Description: SPIND (sparse-pattern indexing) is an auto-indexing algorithm for sparse snapshot diffraction patterns (`stills') that requires the positions of only five Bragg peaks in a single pattern, when provided with unit-cell parameters. The capability of SPIND is demonstrated for the orientation determination of sparse diffraction patterns using simulated data from microcrystals of a small inorganic molecule containing three iodines, 5-amino-2,4,6-triiodoisophthalic acid monohydrate (I3C) [Beck & Sheldrick (2008), Acta Cryst. E64, o1286], which is challenging for commonly used indexing algorithms. SPIND, integrated with CrystFEL [White et al. (2012), J. Appl. Cryst. 45, 335–341], is then shown to improve the indexing rate and quality of merged serial femtosecond crystallography data from two membrane proteins, the human δ-opioid receptor in complex with a bi-functional peptide ligand DIPP-NH2 and the NTQ chloride-pumping rhodopsin (CIR). The study demonstrates the suitability of SPIND for indexing sparse inorganic crystal data with smaller unit cells, and for improving the quality of serial femtosecond protein crystallography data, significantly reducing the amount of sample and beam time required by making better use of limited data sets. SPIND is written in Python and is publicly available under the GNU General Public License from https://github.com/LiuLab-CSRC/SPIND.
    Keywords: serial crystallographyX-ray free-electron lasersXFELelectron diffractiondiffract-then-destroydynamical studiesauto-indexing algorithmsBragg peaks
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 4
    Publication Date: 2018-12-08
    Description: Metal–organic frameworks with highly ordered porosity have been studied extensively. In this paper, the effect of framework (pore) disorder on the gas sorption of azole-based isoreticular Cu(II) MOFs with rtl topology and characteristic 1D tubular pore channels is investigated for the first time. In contrast to other isoreticular rtl metal–organic frameworks, the Cu(II) metal–organic framework based on 5-(1H-imidazol-1-yl)isophthalate acid has a crystallographically identifiable disordered framework without open N-donor sites. The framework provides a unique example for investigating the effect of pore disorder on gas sorption that can be systematically evaluated. It exhibits remarkable temperature-dependent hysteretic CO2 sorption up to room temperature, and shows selectivity of CO2 over H2, CH4 and N2 at ambient temperature. The unique property of the framework is its disordered structure featuring distorted 1D tubular channels and DMF-guest-remediated defects. The results imply that structural disorder (defects) may play an important role in the modification of the performance of the material.
    Keywords: metal–organic frameworksT-shaped ligandsdisorderMOFssolid propertieschannel structuresgas separation
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 5
    Publication Date: 2018-09-13
    Description: This work demonstrates a new method for investigating time-resolved structural changes in protein conformation and oligomerization via photocage-initiated time-resolved X-ray solution scattering by observing the ATP-driven dimerization of the MsbA nucleotide-binding domain. Photocaged small molecules allow the observation of single-turnover reactions of non-naturally photoactivatable proteins. The kinetics of the reaction can be derived from changes in X-ray scattering associated with ATP-binding and subsequent dimerization. This method can be expanded to any small-molecule-driven protein reaction with conformational changes traceable by X-ray scattering where the small molecule can be photocaged.
    Keywords: biophysicsX-ray solution scatteringphotocagingstructural biology
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 6
    Publication Date: 2018-09-15
    Description: X-ray free-electron lasers (XFELs) broaden horizons in X-ray crystallography. Facilitated by the unprecedented high intensity and ultrashort duration of the XFEL pulses, they enable us to investigate the structure and dynamics of macromolecules with nano-sized crystals. A limitation is the extent of radiation damage in the nanocrystal target. A large degree of ionization initiated by the incident high-intensity XFEL pulse alters the scattering properties of the atoms leading to perturbed measured patterns. In this article, the effective-form-factor approximation applied to capture this phenomenon is discussed. Additionally, the importance of temporal configurational fluctuations at high intensities, shaping these quantities besides the average electron loss, is shown. An analysis regarding the applicability of the approach to targets consisting of several atomic species is made, both theoretically and via realistic radiation-damage simulations. It is concluded that, up to intensities relevant for XFEL-based nanocrystallography, the effective-form-factor description is sufficiently accurate. This work justifies treating measured scattering patterns using conventional structure-reconstruction algorithms.
    Keywords: XFELsX-ray nanocrystallographyeffective form factorionizationradiation damage
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 7
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    Unknown
    International Union of Crystallography (IUCr)
    In: IUCrJ
    Publication Date: 2018-10-09
    Description: Grazing-incidence small-angle X-ray scattering (GISAXS) is a powerful technique for measuring the nanostructure of coatings and thin films. However, GISAXS data are plagued by distortions that complicate data analysis. The detector image is a warped representation of reciprocal space because of refraction, and overlapping scattering patterns appear because of reflection. A method is presented to unwarp GISAXS data, recovering an estimate of the true undistorted scattering pattern. The method consists of first generating a guess for the structure of the reciprocal-space scattering by solving for a mutually consistent prediction from the transmission and reflection sub-components. This initial guess is then iteratively refined by fitting experimental GISAXS images at multiple incident angles, using the distorted-wave Born approximation (DWBA) to convert between reciprocal space and detector space. This method converges to a high-quality reconstruction for the undistorted scattering, as validated by comparing with grazing-transmission scattering data. This new method for unwarping GISAXS images will broaden the applicability of grazing-incidence techniques, allowing experimenters to inspect undistorted visualizations of their data and allowing a broader range of analysis methods to be applied to GI data.
    Keywords: X-ray scatteringGISAXSGTSAXSimage healingreconstructiondistorted-wave Born approximation
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 8
    Publication Date: 2018-10-09
    Description: Under almost all circumstances, electron diffraction patterns contain information about the phases of structure factors, a consequence of the short wavelength of an electron and its strong Coulombic interaction with matter. However, extracting this information remains a challenge and no generic method exists. In this work, a set of simple analytical expressions is derived for the intensity distribution in convergent-beam electron diffraction (CBED) patterns recorded under three-beam conditions. It is shown that these expressions can be used to identify features in three-beam CBED patterns from which three-phase invariants can be extracted directly, without any iterative refinement processes. The octant, in which the three-phase invariant lies, can be determined simply by inspection of the indexed CBED patterns (i.e. the uncertainty of the phase measurement is ±22.5°). This approach is demonstrated with the experimental measurement of three-phase invariants in two simple test cases: centrosymmetric Si and non-centrosymmetric GaAs. This method may complement existing structure determination methods by providing direct measurements of three-phase invariants to replace `guessed' invariants in ab initio phasing methods and hence provide more stringent constraints to the structure solution.
    Keywords: crystallographic phase problemthree-phase invariantsconvergent-beam electron diffractionstructure determinationenantiomorph ambiguitynanocrystalsdynamical studiesmultiple scattering
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 9
    Publication Date: 2018-10-11
    Description: Basement membranes are extracellular structures of epithelia and endothelia that have collagen IV scaffolds of triple α-chain helical protomers that associate end-to-end, forming networks. The molecular mechanisms by which the noncollagenous C-terminal domains of α-chains direct the selection and assembly of the α1α2α1 and α3α4α5 hetero-oligomers found in vivo remain obscure. Autoantibodies against the noncollagenous domains of the α3α4α5 hexamer or mutations therein cause Goodpasture's or Alport's syndromes, respectively. To gain further insight into oligomer-assembly mechanisms as well as into Goodpasture's and Alport's syndromes, crystal structures of noncollagenous domains produced by recombinant methods were determined. The spontaneous formation of canonical homohexamers (dimers of trimers) of these domains of the α1, α3 and α5 chains was shown and the components of the Goodpasture's disease epitopes were viewed. Crystal structures of the α2 and α4 noncollagenous domains generated by recombinant methods were also determined. These domains spontaneously form homo-oligomers that deviate from the canonical architectures since they have a higher number of subunits (dimers of tetramers and of hexamers, respectively). Six flexible structural motifs largely explain the architectural variations. These findings provide insight into noncollagenous domain folding, while supporting the in vivo operation of extrinsic mechanisms for restricting the self-assembly of noncollagenous domains. Intriguingly, Alport's syndrome missense mutations concentrate within the core that nucleates the folding of the noncollagenous domain, suggesting that this syndrome, when owing to missense changes, is a folding disorder that is potentially amenable to pharmacochaperone therapy.
    Keywords: collagen type IVnetwork assembly(IV)NC1 hexamersGoodpasture's diseaseAlport's syndrome
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 10
    Publication Date: 2018-10-12
    Description: The AMPA receptor GluA2 belongs to the family of ionotropic glutamate receptors, which are responsible for most of the fast excitatory neuronal signalling in the central nervous system. These receptors are important for memory and learning, but have also been associated with brain diseases such as Alzheimer's disease and epilepsy. Today, one drug is on the market for the treatment of epilepsy targeting AMPA receptors, i.e. a negative allosteric modulator of these receptors. Recently, crystal structures and cryo-electron microscopy (cryo-EM) structures of full-length GluA2 in the resting (apo), activated and desensitized states have been reported. Here, solution structures of full-length GluA2 are reported using small-angle neutron scattering (SANS) with a novel, fully matched-out detergent. The GluA2 solution structure was investigated in the resting state as well as in the presence of AMPA and of the negative allosteric modulator GYKI-53655. In solution and at neutral pH, the SANS data clearly indicate that GluA2 is in a compact form in the resting state. The solution structure resembles the crystal structure of GluA2 in the resting state, with an estimated maximum distance (Dmax) of 179 ± 11 Å and a radius of gyration (Rg) of 61.9 ± 0.4 Å. An ab initio model of GluA2 in solution generated using DAMMIF clearly showed the individual domains, i.e. the extracellular N-terminal domains and ligand-binding domains as well as the transmembrane domain. Solution structures revealed that GluA2 remained in a compact form in the presence of AMPA or GYKI-53655. At acidic pH only, GluA2 in the presence of AMPA adopted a more open conformation of the extracellular part (estimated Dmax of 189 ± 5 Å and Rg of 65.2 ± 0.5 Å), resembling the most open, desensitized class 3 cryo-EM structure of GluA2 in the presence of quisqualate. In conclusion, this methodological study may serve as an example for future SANS studies on membrane proteins.
    Keywords: ionotropic glutamate receptorsmall-angle neutron scatteringagonistsnegative allosteric modulatorsresting stateAlzheimer's diseaseParkinson's diseaseepilepsy
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 11
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    Unknown
    International Union of Crystallography (IUCr)
    In: IUCrJ
    Publication Date: 2018-11-01
    Keywords: X-ray scatteringGISAXSimage healingreconstructiondistorted-wave Born approximation
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 12
    Publication Date: 2018-11-09
    Description: A new method to estimate the trajectories of particle motion and the amount of cumulative beam damage in electron cryo-microscopy (cryo-EM) single-particle analysis is presented. The motion within the sample is modelled through the use of Gaussian process regression. This allows a prior likelihood that favours spatially and temporally smooth motion to be associated with each hypothetical set of particle trajectories without imposing hard constraints. This formulation enables the a posteriori likelihood of a set of particle trajectories to be expressed as a product of that prior likelihood and an observation likelihood given by the data, and this a posteriori likelihood to then be maximized. Since the smoothness prior requires three parameters that describe the statistics of the observed motion, an efficient stochastic method to estimate these parameters is also proposed. Finally, a practical algorithm is proposed that estimates the average amount of cumulative radiation damage as a function of radiation dose and spatial frequency, and then fits relative B factors to that damage in a robust way. The method is evaluated on three publicly available data sets, and its usefulness is illustrated by comparison with state-of-the-art methods and previously published results. The new method has been implemented as Bayesian polishing in RELION-3, where it replaces the existing particle-polishing method, as it outperforms the latter in all tests conducted.
    Keywords: Bayesian particle polishingbeam-induced motion correctioncryo-EMsingle-particle analysiselectron cryo-microscopy
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 13
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    International Union of Crystallography (IUCr)
    In: IUCrJ
    Publication Date: 2018-11-09
    Description: Cryo-EM now commonly generates close-to-atomic resolution as well as intermediate resolution maps from macromolecules observed in isolation and in situ. Interpreting these maps remains a challenging task owing to poor signal in the highest resolution shells and the necessity to select a threshold for density analysis. In order to facilitate this process, a statistical framework for the generation of confidence maps by multiple hypothesis testing and false discovery rate (FDR) control has been developed. In this way, three-dimensional confidence maps contain signal separated from background noise in the form of local detection rates of EM density values. It is demonstrated that confidence maps and FDR-based thresholding can be used for the interpretation of near-atomic resolution single-particle structures as well as lower resolution maps determined by subtomogram averaging. Confidence maps represent a conservative way of interpreting molecular structures owing to minimized noise. At the same time they provide a detection error with respect to background noise, which is associated with the density and is particularly beneficial for the interpretation of weaker cryo-EM densities in cases of conformational flexibility and lower occupancy of bound molecules and ions in the structure.
    Keywords: electron cryo-microscopysignal detectionfalse discovery ratecryo-EM densitysubtomogram averaginglocal resolutionligand binding
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 14
    Publication Date: 2018-12-05
    Description: During screening of the phase space using KOH and 1-methyl-4-aza-1-azoniabicyclo[2.2.2]octane hydroxide (1-methyl-DABCO) under hydrothermal zeolite synthesis conditions, K-paracelsian was synthesized. Scanning electron microscopy, energy dispersive X-ray spectroscopy and ex situ powder X-ray diffraction analysis revealed a material that is compositionally closely related to the mineral microcline and structurally closely related to the mineral paracelsian, both of which are feldspars. In contrast to the feldspars, K-paracelsian contains intrazeolitic water corresponding to one molecule per cage. In the case of K-paracelsian it might be useful to consider it a link between feldspars and zeolites. It was also shown that K-paracelsian can be described as the simplest endmember of a family of dense double-crankshaft zeolite topologies. By applying the identified building principle, a number of known zeolite topologies can be constructed. Furthermore, it facilitates the construction of a range of hypothetical small-pore structures that are crystallo-chemically healthy, but which have not yet been realized experimentally.
    Keywords: K-paracelsiandense double-crankshaft zeolite topologiesstructure refinementcrystal engineeringinorganic porous solidsmicroporous materials
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 15
    Publication Date: 2018-07-21
    Description: The main descriptors of chemical bonding such as bond order (BO) and electron density at the bond critical point, ρc, are customarily used to understand the crystal and electronic structure of materials, as well as to predict their reactivity and stability. They can be obtained in the framework of crystal chemistry and quantum chemistry approaches, which are mostly applied as alternatives to each other. This paper verifies the convergence of the two approaches by analyzing a plethora of quantum chemistry data available in the literature. The exponential correlation between the electron descriptors [BOij and ρc(ij)] and the length of chemical bonds, Rij, which is basic in crystal chemistry, was confirmed for 72 atom pairs, regardless of the nature of their interactions (ionic/covalent, metal–metal, etc.). The difference between the BOij (Rij) correlations obtained in this work and those accepted in crystal chemistry for the same atomic pairs does not exceed the dispersion of quantum chemistry data, confirming the qualitative validity of the BO conservation principle. Various examples are presented to show that knowledge of the exponential parameters ensures a surprisingly simple determination of two basic electron descriptors in any complex compound with known interatomic distances. In particular, the BO analysis for 20 Re6-cluster complexes illustrates the BO conservation for systems with delocalized electrons. Despite the significant transfer of electron density from the Re–Re to the Re–ligand bonds, the total number of Re valence electrons used in bonding remains close to the formal value of seven electrons.
    Keywords: chemical bondingbond orderbond lengthsbond critical pointelectron densityconservation principles
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 16
    Publication Date: 2018-07-21
    Description: Heterogeneous catalysts are of great interest in many industrial processes for environmental reasons and, during recent years, a great effort has been devoted to obtain metal–organic frameworks (MOFs) with improved catalytic behaviour. Few supramolecular metal–organic frameworks (SMOFs) are stable under ambient conditions and those with anchored catalysts exhibit favourable properties. However, this paper presents an innovative approach that consists of using metal nodes as both structural synthons and catalysts. Regarding the latter, metalloporphyrins are suitable candidates to play both roles simultaneously. In fact, there are a number of papers that report coordination compounds based on metalloporphyrins exhibiting these features. Thus, the aim of this bioinspired work was to obtain stable SMOFs (at room temperature) based on metalloporphyrins and explore their catalytic activity. This work reports the environmentally friendly microwave-assisted synthesis and characterization of the compound [H(bipy)]2[(MnTPPS)(H2O)2]·2bipy·14H2O (TPPS = meso-tetraphenylporphine-4,4′,4′′,4′′′-tetrasulfonic acid and bipy = 4,4′-bipyridine). This compound is the first example of an MnTPPS-based SMOF, as far as we are aware, and has been structurally and thermally characterized through single-crystal X-ray diffraction, IR spectroscopy, thermogravimetry and transmission electron microscopy. Additionally, this work explores not only the catalytic activity of this compound but also of the compounds μ-O-[FeTCPP]2·16DMF and [CoTPPS0.5(bipy)(H2O)2]·6H2O. The structural features of these supramolecular materials, with accessible networks and high thermal stability, are responsible for their excellent behaviour as heterogeneous catalysts for different oxidation, condensation (aldol and Knoevenagel) and one-pot cascade reactions.
    Keywords: metalloporphyrinssupramolecular MOFsheterogeneous catalystsKnoevenagel condensationsaldol condensationsone-pot cascade reactions
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 17
    Publication Date: 2018-07-21
    Description: In recent years, the success of serial femtosecond crystallography and the paucity of beamtime at X-ray free-electron lasers have motivated the development of serial microcrystallography experiments at storage-ring synchrotron sources. However, especially at storage-ring sources, if a crystal is too small it will have suffered significant radiation damage before diffracting a sufficient number of X-rays into Bragg peaks for peak-indexing software to determine the crystal orientation. As a consequence, the data frames of small crystals often cannot be indexed and are discarded. Introduced here is a method based on the expand–maximize–compress (EMC) algorithm to solve protein structures, specifically from data frames for which indexing methods fail because too few X-rays are diffracted into Bragg peaks. The method is demonstrated on a real serial microcrystallography data set whose signals are too weak to be indexed by conventional methods. In spite of the daunting background scatter from the sample-delivery medium, it was still possible to solve the protein structure at 2.1 Å resolution. The ability of the EMC algorithm to analyze weak data frames will help to reduce sample consumption. It will also allow serial microcrystallography to be performed with crystals that are otherwise too small to be feasibly analyzed at storage-ring sources.
    Keywords: X-ray serial microcrystallographysparse dataEMC algorithmprotein microcrystallographystorage-ring synchrotron sources
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 18
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    International Union of Crystallography (IUCr)
    In: IUCrJ
    Publication Date: 2018-07-28
    Description: The hypothesis that H/D exchange affects the structural formation of organic compounds in the solid state is supported by a deeper understanding of the altering polymorphism of ROY (a substance striking for its high number of polymorphic forms) through deuteration. Therefore, ROY was deuterated at its amine function, which leads to a seemingly small yet effective modification of the hydrogen-bond strength. In contrast to the crystallization of the non-deuterated ROY in methanol or ethanol, which leads to the simultaneous formation of two forms (OP and Y polymorphs), so-called concomitant polymorphs, the crystallization of d1-ROY leads to the selective formation of the Y polymorph exclusively. The preferred aggregation behavior of the Y form of d1-ROY is assigned to the weakening of an intramolecular hydrogen bond and a consequently strengthened intermolecular hydrogen bond after deuteration.
    Keywords: concomitant polymorphsdeuterationhydrogen bondsROYcrystal engineeringH/D exchange
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 19
    Publication Date: 2018-07-31
    Description: The recent paper by Belo, Pereira, Freire, Argyriou, Eckert & Bordallo [(2018), IUCrJ, 5, 6–12] reports observations that may lead one to think of very strong and visible consequences of the parity-violation energy difference between enantiomers of a molecule, namely alanine. If proved, this claim would have an enormous impact for research in structural chemistry. However, alternative, more realistic, explanations of their experiments have not been ruled out by the authors. Moreover, the theoretical calculations carried out to support the hypothesis are unable to differentiate between enantiomers (molecules or crystals). Therefore, the conclusions drawn by Belo et al. (2018) are deemed inappropriate as the data presented do not contain sufficient information to reach such a conclusion.
    Keywords: parity-violation energyenantiomersphase transitionsamino acids
    Electronic ISSN: 2052-2525
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  • 20
    Publication Date: 2018-08-09
    Description: Inherent protein flexibility, poor or low-resolution diffraction data or poorly defined electron-density maps often inhibit the building of complete structural models during X-ray structure determination. However, recent advances in crystallographic refinement and model building often allow completion of previously missing parts. This paper presents algorithms that identify regions missing in a certain model but present in homologous structures in the Protein Data Bank (PDB), and `graft' these regions of interest. These new regions are refined and validated in a fully automated procedure. Including these developments in the PDB-REDO pipeline has enabled the building of 24 962 missing loops in the PDB. The models and the automated procedures are publicly available through the PDB-REDO databank and webserver. More complete protein structure models enable a higher quality public archive but also a better understanding of protein function, better comparison between homologous structures and more complete data mining in structural bioinformatics projects.
    Keywords: loop buildingstructural re-buildingPDB-REDOmodel completioncrystallography
    Electronic ISSN: 2052-2525
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  • 21
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    International Union of Crystallography (IUCr)
    In: IUCrJ
    Publication Date: 2018-09-06
    Keywords: single-particle three-dimensional imagingX-ray free electron lasersimaging virus particlesimage analysisthree-dimensional reconstructionatomic scale structure
    Electronic ISSN: 2052-2525
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  • 22
    Publication Date: 2018-07-28
    Description: Liquid microjets are a common means of delivering protein crystals to the focus of X-ray free-electron lasers (FELs) for serial femtosecond crystallography measurements. The high X-ray intensity in the focus initiates an explosion of the microjet and sample. With the advent of X-ray FELs with megahertz rates, the typical velocities of these jets must be increased significantly in order to replenish the damaged material in time for the subsequent measurement with the next X-ray pulse. This work reports the results of a megahertz serial diffraction experiment at the FLASH FEL facility using 4.3 nm radiation. The operation of gas-dynamic nozzles that produce liquid microjets with velocities greater than 80 m s−1 was demonstrated. Furthermore, this article provides optical images of X-ray-induced explosions together with Bragg diffraction from protein microcrystals exposed to trains of X-ray pulses repeating at rates of up to 4.5 MHz. The results indicate the feasibility for megahertz serial crystallography measurements with hard X-rays and give guidance for the design of such experiments.
    Keywords: X-ray free-electron lasersFELsX-ray FEL pulse trainsmegahertz repetition rates
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 23
    Publication Date: 2018-09-06
    Description: In this study, the nature and characteristics of a short Br...π interaction observed in an ebselen derivative, 2-(2-bromophenyl)benzo[d][1,2]selenazol-3(2H)-one, has been explored. The electronic nature of this Br...π interaction was investigated via high-resolution X-ray diffraction and periodic density functional theory calculations using atoms-in-molecules (AIM) analysis. This study unravels the simultaneous presence of σ-hole and π-hole bonding characteristics in the same interaction. The dual characteristics of this unique Br...π interaction are further established via molecular electrostatic potentials (MESPs) and natural bond orbitals (NBOs).
    Keywords: σ-hole bondingπ-hole bondingebselenelectron densitymolecular electrostatic potentialscrystal engineeringcharge, spin and momentum densitiescomputational modellingmolecular crystals
    Electronic ISSN: 2052-2525
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  • 24
    Publication Date: 2018-09-06
    Description: Diffraction before destruction using X-ray free-electron lasers (XFELs) has the potential to determine radiation-damage-free structures without the need for crystallization. This article presents the three-dimensional reconstruction of the Melbournevirus from single-particle X-ray diffraction patterns collected at the LINAC Coherent Light Source (LCLS) as well as reconstructions from simulated data exploring the consequences of different kinds of experimental sources of noise. The reconstruction from experimental data suffers from a strong artifact in the center of the particle. This could be reproduced with simulated data by adding experimental background to the diffraction patterns. In those simulations, the relative density of the artifact increases linearly with background strength. This suggests that the artifact originates from the Fourier transform of the relatively flat background, concentrating all power in a central feature of limited extent. We support these findings by significantly reducing the artifact through background removal before the phase-retrieval step. Large amounts of blurring in the diffraction patterns were also found to introduce diffuse artifacts, which could easily be mistaken as biologically relevant features. Other sources of noise such as sample heterogeneity and variation of pulse energy did not significantly degrade the quality of the reconstructions. Larger data volumes, made possible by the recent inauguration of high repetition-rate XFELs, allow for increased signal-to-background ratio and provide a way to minimize these artifacts. The anticipated development of three-dimensional Fourier-volume-assembly algorithms which are background aware is an alternative and complementary solution, which maximizes the use of data.
    Keywords: XFELsMelbourneviruscoherent diffractive imagingLCLSimage reconstruction
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 25
    Publication Date: 2018-09-15
    Description: It is shown that the average signal-to-noise ratio (SNR) in the three-dimensional electron-density distribution of a sample reconstructed by coherent diffractive imaging cannot exceed twice the square root of the ratio of the mean total number of scattered photons detected during the scan and the number of spatially resolved voxels in the reconstructed volume. This result leads to an upper bound on Shannon's information capacity of this imaging method by specifying the maximum number of distinguishable density distributions within the reconstructed volume when the radiation dose delivered to the sample and the spatial resolution are both fixed. If the spatially averaged SNR in the reconstructed electron density is fixed instead, the radiation dose is shown to be proportional to the third or fourth power of the spatial resolution, depending on the sampling of the three-dimensional diffraction space and the scattering power of the sample.
    Keywords: coherent diffractive imagingsignal-to-noise ratiospatial resolutioninformation capacity
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 26
    Publication Date: 2018-10-18
    Description: This study investigated the structural and magnetic properties of Mn3−xFexGa alloys (x = 0, 0.2, 0.4, 0.6, 0.8, 1) under different heat-treatment conditions. A tetragonal structure was observed in samples that were heat treated at 623 K for three days followed by quenching in ice water. These tetragonal alloys present large coercive fields in the range 0.8–5 kOe and low saturation magnetization, and have great potential for application in spin-transfer torque-based devices. A hexagonal structure was observed in samples subjected to heat treatment at 883 K for three days following quenching in ice water. A moderate decrease in the coercive field has been observed for the hexagonal alloys compared with those with a tetragonal structure. However, the Mn3−xFexGa alloys with a hexagonal structure exhibit other attractive magnetic properties, including collinear and non-collinear magnetic properties, holding high promise for technological applications. A face-centred-cubic (f.c.c.) structure was observed when subjected to annealing at 1073 K for three days followed by quenching in ice water. In contrast to the tetragonal and hexagonal structures, all f.c.c. alloys exhibit antiferromagnetic behaviour. This versatile material can display a wide range of multi-functionalities attributed to its tuneable crystal structure. This investigation will guide the design of multiple structures of these materials in order to utilise the wide functionalities for practical applications.
    Keywords: Mn–Fe–Ga alloystetragonal Heusler alloysmultiple structural materials
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 27
    Publication Date: 2018-10-30
    Description: The crystal and molecular structure of the pure (S)-enantiomer of the popular analgesic and anti-inflammatory drug ketoprophen (α-ket) is reported. A detailed aspherical charge-density model based on high-resolution X-ray diffraction data has been refined, yielding a high-precision geometric description and classification of the O—H...O interactions as medium strength hydrogen bonds. The crystal structure of the racemic form of ketoprophen (β-ket) was also redetermined at 100 K, at 0.5 Å resolution. A previously unreported disorder (10% occupancy) was discovered. In contrast to the racemic β-ket case, the (S)-enantiomer crystallizes with two independent molecules in the asymmetric unit with two distinct conformations. The major difference between the β-ket and α-ket crystal forms lies in the formation of distinct hydrogen-bonded motifs: a closed ring motif in β-ket versus infinite chains of hydrogen bonds in the chiral α-ket structure. However, the overall crystal packing of both forms is surprisingly similar, with close-packed layers of antiparallel-oriented benzophenone moieties bound by C—H...π interactions. Notably, the most important stabilizing term in the total lattice energies in both instances proved to be the dispersion related to these interactions. Both forms of the title compound (α- and β-ket) were additionally characterized by differential scanning calorimetry and thermogravimetric analysis.
    Keywords: ketoprophencharge densitycrystal structurespharmaceuticalsbioinversion
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 28
    Publication Date: 2018-10-30
    Description: Single-particle cryo-electron microscopy (cryo-EM) has recently become a mainstream technique for the structural determination of macromolecules. Typical cryo-EM workflows collect hundreds of thousands of single-particle projections from thousands of micrographs using particle-picking algorithms. However, the number of false positives selected by these algorithms is large, so that a number of different `cleaning steps' are necessary to decrease the false-positive ratio. Most commonly employed techniques for the pruning of false-positive particles are time-consuming and require user intervention. In order to overcome these limitations, a deep learning-based algorithm named Deep Consensus is presented in this work. Deep Consensus works by computing a smart consensus over the output of different particle-picking algorithms, resulting in a set of particles with a lower false-positive ratio than the initial set obtained by the pickers. Deep Consensus is based on a deep convolutional neural network that is trained on a semi-automatically generated data set. The performance of Deep Consensus has been assessed on two well known experimental data sets, virtually eliminating user intervention for pruning, and enhances the reproducibility and objectivity of the whole process while achieving precision and recall figures above 90%.
    Keywords: cryo-EMdeep learningimage processingparticle pruningthree-dimensional reconstruction
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 29
    Publication Date: 2018-10-30
    Description: A method has been developed to measure the similarity between materials, focusing on specific physical properties. The information obtained can be utilized to understand the underlying mechanisms and support the prediction of the physical properties of materials. The method consists of three steps: variable evaluation based on nonlinear regression, regression-based clustering, and similarity measurement with a committee machine constructed from the clustering results. Three data sets of well characterized crystalline materials represented by critical atomic predicting variables are used as test beds. Herein, the focus is on the formation energy, lattice parameter and Curie temperature of the examined materials. Based on the information obtained on the similarities between the materials, a hierarchical clustering technique is applied to learn the cluster structures of the materials that facilitate interpretation of the mechanism, and an improvement in the regression models is introduced to predict the physical properties of the materials. The experiments show that rational and meaningful group structures can be obtained and that the prediction accuracy of the materials' physical properties can be significantly increased, confirming the rationality of the proposed similarity measure.
    Keywords: data miningmaterials informaticsfirst-principles calculationsphysical properties of materialsmachine learningsimilarity
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 30
    Publication Date: 2018-11-30
    Description: Chemical bonding and all intermolecular interactions in the highly insoluble carbonate salt of a 2,6-pyridine-bis(iminoguanidine), (PyBIGH2)(CO3)(H2O)4, recently employed in the direct air capture of CO2 via crystallization, have been analyzed within the framework of the quantum theory of atoms in molecules (QTAIM) based on the experimental electron density derived from X-ray diffraction data obtained at 20 K. Accurate hydrogen positions were included based on an analogous neutron diffraction study at 100 K. Topological features of the covalent bonds demonstrate the presence of multiple bonds of various orders within the PyBIGH22+ cation. Strong hydrogen bonds define ribbons comprising carbonate anions and water molecules. These ribbons are linked to stacks of essentially planar dications via hydrogen bonds from the guanidinium moieties and an additional one to the pyridine nitrogen. The linking hydrogen bonds are approximately perpendicular to the anion–water ribbons. The observation of these putative interactions provided motivation to characterize them by topological analysis of the total electron density. Thus, all hydrogen bonds have been characterized by the properties of their (3,−1) bond critical points. Weaker interactions between the PyBIGH22+ cations have similarly been characterized. Integrated atomic charges are also reported. A small amount of cocrystallized hydroxide ion (∼2%) was also detected in both the X-ray and neutron data, and included in the multipole model for the electron-density refinement. The small amount of additional H+ required for charge balance was not detected in either the X-ray or the neutron data. The results are discussed in the context of the unusually low aqueous solubility of (PyBIGH2)(CO3)(H2O)4 and its ability to sequester atmospheric CO2.
    Keywords: carbon captureguanidineX-ray diffractionneutron diffractioncharge densitytopological analysiscrystal engineeringintermolecular interactionshydrogen bondingenvironmental chemistry
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 31
    Publication Date: 2018-02-17
    Description: Suboptimal environmental conditions are ubiquitous in nature and commonly drive the outcome of biological interactions in community processes. Despite the importance of biological interactions for community processes, knowledge on how species interactions are affected by a limiting resource, for example, low food availability, remains limited. Here, we tested whether variation in food supply causes nonadditive consumption patterns, using the macroinvertebrate community of intertidal sandy beaches as a model system. We quantified isotopically labeled diatom consumption by three macroinvertebrate species ( Bathyporeia pilosa , Haustorius arenarius, and Scolelepis squamata ) kept in mesocosms in either monoculture or a three-species community at a range of diatom densities. Our results show that B. pilosa was the most successful competitor in terms of consumption at both high and low diatom density, while H. arenarius and especially S. squamata consumed less in a community than in their respective monocultures. Nonadditive effects on consumption in this macroinvertebrate community were present and larger than mere additive effects, and similar across diatom densities. The underlying species interactions, however, did change with diatom density. Complementarity effects related to niche-partitioning were the main driver of the net diversity effect on consumption, with a slightly increasing contribution of selection effects related to competition with decreasing diatom density. For the first time, we showed that nonadditive effects of consumption are independent of food availability in a macroinvertebrate community. This suggests that, in communities with functionally different, and thus complementary, species, nonadditive effects can arise even when food availability is low. Hence, at a range of environmental conditions, species interactions hold important potential to alter ecosystem functioning. To test whether variation in food supply causes nonadditive consumption patterns, we quantified isotopically labeled diatom consumption by three intertidal macroinvertebrate species kept in mesocosms in either monoculture or a community at a range of diatom densities. Complementarity effects on consumption were the main driver of the net diversity effect, with a slightly increasing contribution of selection effects with decreasing diatom density. For the first time, we have shown that nonadditive effects of consumption are independent from food availability in a macroinvertebrate community.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
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  • 32
    Publication Date: 2018-02-27
    Description: The purpose of this study was to measure the sodium transverse relaxation time T 2 * in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T 2 * values were fitted on a voxel-by-voxel basis using a bi-exponential model. Data were also analysed using a continuous distribution fit with a region of interest-based inverse Laplace transform. Average T 2 * values were 3.4 ± 0.2 ms and 23.5 ± 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 ± 0.5 ms and 26.3 ± 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi-exponential model. Continuous distribution fits yielded results of 3.1 ± 0.3 ms and 18.8 ± 3.2 ms in WM for the short and long components, respectively, and 2.9 ± 0.4 ms and 17.2 ± 2 ms in GM for the short and long components, respectively. 23 Na T 2 * values of the brain for the short and long components for various anatomical locations using ultra-short TEs are presented for the first time. Healthy subjects were scanned using 23 Na ultra-short echo time (UTE) magnetic resonance imaging (MRI) with 18 TEs between 0.17 and 67 ms. T 2 * values were fitted on a voxel-by-voxel basis using a bi-exponential model and using a continuous distribution fit with a region of interest-based inverse Laplace transform. Detailed 23 Na T 2 * values of the brain for the short and long components for various anatomical locations using UTEs are presented for the first time.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 33
    Publication Date: 2018-02-28
    Description: A patient in whom organs or molecules are affected sequentially by an autoimmune response prompted us to propose a hypothesis that epitope spreading may account for the sequential involvement of different cells. A 27-year old male patient was diagnosed in January 2005 with idiopathic thrombocytopenic purpura (ITP), since all autoantibodies relevant to autoimmune diseases were negative. He was treated with immunosuppression and spenectomy. In 2014, the patient developed transient blurred vision, dizziness and walking instability and autoimmune chylomicronemia was diagnosed, based on the presence of autoantibodies to lipoprotein lipase (LPL) (1). This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
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  • 34
    Publication Date: 2018-02-28
    Description: Sepsis is a condition caused by infection followed by unregulated inflammatory response which may lead to the organ dysfunction. During such condition, over-production of oxidants is one of the factors which contribute cellular toxicity and ultimately organ failure and mortality. Antioxidants having free radicals scavenging activity exert protective role in various diseases. The present study has been designed to evaluate the levels of oxidative and anti-oxidative activity in sepsis patients and their correlation with the severity of the sepsis. A total of 100 sepsis patients and 50 healthy controls subjects were enrolled in this study from the period October 2016 to June 2017. The investigation included measurements of oxidative enzyme, myeloperoxidase (MPO), antioxidant enzymes including superoxide dismutase activity (SOD) and catalase activity (CAT) and cytokines (TNF-α, IL-8 and IFN-γ). Furthermore, the level of these activities was correlated with severity of sepsis. Augmented levels of oxidants were found in sepsis as demonstrated by DMPO nitrone adduct formation and plasma MPO level activity (1.37 ± 0.51 in sepsis vs 0.405 ± 0.16 in control subjects). Cytokines were also found to be increased in sepsis patients. However, plasma SOD and CAT activities were significantly attenuated (p〈0.001) in the sepsis patients compared with controls subjects. Moreover, inverse relation between antioxidant enzymes (SOD and CAT) and organ failure assessment (SOFA), physiological score (APACHE II), organ toxicity specific markers have been observed as demonstrated by Pearson's correlation coefficient. This study suggests that imbalance between oxidant and antioxidant play key role in the severity of sepsis. This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
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  • 35
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    Wiley-Blackwell
    Publication Date: 2018-02-28
    Description: Modern diffusion magnetic resonance imaging (dMRI) acquires intricate volume datasets and biological meaning can only be found in the relationship between its different measurements. Suitable strategies for visualizing these complicated data have been key to interpretation by physicians and neuroscientists, for drawing conclusions on brain connectivity and for quality control. This article provides an overview of visualization solutions that have been proposed to date, ranging from basic grayscale and color encodings to glyph representations and renderings of fiber tractography. A particular focus is on ongoing and possible future developments in dMRI visualization, including comparative, uncertainty, interactive and dense visualizations. This paper provides an overview of visualization solutions that have been proposed to date for diffusion MRI, ranging from basic grayscale and color encodings to glyph representations and renderings of fiber tractography. A particular focus is on ongoing and possible future developments in dMRI visualization, including comparative, uncertainty, interactive, and dense visualizations.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 36
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    Wiley-Blackwell
    Publication Date: 2018-03-06
    Description: Cover illustration. Additive manufacturing offers the capability to build reactors and components with complex geometries and topologies previously unaccessible to the reactor design engineer. These capabilities could allow a transition from site-built facilities [left, courtesy of Matt Jiggins, https://www.flickr.com/photos/mattjiggins/3948811131 ] to optimized additively manufactured designs [right, examples of metal objects built using Direct Metal Laser Sintering (DMLS) courtesy of Oakridge National Laboratory, https://www.flickr.com/photos/oakridgelab/9067742195 ]. 10.1002/aic.16118
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 37
    Publication Date: 2018-03-06
    Description: The cartwheel is a striking structure critical for building the centriole, a microtubule-based organelle fundamental for organizing centrosomes, cilia, and flagella. Over the last 50 years, the cartwheel has been described in many systems using electron microscopy, but the molecular nature of its constituent building blocks and their assembly mechanisms have long remained mysterious. Here, we review discoveries that led to the current understanding of cartwheel structure, assembly, and function. We focus on the key role of SAS-6 protein self-organization, both for building the signature ring-like structure with hub and spokes, as well as for their vertical stacking. The resemblance of assembly intermediates in vitro and in vivo leads us to propose a novel registration step in cartwheel biogenesis, whereby stacked SAS-6-containing rings are put in register through interactions with peripheral elements anchored to microtubules. We conclude by evoking some avenues for further uncovering cartwheel and centriole assembly mechanisms. The cartwheel is crucial for centriole assembly. Despite this fundamental role, cartwheel structure and assembly mechanisms remain unclear for a long time. Here we review five decades of research that led to our current understanding of these questions, highlighting the central role of the SAS-6 protein family.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 38
    Publication Date: 2018-03-06
    Description: Despite the existence of well-established international environmental and nature conservation policies (e.g., the Ramsar Convention and Convention on Biological Diversity) ponds are largely missing from national and international legislation and policy frameworks. Ponds are among the most biodiverse and ecologically important freshwater habitats, and their value lies not only in individual ponds, but more importantly, in networks of ponds (pondscapes). Ponds make an important contribution to society through the ecosystem services they provide, with effective conservation of pondscapes essential to ensuring that these services are maintained. Implementation of current pond conservation through individual site designations does not function at the landscape scale, where ponds contribute most to biodiversity. Conservation and management of pondscapes should complement current national and international nature conservation and water policy/legislation, as pondscapes can provide species protection in landscapes where large-scale traditional conservation areas cannot be established (e.g., urban or agricultural landscapes). We propose practical steps for the effective incorporation or enhancement of ponds within five policy areas: through open water sustainable urban drainage systems in urban planning, increased incentives in agri-environment schemes, curriculum inclusion in education, emphasis on ecological scale in mitigation measures following anthropogenic developments, and the inclusion of pondscapes in conservation policy. This article is protected by copyright. All rights reserved
    Print ISSN: 1755-263X
    Electronic ISSN: 1755-263X
    Topics: Biology
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  • 39
    Publication Date: 2018-03-06
    Description: Several different assay methodologies have been described for the evaluation of HIV or SIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC). Commonly used assays measure ADCC by evaluating effector cell functions, or by detecting elimination of target cells. Signaling through Fc receptors, cellular activation, cytotoxic granule exocytosis, or accumulation of cytolytic and immune signaling factors have been used to evaluate ADCC at the level of the effector cells. Alternatively, assays that measure killing or loss of target cells provide a direct assessment of the specific killing activity of antibodies capable of ADCC. Thus, each of these two distinct types of assays provides information on only one of the critical components of an ADCC event; either the effector cells involved, or the resulting effect on the target cell. We have developed a simple modification of our previously described high-throughput ADCC GranToxiLux (GTL) assay that uses area scaling analysis (ASA) to facilitate simultaneous quantification of ADCC activity at the target cell level, and assessment of the contribution of natural killer cells and monocytes to the total observed ADCC activity when whole human peripheral blood mononuclear cells are used as a source of effector cells. The modified analysis method requires no additional reagents and can, therefore, be easily included in prospective studies. Moreover, ASA can also often be applied to pre-existing ADCC-GTL datasets. Thus, incorporation of ASA to the ADCC-GTL assay provides an ancillary assessment of the ability of natural and vaccine-induced antibodies to recruit natural killer cells as well as monocytes against HIV or SIV; or to any other field of research for which this assay is applied. © 2018 International Society for Advancement of Cytometry
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 40
    Publication Date: 2018-03-06
    Description: Flow cytometric cell surface proteomics provides a new and powerful tool to determine changes accompanying neoplastic transformation and invasion, providing clues to essential interactions with the microenvironment as well as leads for potential therapeutic targets. One of the most important advantages of flow cytometric cell surface proteomics is that it can be performed on living cells that can be sorted for further characterization and functional studies. Here, we document the surface proteome of clonogenic metastatic breast cancer (MBrCa) explants, which was strikingly similar to that of normal mesenchymal stromal cells ( P  = 0.017, associated with Pearson correlation coefficient) and transformed mammary epithelial cells ( P  = 0.022). Markers specifically upregulated on MBrCa included CD200 (Ox2), CD51/CD61 (Integrin α5/β3), CD26 (dipeptidyl peptidase-4), CD165 (c-Cbl), and CD54 (ICAM-1). Proteins progressively upregulated in a model of neoplastic transformation and invasion included CD26, CD63 (LAMP3), CD105 (Endoglin), CD107a (LAMP1), CD108 (Semaphorin 7A), CD109 (Integrin β4), CD151 (Raph blood group), and disialoganglioside G2. The proteome of the commonly used cell lines MDA-MB-231, MCF7, and BT-474 were uncorrelated with that of MBrCa ( P  = 1.0, 1.0, 0.9, respectively). The comparison has demonstrated the mesenchymal nature of clonogenic cells isolated by short-term culture of metastatic breast cancer, provided several leads for biomarkers and potential targets for anti-invasive therapy, including CD200, and highlighted the limitations of breast cancer cell lines for representing the cell surface biology of breast cancer. © 2017 International Society for Advancement of Cytometry
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 41
    Publication Date: 2018-03-06
    Description: Implantation of micromass cultures of osteoblastic cells offers the possibility of scaffold free tissue engineering for example, regeneration of bone defects. However, the details of cell dynamics during the formation of these micromasses are still not well understood. This study aims to investigate and clarify the extent to which cell quantity influences the dynamics of micromass formation of osteoblastic cell cultures. For this purpose, the migration and aggregation during this process are investigated by optical inspection employing image processing software that allows for automated tracking of cell groups using digital image correlation. An exponential time behavior is observed with respect to the velocity of the cells and the distance of the cells to their common center of gravity. Characteristic time constants are derived as quantitative measures of the cell dynamics. The results indicate that the time constants strongly depend on the quantity of cells, that is, will decrease with increasing cell quantity. © 2018 International Society for Advancement of Cytometry Implantation of micromass cultures of osteoblastic cells offers the possibility of scaffold free tissue engineering for example, regeneration of bone defects. This study aims to clarify the extent to which cell quantity influences the dynamics of micro-mass formation of osteoblastic cell cultures. The migrations during these processes are investigated by optical inspection employing image processing software that allows for automated tracking of cell groups using digital image correlation (DIC).
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 42
    Publication Date: 2018-03-06
    Description: Background : Traditionally, the central nervous system (CNS) has been viewed as an immune-privileged environment with no lymphatic vessels. This view was partially overturned by the discovery of lymphatic vessels in the dural membrane that surrounds the brain, in contact with the interior surface of the skull. We here examine the distribution and developmental timing of these lymphatic vessels. Results : Using the Prox1-GFP BAC transgenic reporter and immunostaining with antibodies to lymphatic markers LYVE-1, Prox1, and Podoplanin, we have carried out whole-mount imaging of dural lymphatic vasculature at postnatal stages. We have found that between birth – postnatal day 13 (P)13, lymphatic vessels extend alongside dural blood vessels from the side of the skull towards the midline. Between P13 - P20, lymphatic vessels along the transverse sinuses (TS) reach the superior sagittal sinus (SSS) and extend along the SSS towards the olfactory bulb. Conclusion : Compared with the embryonic developmental timing of lymphatic vessels in other tissues, e.g. skin, dural lymphatic vessel development is dramatically delayed. This study provides useful anatomical data for continuing investigations of the fundamental mechanisms that underlie dural lymphatic vessel development. This article is protected by copyright. All rights reserved.
    Electronic ISSN: 1097-0177
    Topics: Medicine
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  • 43
    Publication Date: 2018-03-06
    Description: Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with MCMV intraperitoneally is a well-established model of congenital HCMV infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here we used this model to investigate the role, dynamics and phenotype of CD8 + T cells in the brain following infection of newborn mice. We show that CD8 + T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T RM cells) that persist for lifetime. Adoptively transferred virus-specific CD8 + T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology and remain in the brain as T RM cells. Brain CD8 + T RM cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8 + T RM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
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  • 44
    Publication Date: 2018-03-06
    Description: Although previous reports suggest that tumor-induced myeloid-derived suppressor cells (MDSC) inhibit T cells by L-arginine depletion through arginase-1 activity, we herein show that arginase-1 is neither inherently expressed in MDSC nor required for MDSC-mediated inhibition. Employing Percoll density gradients, large expansions of MDSC in the bone marrow of tumor-bearing mice were isolated and demonstrated potent inhibition in T cell proliferation activated by TCR-ligation, Concanavalin A, PMA plus ionomycin, or IL-2. Despite demonstrating characteristic immunosuppressive capacity, these MDSC exhibit no arginase-1 expression and/or exert their inhibitory effects independent of arginase-1 activity. However, arginase-1 expression in MDSC can be induced by exposure to TCR-activated T cells or their culture medium, but not T cells activated by other means or growing tumor cells. Further investigation reveals multiple cytokines secreted by TCR-activated T cells as orchestrating two signaling-relay axes, IL-6-to-IL-4 and GM-CSF/IL-4-to-IL-10, leading to arginase-1 expression in MDSC. Specifically, IL-6 signaling increases IL-4R, enabling IL-4 to induce arginase-1 expression; similarly, GM-CSF in concert with IL-4 induces IL-10R, allowing IL-10-mediated induction. Surprisingly, our study indicates that induction of arginase-1 expression is not conducive to the critical MDSC-mediated inhibition toward T cells, which is rather dependent on direct cell contacts undiminished by PD-L1 blockade or SIRPα deficiency. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
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  • 45
    Publication Date: 2018-03-06
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
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  • 46
    Publication Date: 2018-03-06
    Description: Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with rising incidence. Biomarkers that would help the prognostic stratification of patients are urgently needed. Although tumour budding (BD) is a strong and independent prognostic factor in PDAC, is not included in histopathology reports, partly due to lack of standardized scoring system. Aim Aim of the present work is to assess the reliability and reproducibility of the BD scoring system recently proposed by the International Tumour Budding Concensus Conference (ITBCC) 2016, in a well-characterized PDAC-cohort (n=120) with complete clinico-pathological and follow-up information. Methods BD was scored independently by two pathologists on H&E-stained PDAC-sections by assessing the densest budding area at 20x-magnification (one “hotspot”, 0.785mm 2 ) regardless of intra-or peritumoural localisation and assigned into four categories: BD0: 0 buds; BD1: 1-4 buds; BD2: 5-9 buds; and BD3: ≥10 buds. Findings were correlated to patient and tumour characteristics und inter-observer agreement was assessed. Results Weighted kappa value for BD-category was 0.62 (0.5-0.73) indicating strong agreement. Increasing BD-category (BD3 versus BD0-2) correlated with higher grade (p=0.002) and shorter overall (OS, p〈0.0001; HR(95%CI)=3.234(1.95-5.37)) and disease-free survival (DFS, p=0.0135; HR(95%CI)=1.974(1.15-3.39)). BD (BD3 versus BD0-2) was an independent prognostic factor for OS and DFS, after adjusting for TNM-stage by using both the 8 th AJCC Edition (OS; p=0.0031;HR(95%CI)=2.298(1.32-.99)); (DFS; p=0.0458;HR(95%CI)=1.713(1.01-2.91)) and the 7 th AJCC Edition (OS; p〈0.0001;HR(95%CI)=2.795(1.71-4.57)) and (DFS; p=0.00786;HR(95%CI)=1.643(0.95-2.86)). Conclusions ITBCC-scoring is a simple, reliable and reproducible method to evaluate BD in PDAC and facilitates its documentation in histopathology reports allowing the prognostic stratification of PDAC-patients. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
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  • 47
    Publication Date: 2018-03-06
    Description: Aims Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. Dedifferentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumor (MPNST) are the two most common types of sarcoma that can harbor heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST. Methods and results We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, 2 of which contained a low-grade component. The ESOSs affected deep soft tissues (n=10), superficial soft tissues (n=3), and organs (n=6). Among 10 deep soft-tissue ESOSs, 6 showed MDM2 amplification, 4 of which also harbored CDK4 co-amplification. Both ESOSs with a low-grade component showed co-amplification for MDM2 and CDK4 . Among the 6 organ-based ESOSs, 3 giant cell-rich ESOSs showed an H3K27me3 deficiency (1 in primary and 2 in metastatic sites). Using targeted next generation sequencing, an H3K27me3-deficient ESOS showed EED homozygous deletion, while none of the 3 showed alterations in NF1 , CDKN2A , or SUZ12 genes. During median follow-up of 20 months, all 6 patients with MDM2 -amplified ESOS lived for 3–103 months, while 2 of the 3 patients with H3K27me3-deficient ESOS died from this disease in 4 and 20 months, respectively. Conclusion We demonstrate that ESOS may include at least two small subsets: an MDM2 -amplified deep soft-tissue ESOS (which may be related to DDLPS) and an H3K27me3-deficient organ-based ESOS (which is probably unrelated to MPNST). Larger studies are required to validate the present observations and investigate the clinical implications of such subcategorization. This article is protected by copyright. All rights reserved.
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  • 48
    Publication Date: 2018-03-06
    Description: Pulmonary Sarcomatoid Carcinoma (PSC) is a poorly-differentiated non-small cell lung carcinoma (NSCLC) with aggressive behavior. This study aimed to evaluate the prognostic clinicopathologic and genetic characteristics of PSCs. Fifty-three cases of surgically treated PSCs were selected, of which 23 were subjected to mutation and copy number variation analysis using 50-gene Ion AmpliSeq Cancer Panel. Majority of the patients were male (32/53, 60.3%) and smoker (51/53, 96.2%). Overall, 25 (47.1%) patients died within 2 to 105 months (mean 22.7 months, median 15 months) after diagnosis, and 28 were alive as of 3 to 141 months (mean 38.7 months, median 21.5 months) after diagnosis. Five-year overall survival was 12.5%. KRAS codon 12/13 mutation in adenocarcinomas (p= 0.01), age over 70 years (p=0.008) and tumor size ≥ 4.0 cm (p= 0.02) were strongly associated with worse outcome. TP53 (17/23, 74.0%) and KRAS  codon 12/13 mutations (10/23, 43.4%) were the most common genetic alterations. Potentially actionable variants were identified including ATM (4/23, 17.3%), MET, FBXW7 and EGFR (2/23, 8.7%) , AKT1, KIT, PDGFRA, HRAS, JAK3 , and SMAD4 (1/23, 4.3%). MET exon 14 skipping and missense mutations were identified in two (11.1%) cases with adenocarcinoma histology. Copy number analysis showed loss of RB1 (3/23, 13%) and ATM (2/23, 8.7%). Copy number gains were seen in EGFR (2/23, 13.0%), and in one (4.3%) of each PIK3CA , KRAS, MET , and STK11 . Potentially targetable mutations can be identified in a subset of PSC although most tumors harbor currently untargetable prognostically adverse TP53 and KRAS mutations. This article is protected by copyright. All rights reserved.
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  • 49
    Publication Date: 2018-03-06
    Description: Aims To establish whether core needle biopsy (CNB) specimens processed with an accelerated processing method with short fixation time can be used to accurately determine HER2 status of breast cancer. Methods and results A consecutive case series from two high volume breast clinics was created. We compared routine HER2 immunohistochemistry (IHC) assessment between accelerated processing CNB specimens and routinely processed postoperative excision specimens. Additional amplification-based testing was performed in cases with equivocal results. The formalin fixation time was less than 2 hours and between 6 and 72 hours, respectively. Fluorescent in situ hybridization and multiplex ligation-dependent probe amplification were used for amplification testing. One hundred and forty-four cases were included, 15 of which were HER2 positive on the routinely processed excision specimens. On the CNB specimens, 44 were equivocal on IHC and required an amplification-based test. Correlation between the CNB specimens and the corresponding excision specimens was high for final HER2 status, with an accuracy of 97% and a kappa of 0.85. Conclusions HER2 status can be reliably determined on CNB specimens with accelerated processing time using standard clinical testing methods. Using this accelerated technology, the minimum six hours of formalin fixation which current guidelines consider necessary, can safely be decreased. This allows for a complete and expedited histology-based diagnosis of breast lesions in the setting of a one-stop-shop, same-day breast clinic. This article is protected by copyright. All rights reserved.
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  • 50
    Publication Date: 2018-03-06
    Description: Introduction The tumor microenvironment is increasingly important in several tumors. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas. Methods Tissue microarrays were constructed from gastrectomy specimens, 2004-2013. Immunohistochemistry was performed for programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate-binding protein 5 (GBP5), tumor-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1, and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6. Clinicopathological parameters and clinical follow-up were recorded. Results The study included 86 patients, median follow-up was 34 months (0-148). Tumor types were 45% tubular, 38% diffuse, 17% mixed. PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53%, and stromal GBP5 in 71%. MMR-deficiency was found in 22%. There was no difference in biomarker expression by histological subtype, with exception fewer diffuse-type being MMR-deficient. Low stromal IDO was associated with decreased progression-free, overall and disease-specific survival. PD-L1-positive tumors were larger with MMR-deficiency and with increasing TILs, and had significantly higher FoxP3- TILs. Conclusions PD-L1 is expressed in a large proportion of gastric carcinomas suggesting that therapy targeting this pathway could be relevant to many patients. PD-L1 expression and MMR-deficiency are associated with increased TILs and larger tumor size, emphasizing their role in tumor biology. Higher stromal IDO expression is associated with better prognosis. Finally, we observed that immune modulators WARS and GBP5 are highly expressed in gastric adenocarcinomas, suggesting an important role in tumor pathobiology. This article is protected by copyright. All rights reserved.
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  • 51
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    Publication Date: 2018-03-06
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
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  • 52
    Publication Date: 2018-03-06
    Description: Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, Androgen Receptor (AR) and Human Epidermal Growth Factor Receptor 2 (HER2) expression. SDC patients diagnosed between 1990 – 2014 were identified by the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease free survival (DFS), distant metastasis free survival (DMFS), and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent-in-situ-hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and, to a lesser extent, HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 53
    Publication Date: 2018-03-06
    Description: Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes, and homeostasis model-insulin resistance (HOMA-IR – a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-〈25.0, 25.0-〈30.0, and ≥30.0 kg/m 2 ) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis. This article is protected by copyright. All rights reserved.
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  • 54
    Publication Date: 2018-03-06
    Description: The role of host epigenetic mechanisms in the natural history of low-grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression. A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow-up visits over three years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine-phosphate-guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non-regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time-point), adjusting for age, race, high-risk HPV (hrHPV), parity, oral contraceptive and smoking status. Median participant age was 26.6 years (range: 21-64.4 years), 39.0% were African-American, and 11% were current smokers. Most participants were hrHPV-positive at enrollment (80.5%). Over one-third of cases regressed (n=53, 35.1%). Median time-to-regression was 12.6 months (range: 4.5-24.0 months). Probability of CIN1 regression was negatively correlated to methylation at IGF2AS CpG 5 (HR=0.41; 95% CI=0.23-0.77) and PEG10 DMR (HR=0.80; 95% CI=0.65-0.98). Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening. This article is protected by copyright. All rights reserved.
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  • 55
    Publication Date: 2018-03-06
    Description: Background Glioma cells may infiltrate beyond the tumor margins revealed on conventional structural images. Purpose To investigate whether the presence of a glioma infiltration sign on high b-value diffusion-weighted imaging (DWI) can predict the prognosis of gliomas. Study Type Retrospective cohort. Subjects Fifty-two patients with gliomas (14 WHO grade II; 13 WHO grade III; 25 WHO grade IV). Field Strength/Sequence 3.0T, including a T 1 -weighted contrast-enhanced (T 1 w-CE) sequence, contrast-enhanced T 2 -flair sequence, and a DWI sequence. Assessment T 1 w-CE images and contrast-enhanced T 2 -flair images were used for identifying the tumor region for enhancing and nonenhancing gliomas, respectively. The glioma infiltration sign was defined as the presence of a peritumoral abnormal high signal region on DWI map, which was adjacent to the tumor region and had higher signal than surrounding areas. This sign was assessed on a high b-value DWI map with b  = 3000 s/mm 2 . For patients with glioma infiltration sign, DWI3000 max , DWI1000 max , ADC3000 min , and ADC1000 min were measured by drawing a region of interest over the peritumoral abnormal high signal region. Statistical Tests Survival analysis was conducted by using Cox regression. Results Glioma infiltration sign was observed in 28 (53.8%) patients. The occurrence rate of this sign was 92.0% in grade IV gliomas, 30.8% in grade III gliomas, and 7.1% in grade II gliomas. The glioma infiltration sign could independently predict both the progression-free survival (hazard ratio [HR], 95% confidence interval [CI] = 8.58 [3.19–23.03], P  〈 0.001) and overall survival (HR, 95% CI = 11.90 [3.41–41.55], P  〈 0.001) after adjustment. For patients with glioma infiltration sign, DWI3000 max ( P  = 0.005) and ADC3000 min ( P  = 0.008) were both independent predictors of overall survival after adjustment, while DWI1000 max and ADC1000 min were not. Data Conclusion The glioma infiltration sign on high b-value DWI is an independent predictor of poor prognosis in glioma patients. High b-value DWI might be a convenient method to detect glioma infiltration. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
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  • 56
    Publication Date: 2018-03-06
    Description: One of the therapeutic options for the treatment of fulminant hepatitis is re-population of intrahepatic regulatory cells since their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of T regulatory cells (Tregs) and B regulatory cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure. MSC-dependent attenuation of α-galactosylceramide (α-GalCer)-induced acute liver injury in mice was accompanied with an increased presence of IL-10 producing CD4 + CD25 + FoxP3 + Tregs and IL-10 and TGF-β producing marginal zone (MZ)-like Bregs in the liver. Depletion of Bregs did not alter MSC-based alleviation of acute liver failure, while depletion of Tregs completely abrogated hepato-protective effects of MSCs and inhibit their capacity to attenuate hepatotoxicity of liver natural killer T (NKT) cells, indicating that Tregs, and not Bregs, were critically involved in MSC-based modulation of acute liver inflammation. MSCs, in paracrine, indoleamine 2,3-dioxygenase (IDO)-dependent manner, significantly increased capacity of Tregs to produce immunosuppressive IL-10 and to suppress hepatotoxicity of liver NKT cells. Accordingly, adoptive transfer of MSC-primed Tregs resulted with the complete attenuation of α-GalCer-induced acute liver failure. In conclusion, our findings highlighted the crucial importance of Tregs for MSC-based attenuation of acute liver failure and indicate the significance of MSC-mediated priming of Tregs as new therapeutic approach in Tregs-based therapy of acute liver injury. This article is protected by copyright. All rights reserved.
    Print ISSN: 1527-6465
    Electronic ISSN: 1527-6473
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  • 57
    Publication Date: 2018-03-06
    Print ISSN: 1527-6465
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  • 58
    Publication Date: 2018-03-06
    Description: ABSTRACT Background : Although the type of hepatic artery revascularization technique is known to impact on patency rates, independent perioperative risk factors on patient outcomes are poorly defined. Methods : All consecutive adult patients undergoing cadaveric liver transplantation (n=361) from July 2007 to June 2016 in a single institution were analyzed. Primary outcomes were early (〈30 days) hepatic artery occlusion and primary hepatic artery patency rate. A multivariate model was used to identify independent risk factors for occlusion and the need of arterial conduit, as well as their impact on graft and patient survival. Results : Arterial revascularization without additional reconstruction (AA) was performed in 77% (n=279), arterial reconstruction (AR) in 15% (n=53), and aorto-hepatic conduit (AHC) in 8% (n=29) of cases, respectively. AHC had the highest mean intraoperative flow (275 ml/min; p=0.024) compared to AA (250 ml/min) and AR (200 ml/min), p=0.024. 43 recipients (12%) had an occlusive event with successful revascularization in 20 recipients (47%). One-year primary patency rates of AA, AR, and AHC were 97, 88, and 74%. Aortic calcification had an impact on early occlusion. AR (OR 3.68 (1.26-10.75), p=0.017) and AHC (OR 6.21 (2.02-18.87, p=0.001) were independent risk factors for early occlusion. Dyslipidemia additionally independently contributed to early occlusion (OR 2.74 (0.96-7.87), p=0.06). One- and five-year graft survival were 83% and 70% for AA, 75% and 69% for AR, and 59% and 50% for AHC (p=0.004). Conclusions : Arterial patency is primarily determined by the type of vascular reconstruction rather than patient or disease characteristics. The preoperative lipid status is an independent risk factor for early occlusion, while overall occlusion is only based on the performed vascular reconstruction, which is also associated with reduced graft and patient survival. This article is protected by copyright. All rights reserved.
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  • 59
    Publication Date: 2018-03-06
    Description: We investigated the adhesive behaviour of mesenchymal stem cells (MSC) in blood, which might influence their fate when infused as therapy. Isolated human bone marrow (BM) or umbilical cord (UC) MSC adhered efficiently from flow to the matrix proteins, collagen or fibronectin, but did not adhere to endothelial selectins. However, when suspended in blood, BMMSC no longer adhered to collagen, while UCMSC adhered along with many aggregated platelets. Neither MSC adhered to fibronectin from flowing blood, although the fibronectin surface did become coated with a platelet monolayer. UCMSC induced platelet aggregation in platelet rich plasma, and caused a marked drop in platelet count when mixed with whole human or mouse blood in vitro, or when infused into mice. In contrast, BMMSC did not activate platelets or induce changes in platelet count. Interestingly, isolated UCMSC and BMMSC both adhered to pre-deposited platelets. The differences in behaviour in blood were attributable to expression of podoplanin (an activating ligand for the platelet receptor CLEC-2), which was detected on UCMSC, but not BMMSC. Thus, platelets were activated when bound to UCMSC, but not BMMSC. Platelet aggregation by UCMSC was inhibited by recombinant soluble CLEC-2, and UCMSC did not cause a reduction in platelet count when mixed with blood from mice deficient in CLEC-2. We predict that both MSC would carry platelets in the blood, but their interaction with vascular endothelium would depend on podoplanin-induced activation of the bound platelets. Such interactions with platelets might target MSC to damaged tissue, but could also be thrombotic. This article is protected by copyright. All rights reserved. BMMSC and UCMSC are both able to bind directly to collagen and fibronectin. However, in blood, BMMSC bind platelets which are inactive and effectively shield them so that they do not adhere to platelets deposited on fibronectin or collagen. UCMSC express podoplanin (PDPN) so that they not only bind platelets but also activated them through CLEC-2. They bind with activated platelets on collagen but do not adhere to the minimally activated platelets on fibronectin. In the flowing blood, the UCMSC with bound platelets may be able to drive wider-spread activation and aggregation of platelets, that leads to a reduction in platelet count in vitro or in vivo.
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
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  • 60
    Publication Date: 2018-03-07
    Description: Despite their diversity and ecological importance, many areas of the SAR—Stramenopila, Alveolata, and Rhizaria—clade are poorly understood as the majority (90%) of SAR species lack molecular data and only 5% of species are from well-sampled families. Here, we review and summarize the state of knowledge about the three major clades of SAR, describing the diversity within each clade and identifying synapomorphies when possible. We also assess the “dark area” of SAR: the morphologically described species that are missing molecular data. The majority of molecular data for SAR lineages are characterized from marine samples and vertebrate hosts, highlighting the need for additional research effort in areas such as freshwater and terrestrial habitats and “non-vertebrate” hosts. We also describe the paucity of data on the biogeography of SAR species, and point to opportunities to illuminate diversity in this major eukaryotic clade. See also the video abstract here: https://youtu.be/_VUXqaX19Rw . Despite their diversity, abundance, and importance, fewer than 10% of the species within the SAR—Stramenopila, Alveolata, and Rhizaria—clade have been assessed using molecular tools. Only a small percentage of the molecular records contain information on ecology or have associate location data, indicating a tremendous dark area.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 61
    Publication Date: 2018-03-07
    Description: The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen.In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m² was administered every three or four weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS).An upfront dose-reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G-CSF was prescribed to all the patients. Grade ≥3 neutropenia and Febrile neutropenia occurred in 21 patients and (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated with a median of 5 cycles (range 1-17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 months and 15.0 months (95% CI 8.9– 21.2), respectively. Waterfall plot analysis revealed a PSA decline 〉 50% was noticed in n=11 patients receiving cabazitaxel (26.8%).Univariate analysis revealed that an poor performance status, PSA ≥100 ng/mL prior to cabazitaxel treatment, visceral metastasis, the absence of grade 3/4 neutropenia during cabazitaxel therapy and NLR were significantly associated with shorter overall survival. Multivariate analysis revealed that poor PS, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its haematological effects. This article is protected by copyright. All rights reserved.
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  • 62
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    Publication Date: 2018-03-07
    Description: Cover of this issue. Cladogran of taxa of microbiota in the mice in the model and Bifico group. See also Song et al. (pp. 666–677 of this issue).
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  • 63
    Publication Date: 2018-03-07
    Description: Despite considerable research on K-Ras inhibitors, none had been developed until now. We synthesized nuclease-resistant synthetic miR-143 (miR-143#12), which strongly silenced K-Ras, its effector signal molecules AKT and ERKs, and the K-Ras activator Sos1. We examined the anti-proliferative effect of miR-143#12 and the mechanism in human colon cancer DLD-1 cell (G13D) and other cell types harboring K-Ras mutations. Cell growth was markedly suppressed in a concentration-dependent manner by miR-143#12 (IC 50 : 1.32 nM) with a decreased in the K-Ras mRNA level. Interestingly, this mRNA level was also down-regulated by either a PI3K/AKT or MEK inhibitor, which finding indicates a positive circuit of K-Ras mRNA expression. MiR-143#12 silenced cytoplasmic K-Ras mRNA expression and impaired the positive circuit by directly targeting AKT and ERK mRNAs. Combination treatment with miR-143#12 and a low-dose EGFR inhibitor induced a synergistic inhibition of growth with a marked inactivation of both PI3K/AKT and MAPK/ERK signaling pathways. However, silencing K-Ras by siR-KRas instead of miR-143#12 did not induce this synergism by the combined treatment with the EGFR inhibitor. Thus, miR-143#12 perturbed the K-Ras expression system and K-Ras activation by silencing Sos1 and resultantly, recovered the efficacy of the EGFR inhibitors. In vivo results also supported those of the in vitro experiments. The extremely potent miR-143#12 enabled us to well understand K-Ras signaling networks and shut them down by combination treatment with this miRNA and EGFR inhibitor in K-Ras-driven colon cancer cell lines. This article is protected by copyright. All rights reserved.
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  • 64
    Publication Date: 2018-03-07
    Description: In boron neutron capture therapy (BNCT), 10 B-4-borono-L-phenylalanine (BPA) is commonly used as a 10 B carrier. Positron emission tomography using 4-borono-2- 18 F-fluoro-phenylalanine ( 18 F-FBPA PET) has been performed to estimate boron concentration and predict the therapeutic effects of BNCT; however, the association between tumor uptake of 18 F-FBPA and boron concentration in tumors remains unclear. The present study investigated the transport mechanism of 18 F-FBPA and BPA, and evaluated the utility of 18 F-FBPA PET in predicting boron concentration in tumors. The transporter assay revealed that 2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid, an inhibitor of the L-type amino acid transporter, significantly inhibited 18 F-FBPA and 14 C-BPA uptake in FaDu and LN-229 human cancer cells. 18 F-FBPA uptake strongly correlated with 14 C-BPA uptake in seven human tumor cell lines (r = 0.93; p 〈0.01). PET experiments demonstrated that tumor uptake of 18 F-FBPA was independent of the administration method, and uptake of 18 F-FBPA by bolus injection correlated well with BPA uptake by continuous intravenous infusion. The results of this study revealed that evaluating tumor uptake of 18 F-FBPA by PET was useful for estimating 10 B concentration in tumors. This article is protected by copyright. All rights reserved.
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  • 65
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    Publication Date: 2018-03-07
    Print ISSN: 0007-9235
    Electronic ISSN: 1542-4863
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of American Cancer Society.
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  • 66
    Publication Date: 2018-03-07
    Description: Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 as predictive biomarker is still under critical evaluation. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO-1 and other immune inhibitory molecules (PD-L1, PD-L2, FOXP3) as well as immune cell subsets (CD3, CD4, CD8) were measured on formalin-fixed, paraffin-embedded sections of RCC specimens by immunohistochemistry. IDO-1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO-1 overexpression (〉10%) could be detected more frequently in responders (100%, n=6/6) compared to non-responders (33.3%, n=3/9; p =0.028), resulting in a better progression-free survival during immunotherapy (IDO-1 ≤10% vs . 〉10%, median: 3.5 vs . NE months, p =0.01 by log-rank test). In addition, IDO-1 was positively correlated with CD8 + T cell expression (r s =0.691, p =0.006). PD-L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs . non-responders: 83.3% vs . 88.9%). No differences were noticed in the PD-L1 expression on tumor-infiltrating immune cells (PD-L1〈1% in 66.7% of both responders and non-responders). In contrast to PD-L1, these results suggest that IDO-1 may be a more promising predictive biomarker for response to immune-based cancer therapy in mRCC. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 67
    Publication Date: 2018-03-07
    Description: Metastasis is the leading cause of cancer deaths. A tumor-supportive microenvironment, or premetastatic niche, at potential secondary tumor sites plays an important role in metastasis, especially in tumor cell colonization. Although a fibrotic milieu is known to promote tumorigenesis and metastasis, the underlying molecular contributors to this effect have remained unclear. Here we show that periostin, a component of the extracellular matrix that functions in tissue remodeling, has a key role in formation of a fibrotic environment that promotes tumor metastatic colonization. We found that periostin was widely expressed in fibrotic lesions of mice with bleomycin-induced lung fibrosis, and that up-regulation of periostin expression coincided with activation of myofibroblasts positive for α–smooth muscle actin. We established a lung metastasis model for B16 murine melanoma cells and showed that metastatic colonization of the lung by these cells was markedly promoted by bleomycin-induced lung fibrosis. Inhibition of periostin expression by intratracheal administration of an antisense oligonucleotide targeting periostin mRNA was found to suppress bleomycin-induced lung fibrosis and thereby to attenuate metastatic colonization of the lung by melanoma cells. Our results indicate that periostin is a key player in the development of bleomycin-induced fibrosis and consequent enhancement of tumor cell colonization in the lung, and they therefore implicate periostin as a potential target for prevention or treatment of lung metastasis. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 68
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    Wiley-Blackwell
    Publication Date: 2018-03-07
    Topics: Medicine
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  • 69
    Publication Date: 2018-03-07
    Description: Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of nodal peripheral T-cell lymphomas. Somatic RHOA mutations, most frequently found at the hotspot site c.50G〉T, p. Gly17Val (G17V RHOA mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next generation sequencing (NGS), droplet digital PCR (ddPCR) and PNA-LNA clamp method for detecting the G17V RHOA mutations. The G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA-LNA clamp method both detected the G17V mutations in 4 samples in addition to those detected with NGS (31of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance ( P 〈0.001). Three other RHOA mutations involving the p.Gly17 position (c.[49G〉T;50G〉T], p.Gly17Leu in PTCL198; c.[50G〉T;51A〉C], p.Gly17Val in PTCL216; and c.50G〉A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and PNA-LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had the RHOA mutations at the p.Gly17Val position. In conclusion, our results suggested that combination of ddPCR/PNA-LNA clamp methods and NGS are best feasible to assist the diagnosis of AITL by detecting the RHOA mutations at the p.Gly17 position. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 70
    Publication Date: 2018-03-07
    Description: Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signaling molecules. The presence of many activating receptors and many members of a given family of signaling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signaling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 71
    Publication Date: 2018-03-07
    Description: A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22 , that encodes a tyrosine phosphatase, has been associated with the development of several autoimmune diseases including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates the activity and effector functions of multiple important immune cell types including lymphocytes, granulocytes and myeloid cells. In this review, we describe the role of PTPN22 in regulating T cell activation and effector responses. We discuss progress in our understanding of the impact of PTPN22 in autoimmune disease in humans and mouse models as well as recent evidence suggesting that genetic manipulation of PTPN22 expression might enhance the efficacy of anti-tumour T cell responses. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 72
    Publication Date: 2018-03-07
    Description: Background Protective roles have been proposed for vitamin D in prostate cancer, which has the advanced age as the major risk factor. However, little is known about the expression of the vitamin D receptor (VDR) in the aging prostate and its association with the development of epithelial lesions that affect tissue homeostasis and may precede prostate tumors. Methods VDR expression in the prostatic complex of young adults to senile Wistar rats, a natural model to study age-related prostatic disorders, was evaluated by immunohistochemical, Western blotting, and image-assisted analyzes. Results were correlated with the plasma levels of vitamin D and testosterone, the occurrence of punctual histopathological changes in the aging prostate, and the expression of retinoid X receptors (RXR). Results VDR was widely distributed in the prostatic complex at all ages analyzed, with the highest immunoexpression found in basal epithelial cells. As the animals aged, VDR levels increased, except in punctual areas with intraepithelial proliferation, metaplasia, or proliferative inflammatory atrophy, which had reduced expression of this receptor concomitantly with increased cell proliferation. Interestingly, RXR expression in the aging prostate was similar to that found for its partner VDR, indicating that components of the VDR/RXR complex required for vitamin D signaling are affected in aging-related prostatic lesions. Moreover, plasma vitamin D levels declined at the same ages when prostatic alterations appeared. Although circulating levels of testosterone also decreased with aging, the changes observed in the components of the vitamin D system were not correlated with androgens. Conclusions Our data indicate that the aging prostate suffers from an imbalance on the intricate mechanism of tissue regulation by the vitamin D responsive system. We argue that the status of VDR expression might be determinant for the development of histopathological alterations in the aging prostate, which include premalignant lesions.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 73
    Publication Date: 2018-03-07
    Description: Terrestrial primary production is a fundamental ecological process and a crucial component in understanding the flow of energy through trophic levels. The global MODIS gross primary production (GPP) and net primary production (NPP) products (MOD17) are widely used for monitoring GPP and NPP at coarse resolutions across broad spatial extents. The coarse input datasets and global biome-level parameters, however, are well-known limitations to the applicability of the MOD17 product at finer scales. We addressed these limitations and created two improved products for the conterminous United States (CONUS) that capture the spatiotemporal variability in terrestrial production. The MOD17 algorithm was utilized with medium resolution land cover classifications and improved meteorological data specific to CONUS in order to produce: (a) Landsat derived 16-day GPP and annual NPP at 30 m resolution from 1986 to 2016 (GPP L 30 and NPP L 30 , respectively); and (b) MODIS derived 8-day GPP and annual NPP at 250 m resolution from 2001 to 2016 (GPP M 250 and NPP M 250 respectively). Biome-specific input parameters were optimized based on eddy covariance flux tower-derived GPP data from the FLUXNET2015 database. We evaluated GPP L 30 and GPP M 250 products against the standard MODIS GPP product utilizing a select subset of representative flux tower sites, and found improvement across all land cover classes except croplands. We also found consistent interannual variability and trends across NPP L 30 , NPP M 250 , and the standard MODIS NPP product. We highlight the application potential of the production products, demonstrating their improved capacity for monitoring terrestrial production at higher levels of spatial detail across broad spatiotemporal scales. We produced two higher resolution primary production datasets, using better input data than currently existing datasets. These products more closely match the scale of many ecological processes and management activities, and will facilitate better understandings of production dynamics. Our products correspond well with other production datasets at multiple scales. The products fill a critical gap in our ability to monitor and assess terrestrial production dynamics in relation to many ecological processes and land use change. As production is a foundational ecological process and ecosystem service, understanding these dynamics is critical for environmental sustainability.
    Electronic ISSN: 2056-3485
    Topics: Architecture, Civil Engineering, Surveying , Biology
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  • 74
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    Wiley-Blackwell
    Publication Date: 2018-03-07
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
    Published by Wiley-Blackwell
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