The key to perfect radiation endurance is perfect recovery. Since surfaces are perfect sinks for defects, a porous material with a high surface to volume ratio has the potential to be extremely ...radiation tolerant, provided it is morphologically stable in a radiation environment. Experiments and computer simulations on nanoscale gold foams reported here show the existence of a window in the parameter space where foams are radiation tolerant. We analyze these results in terms of a model for the irradiation response that quantitatively locates such window that appears to be the consequence of the combined effect of two length scales dependent on the irradiation conditions: (i) foams with ligament diameters below a minimum value display ligament melting and breaking, together with compaction increasing with dose (this value is typically ∼5 nm for primary knock on atoms (PKA) of ∼15 keV in Au), while (ii) foams with ligament diameters above a maximum value show bulk behavior, that is, damage accumulation (few hundred nanometers for the PKA's energy and dose rate used in this study). In between these dimensions, (i.e., ∼100 nm in Au), defect migration to the ligament surface happens faster than the time between cascades, ensuring radiation resistance for a given dose-rate. We conclude that foams can be tailored to become radiation tolerant.
Global concern for the illicit transportation and trafficking of nuclear materials and other radioactive sources is on the rise, with efficient and rapid security and non-proliferation technologies ...in more demand than ever. Many factors contribute to this issue, including the increasing number of terrorist cells, gaps in security networks, politically unstable states across the globe and the black-market trading of radioactive sources to unknown parties. The use of passive gamma-ray and neutron detection and imaging technologies in security-sensitive areas and ports has had more impact than most other techniques in detecting and deterring illicit transportation and trafficking of illegal radioactive materials. This work reviews and critically evaluates these techniques as currently utilised within national security and non-proliferation applications and proposes likely avenues of development.
Recent Advances in Imprinting Disorders Soellner, L.; Begemann, M.; Mackay, D.J.G. ...
Clinical genetics,
January 2017, Letnik:
91, Številka:
1
Journal Article
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Imprinting disorders (ImpDis) are a group of currently 12 congenital diseases with common underlying (epi)genetic etiologies and overlapping clinical features affecting growth, development and ...metabolism. In the last years it has emerged that ImpDis are characterized by the same types of mutations and epimutations, i.e. uniparental disomies, copy number variations, epimutations, and point mutations. Each ImpDis is associated with a specific imprinted locus, but the same imprinted region can be involved in different ImpDis. Additionally, even the same aberrant methylation patterns are observed in different phenotypes. As some ImpDis share clinical features, clinical diagnosis is difficult in some cases. The advances in molecular and clinical diagnosis of ImpDis help to circumvent these issues, and they are accompanied by an increasing understanding of the pathomechanism behind them. As these mechanisms have important roles for the etiology of other common conditions, the results in ImpDis research have a wider effect beyond the borders of ImpDis. For patients and their families, the growing knowledge contributes to a more directed genetic counseling of the families and personalized therapeutic approaches.
We employ molecular dynamics (MD) simulation and experiment to investigate the structure, thermodynamics, and transport of N-methyl-N-butylpyrrolidinium bis(trifluoromethylsufonyl)imide (pyr14TFSI), ...N-methyl-N-propylpyrrolidinium bis(fluorosufonyl)imide (pyr13FSI), and 1-ethyl-3-methylimidazolium boron tetrafluoride (EMIMBF4), as a function of Li-salt mole fraction (0.05 ≤ x Li+ ≤ 0.33) and temperature (298 K ≤ T ≤ 393 K). Structurally, Li+ is shown to be solvated by three anion neighbors in pyr14TFSI and four anion neighbors in both pyr13FSI and EMIMBF4, and at all levels of x Li+ we find the presence of lithium aggregates. Pulsed field gradient spin-echo NMR measurements of diffusion and electrochemical impedance spectroscopy measurements of ionic conductivity are made for the neat ionic liquids as well as 0.5 molal solutions of Li-salt in the ionic liquids. Bulk ionic liquid properties (density, diffusion, viscosity, and ionic conductivity) are obtained with MD simulations and show excellent agreement with experiment. While the diffusion exhibits a systematic decrease with increasing x Li+ , the contribution of Li+ to ionic conductivity increases until reaching a saturation doping level of x Li+ = 0.10. Comparatively, the Li+ conductivity of pyr14TFSI is an order of magnitude lower than that of the other liquids, which range between 0.1 and 0.3 mS/cm. Our transport results also demonstrate the necessity of long MD simulation runs (∼200 ns) to converge transport properties at room temperature. The differences in Li+ transport are reflected in the residence times of Li+ with the anions (τLi/–), which are revealed to be much larger for pyr14TFSI (up to 100 ns at the highest doping levels) than in either EMIMBF4 or pyr13FSI. Finally, to comment on the relative kinetics of Li+ transport in each liquid, we find that while the net motion of Li+ with its solvation shell (vehicular) significantly contributes to net diffusion in all liquids, the importance of transport through anion exchange increases at high x Li+ and in liquids with large anions.
Disease outbreaks induced by humans increasingly threaten wildlife communities worldwide. Like predators, pathogens can be key top‐down forces in ecosystems, initiating trophic cascades that may ...alter food webs. An outbreak of mange in a remote Andean protected area caused a dramatic population decline in a mammalian herbivore (the vicuña), creating conditions to test the cascading effects of disease on the ecological community. By comparing a suite of ecological measurements to pre‐disease baseline records, we demonstrate that mange restructured tightly linked trophic interactions previously driven by a mammalian predator (the puma). Following the mange outbreak, scavenger (Andean condor) occurrence in the ecosystem declined sharply and plant biomass and cover increased dramatically in predation refuges where herbivory was historically concentrated. The evidence shows that a disease‐induced trophic cascade, mediated by vicuña density, could supplant the predator‐induced trophic cascade, mediated by vicuña behaviour, thereby transforming the Andean ecosystem.
An outbreak of Sarcoptic mange in a vicuña population in a remote protected area in the Argentine Andes reconfigured the tightly‐linked vertebrate food web, transforming a trophic cascade. Mange triggered a population crash in the large mammalian herbivore that released vegetation in predation refuge habitats, but not in habitats with high predation risk, where a behaviourally mediated trophic cascade driven by puma predation shielded vegetation from the effects of herbivory. This disease‐mediated shift also led to the near‐abandonment of the protected area by the dominant scavenger, the Andean condor, which was previously tethered to the region by a steady provisioning of vicuña carcasses from puma predation.
A compact back-end interface for silicon photomultipliers (SiPMs) implementing Zener diode-based temperature compensation has been developed for the remote detection of beta and gamma radiation. ...Remote detection is facilitated by the development of an efficient data management system utilising MySQL database storage for recording periodic spectra data for wireless access over a private Wi-Fi network. A trapezoidal peak shaping algorithm has been implemented on an FPGA for the continuous conversation of pulses from the SiPM, signifying the detection of a radiological particle, into spectra. This system has been designed to fit within a 46 mm cylindrical diameter for in situ characterization, and can be attached to one or more SiPMs used in conjunction with a range of scintillators. LED blink tests have been used to optimise the trapezoidal shaper coefficients to maximise the resolution of the recorded spectra. Experiments with an array of SiPMs integrated with a NaI(Tl) scintillator exposed to sealed sources of Co-60, Cs-137, Na-22 and Am-241 have shown that the detector achieves a peak efficiency of 27.09 ± 0.13% for a gamma peak at 59.54 keV produced by Am-241, and a minimum energy resolution (Delta E/E) of 4.27 ± 1.16% for the 1332.5 keV gamma peak from Co-60.
Algorithms to generate atomistic models of cross-linked phenolic resins suitable for molecular dynamics simulations were investigated. The influence of five parameters (initial volume of ...uncross-linked material, cross-linking approach, relaxation time, equilibration temperature) on generating cross-linked structures was studied quantitatively using a full factorial sensitivity analysis. The parameters were found to be dependent on the degree of cross linking (D). For low cross-linking, only the equilibration temperature has a significant impact on the final energetics and densities. However, for higher cross-linking (D > 70%), the equilibration temperature, initial volume and cross-linking approach were shown to influence the phenolic structures. Iterative, rather than single step, methods were shown to produce better structures. The initial volume of the uncross-linked material was identified as having the most influence on the final volume of fully cross-linked systems. By optimizing all five parameters, highly cross-linked samples with low energetics and consistent densities could be generated. To validate the models, thermo-mechanical properties of cross-linked phenolic samples were characterized as a function of density and degree of cross-linking. Good agreement with experimental values was obtained for properties such as the glass transition temperature, coefficient of thermal expansion (CTE), elastic moduli, and thermal conductivity.
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•Analysis of algorithms to produce cross-linked phenolic structures.•Iterative cross-linking approach produced low variability high cross-linked configurations.•Algorithm parameters influence the final densities and energetics of cross-linked phenolic.•Mechanical and thermal properties depend strongly on density and degree of cross-linking.•Good agreement with experiments was found for thermal conductivity and Young's modulus.
BACKGROUND AND PURPOSE IL‐13 is a pleiotropic Th2 cytokine considered likely to play a pivotal role in asthma. Here we describe the preclinical in vitro and in vivo characterization of CAT‐354, an ...IL‐13‐neutralizing IgG4 monoclonal antibody (mAb), currently in clinical development.
EXPERIMENTAL APPROACH In vitro the potency, specificity and species selectivity of CAT‐354 was assayed in TF‐1 cells, human umbilical vein endothelial cells and HDLM‐2 cells. The ability of CAT‐354 to modulate disease‐relevant mechanisms was tested in human cells measuring bronchial smooth muscle calcium flux induced by histamine, eotaxin generation by normal lung fibroblasts, CD23 upregulation in peripheral blood mononuclear cells and IgE production by B cells. In vivo CAT‐354 was tested on human IL‐13‐induced air pouch inflammation in mice, ovalbumin‐sensitization and challenge in IL‐13 humanized mice and antigen challenge in cynomolgus monkeys.
KEY RESULTS CAT‐354 has a 165 pM affinity for human IL‐13 and functionally neutralized human, human variant associated with asthma and atopy (R130Q) and cynomolgus monkey, but not mouse, IL‐13. CAT‐354 did not neutralize human IL‐4. In vitro CAT‐354 functionally inhibited IL‐13‐induced eotaxin production, an analogue of smooth muscle airways hyperresponsiveness, CD23 upregulation and IgE production. In vivo in humanized mouse and cynomolgus monkey antigen challenge models CAT‐354 inhibited airways hyperresponsiveness and bronchoalveolar lavage eosinophilia.
CONCLUSIONS AND IMPLICATIONS CAT‐354 is a potent and selective IL‐13‐neutralizing IgG4 mAb. The preclinical data presented here support the trialling of this mAb in patients with moderate to severe uncontrolled asthma.
Molecular dynamics simulations and experimental measurements were used to investigate the thermal and mechanical properties of cross-linked phenolic resins as a function of the degree of ...cross-linking, the chain motif (ortho–ortho versus ortho–para), and the chain length. The chain motif influenced the type (interchain or intrachain) as well as the amount of hydrogen bonding. Ortho–ortho chains favored internal hydrogen bonding whereas ortho–para favored hydrogen bonding between chains. Un-cross-linked ortho–para systems formed percolating 3D networks of hydrogen bonds, behaving effectively as “hydrogen gels”. This resulted in differing thermal and mechanical properties for these systems. As cross-linking increased, the chain motif, chain length, and hydrogen bonding networks became less important. Elastic moduli, thermal conductivity, and glass transition temperatures were characterized as a function of cross-linking and temperature. Both our own experimental data and literature values were used to validate our simulation results.
The epigenetic phenomenon of genomic imprinting provides an additional level of gene regulation that is confined to a limited number of genes, frequently, but not exclusively, important for embryonic ...development. The evolution and maintenance of imprinting has been linked to the balance between the allocation of maternal resources to the developing fetus and the mother's well being. Genes that are imprinted in both the embryo and extraembryonic tissues show extensive conservation between a mouse and a human. Here we examine the human orthologues of mouse genes imprinted only in the placenta, assaying allele-specific expression and epigenetic modifications. The genes from the KCNQ1 domain and the isolated human orthologues of the imprinted genes Gatm and Dcn all are expressed biallelically in the human, from first-trimester trophoblast through to term. This lack of imprinting is independent of promoter CpG methylation and correlates with the absence of the allelic histone modifications dimethylation of lysine-9 residue of H3 (H3K9me2) and trimethylation of lysine-27 residue of H3 (H3K27me3). These specific histone modifications are thought to contribute toward regulation of imprinting in the mouse. Genes from the IGF2R domain show polymorphic concordant expression in the placenta, with imprinting demonstrated in only a minority of samples. Together these findings have important implications for understanding the evolution of mammalian genomic imprinting. Because most human pregnancies are singletons, this absence of competition might explain the comparatively relaxed need in the human for placentalspecific imprinting.
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