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For a given subcritical discrete Schrodinger operator H on a weighted infinite graph X, we construct a Hardy-weight w which is optimal in the following sense. The operator H - lambda w is subcritical in X for all lambda < 1, null-critical in X for lambda = 1, and supercritical near any neighborhood of infinity in X for any lambda > 1. Our results rely on a criticality theory for Schrodinger operators on general weighted graphs.
Background and objective Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort (R) oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency. Methods Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort (R) or 20 mg of Infacort (R)/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model. Results Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline (cort),15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing < 20 kg. Conclusions Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing < 20 kg.
The simultaneous detection of energy, momentum and temporal information in electron spectroscopy is the key aspect to enhance the detection efficiency in order to broaden the range of scientific applications. Employing a novel 60 degrees wide angle acceptance lens system, based on an additional accelerating electron optical element, leads to a significant enhancement in transmission over the previously employed 30 degrees electron lenses. Due to the performance gain, optimized capabilities for time resolved electron spectroscopy and other high transmission applications with pulsed ionizing radiation have been obtained. The energy resolution and transmission have been determined experimentally utilizing BESSY II as a photon source. Four different and complementary lens modes have been characterized. (C) 2017 The Authors. Published by Elsevier B.V.
We prove finiteness and diameter bounds for graphs having a positive Ricci-curvature bound in the Bakry–Émery sense. Our first result using only curvature and maximal vertex degree is sharp in the case of hypercubes. The second result depends on an additional dimension bound, but is independent of the vertex degree. In particular, the second result is the first Bonnet–Myers type theorem for unbounded graph Laplacians. Moreover, our results improve diameter bounds from Fathi and Shu (Bernoulli 24(1):672–698, 2018) and Horn et al. (J für die reine und angewandte Mathematik (Crelle’s J), 2017, https://doi.org/10.1515/crelle-2017-0038) and solve a conjecture from Cushing et al. (Bakry–Émery curvature functions of graphs, 2016).
We complete the picture how the asymptotic behavior of a dynamical system is reflected by properties of the associated Perron-Frobenius operator. Our main result states that strong convergence of the powers of the Perron-Frobenius operator is equivalent to setwise convergence of the underlying dynamic in the measure algebra. This situation is furthermore characterized by uniform mixing-like properties of the system.
ShapeRotator
(2018)
The quantification of complex morphological patterns typically involves comprehensive shape and size analyses, usually obtained by gathering morphological data from all the structures that capture the phenotypic diversity of an organism or object. Articulated structures are a critical component of overall phenotypic diversity, but data gathered from these structures are difficult to incorporate into modern analyses because of the complexities associated with jointly quantifying 3D shape in multiple structures. While there are existing methods for analyzing shape variation in articulated structures in two-dimensional (2D) space, these methods do not work in 3D, a rapidly growing area of capability and research. Here, we describe a simple geometric rigid rotation approach that removes the effect of random translation and rotation, enabling the morphological analysis of 3D articulated structures. Our method is based on Cartesian coordinates in 3D space, so it can be applied to any morphometric problem that also uses 3D coordinates (e.g., spherical harmonics). We demonstrate the method by applying it to a landmark-based dataset for analyzing shape variation using geometric morphometrics. We have developed an R tool (ShapeRotator) so that the method can be easily implemented in the commonly used R package geomorph and MorphoJ software. This method will be a valuable tool for 3D morphological analyses in articulated structures by allowing an exhaustive examination of shape and size diversity.
We analyze a general class of self-adjoint difference operators H-epsilon = T-epsilon + V-epsilon on l(2)((epsilon Z)(d)), where V-epsilon is a multi-well potential and v(epsilon) is a small parameter. We give a coherent review of our results on tunneling up to new sharp results on the level of complete asymptotic expansions (see [30-35]). Our emphasis is on general ideas and strategy, possibly of interest for a broader range of readers, and less on detailed mathematical proofs. The wells are decoupled by introducing certain Dirichlet operators on regions containing only one potential well. Then the eigenvalue problem for the Hamiltonian H-epsilon is treated as a small perturbation of these comparison problems. After constructing a Finslerian distance d induced by H-epsilon, we show that Dirichlet eigenfunctions decay exponentially with a rate controlled by this distance to the well. It follows with microlocal techniques that the first n eigenvalues of H-epsilon converge to the first n eigenvalues of the direct sum of harmonic oscillators on R-d located at several wells. In a neighborhood of one well, we construct formal asymptotic expansions of WKB-type for eigenfunctions associated with the low-lying eigenvalues of H-epsilon. These are obtained from eigenfunctions or quasimodes for the operator H-epsilon acting on L-2(R-d), via restriction to the lattice (epsilon Z)(d). Tunneling is then described by a certain interaction matrix, similar to the analysis for the Schrodinger operator (see [22]), the remainder is exponentially small and roughly quadratic compared with the interaction matrix. We give weighted l(2)-estimates for the difference of eigenfunctions of Dirichlet-operators in neighborhoods of the different wells and the associated WKB-expansions at the wells. In the last step, we derive full asymptotic expansions for interactions between two "wells" (minima) of the potential energy, in particular for the discrete tunneling effect. Here we essentially use analysis on phase space, complexified in the momentum variable. These results are as sharp as the classical results for the Schrodinger operator in [22].
Rapid population and economic growth in Southeast Asia has been accompanied by extensive land use change with consequent impacts on catchment hydrology. Modeling methodologies capable of handling changing land use conditions are therefore becoming ever more important and are receiving increasing attention from hydrologists. A recently developed data-assimilation-based framework that allows model parameters to vary through time in response to signals of change in observations is considered for a medium-sized catchment (2880 km(2)) in northern Vietnam experiencing substantial but gradual land cover change. We investigate the efficacy of the method as well as the importance of the chosen model structure in ensuring the success of a time-varying parameter method. The method was used with two lumped daily conceptual models (HBV and HyMOD) that gave good-quality streamflow predictions during pre-change conditions. Although both time-varying parameter models gave improved streamflow predictions under changed conditions compared to the time-invariant parameter model, persistent biases for low flows were apparent in the HyMOD case. It was found that HyMOD was not suited to representing the modified baseflow conditions, resulting in extreme and unrealistic time-varying parameter estimates. This work shows that the chosen model can be critical for ensuring the time-varying parameter framework successfully models streamflow under changing land cover conditions. It can also be used to determine whether land cover changes (and not just meteorological factors) contribute to the observed hydrologic changes in retrospective studies where the lack of a paired control catchment precludes such an assessment.
We establish essential steps of an iterative approach to operator algebras, ellipticity and Fredholm property on stratified spaces with singularities of second order. We cover, in particular, corner-degenerate differential operators. Our constructions are focused on the case where no additional conditions of trace and potential type are posed, but this case works well and will be considered in a forthcoming paper as a conclusion of the present calculus.
Earthquake rates are driven by tectonic stress buildup, earthquake-induced stress changes, and transient aseismic processes. Although the origin of the first two sources is known, transient aseismic processes are more difficult to detect. However, the knowledge of the associated changes of the earthquake activity is of great interest, because it might help identify natural aseismic deformation patterns such as slow-slip events, as well as the occurrence of induced seismicity related to human activities. For this goal, we develop a Bayesian approach to identify change-points in seismicity data automatically. Using the Bayes factor, we select a suitable model, estimate possible change-points, and we additionally use a likelihood ratio test to calculate the significance of the change of the intensity. The approach is extended to spatiotemporal data to detect the area in which the changes occur. The method is first applied to synthetic data showing its capability to detect real change-points. Finally, we apply this approach to observational data from Oklahoma and observe statistical significant changes of seismicity in space and time.
Paleoearthquakes and historic earthquakes are the most important source of information for the estimation of long-term earthquake recurrence intervals in fault zones, because corresponding sequences cover more than one seismic cycle. However, these events are often rare, dating uncertainties are enormous, and missing or misinterpreted events lead to additional problems. In the present study, I assume that the time to the next major earthquake depends on the rate of small and intermediate events between the large ones in terms of a clock change model. Mathematically, this leads to a Brownian passage time distribution for recurrence intervals. I take advantage of an earlier finding that under certain assumptions the aperiodicity of this distribution can be related to the Gutenberg-Richter b value, which can be estimated easily from instrumental seismicity in the region under consideration. In this way, both parameters of the Brownian passage time distribution can be attributed with accessible seismological quantities. This allows to reduce the uncertainties in the estimation of the mean recurrence interval, especially for short paleoearthquake sequences and high dating errors. Using a Bayesian framework for parameter estimation results in a statistical model for earthquake recurrence intervals that assimilates in a simple way paleoearthquake sequences and instrumental data. I present illustrative case studies from Southern California and compare the method with the commonly used approach of exponentially distributed recurrence times based on a stationary Poisson process.
Cell-free protein synthesis as a novel tool for directed glycoengineering of active erythropoietin
(2018)
As one of the most complex post-translational modification, glycosylation is widely involved in cell adhesion, cell proliferation and immune response. Nevertheless glycoproteins with an identical polypeptide backbone mostly differ in their glycosylation patterns. Due to this heterogeneity, the mapping of different glycosylation patterns to their associated function is nearly impossible. In the last years, glycoengineering tools including cell line engineering, chemoenzymatic remodeling and site-specific glycosylation have attracted increasing interest. The therapeutic hormone erythropoietin (EPO) has been investigated in particular by various groups to establish a production process resulting in a defined glycosylation pattern. However commercially available recombinant human EPO shows batch-to-batch variations in its glycoforms. Therefore we present an alternative method for the synthesis of active glycosylated EPO with an engineered O-glycosylation site by combining eukaryotic cell-free protein synthesis and site-directed incorporation of non-canonical amino acids with subsequent chemoselective modifications.
Frühe mathematische Bildung
(2018)
Im vorliegenden Beitrag werden aktuelle Forschungstrends im Bereich der frühen mathematischen Bildung im Kontext jüngst formulierter Zieldimensionen für die frühe mathematische Bildung (siehe Benz et al., 2017) dargestellt. Es wird auf spielbasierte Fördermaßnahmen, Kompetenzen im Bereich „Raum und Form“, den Einfluss sprachlicher Parameter auf die Entwicklung mathematischer Kompetenzen sowie auf mathematikbezogene Kompetenzen frühpädagogischer Fachkräfte eingegangen. Darüber hinaus werden die Ergebnisse einer aktuellen Feldstudie zur Förderung früher mathematischer Kompetenzen (siehe Dillon, Kannan, Dean, Spelke & Duflo, 2017) vorgestellt. Abschließend wird die Entwicklung und Implementierung anschlussfähiger Bildungskonzepte als eine der zentralen Herausforderungen zukünftiger Forschungs- und Bildungsbemühungen diskutiert
We consider the problem of low rank matrix recovery in a stochastically noisy high-dimensional setting. We propose a new estimator for the low rank matrix, based on the iterative hard thresholding method, that is computationally efficient and simple. We prove that our estimator is optimal in terms of the Frobenius risk and in terms of the entry-wise risk uniformly over any change of orthonormal basis, allowing us to provide the limiting distribution of the estimator. When the design is Gaussian, we prove that the entry-wise bias of the limiting distribution of the estimator is small, which is of interest for constructing tests and confidence sets for low-dimensional subsets of entries of the low rank matrix.
We consider a statistical inverse learning (also called inverse regression) problem, where we observe the image of a function f through a linear operator A at i.i.d. random design points X-i , superposed with an additive noise. The distribution of the design points is unknown and can be very general. We analyze simultaneously the direct (estimation of Af) and the inverse (estimation of f) learning problems. In this general framework, we obtain strong and weak minimax optimal rates of convergence (as the number of observations n grows large) for a large class of spectral regularization methods over regularity classes defined through appropriate source conditions. This improves on or completes previous results obtained in related settings. The optimality of the obtained rates is shown not only in the exponent in n but also in the explicit dependency of the constant factor in the variance of the noise and the radius of the source condition set.
Left-right (L-R) asymmetry in the body plan is determined by nodal flow in vertebrate embryos. Shinohara et al. (Shinohara K et al. 2012 Nat. Commun. 3, 622 (doi:10.1038/ncomms1624)) used Dpcd and Rfx3 mutant mouse embryos and showed that only a few cilia were sufficient to achieve L-R asymmetry. However, the mechanism underlying the breaking of symmetry by such weak ciliary flow is unclear. Flow-mediated signals associated with the L-R asymmetric organogenesis have not been clarified, and two different hypotheses-vesicle transport and mechanosensing-are now debated in the research field of developmental biology. In this study, we developed a computational model of the node system reported by Shinohara et al. and examined the feasibilities of the two hypotheses with a small number of cilia. With the small number of rotating cilia, flow was induced locally and global strong flow was not observed in the node. Particles were then effectively transported only when they were close to the cilia, and particle transport was strongly dependent on the ciliary positions. Although the maximum wall shear rate was also influenced by ciliary position, the mean wall shear rate at the perinodal wall increased monotonically with the number of cilia. We also investigated the membrane tension of immotile cilia, which is relevant to the regulation of mechanotransduction. The results indicated that tension of about 0.1 mu Nm(-1) was exerted at the base even when the fluid shear rate was applied at about 0.1 s(-1). The area of high tension was also localized at the upstream side, and negative tension appeared at the downstream side. Such localization may be useful to sense the flow direction at the periphery, as time-averaged anticlockwise circulation was induced in the node by rotation of a few cilia. Our numerical results support the mechanosensing hypothesis, and we expect that our study will stimulate further experimental investigations of mechanotransduction in the near future.
Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the "missing heritability" between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure.
In paper (Flad and Harutyunyan in Discrete Contin Dyn Syst 420-429, 2011) is shown that the Hamiltonian of the helium atom in the Born-Oppenheimer approximation, in the case if two particles coincide, is an edge-degenerate operator, which is elliptic in the corresponding edge calculus. The aim of this paper is an analogous investigation in the case if all three particles coincide. More precisely, we show that the Hamiltonian in the mentioned case is a corner-degenerate operator, which is elliptic as an operator in the corner analysis.