Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Simple new methods for deducing lifetimes in recoil distance Doppler-shift measurements.

New approaches for lifetime determination using data from recoil distance Doppler-shift experiments are presented based on the fundamental properties of the functions describing the time evolution of the population of excited nuclear states. To some extent, one of them represents a contraction of the well-known Differential decay-curve method (DDCM) by using the most reliable data point [the maximum of the ni(t) function describing the population of level i in time] and a purely numerical procedure avoiding any fitting of decay curves. The combination with the standard DDCM analysis is promising for improving the reliability and the precision of the results for the lifetimes obtained. The novel part of the approach consists of using a chain of equations at the consecutive maxima of the ni(t) functions, which allow us to precisely determine the ratio of the lifetimes of two consecutive levels and, in the case where one of these lifetimes is known, to determine the unknown one. In addition, a simple integral derivation of the lifetime is presented involving the peak areas measured at different distances, and an application of the first moments (expectation values and centroids in time) of the ni(t) functions for determining lifetimes is also demonstrated to be useful.

Computational study of solution behavior of magainin 2 monomers.

Antimicrobial peptides (AMPs) play crucial role as mediators of the primary host defense against microbial invasion. They are considered a promising alternative to antibiotics for multidrug resistant bacterial strains. For complete understanding of the antimicrobial defense mechanism, a detailed knowledge of the dynamics of peptide-membrane interactions, including atomistic studies on AMPs geometry and both peptide and membrane structural changes during the whole process is a prerequisite. We aim at clarifying the conformation dynamics of small linear AMPs in solution as a first step of in silico protocol for establishing a correspondence between certain amino-acid sequence motifs, secondary-structure elements, conformational dynamics in solution and the intensity and mode of interaction with the bacterial membrane. To this end, we use molecular dynamics simulations augmented by well-tempered metadynamics to study the free-energy landscape of two AMPs with close primary structure and different antibacterial activity - the native magainin 2 (MG2) and an analog (MG2m, with substitutions F5Y and F16W) in aqueous solution. We observe that upon solvation, the initial α-helical structures change differently. The native form remains structured, with three shorter α-helical motifs, connected by random coils, while the synthetic analog tends predominantly to a disordered conformation. Our results indicate the importance of the side-chains at positions 5 and 16 for maintaining the solvated peptide conformation. They also provide a modeling background for recent experimental observations, relating the higher α-helical content in solution (peptide pre-folding) in the case of small linear AMPs to a lower antibacterial activity.

Multifaceted Quadruplet of Low-Lying Spin-Zero States in

A search for shape isomers in the ^{66}Ni nucleus was performed, following old suggestions of various mean-field models and recent ones, based on state-of-the-art Monte Carlo shell model (MCSM), all considering ^{66}Ni as the lightest nuclear system with shape isomerism. By employing the two-neutron transfer reaction induced by an ^{18}O beam on a ^{64}Ni target, at the sub-Coulomb barrier energy of 39 MeV, all three lowest-excited 0^{+} states in ^{66}Ni were populated and their γ decay was observed by γ-coincidence technique. The 0^{+} states lifetimes were assessed with the plunger method, yielding for the 0_{2}^{+}, 0_{3}^{+}, and 0_{4}^{+} decay to the 2_{1}^{+} state the B(E2) values of 4.3, 0.1, and 0.2 Weisskopf units (W.u.), respectively. MCSM calculations correctly predict the existence of all three excited 0^{+} states, pointing to the oblate, spherical, and prolate nature of the consecutive excitations. In addition, they account for the hindrance of the E2 decay from the prolate 0_{4}^{+} to the spherical 2_{1}^{+} state, although overestimating its value. This result makes ^{66}Ni a unique nuclear system, apart from ^{236,238}U, in which a retarded γ transition from a 0^{+} deformed state to a spherical configuration is observed, resembling a shape-isomerlike behavior.

Substrate surface patterning by optical near field modulation around colloidal particles immersed in a liquid.

Optical near field enhancements in the vicinity of particles illuminated by laser light are increasingly recognized as a powerful tool for nanopatterning applications, but achieving sub-wavelength details from the near-field distribution remains a challenge. Here we present a quantitative analysis of the spatial modulation of the near optical fields generated using single 8 ps, 355 nm (and 532 nm) laser pulses around individual colloidal particles and small close packed arrays of such particles on silicon substrates. The analysis is presented for particles in air and, for the first time, when immersed in a range of liquid media. Immersion in a liquid allows detailed exploration of the effects on the near field of changing not just the magnitude but also the sign of the refractive index difference between the particle and the host medium. The level of agreement between the results of ray tracing and Mie scattering simulations, and the experimentally observed patterns on solid surfaces, should encourage further modelling, predictions and demonstrations of the rich palette of sub-wavelength surface profiles that can be achieved using colloidal particles immersed in liquids.

Controlling embedment and surface chemistry of nanoclusters in metal-organic frameworks.

A combined theoretical and experimental approach demonstrates that nanocluster embedment into the pores of metal-organic frameworks (MOF) may be influenced by the chemical functionalisation of the MOF. Furthermore, this results in the surface functionalisation of the embedded nanoclusters, highlighting the potential of MOF scaffolds for the design and synthesis of novel functional materials.

[Novelties in the Treatment of Colorectal Diseases - An Echo from the 10-th ESCP Congress].

Treatment of colorectal pathology stands continuous development. One of the promotional leaders of the new therapeutic approaches is the European Society of Coloproctology (ESCP). The annual congress of the organization held in Dublin, Ireland and it unites the elite of European Community countries. The most advanced scientific knowledge of the diseases of the colon and rectum, anal canal and perineum was presented.

Pattern formation on silicon by laser-initiated liquid-assisted colloidal lithography.

We report sub-diffraction limited patterning of Si substrate surfaces by laser-initiated liquid-assisted colloidal lithography. The technique involves exposing a two-dimensional lattice of transparent colloidal particles spin coated on the substrate of interest (here Si) immersed in a liquid (e.g. methanol, acetone, carbon tetrachloride, toluene) to a single picosecond pulse of ultraviolet laser radiation. Surface patterns formed using colloidal particles with different radii in the range 195 nm ≤ R ≤ 1.5 µm and liquids with differing indices of refraction (n(liquid)) are demonstrated, the detailed topographies of which are sensitively dependent upon whether the index of refraction of the colloidal particle (n(colloid)) is greater or smaller than n liquid (i.e. upon whether the incident light converges or diverges upon interaction with the particle). The spatial intensity modulation formed by diffraction of the single laser pulse by the colloidal particles is imprinted into the Si substrate.

Ultrafast hydrogen bond dynamics and partial electron transfer after photoexcitation of diethyl ester of 7-(diethylamino)-coumarin-3-phosphonic acid and its benzoxaphosphorin analog.

The solvation dynamics after optical excitation of two phosphono-substituted coumarin derivatives dissolved in various solutions are studied by fluorescence up-conversion spectroscopy and quantum chemical simulations. The Kamlet-Taft analysis of the conventional absorption and emission spectra suggests weakening of the solvent-solute H-bonds upon optical excitation, which is in contrast to the results gained by the quantum simulations and earlier studies reported for coumarin derivatives without phosphono groups. The simulations give evidence that the solvent reorganisation around the excited fluorophore leads to partial electron transfer to the first solvation shell. The process occurs on a timescale between 1 and 10 ps depending on the solvent polarity and leads to a fast decay of the time-resolved emission signal. Using the ultrafast spectral shift of the time-dependent fluorescence we estimated the relaxation time of the H-bonds in the electronically excited state to be about 0.6 ps in water, 1.5 ps in ethanol and 2.8 ps in formamide.

Candidates for twin chiral bands in 102Rh.

Excited states in 102Rh, populated in the fusion-evaporation reaction Zr94(11B,3n)102Rh at a beam energy of 36 MeV, were studied using the Indian National Gamma Array spectrometer at Inter University Accelerator Center, New Delhi. The angular correlations and the electromagnetic character of some of the gamma-ray transitions observed were investigated in detail. A new chiral candidate sister band was found. Lifetimes of exited states in both chiral candidate bands of 102Rh were measured for the first time in the A∼100 mass region by means of the Doppler-shift attenuation technique. The derived reduced transition probabilities are compared to the predictions of the two quasiparticles plus triaxial rotor model. Both experimental results and calculations do not support the presence of static chirality in 102Rh.

Palladium or palladium hydride nanoparticles synthesized by laser ablation of a bulk palladium target in liquids.

Laser ablation of a bulk Pd target in DIW, acetone or ethanol was carried out for the production of nanoparticles colloidal solutions. The size distribution of the nanoparticles follows log-normal function for all three liquids, with a median diameter of 3, 1.1 and 1.5 nm and standard deviation of 0.65, 1 and 1, respectively. Amorphous carbon is found on the nanoparticles synthesized in the hydrocarbons (acetone or ethanol). In DIW pure Pd nanoparticles were generated while ablation in acetone or ethanol lead to the synthesis of palladium hydride (PdHx) nanoparticles. These nanoparticles can be used in hydrogen storage applications.

Simulation of chemical metabolism for fate and hazard assessment. V. Mammalian hazard assessment.

Animals and humans are exposed to a wide array of xenobiotics and have developed complex enzymatic mechanisms to detoxify these chemicals. Detoxification pathways involve a number of biotransformations, such as oxidation, reduction, hydrolysis and conjugation reactions. The intermediate substances created during the detoxification process can be extremely toxic compared with the original toxins, hence metabolism should be accounted for when hazard effects of chemicals are assessed. Alternatively, metabolic transformations could detoxify chemicals that are toxic as parents. The aim of the present paper is to describe specificity of eukaryotic metabolism and its simulation and incorporation in models for predicting skin sensitization, mutagenicity, chromosomal aberration, micronuclei formation and estrogen receptor binding affinity implemented in the TIMES software platform. The current progress in model refinement, data used to parameterize models, logic of simulating metabolism, applicability domain and interpretation of predictions are discussed. Examples illustrating the model predictions are also provided.

Enhanced quadrupole collectivity at N = 40: the case of neutron-rich Fe isotopes.

The transition rates for the 2(1)+ states in (62,64,66)Fe were studied using the recoil distance Doppler-shift technique applied to projectile Coulomb excitation reactions. The deduced E2 strengths illustrate the enhanced collectivity of the neutron-rich Fe isotopes up to N = 40. The results are interpreted using the generalized concept of valence proton symmetry which describes the evolution of nuclear structure around N = 40 as governed by the number of valence protons with respect to Z ≈ 30. The trend of collectivity suggested by the experimental data is described by state-of-the-art shell-model calculations with a new effective interaction developed for the fpgd valence space.

Improvement of the intrinsic time resolving power of the Cologne iron-free orange type electron spectrometers.

Conversion electron spectroscopy represents an important tool for nuclear structure analysis of medium and heavy nuclei. Two iron-free magnetic electron spectrometers of the orange type have been installed at the Institute for Nuclear Physics of the University of Cologne. The very large transmission of 15% and the very good energy resolution of 1% makes the iron-free orange spectrometer a powerful instrument. By means of fast timing techniques, lifetimes of nuclear excited states can be measured with an accuracy better than 20 ps. For the first time, the energy dependent centroid position of prompt events yielding the time-walk characteristics (the prompt curve) of the orange spectrometer fast timing setup has been measured using prompt secondary δ-electrons generated in a pulsed beam experiment. The prompt curve calibrated as a function of energy allows precise lifetime determination down to a few tens of picoseconds by the use of the centroid shift method.

Ultrahigh-resolution γ-ray spectroscopy of 156Gd: a test of tetrahedral symmetry.

Tetrahedral symmetry in strongly interacting systems would establish a new class of quantum effects at subatomic scale. Excited states in 156Gd that could carry the information about the tetrahedral symmetry were populated in the 155Gd(n,γ)156Gd reaction and studied using the GAMS4/5 Bragg spectrometers at the Institut Laue-Langevin. We have identified the 5(1)- → 3(1)- transition of 131.983(12) keV in 156Gd and determined its intensity to be 1.9(3)x10(-6) per neutron capture. The lifetime τ=220(-30)(+180) fs of the 5(1)- state in 156Gd has been measured using the GRID technique. The resulting B(E2)=293(-134)(+6) Weisskopf unit rate of the 131.983 keV transition provides the intrinsic quadrupole moment of the 5(1)- state in 156Gd to be Q0=7.1(-1.6)(+0.7) b. This large value, comparable to the quadrupole moment of the ground state in 156Gd, gives strong evidence against tetrahedral symmetry in the lowest odd-spin, negative-parity band of 156Gd.

Mechanism-based common reactivity pattern (COREPA) modelling of aryl hydrocarbon receptor binding affinity.

The aryl hydrocarbon receptor is a ligand-activated transcription factor responsive to both natural and synthetic environmental compounds, with the most potent agonist being 2,3,7,8-tetrachlotrodibenzo-p-dioxin. The aim of this work was to develop a categorical COmmon REactivity PAttern (COREPA)-based structure-activity relationship model for predicting aryl hydrocarbon receptor ligands within different binding ranges. The COREPA analysis suggested two different binding mechanisms called dioxin- and biphenyl-like, respectively. The dioxin-like model predicts a mechanism that requires a favourable interaction with a receptor nucleophilic site in the central part of the ligand and with electrophilic sites at both sides of the principal molecular axis, whereas the biphenyl-like model predicted a stacking-type interaction with the aryl hydrocarbon receptor allowing electron charge transfer from the receptor to the ligand. The current model was also adjusted to predict agonistic/antagonistic properties of chemicals. The mechanism of antagonistic properties was related to the possibility that these chemicals have a localized negative charge at the molecule's axis and ultimately bind with the receptor surface through the electron-donating properties of electron-rich groups. The categorization of chemicals as agonists/antagonists was found to correlate with their gene expression. The highest increase in gene expression was elicited by strong agonists, followed by weak agonists producing lower increases in gene expression, whereas all antagonists (and non-aryl hydrocarbon receptor binders) were found to have no effect on gene expression. However, this relationship was found to be quantitative for the chemicals populating the areas with extreme gene expression values only, leaving a wide fuzzy area where the quantitative relationship was unclear. The total concordance of the derived aryl hydrocarbon receptor binding categorical structure-activity relationship model was 82% whereas the Pearson's coefficient was 0.88.

Novel manifestation of alpha-clustering structures: new "alpha+208Pb" states in 212Po revealed by their enhanced E1 decays.

Excited states in 212Po were populated by alpha transfer using the 208Pb(18O,14C) reaction, and their deexcitation gamma rays were studied with the Euroball array. Several levels were found to decay by a unique E1 transition (Egamma<1 MeV) populating the yrast state with the same spin value. Their lifetimes were measured by the Doppler-shift attenuation method. The values, found in the range 0.1-1.4 ps, lead to very enhanced transitions, B(E1)=2x10(-2)-1x10(-3) W.u. These results are discussed in terms of an alpha-cluster structure which gives rise to states with non-natural-parity values, provided that the composite system cannot rotate collectively, as expected in the "alpha+208Pb" case. Such states due to the oscillatory motion of the alpha-core distance are observed for the first time.

Structure of GeSe4-In and GeSe5-In glasses.

(Ge(0.2)Se(0.8))(100-x)In(x) and (Ge(0.17)Se(0.83))(100-x)In(x) (x = 0, 5, 10, 15 at.%) chalcogenide glasses have been studied with high-energy x-ray diffraction, neutron diffraction and extended x-ray absorption spectroscopy at Ge, Se and In K-edges. The experimental data were modelled simultaneously with the reverse Monte Carlo simulation method. GeSe(4/2) tetrahedra are shown to be the main structural units in the binary and ternary glasses investigated. Indium bonds to the excess Se atoms in the ternary Ge-Se-In glasses. While the majority of In atoms have three Se neighbours, some In atoms may be tetrahedrally coordinated by Se.

Induction of abortion with aglepristone in cats on day 45 and 46 after mating.

The aim of this study was to test for the efficacy and safety of the use of aglepristone for pregnancy termination on day 45 in cats. Six healthy cats were treated with 10 mg/kg aglepristone sc on day 45 and 46 after mating; six other cats served as untreated controls. The effect of treatment was monitored by general examination, vaginal cytology, ultrasonography and blood sampling for haematology and progesterone determination. Besides, interoestrus interval and next pregnancy including litter size were recorded. The efficacy of treatment was approximately 67% (4/6) with abortion occurring 4-7 days after the first injection and a sanguineous discharge and erythrocytes in vaginal smears for at least 6 days afterwards. The two treated cats that did not abort gave birth to two kittens on day 67 and had a stillbirth of a single kitten on day 71, respectively. As expected enlargement of the mammary glands and lactation were observed in all treated cats. No other treatment-induced side effects were observed. Progesterone levels at abortion were high (30-140 nmol/l), but were decreased on day 55. Aglepristone treatment did not affect fertility in following cycles. Finally, it can be concluded that late-term pregnancy termination with aglepristone is possible but due to a success rate of 67% an ultrasonographical examination 7 days after treatment is an inherent necessity to control the effect of treatment.

Mechanism-based categorization of aromatase inhibitors: a potential discovery and screening tool.

Cytochrome P450 aromatase is a key steroidogenic enzyme that converts androgens to estrogens in vertebrates. There is much interest in aromatase inhibitors (AIs) both because of their use as pharmaceuticals in the treatment of estrogen-sensitive breast cancers, and because a number of environmental contaminants can act as AIs, thereby disrupting endocrine function in humans and wildlife through suppression of circulating estrogen levels. The goal of the current work was to develop a mechanism-based structure-activity relationship (SAR) categorization framework highlighting the most important chemical structural features responsible for inhibition of aromatase activity. Two main interaction mechanisms were discerned: steroidal and non-steroidal. The steroid scaffold is most prominent when the structure of the target chemical is similar to the natural substrates of aromatase - androstenedione and testosterone. Chemicals acting by non-steroidal mechanism(s) possess a heteroatom (N, O, S) able to coordinate the heme iron of the cytochrome P450, and thus interfere with steroid hydroxylation. The specific structural boundaries controlling AI for both analyzed mechanisms were defined, and a software tool was developed that allowed a decision tree (profile) to be built discriminating AIs by mechanism and potency. An input chemical follows a profiling path and the structure is examined at each step to decide whether it conforms with the structural boundaries implemented in the decision tree node. Such a system would aid drug discovery efforts, as well as provide a screening tool to detect environmental contaminants that could act as AIs.