On the identification of twinning in body-centred cubic nanoparticles

Many metals and alloys, including Fe and W, adopt body-centred cubic (BCC) crystal structures and nanoparticles of these metals are gaining significant scientific and industrial relevance. Twinning has a marked effect on catalytic activity, yet there is little evidence for or against the presence of twinning in BCC nanoparticles. Here, we explore the potential shapes of twinned BCC nanoparticles, and predict their electron microscopy and diffraction signatures. BCC single crystal and twinned shapes often appear similar and diffraction patterns along common, low-index zone axes are often indistinguishable, casting doubt on many claims of single crystallinity. We conclude by outlining how nanoparticles can be characterized to conclusively prove the presence or absence of twinning

A homogenizing process of selection has maintained an \u27ultra-slow\u27 acetylation NAT2 variant in humans

N-acetyltransferase 2 (NAT2) is an important enzyme involved in the metabolism of a wide spectrum of naturally occurring xenobiotics, including therapeutic drugs and common environmental carcinogens. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in acetylation capacity which influences individual susceptibility to various drug-induced adverse reactions and cancers. Striking patterns of geographic differentiation have been described for the main slow acetylation variants of the NAT2 gene, suggesting the action of natural selection at this locus. In the present study, we took advantage of the whole-genome sequence data available from the 1000 Genomes project to investigate the global patterns of population genetic differentiation at NAT2 and determine whether they are atypical compared to the remaining variation of the genome. The non-synonymous substitution c.590G\u3eA (rs1799930) defining the slow NAT2*6 haplotype cluster exhibited an unusually low FST value when compared to the genome average (FST = 0.006, P-value = 0.016). It was pointed out as the most likely target of a homogenizing process of selection promoting the same allelic variant in globally distributed populations. The rs1799930 A allele has been associated with the slowest acetylation capacity in vivo and its substantial correlation with the subsistence strategy adopted by past human populations suggests that it may have conferred a selective advantage in populations shifting from foraging to agricultural and pastoral activities in the Neolithic period. Results of neutrality tests further supported an adaptive evolution of the NAT2 gene through either balancing selection or directional selection acting on multiple standing slow-causing variants

Decoration of plasmonic Mg nanoparticles by partial galvanic replacement.

Plasmonic structures have attracted much interest in science and engineering disciplines, exploring a myriad of potential applications owing to their strong light-matter interactions. Recently, the plasmonic concentration of energy in subwavelength volumes has been used to initiate chemical reactions, for instance by combining plasmonic materials with catalytic metals. In this work, we demonstrate that plasmonic nanoparticles of earth-abundant Mg can undergo galvanic replacement in a nonaqueous solvent to produce decorated structures. This method yields bimetallic architectures where partially oxidized 200-300 nm Mg nanoplates and nanorods support many smaller Au, Ag, Pd, or Fe nanoparticles, with potential for a stepwise process introducing multiple decoration compositions on a single Mg particle. We investigated this mechanism by electron-beam imaging and local composition mapping with energy-dispersive X-ray spectroscopy as well as, at the ensemble level, by inductively coupled plasma mass spectrometry. High-resolution scanning transmission electron microscopy further supported the bimetallic nature of the particles and provided details of the interface geometry, which includes a Mg oxide separation layer between Mg and the other metal. Depending on the composition of the metallic decorations, strong plasmonic optical signals characteristic of plasmon resonances were observed in the bulk with ultraviolet-visible spectrometry and at the single particle level with darkfield scattering. These novel bimetallic and multimetallic designs open up an exciting array of applications where one or multiple plasmonic structures could interact in the near-field of earth-abundant Mg and couple with catalytic nanoparticles for applications in sensing and plasmon-assisted catalysis.Support for this project was provided by the EU Framework Programme for Research and Innovation Horizon 2020 (Starting Grant SPECs 804523). J.A. wishes to acknowledge financial support from Natural Sciences and Engineering Research Council of Canada and “Fonds de Recherche Québec – Nature et Technologies” postdoctoral fellowships (BP and B3X programs). C.B. is thankful for funding from the Engineering and Physical Sciences Research Council (Standard Research Studentship (DTP) EP/R513180/1), and E.R.H. for support from the EPSRC NanoDTC Cambridge (EP/L015978/1). S.M.C. acknowledges support from the Henslow Research Fellowship at Girton College, Cambridge. We acknowledge access and support in the use of the electron Physical Sciences Imaging Centre (MG21980) at the Diamond Light Source, U.K

Continuous relaxation of MINLP problems by penalty functions: a practical comparison

A practical comparison of penalty functions for globally solving mixed-integer nonlinear programming (MINLP) problems is presented. The penalty approach relies on the continuous relaxation of the MINLP problem by adding a specific penalty term to the objective function. A new penalty algorithm that addresses simultaneously the reduction of the error tolerances for optimality and feasibility, as well as the reduction of the penalty parameter, is designed. Several penalty terms are tested and different penalty parameter update schemes are analyzed. The continuous nonlinear optimization problem is solved by the deterministic DIRECT optimizer. The numerical experiments show that the quality of the produced solutions are satisfactory and that the selected penalties have different performances in terms of efficiency and robustness.This work has been supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT - Fundação para a Ciência e Tecnologia, within the projects UID/CEC/00319/2013 and UID/MAT/00013/2013.info:eu-repo/semantics/publishedVersio

Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation

BACKGROUND: Arylamine N-acetyltransferase 2 (NAT2) is an important catalytic enzyme that metabolizes the carcinogenic arylamines, hydrazine drugs and chemicals. This enzyme is highly polymorphic in different human populations. Several polymorphisms of NAT2, including the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E, are classified as slow acetylators, whereas the wild-type NAT2 is classified as a fast acetylator. The slow acetylators are often associated with drug toxicity and efficacy as well as cancer susceptibility. The biological functions of these 7 mutations have previously been characterized, but the structural basis behind the reduced catalytic activity and reduced protein level is not clear. METHODOLOGY/PRINCIPAL FINDINGS: We performed multiple molecular dynamics simulations of these mutants as well as NAT2 to investigate the structural and dynamical effects throughout the protein structure, specifically the catalytic triad, cofactor binding site, and the substrate binding pocket. None of these mutations induced unfolding; instead, their effects were confined to the inter-domain, domain 3 and 17-residue insert region, where the flexibility was significantly reduced relative to the wild-type. Structural effects of these mutations propagate through space and cause a change in catalytic triad conformation, cofactor binding site, substrate binding pocket size/shape and electrostatic potential. CONCLUSIONS/SIGNIFICANCE: Our results showed that the dynamical properties of all the mutant structures, especially in inter-domain, domain 3 and 17-residue insert region were affected in the same manner. Similarly, the electrostatic potential of all the mutants were altered and also the functionally important regions such as catalytic triad, cofactor binding site, and substrate binding pocket adopted different orientation and/or conformation relative to the wild-type that may affect the functions of the mutants. Overall, our study may provide the structural basis for reduced catalytic activity and protein level, as was experimentally observed for these polymorphisms

Influence of genetic factors on toluene diisocyanate-related symptoms: evidence from a cross-sectional study

Background: Toluene diisocyanate (TDI) is a highly reactive compound used in the production of, e. g., polyurethane foams and paints. TDI is known to cause respiratory symptoms and diseases. Because TDI causes symptoms in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Methods: Workers (N = 132) exposed to TDI and a non-exposed group ( N = 114) were analyzed for genotype (metabolising genes: CYP1A1*2A, CYP1A1*2B, GSTM1*O, GSTM3*B, GSTP1 1105V, GSTP1 A114V, GSTT1*O, MPO -463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, SULT1A1 R213H; immune-related genes: CCL5 -403, HLA-DQB1* 05, TNF-308, TNF-863) and symptoms of the eyes, upper and lower airways ( based on structured interviews). Results: For three polymorphisms: CYP1A1*2A, CYP1A1*2B, and TNF -308 there was a pattern consistent with interaction between genotype and TDI exposure status for the majority of symptoms investigated, although it did reach statistical significance only for some symptoms: among TDI-exposed workers, the CYP1A1 variant carriers had increased risk (CYP1A1*2A and eye symptoms: variant carriers OR 2.0 95% CI 0.68-6.1, p-value for interaction 0.048; CYP1A1*2B and wheeze: IV carriers OR = 12, 1.4-110, p-value for interaction 0.057). TDI-exposed individuals with TNF-308 A were protected against the majority of symptoms, but it did not reach statistical significance. In the non-exposed group, however, TNF -308 A carriers showed higher risk of the majority of symptoms ( eye symptoms: variant carriers OR = 2.8, 1.1-7.1, p-value for interaction 0.12; dry cough OR = 2.2, 0.69-7.2, p-value for interaction 0.036). Individuals with SULT1A1 213H had reduced risk both in the exposed and non-exposed groups. Other polymorphisms, showed associations to certain symptoms: among TDI-exposed, NAT1*10 carriers had a higher risk of eye symptoms and CCL5 -403 AG+AA as well as HLA-DQB1 *05 carriers displayed increased risk of symptoms of the lower airways. GSTM1, GSTM3 and GSTP1 only displayed effects on symptoms of the lower airways in the non-exposed group. Conclusion: Specific gene-TDI interactions for symptoms of the eyes and lower airways appear to exist. The results suggest different mechanisms for TDI- and non- TDI-related symptoms of the eyes and lower airways

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting

This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward

Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

Background: Genetic variation at NAT2 has been long recognized as the cause of differential ability to metabolize a wide variety of drugs of therapeutic use. Here, we explore the pattern of genetic variation in 12 human populations that significantly extend the geographic range and resolution of previous surveys, to test the hypothesis that different dietary regimens and lifestyles may explain inter-population differences in NAT2 variation. Methodology/Principal Findings: The entire coding region was resequenced in 98 subjects and six polymorphic positions were genotyped in 150 additional subjects. A single previously undescribed variant was found (34T>C; 12Y>H). Several aspects of the data do not fit the expectations of a neutral model, as assessed by coalescent simulations. Tajima's D is positive in all populations, indicating an excess of intermediate alleles. The level of between-population differentiation is low, and is mainly accounted for by the proportion of fast vs. slow acetylators. However, haplotype frequencies significantly differ across groups of populations with different subsistence. Conclusions/Significance: Data on the structure of haplotypes and their frequencies are compatible with a model in which slow-causing variants were present in widely dispersed populations before major shifts to pastoralism and/or agriculture. In this model, slow-causing mutations gained a selective advantage in populations shifting from hunting-gathering to pastoralism/agriculture. We suggest the diminished dietary availability of folates resulting from the nutritional shift, as the possible cause of the fitness increase associated to haplotypes carrying mutations that reduce enzymatic activity. © 2008 Luca et al