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This paper further improves the Lie group method with Magnus expansion proposed in a previous paper by the authors, to solve some types of direct singular Sturm-Liouville problems. Next, a concrete implementation to the inverse Sturm-Liouville problem algorithm proposed by Barcilon (1974) is provided. Furthermore, computational feasibility and applicability of this algorithm to solve inverse Sturm-Liouville problems of higher order (for n=2,4) are verified successfully. It is observed that the method is successful even in the presence of significant noise, provided that the assumptions of the algorithm are satisfied. In conclusion, this work provides a method that can be adapted successfully for solving a direct (regular/singular) or inverse Sturm-Liouville problem (SLP) of an arbitrary order with arbitrary boundary conditions.
Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.
Background/Aims: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. Methods: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. Results: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. Conclusion: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade.
SmB6 is predicted to be the first member of the intersection of topological insulators and Kondo insulators, strongly correlated materials in which the Fermi level lies in the gap of a many-body resonance that forms by hybridization between localized and itinerant states. While robust, surface-only conductivity at low temperature and the observation of surface states at the expected high symmetry points appear to confirm this prediction, we find both surface states at the (100) surface to be topologically trivial. We find the (Gamma) over bar state to appear Rashba split and explain the prominent (X) over bar state by a surface shift of the many-body resonance. We propose that the latter mechanism, which applies to several crystal terminations, can explain the unusual surface conductivity. While additional, as yet unobserved topological surface states cannot be excluded, our results show that a firm connection between the two material classes is still outstanding.
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.
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.
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.
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.
Transition metals in inorganic systems and metalloproteins can occur in different oxidation states, which makes them ideal redox-active catalysts. To gain a mechanistic understanding of the catalytic reactions, knowledge of the oxidation state of the active metals, ideally in operando, is therefore critical. L-edge X-ray absorption spectroscopy (XAS) is a powerful technique that is frequently used to infer the oxidation state via a distinct blue shift of L-edge absorption energies with increasing oxidation state. A unified description accounting for quantum-chemical notions whereupon oxidation does not occur locally on the metal but on the whole molecule and the basic understanding that L-edge XAS probes the electronic structure locally at the metal has been missing to date. Here we quantify how charge and spin densities change at the metal and throughout the molecule for both redox and core-excitation processes. We explain the origin of the L-edge XAS shift between the high-spin complexes Mn-II(acac)(2) and Mn-III(acac)(3) as representative model systems and use ab initio theory to uncouple effects of oxidation-state changes from geometric effects. The shift reflects an increased electron affinity of Mn-III in the core-excited states compared to the ground state due to a contraction of the Mn 3d shell upon core-excitation with accompanied changes in the classical Coulomb interactions. This new picture quantifies how the metal-centered core hole probes changes in formal oxidation state and encloses and substantiates earlier explanations. The approach is broadly applicable to mechanistic studies of redox-catalytic reactions in molecular systems where charge and spin localization/delocalization determine reaction pathways.
Local observations indicate that climate change and shifting disturbance regimes are causing permafrost degradation. However, the occurrence and distribution of permafrost region disturbances (PRDs) remain poorly resolved across the Arctic and Subarctic. Here we quantify the abundance and distribution of three primary PRDs using time-series analysis of 30-m resolution Landsat imagery from 1999 to 2014. Our dataset spans four continental-scale transects in North America and Eurasia, covering similar to 10% of the permafrost region. Lake area loss (-1.45%) dominated the study domain with enhanced losses occurring at the boundary between discontinuous and continuous permafrost regions. Fires were the most extensive PRD across boreal regions (6.59%), but in tundra regions (0.63%) limited to Alaska. Retrogressive thaw slumps were abundant but highly localized (< 10(-5)%). Our analysis synergizes the global-scale importance of PRDs. The findings highlight the need to include PRDs in next-generation land surface models to project the permafrost carbon feedback.