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The role of nanozinc source (nanohydrozincite: nHZ; nanozinc oxide: nZO) on the performance of alkali-activated slag (AAS) was explored for the first time in the present work. The results showed that nHZ with different contents (0.5, 1.0, and 1.5 wt%) retards the early hydration rate of AAS, whereas nZO showed the lowest retardation effect. Zn(OH)

We present the results of the light sterile neutrino search from the second KATRIN measurement campaign in 2019. Approaching nominal activity, $3.76 \times 10^6$ tritium $\beta$-electrons are analyzed in an energy window extending down to $40\,$eV below the tritium endpoint at $E_0 = 18.57\,$keV. We consider the $3\nu+1$ framework with three active and one sterile neutrino flavor. The analysis is sensitive to a fourth mass eigenstate $m_4^2\lesssim1600\,$eV$^2$ and active-to-sterile mixing $|U_{e4}|^2 \gtrsim 6 \times 10^{-3}$. As no sterile-neutrino signal was observed, we provide improved exclusion contours on $m_4^2$ and $|U_{e4}|^2$ at $95\,$% C.L. Our results supersede the limits from the Mainz and Troitsk experiments. Furthermore, we are able to exclude the large $\Delta m_{41}^2$ solutions of the reactor antineutrino and gallium anomalies to a great extent. The latter has recently been reaffirmed by the BEST collaboration and could be explained by a sterile neutrino with large mixing. While the remaining solutions at small $\Delta m_{41}^2$ are mostly excluded by short-baseline reactor experiments, KATRIN is the only ongoing laboratory experiment to be sensitive to relevant solutions at large $\Delta m_{41}^2$ through a robust spectral shape analysis., Comment: 14 pages, 8 figures, 2 tables

© 2019 The Royal Society of Chemistry. Droplet based scRNA-seq systems such as Drop-seq, inDrop and Chromium 10X have been the catalyst for the wide adoption of high-throughput scRNA-seq technologies in the research laboratory. In order to understand the capabilities of these systems to deeply interrogate biology; here we provide a practical guide through all the steps involved in a typical scRNA-seq experiment. Through comparing and contrasting these three main droplet based systems (and their derivatives), we provide an overview of all critical considerations in obtaining high quality and biologically relevant data. We also discuss the limitations of these systems and how they fit into the emerging field of Genomic Cytometry.

This paper primarily focuses on Entine's assertion that SRI research is hopelessly flawed. Although SRI researchers have primarily chosen to pluck the low-hanging fruit in this line of inquiry, it is possible to obtain unbiased higher level insight. SRI research best functions as a means of helping firms and investors identify what the market wants. As Entine points out, the definition of what is and is not moral behavior for a firm is a quagmire, and the ability to measure whether socially responsible investors have forced firms to become moral is suspect. The paper also agrees with Waddock that socially responsible investors have caused firms to take certain actions that, without such pressure, they would have taken much later or not at all. However, whether these actions have made firms moral is not a debate that SRI researchers should enter. Certainly, events of late would suggest that although firms, by and large, are now more responsive to a variety of social issues, they are not moral entities, and should not be viewed as such.

Two linear scaling schemes for the search of stationary points on the nuclear potential energy surface have been developed and implemented for density functional theory programs using plane waves: a geometry optimizer based on the limited-memory Broyden–Fletcher–Goldfarb–Shanno (L-BFGS) method and a linear scaling method for transition-state search based on the microiterative scheme using the partitioned rational function optimizer (P-RFO) and L-BFGS. These optimizers are written with parallelized execution in mind. It is shown that the electronic wavefunction does not need to be fully optimized in the earlier stages of geometry optimization. The reasons for the robustness and good performance of the proposed schemes are identified. Test calculations are presented that use our implementation in the CPMD code.

Mixed quantum/classical molecular dynamics simulations of the hydride transfer reaction catalyzed by dihydrofolate reductase are presented. The nuclear quantum effects such as zero point energy and hydrogen tunneling, as well as the motion of the entire solvated enzyme, are included during the generation of the free energy profiles and the real-time dynamical trajectories. The calculated deuterium kinetic isotope effect agrees with the experimental value. The simulations elucidate the fundamental nature of the nuclear quantum effects and provide evidence of hydrogen tunneling in the direction along the donor−acceptor axis. The transmission coefficient was found to be 0.80 for hydrogen and 0.85 for deuterium, indicating the significance of dynamical barrier recrossings. Nonadiabatic transitions among the vibrational states were observed but did not strongly affect the transmission coefficient. A study of motions involving residues conserved over 36 diverse species from Escherichia coli to human implies tha...

A hybrid approach for simulating proton and hydride transfer reactions in solution and proteins is described. The electronic quantum effects are incorporated with an empirical valence bond potential. The nuclear quantum effects are included with a mixed quantum‐classical molecular dynamics method in which the transferring hydrogen nuclei are represented by multidimensional vibrational wavefunctions. The free energy profiles are obtained as functions of a collective reaction coordinate, and a mapping or umbrella potential is utilized to drive the reaction over the barrier for infrequent events. The vibrationally adiabatic nuclear quantum effects are incorporated into the free energy profiles. The dynamics are described with the molecular dynamics with quantum transitions (MDQT) surface hopping method, which incorporates vibrationally non-adiabatic effects. The MDQT method is combined with a reactive flux approach to calculate the transmission coefficient and to investigate the real-time dynamics of reactiv...

A partial multidimensional grid generation method for the efficient calculation of nuclear wavefunctions is presented. This method substantially decreases the number of potential energy calculations by avoiding this calculation for grid points with high potential energy. The application of this method to the calculation of three-dimensional hydrogen nuclear wavefunctions for hydride transfer in the enzyme liver alcohol dehydrogenase is presented. The results indicate that the partial multidimensional grid generation method is nearly as accurate as and significantly faster than the standard full grid method.

International audience; Aims The aim of this study was to evaluate the effect of valve surgery (VS) in infective endocarditis (IE) on 5-year mortality and to evaluate whether conflicting results reported by previous studies could be due to differences in their methodological approaches. Methods and results Four hundred and forty-nine patients with a definite left-sided IE were selected from a prospective, population-based study. Association between VS and 5-year mortality was examined with a Cox model. To determine the impact of different methodological approaches, we also analysed the relationship between VS and mortality in our database, according to each method used in the five previous studies. Valve surgery was performed in 240 patients (53%). It was associated with an increase in short-term mortality [within the first 14 post-operative days; adjusted hazard ratio (HR), 3.69; 95% confidence interval (CI), 2.17-6.25; P < 0.0001] and a decrease in long-term mortality (adjusted HR, 0.55; 95% CI, 0.35-0.87; P = 0.01). At least 188 days of follow-up were required for VS to provide an overall survival advantage. When applying each study's method to our database, we obtained results similar to those reported. Conclusion Previous conflicting results appear to be related to differences in statistical methods. When using appropriate models, we found that VS was significantly associated with reduced long-term mortality.

By using calculations based on density functional theory, we investigate the physical factors determining the elemental charge transfer in Alq3, taken as a prototype of molecular systems in condensed phase. The effect of the environment on the hopping of the charge carrier is evaluated self-consistently in a model in which an Alq3 dimer is embedded in an ensemble of permanent and polarizable dipoles, including orientational disorder and the presence of impurities. The results indicate that the origin of the activation barrier is mainly extrinsic and that the local orientation of the dipole moments plays a major role. The influence of nonadiabaticity is also studied and found to be more important for a hole than for an electron.

This paper generalizes the recently proposed approaches for calculating the derivative couplings between adiabatic states in density-functional theory (DFT) based on a Slater transition-state density to transitions such as singlet-singlet excitations, where a single-determinant ansatz is insufficient. The proposed approach is based on restricted open-shell Frank et al. [J. Chem. Phys. 108, 4060 (1998)] theory used to describe a spin-adapted Slater transition state. To treat the dependence of electron-electron interactions on the nuclear positions, variational linear-response density-functional perturbation theory is generalized to reference states with an orbital-dependent Kohn-Sham Hamiltonian and nontrivial occupation patterns. The methods proposed in this paper are not limited to the calculation of derivative coupling vectors, but can also be used for the calculation of other transition matrix elements. Moreover, they can be used to calculate the linear response of open-shell systems to arbitrary external perturbations in DFT.

Coordination-dependent interatomic potentials are proposed for silicon oxides and oxynitrides---also hydrogenated ones---with a functional form based on the widely used Tersoff silicon potential. They are intended for an accurate sampling of the configurational space of realistic silicon oxynitride systems and their interfaces with silicon, including defects and changes of oxidation states. The parameters, which are given in the text, are obtained by simultaneously mapping forces and energies onto the results of density-functional-theory calculations performed for a set of diverse systems and configurations and a wide composition range. Application to a larger set of systems and configurations shows the transferability of these augmented Tersoff potentials and their validity in predicting bulk lattice parameters, energetics of defect relaxation, and vibrational spectra.

By combining large-scale classical molecular dynamics simulations, the replica exchange method and ab initio calculations, we have studied how the incorporation of nitrogen and hafnium affects the physical and chemical properties of the silicon/silicon dioxide interface. This paper focuses on the determination of the structure of the SiO2/Si(100) interface and on the changes induced on its microscopic characteristics by nitrogen introduced at different concentrations (in the range from 1% to 14%). Characteristic Siand Ocentered defects are observed and in particular N-centered defects—also unforeseen ones. Additional defects emerging after hydrogenation are also considered. The effects of silicon replacement with hafnium atoms at various levels in the interface region are also studied, both in the stoichiometric and substoichiometric oxide.

This paper proposes methods for calculating the derivative couplings between adiabatic states in density-functional theory (DFT) and compares them with each other and with multiconfigurational self-consistent field calculations. They are shown to be accurate and, as expected, the costs of their calculation scale more favorably with system size than post-Hartree-Fock calculations. The proposed methods are based on single-particle excitations and the associated Slater transition-state densities to overcome the problem of the unavailability of multielectron states in DFT which precludes a straightforward calculation of the matrix elements of the nuclear gradient operator. An iterative scheme employing linear-response theory was found to offer the best trade-off between accuracy and efficiency. The algorithms presented here have been implemented for doublet-doublet excitations within a plane-wave-basis and pseudopotential framework but are easily generalizable to other excitations and basis sets. Owing to their fundamental importance in cases where the Born-Oppenheimer separation of motions is not valid, these derivative couplings can facilitate, for example, the treatment of nonadiabatic charge transfers, of electron-phonon couplings, and of radiationless electronic transitions in DFT.

By combining ab initio calculations and classical molecular dynamics, we determine how the inclusion of nitrogen in a silica matrix changes its dielectric constant, and elucidate the underlying mechanisms. We find that there is an entire range of nitrogen concentrations (up to approximately 25%) for which the structural pattern of the oxide is preserved in bulk SiON, and the dielectric constant increases mainly because of the variation of the ionic polarizability. This behavior is not sensitive to hydrogen passivation of nitrogen. The few defects, which are associated with electron states near the gap, are mainly centered on undercoordinated nitrogen and undercoordinated silicon, and tend to be removed by hydrogen.

A general analytic expression for the second variational derivative of gradient-corrected exchange-correlation energy functionals is derived, and the terms for the widely used Becke/Perdew, Becke/Lee-Yang-Parr, and Perdew-Burke-Ernzerhof exchange-correlation functionals are given. These analytic derivatives can be used for all applications employing linear-response theory or time-dependent density-functional theory. Calculations are performed in a plane-wave scheme and shown to be numerically more stable, more accurate, and computationally less costly than the most widely used finite-difference scheme.

A network of coupled promoting motions in the enzyme dihydrofolate reductase is identified and characterized. The present identification is based on genomic analysis for sequence conservation, kinetic measurements of multiple mutations, and mixed quantum/classical molecular dynamics simulations of hydride transfer. The motions in this network span time scales of femtoseconds to milliseconds and are found on the exterior of the enzyme as well as in the active site. This type of network has broad implications for an expanded role of the protein fold in catalysis as well as ancillaries such as the engineering of altered protein function and the action of drugs distal to the active site.

The quantum dynamics of the hydride transfer reaction catalyzed by liver alcohol dehydrogenase (LADH) are studied with real-time dynamical simulations including the motion of the entire solvated enzyme. The electronic quantum effects are incorporated with an empirical valence bond potential, and the nuclear quantum effects of the transferring hydrogen are incorporated with a mixed quantum/classical molecular dynamics method in which the transferring hydrogen nucleus is represented by a three-dimensional vibrational wave function. The equilibrium transition state theory rate constants are determined from the adiabatic quantum free energy profiles, which include the free energy of the zero point motion for the transferring nucleus. The nonequilibrium dynamical effects are determined by calculating the transmission coefficients with a reactive flux scheme based on real-time molecular dynamics with quantum transitions (MDQT) surface hopping trajectories. The values of nearly unity for these transmission coefficients imply that nonequilibrium dynamical effects such as barrier recrossings are not dominant for this reaction. The calculated deuterium and tritium kinetic isotope effects for the overall rate agree with experimental results. These simulations elucidate the fundamental nature of the nuclear quantum effects and provide evidence of hydrogen tunneling in the direction along the donor-acceptor axis. An analysis of the geometrical parameters during the equilibrium and nonequilibrium simulations provides insight into the relation between specific enzyme motions and enzyme activity. The donor-acceptor distance, the catalytic zinc-substrate oxygen distance, and the coenzyme (NAD(+)/NADH) ring angles are found to strongly impact the activation free energy barrier, while the donor-acceptor distance and one of the coenzyme ring angles are found to be correlated to the degree of barrier recrossing. The distance between VAL-203 and the reactive center is found to significantly impact the activation free energy but not the degree of barrier recrossing. This result indicates that the experimentally observed effect of mutating VAL-203 on the enzyme activity is due to the alteration of the equilibrium free energy difference between the transition state and the reactant rather than nonequilibrium dynamical factors. The promoting motion of VAL-203 is characterized in terms of steric interactions involving THR-178 and the coenzyme.

The structure of the interface between SiO2 and Si(100) is investigated using the replica-exchange method driven by classical molecular dynamics simulations based on ab initio-derived interatomic potentials. Abrupt interfaces are shown to be unstable, whereas a substoichiometric oxide forms at the transition between the two materials that exhibits Si atoms in all three intermediate oxidation states, in agreement with experiment. A number of physical characteristics are found to be consistent with experimental data, including the distribution of Si atoms with different oxidation states, the increase in atom density and the stability of a pseudo-cristobalite pattern at the interface as well as the presence of Si–O–Si bridge bonds between the substrate and the suboxide.

Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB and EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.

Background: Schneiderian first rank symptoms (FRS) are characterized by a diminished demarcation of self-other boundaries, causing misattribution of self-generated thoughts and actions to external sources. We have shown that introducing sensorimotor prediction error (SPE) by a robotic device in healthy subjects can induce a Feeling of a Presence (FoP) which is related to the FRS (Blanke et al. 2014). Here, we tested if SPE may induce auditory misattribution in psychotic patients and if this is related to neural connectivity in the temporoparietal cortex, insular cortex and fronto-parietal cortex (FoP Network). Methods: Participants manipulated a haptic robotic system inducing a sensorimotor conflict while performing a self-other auditory discrimination task. 31 early psychotic patients (19 with and 12 without FRS) and 20 controls participated in the experiment. We measured accuracy (d′) on auditory self-other discrimination task during sensorimotor conflict induction or control condition, functional connectivity magnitude in a priori FoP network, and calculated correlation between the two measures. Results: Patients with FRS had reduced accuracy in auditory self-other discrimination when sensorimotor conflict was induced (F(2, 44)=6.68, p=.002). rsfMRI connectivity analysis indicated lower connectivity for these patients in regions of the FoP network compared to the non-first rank and control groups (p=.015, p=.014). The level of functional connectivity in the FoP network correlated with the reduction of self-other discrimination in the FRS+ group (r=-0.56, p=.03). Conclusions: Experimental induction of SPE can cause self-other confusion in the auditory domain. This deficit in self-other discrimination was correlated to specifically reduced connectivity in the FoP network related to sensorimotor self-representation.

Purpose Lipid oxidation has been proposed to be a factor in the pathophysiology of glaucoma. We investigated whether elevated levels of isolevuglandin (iso[4]LGE2) protein adducts are associated with astrocytes derived from the glaucomatous optic nerve head. In addition, we examined whether the iso[4]LGE2 protein adducts are altered following exposure of astrocytes to elevated pressure. Methods Astrocytes were isolated from rat brain cortex and human optic nerve and were subjected to pressure treatments, western blot analyses, liquid chromatography tandem mass spectrometry, and immunocytochemistry. Results Elevated levels of isolevuglandin (iso[4]LGE2) protein adducts were associated with astrocytes derived from the glaucomatous (n=10) optic nerve head when compared to those from controls (n=6). Astrocytes subjected to in vitro pressure treatment resulted in increased levels of iso[4]LGE2 protein adducts. Pressure exposure and the recovery period affect iso[4]LGE2 protein modification, and pyridoxamine was effective in decreasing the appearance of iso[4]LGE2 protein adduct immunoreactivity when applied immediately after pressure treatment. Conclusions These results suggest that the elevated iso[4]LGE2 protein adduct immunoreactivity observed in glaucomatous astrocytes may be due to chronic and/or prolonged exposure to pressure, and pyridoxamine may have prophylactic utility against such oxidative protein modification.

Recent studies have shown the importance of integrating multisensory information in the body representation for constituting self-consciousness. However, one idea that has received only scant attention is that our body representation is also constituted by knowledge of bodily visual characteristics (i.e. 'what I look like'). Here in two experiments we used a full body crossmodal congruency task in which visual distractors were presented on a photograph of the participant, another person, who was either familiar or unfamiliar, or an object. Results revealed that during the 'self-condition' CCEs were enhanced compared to the 'other condition'. The CCE was similar for unfamiliar and familiar others. CCEs for the object condition were significantly smaller. The results show that presentation of an irrelevant image of a body affects multimodal processing and that the effect is enhanced when that image is of the self. The results hold intriguing implications for body representation in social situations.

Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB an EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.

Hirschsprung disease (HD) is one of the commonest gastro-intestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed the localization and then the identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelin beta receptor (EDNRB) gene. Two homozygous mutations have been identified in two consanguineous families, in which HD is associated with Waardenburg syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and 5% of cases can be considered to present mutations of this gene. Finally the authors have recently identified a mutation of the endothelin 3 gene (EDN3), one of EDNRB ligands in a patient presenting a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.

The total photoproduction cross section is determined from a measurement of electroproduction with the ZEUS detector at HERA. The Q2 values of the virtual photons are in the range 10-7 < Q2 < 2 × 10-2 GeV2. The γp total cross section in the γp centre of mass energy range 186-233 GeV is 154 ± 16 (stat.) ± 32 (syst.) μb.

Aims and methods. - Hirschsprung's disease is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been identified in Hirschsprung's disease, namely the RET proto-oncogene, the Glial cell line-Derived Neurotrophic Factor and the endothelin B receptor. A total of 174 probands with isolated Hirschsprung's disease (59 familial, 117 sporadic cases), and 4 patients with associated Waardenburg's syndrome and Hirschsprung's disease (1 familial, 3 sporadic cases) were screened for mutations in the coding sequence of the endothelin 3 gene. The coding sequence of the endothelin 3 gene was analyzed for point mutations, using a combination of SSCP analysis and direct DNA sequencing. Results. - Two heterozygous mutations (A17T and A224T) were identified in two patients with isolated Hirschsprung's disease. Two homozygous truncations mutations (E55X and GC262- > T) were identified in patients with the Waardenburg's syndrome/Hirschsprung's disease association. Conclusion. - The present data give further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggest that either recessive and weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.

Physics reports 276(5-6), 224 - 405 (1996). doi:10.1016/S0370-1573(96)00008-7, The impact of the ARGUS experiment to elementary particle physics is reviewed. More than ten years of data taking has allowed ARGUS to contribute significantly to our understanding of beauty and charmed hadrons, τ Leptons, ϒ mesons, ϒϒ interactions and fragmentation processes. In particular the ARGUS measurements of CKM matrix elements opened up a new window on the Standard Model., Published by Elsevier Science, North-Holland, Amsterdam [u.a.]

Hirschsprung's disease is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been identified in Hirschsprung's disease, namely the RET proto-oncogene, the Glial cell line-Derived Neurotrophic Factor and the endothelin B receptor. A total of 174 probands with isolated Hirschsprung's disease (59 familial, 117 sporadic cases), and 4 patients with associated Waardenburg's syndrome and Hirschsprung's disease (1 familial, 3 sporadic cases) were screened for mutations in the coding sequence of the endothelin 3 gene. The coding sequence of the endothelin 3 gene was analyzed for point mutations, using a combination of SSCP analysis and direct DNA sequencing.Two heterozygous mutations (A17T and A224T) were identified in two patients with isolated Hirschsprung's disease. Two homozygous truncations mutations (E55X and GC262-T) were identified in patients with the Waardenburg's syndrome/Hirschsprung's disease association.The present data give further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggest that either recessive and weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.