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We introduce HistoNet, a deep neural network trained on normal tissue. On 1690 slides with rat tissue samples from 6 preclinical toxicology studies, tissue regions were outlined and annotated by pathologists into 46 different tissue classes. From these annotated regions, we sampled small 224 × 224 pixels images (patches) at 6 different levels of magnification. Using 4 studies as training set and 2 studies as test set, we trained VGG-16, ResNet-50, and Inception-v3 networks separately at each magnification level. Among these model architectures, Inception-v3 and ResNet-50 outperformed VGG-16. Inception-v3 identified the tissue from query images, with an accuracy up to 83.4%. Most misclassifications occurred between histologically similar tissues. Investigation of the features learned by the model (embedding layer) using Uniform Manifold Approximation and Projection revealed not only coherent clusters associated with the individual tissues but also subclusters corresponding to histologically meaningful structures that had not been annotated or trained for. This suggests that the histological representation learned by HistoNet could be useful as the basis of other machine learning algorithms and data mining. Finally, we found that models trained on rat tissues can be used on non-human primate and minipig tissues with minimal retraining.

The influence of the configuration at the C8 and C9 positions of cinchona alkaloids was investigated by comparing the efficiency of cinchonidine, cinchonine, and 9-epi-cinchonidine as chiral modifiers. In the hydrogenation of ketones (methyl benzoylformate, ketopantolactone, methylglyoxal dimethylacetal, 2,2,2-trifluoroacetophenone) on Pt, a change in the configuration at C9 did not affect the absolute configuration of the main products; however, the ees and rates dropped significantly. In the hydrogenation of α-functionalized olefins (E-2-methyl-2-hexenoic acid, 2-phenylcinnamic acid, and 4-methoxy-6-methyl-2H-pyran-2-one) on Pd, replacement of cinchonidine or cinchonine by epi-cinchonidine diminished the rates and almost eliminated the enantioselection, indicating that a subtle combination of C8 and C9 configurations is required on Pd. DFT calculations of the adsorption of the modifiers and the nonlinear behavior of modifier mixtures revealed that the lower reaction rates observed for 9-epi-cinchonidine-modified surfaces cannot be related to different adsorption strength of this modifier. Additionally, substrate–modifier docking interactions are presented.

Both associative and dissociative H(2)O adsorption on SnO(2)(110), TiO(2)(110), and Ti-enriched Sn(1-x)Ti(x)O(2)(110) surfaces have been investigated at low ((1)/(12) monolayer (ML)) and high coverage (1 ML) by density functional theory calculations using the Gaussian and plane waves formalism. The use of a large supercell allowed the simulation at low symmetry levels. On SnO(2)(110), dissociative adsorption was favored at all coverages and was accompanied by stable associative H(2)O configurations. Increasing the coverage from (1)/(12) to 1 ML stabilized the (associatively or dissociatively) adsorbed H(2)O on SnO(2)(110) because of the formation of intermolecular H bonds. In contrast, on TiO(2)(110), the adsorption of isolated H(2)O groups ((1)/(12) ML) was more stable than at high coverage, and the favored adsorption changed from dissociative to associative with increasing coverage. For dissociative H(2)O adsorption on Ti-enriched Sn(1-x)Ti(x)O(2)(110) surfaces with Ti atoms preferably located on 6-fold-coordinated surface sites, the analysis of the Wannier centers showed a polarization of electrons surrounding bridging O atoms that were bound simultaneously to 6-fold-coordinated Sn and Ti surface atoms. This polarization suggested the formation of an additional bond between the 6-fold-coordinated Ti(6c) and bridging O atoms that had to be broken upon H(2)O adsorption. As a result, the H(2)O adsorption energy initially decreased, with increasing surface Ti content reaching a minimum at 25% Ti for (1)/(12) ML. This behavior was even more accentuated at high H(2)O coverage (1 ML) with the adsorption energy decreasing rapidly from 145.2 to 101.6 kJ/mol with the surface Ti content increasing from 0 to 33%. A global minimum of binding energies at both low and high coverage was found between 25 and 33% surface Ti content, which may explain the minimal cross-sensitivity to humidity previously reported for Sn(1-x)Ti(x)O(2) gas sensors. Above 12.5% surface Ti content, the binding energy decreased with increasing coverage, suggesting that the partial desorption of H(2)O is facilitated at a high fractional coverage.

The composition and thermodynamic stability of the (110) surface of Sn 1 - x Ti x O 2 rutile solid solutions was investigated as a function of Ti-distribution and content up to the formation of a full TiO 2 surface monolayer. The bulk and (110) surface properties of Sn 1 - x Ti x O 2 were compared to that of the pure SnO 2 and TiO 2 crystal. A large supercell of 720 atoms and a localized basis set based on the Gaussian and plane wave scheme allowed the investigation of very low Ti-content and symmetry. For the bulk, optimization of the crystal structure confirmed that up to a Ti-content of 3.3 at.%, the lattice parameters ( a , c ) of SnO 2 do not change. Increasing further the Ti-content decreased both lattice parameters down to those of TiO 2 . The surface energy of these solid solutions did not change for Ti-substitution in the bulk of up to 20 at.%. In contrast, substitution in the surface layer rapidly decreased the surface energy from 0.99 to 0.74 J/m 2 with increasing Ti-content from 0 to 20 at.%. As a result, systems with Ti atoms distributed in the surface (surface enrichment) had always lower energies and thus were thermodynamically more favorable than those with Ti homogeneously distributed in the bulk. This was attributed to the lower energy necessary to break the Ti O bonds than Sn O bonds in the surface layer. In fact, distributing the Ti atoms homogeneously or segregated in the (110) surface led to the same surface energy indicating that restructuring of the surface bond lengths has minimal impact on thermodynamic stability of these rutile systems. As a result, a first theoretical prediction of the composition of Sn 1 - x Ti x O 2 solid solutions is proposed.

By means of ab initio molecular dynamics, we have investigated the molecular adsorption of acetaldehyde on Pt 13 nanoparticles in the presence of coadsorbed hydrogen on the surface of the metal par...

The presence of a tertiary amine plays a role in accelerating the catalysis of ketones hydrogenation on a platinum surface covered by hydrogen. Ab initio molecular dynamics has been applied to achieve an atomistic understanding of this base effect. The interaction of trimethylamine with hydrogen adsorbed on a platinum nanoparticle has been simulated for 22 ps revealing that hydrogen increases its oscillatory modes upon interaction with the base therefore its activation. Nonetheless in the case of trimethylamine, competing interactions appear in the form of skeletal hydrogen (from the methyl group) interacting with the metal particle. Such interactions distract the action of the base and predominate at the end of the simulation. The interaction of the trimethylamine molecule with hydrogen adsorbed on platinum is compared to the corresponding interaction of the quinuclidine moiety of cinchonidine, which is the most widely applied chiral modifier for the platinum catalyzed enantioselective hydrogenations. Th...

A series of peptides, all containing the natural amino acid tryptophan (Trp), have been used as chiral surface modifiers for asymmetric hydrogenation reactions on alumina supported platinum catalysts. The surface chiral sites have been investigated using density functional theory calculations in order to elucidate the structure of the asymmetric environment produced by the adsorption of the peptides on the metal surface. As a test reaction, ketopantolactone (KPL) has been asymmetrically hydrogenated using the modified catalyst. Catalytic results were tested against a computational model to shed light on the phenomenon of chiral induction. The choice of Trp as the first member of the peptidic chain is due to its structural resemblance to cinchona alkaloids, already successfully used as modifiers for asymmetric hydrogenation reactions. The amino acidic moiety of Trp was elongated by addition of other natural amino acids via a peptidic bond, and the resulting peptides were tested as chiral modifiers. The ind...

The adsorption of naphthalene and quinoline on Pt(111), Pd(111) and Rh(111) surfaces is studied using density functional theory. The metal surfaces are simulated by means of large confined clusters and for Pt by means of a slab with periodic boundary conditions (PBC). Calculation parameters such as basis set convergence, basis set superposition error and effects of cluster relaxation and size are analyzed in order to assess the aptness of the cluster model. For all the metals, the preferred sites of adsorption are analyzed, thus revealing their different behaviors concerning structure and stability of adsorption modes. On Pt, the molecules have the richest theoretical configurational variety. Naphthalene and quinoline are found to adsorb preferentially on di-bridge[7] sites on the three metals, and Rh exhibits higher adsorption energies than Pt and Pd. Structural features of the adsorbed molecules are correlated to the calculated adsorption energies. The di-bridge[7] adsorption modes are studied in deeper detail decomposing the adsorption energies in two terms arising from molecular distortion and binding interaction to the metal. Molecular distortion is correlated to the HOMO-LUMO energy gap. The larger adsorption energies found for interactions with Rh result from the lower contribution of the distortion term. Binding interactions are described by analyzing the wave functions of naphthalene and quinoline adsorbed on a subunit of the large clusters in order to reduce the complexity of the analysis. Molecular orbitals are studied using concepts of Frontier Molecular Orbitals theory. This approach reveals that in the adsorption of naphthalene and quinoline on Pt and Pd, an antibonding state lies below the Fermi energy, while on Rh all antibonding states are empty, in agreement with the larger interaction energies. In addition, further insight is gained by projecting the density of states on the d band of the clean surfaces and of the adsorbed systems. This results in the rationalization of the structural features in terms of the concepts of electronic structure theory. The distributions of electronic density are described by means of Hirshfeld charges and isosurfaces of differential electron density. The net electron transfer from the metals to the molecules for most of the sites correlates with the trends of the adsorption energies.

A molecular understanding of the adsorption of water on SnO2 surfaces is crucial for several applications of this metal oxide, including catalysis and gas sensing. We have investigated water adsorption on the SnO2(110) surface using a combination of dynamic and static calculations to gain fundamental insight into the reaction mechanism at room temperature. The reaction dynamics are studied by following water adsorption and dissociation on the SnO2 surface with metadynamics calculations at low and high coverage. The electronic structure in the relevant isolated minima is investigated through Mulliken charge analysis and projected density of states analysis. Surface bridging oxygen (Obr) is found to play a decisive role in water adsorption forming rooted hydroxyl groups with the water H atoms. Bond formation with H significantly changes the electronic configuration of Obr and presumably leads to reduced band bending at the SnO2 surface. The free-energy estimation indicates that on a clean SnO2(110) surface at room temperature both associative and dissociative adsorption occur, with the latter being thermodynamically favored. Oxygen coverage strongly affects the ratio between associatively and dissociatively adsorbed H2O, favoring associative adsorption at high oxygen coverage (oxidized surface) and dissociative adsorption at low oxygen coverage (reduced surface). Electronic analyses of isolated surface minima show the existence of two different electron-transfer phenomena occurring at the surface, depending on the water adsorption mechanism. The relevance of these findings in explaining the changes in electric conductivity occurring in SnO2-based gas sensors upon water adsorption is discussed. Whereas associative adsorption leads to electron enrichment of the metal oxide surface, dissociative adsorption induces surface electron depletion. Both mechanisms are consistent with the electrical conductivity changes occurring upon interaction of SnO2 with water, causing cross sensitivity to the latter. The theoretical results form the basis for correlating the existing atomistic models with the experimental data and offer a coherent description of the reaction events on the surface at room temperature.

The description of the conformational space generated by metal nanoparticles is a fundamental issue for the study of their physicochemical properties. In this investigation, an exhaustive exploration and a unified view of the conformational space of a gold nanocluster is provided using a Au 12 cluster as an example. Such system is characterized by coexisting planar/quasiplanar and tridimensional conformations separated by high-energy barriers. The conformational space of Au 12 has been explored by means of Born-Oppenheimer ab initio metadynamics, i.e., a molecular dynamics simulation coupled with a history dependent potential to accelerate events that might occur on a long time scale compared to the time step used in the simulations (rare events). The sampled conformations have complex, in general not intuitive topologies that we have classified as planar/quasiplanar or tridimensional, belonging to different regions of the free energy surface. Three conformational free energy basins were identified, one for the planar/quasiplanar and two for the tridimensional structures. At thermodynamic equilibrium, the planar/quasi-planar and tridimensional conformations were found to coexist, to be fluxional and to be separated by high-free-energy barriers. The comparison between the free energy and the potential energy revealed the relevance of the entropic contribution in the equilibrium distribution of the conformations of the cluster.

The structure and electronic properties of gold nanoparticles (Au 12, Au 13, Au 14, Au 15, Au 20, Au 34, and Au 55) have been investigated using Born-Oppenheimer ab initio molecular dynamic simulations of 50 to 80 ps in order to have an insight in the recently proposed fluxional character of nanosized gold. The dynamic changes in shape, symmetry, and atomic coordination of atoms within clusters, occurring in the time scale of picoseconds, which are characteristic of fluxionality, have been investigated for all the above systems at 300 K. Except for Au 20, all systems have been found to have fluxional properties. The extent and the type of fluxional behavior changed according to the number of atoms constituting the particle. At 300 K Au 12 and Au 13 rapidly generate several different topologies which cyclically interconvert. Au 14 shows a rotation of 8 external gold atoms around a core of six atoms. Au 15 is more rigid, but interestingly shows the interconversion between enantiomeric structures within the time scale of the simulation. Au 20 shows a high stability of the pyramidal topology and is the only one of the investigated systems not to show fluxionality within the assigned temperature and time scale. Au 34 and Au 55 show fluxionality of the outer shell and within the sampled time scale are able to change coordination of the outer shell atoms and thus open and close surface holes. For all the particles in study the structures forming the local minima were isolated and separately optimized, and the electronic properties of the thus obtained structures were analyzed.

We present a study on structural and electronic properties of bulk platinum and the two surfaces (111) and (100) comparing the Gaussian and plane wave method to standard plane wave schemes, normally employed for density functional theory calculations on metallic systems. The aim of this investigation is the assessment of methods based on the expansion of the Kohn-Sham orbitals into localized basis sets and on the supercell approach, in the description of the metallicity of Pt. Electronic structure calculations performed at Gamma-point only on supercells of different sizes, from 108 up to 864 atoms, are compared to the results obtained for the unit cell of four Pt atoms where the k-point expansion of the wave function over Monkhorst-Pack grids up to (10x10x10) has been employed. The evaluation of the two approaches with respect to bulk properties is done through the calculation of the equilibrium lattice constant, the bulk modulus, and the total and the d-projected density of states. For the Pt(111) and Pt(100) surfaces, we consider the relaxation of the first layers, the surface energies, the work function, the total density of states, as well as the center and filling of the d bands. Our results confirm that the accuracy of two approaches in the description of electronic and structural properties of Pt is equivalent, providing that consistent supercells and k-point meshes are used. Moreover, we estimate the supercell size that can be safely adopted in the Gaussian and plane wave method in order to obtain the same reliability of previous theoretical studies based on well converged plane wave calculations available in literature. The latter studies, in turn, set the level of agreement with experimental data. In particular, we obtain excellent agreement in the evaluation of the density of states for either bulk and surface systems, and our data are also in good agreement with previous works on Pt reported in literature. We conclude that Gaussian and plane wave calculations, with simulation cells of 400-800 atoms, can be safely used in the study of chemistry related problems involving transition metal surfaces.

Docking of molecules to surface chiral sites generated by adsorbed chiral organic modifiers is a fundamental step in heterogeneous metal-catalyzed asymmetric hydrogenation. The understanding of such docking events is nonetheless limited by the technical difficulties in obtaining experimental submolecular information for complex adsorbed structures. In addition an accurate theoretical analysis is computationally very demanding due to the need of including the metal surface. The present investigation explores by means of density functional theory the supramolecular docking structures of ketopantolactone within the chiral sites formed by cinchonidine adsorbed on a platinum surface, a crucial step in the enantioselective hydrogenation of ketopantolactone over cinchonidine-modified platinum. The study is performed using periodic slabs exposing Pt(111) surfaces of (6 × 6) and (8 × 8) atoms with a depth of four layers and including complete relaxation of the first three. Twenty six docking sites are investigated...

A recombinant lipase cloned from Pseudomonas fragi strain IFO 3458 (PFL) was found to retain significant activity at low temperature. In an attempt to elucidate the structural basis of this behaviour, a model of its three-dimensional structure was built by homology and compared with homologous mesophilic lipases, i.e. the Pseudomonas aeruginosa lipase (45% sequence identity) and Burkholderia cepacia lipase (38%). In this model, features common to all known lipases have been identified, such as the catalytic triad (S83, D238 and H260) and the oxyanion hole (L17, Q84). Structural modifications recurrent in cold-adaptation, i.e. a large amount of charged residues exposed at the protein surface, have been detected. Noteworthy is the lack of a disulphide bridge conserved in homologous Pseudomonas lipases that may contribute to increased conformational flexibility of the cold-active enzyme.

Desirable features for the computational investigation of catalytic surfaces and chemisorption phenomena are: i) large surface areas, in order to accommodate reactants, products, and possible surface functionalities, ii) the inclusion of finite temperature effects through the generation of molecular dynamics trajectories and, iii) basis sets constituted of localized orbitals. The application of the Gaussian and Plane Waves (GPW) formalism [1] in the description of the metallicity of Pt bulk, Pt(111) and Pt(100) surfaces is shown to yield excellent agreement with standard Plane Waves (PW) calculations in the evaluation of structural, electronic and dynamic properties for either bulk and surface systems [2]. The GPW formalism, with simulation cells of 400-800 atoms, can be safely used in the study of chemistry related problems involving transition metal surfaces. The methodology is applied to the study of chirally modified surfaces [3].

Stable free radicals have a variety of applications. Particularly, the aminoxyl group is frequently used in spin-labeling experiments. Nitroxides may also exhibit intriguing chiral and magnetic properties, and can be of interest for studies of molecular parity violation. We present results for three different groups of persistent nitroxide radicals: i) acyclic: dimethylaminoxyl (Me2NO), bis(trifluoromethyl)aminoxyl (CF3)2NO, and di-tert-butyl nitroxyl [(Me3C)2NO]; ii) cyclic: aziridine-N-oxyl, azetidine-N-oxyl, pyrrolidine-N-oxyl and piperidine-N-oxyl; and iii) imino nitroxides. We used density functional and ab initio (MP2, coupled cluster) methods to obtain insight into the underlying chemistry. The molecular structures, harmonic vibrational frequencies, inversion barriers, and hyperfine coupling constants are reported. The cyclic aziridine-N-oxyl exhibits a considerable inversion barrier of ∼hc 3500 cm-1 compared to only ∼hc 500 cm-1 for the other examples. Stable imino nitroxides are theoretically characterized for the first time in our work. We discuss the possibilities that some of the chiral derivatives may be dominated by molecular parity violation in their dynamics.

The cold-adapted Pseudomonas fragi lipase (PFL) displays highest activity on short-chain triglyceride substrates and is rapidly inactivated at moderate temperature. Sequence and structure comparison with homologous lipases endowed with different substrate specificity and stability, pointed to three polar residues in the lid region, that were replaced with the amino acids conserved at equivalent positions in the reference lipases. Substitutions at residues T137 and T138 modified the lipase chain-length preference profile, increasing the relative activity towards C8 substrates. Moreover, mutations conferred to PFL higher temperature stability. On the other hand, replacement of the serine at position 141 by glycine destabilized the protein.