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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.
The demands of a career in competitive sports can lead to chronic stress perception among athletes if there is a non-conformity of requirements and available coping resources. The Trier Inventory for Chronic Stress (TICS) (Schulz et al., 2004) is said to be thoroughly validated. Nevertheless, it has not yet been subjected to a confirmatory factor analysis. The present study aims (1) to evaluate the factorial validity of the TICS within the context of competitive sports and (2) to adapt a short version (TICS-36). The total sample consisted of 564 athletes (age in years: M = 19.1, SD = 3.70). The factor structure of the original TICS did not adequately fit the present data, whereas the short version presented a satisfactory fit. The results indicate that the TICS-36 is an economical instrument for gathering interpretable information about chronic stress. For assessment in competitive sports with TICS-36, we generated overall and gender-specific norm values.
Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
(2018)
Endothelial cells respond to different levels of fluid shear stress through adaptations of their mechanosensitivity. Currently, we lack a good understanding of how this contributes to sculpting of the cardiovascular system. Cerebral cavernous malformation (CCM) is an inherited vascular disease that occurs when a second somatic mutation causes a loss of CCM1/KRIT1, CCM2, or CCM3 proteins. Here, we demonstrate that zebrafish Krit1 regulates the formation of cardiac valves. Expression of heg1, which encodes a binding partner of Krit1, is positively regulated by blood-flow. In turn, Heg1 stabilizes levels of Krit1 protein, and both Heg1 and Krit1 dampen expression levels of klf2a, a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of klf2a and notch1b throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein mediated repression of klf2a and notch1b ultimately shapes cardiac valve leaflet morphology.
Endothelial cells (ECs) are involved in a variety of cellular responses. As multifunctional components of vascular structures, endothelial (progenitor) cells have been utilized in cellular therapies and are required as an important cellular component of engineered tissue constructs and in vitro disease models. Although primary ECs from different sources are readily isolated and expanded, cell quantity and quality in terms of functionality and karyotype stability is limited. ECs derived from human induced pluripotent stem cells (hiPSCs) represent an alternative and potentially superior cell source, but traditional culture approaches and 2D differentiation protocols hardly allow for production of large cell numbers. Aiming at the production of ECs, we have developed a robust approach for efficient endothelial differentiation of hiPSCs in scalable suspension culture. The established protocol results in relevant numbers of ECs for regenerative approaches and industrial applications that show in vitro proliferation capacity and a high degree of chromosomal stability.
High-throughput sequence data retrieved from ancient or other degraded samples has led to unprecedented insights into the evolutionary history of many species, but the analysis of such sequences also poses specific computational challenges. The most commonly used approach involves mapping sequence reads to a reference genome. However, this process becomes increasingly challenging with an elevated genetic distance between target and reference or with the presence of contaminant sequences with high sequence similarity to the target species. The evaluation and testing of mapping efficiency and stringency are thus paramount for the reliable identification and analysis of ancient sequences. In this paper, we present ‘TAPAS’, (Testing of Alignment Parameters for Ancient Samples), a computational tool that enables the systematic testing of mapping tools for ancient data by simulating sequence data reflecting the properties of an ancient dataset and performing test runs using the mapping software and parameter settings of interest. We showcase TAPAS by using it to assess and improve mapping strategy for a degraded sample from a banded linsang (Prionodon linsang), for which no closely related reference is currently available. This enables a 1.8-fold increase of the number of mapped reads without sacrificing mapping specificity. The increase of mapped reads effectively reduces the need for additional sequencing, thus making more economical use of time, resources, and sample material.
Sex-specific differences in nutritional requirements may crucially influence the performances of the sexes, which may have implications for sexual reproduction and thus is of great ecological and evolutionary interest. In the freshwater model species Daphnia magna, essential lipid requirements have been extensively studied. Dietary deficiencies in sterols and polyunsaturated fatty acids (PUFA) have been shown to constrain somatic growth and parthenogenetic reproduction of female Daphnia. In contrast, nutrient requirements of male Daphnia have not been studied yet. Supplementation experiments were conducted to investigate differences in sterol (cholesterol) and PUFA (eicosapentaenoic acid, EPA) requirements between female and male D. magna. Thresholds for sterol-limited juvenile growth were higher in females than in males, suggesting that females are more susceptible to dietary sterol deficiencies than males. Sex-specific differences in maximum somatic growth rates were evident primarily in the presence of dietary EPA; females could not exploit their generally higher growth potential in the absence of dietary PUFA. However, the thresholds for EPA-limited growth did not differ between sexes, suggesting that both sexes have similar dietary EPA requirements during juvenile growth. During a life history experiment, the gain in body dry mass was higher in females than in males, irrespective of food treatment. In both sexes, the gain in body dry mass increased significantly upon EPA supplementation, indicating that both sexes benefited from dietary EPA supply also later in life. However, the positive effects of EPA supplementation were most pronounced for female reproduction-related traits (i.e., clutch sizes, egg dry masses, and total dry mass investment in reproduction). The high maternal investment in reproduction resulted in a depletion of nutrients in female somata. In contrast, the comparatively low paternal investment in reproduction allowed for the accumulation of nutrients in male somata. We conclude that males are generally less susceptible to dietary nutrient deficiencies than females, because they can rely more on internal body stores. Our data suggest that the performances of the sexes are differentially influenced by lipid-mediated food quality, which may have consequences for sexual reproduction and thus the production of resting eggs and the maintenance of Daphnia populations.
Home range size and resource use of breeding and non-breeding white storks along a land use gradient
(2018)
Biotelemetry is increasingly used to study animal movement at high spatial and temporal resolution and guide conservation and resource management. Yet, limited sample sizes and variation in space and habitat use across regions and life stages may compromise robustness of behavioral analyses and subsequent conservation plans. Here, we assessed variation in (i) home range sizes, (ii) home range selection, and (iii) fine-scale resource selection of white storks across breeding status and regions and test model transferability. Three study areas were chosen within the Central German breeding grounds ranging from agricultural to fluvial and marshland. We monitored GPS-locations of 62 adult white storks equipped with solar-charged GPS/3D-acceleration (ACC) transmitters in 2013-2014. Home range sizes were estimated using minimum convex polygons. Generalized linear mixed models were used to assess home range selection and fine-scale resource selection by relating the home ranges and foraging sites to Corine habitat variables and normalized difference vegetation index in a presence/pseudo-absence design. We found strong variation in home range sizes across breeding stages with significantly larger home ranges in non-breeding compared to breeding white storks, but no variation between regions. Home range selection models had high explanatory power and well predicted overall density of Central German white stork breeding pairs. Also, they showed good transferability across regions and breeding status although variable importance varied considerably. Fine-scale resource selection models showed low explanatory power. Resource preferences differed both across breeding status and across regions, and model transferability was poor. Our results indicate that habitat selection of wild animals may vary considerably within and between populations, and is highly scale dependent. Thereby, home range scale analyses show higher robustness whereas fine-scale resource selection is not easily predictable and not transferable across life stages and regions. Such variation may compromise management decisions when based on data of limited sample size or limited regional coverage. We thus recommend home range scale analyses and sampling designs that cover diverse regional landscapes and ensure robust estimates of habitat suitability to conserve wild animal populations.
Retrogressive thaw slumps (RTSs) are among the most active thermokarst landforms in the Arctic and deliver a large amount of material to the Arctic Ocean. However, their contribution to the organic carbon (OC) budget is unknown. We provide the first estimate of the contribution of RTSs to the nearshore OC budget of the Yukon Coast, Canada, and describe the evolution of coastal RTSs between 1952 and 2011 in this area. We (1) describe the evolution of RTSs between 1952 and 2011; (2) calculate the volume of eroded material and stocks of OC mobilized through slumping, including soil organic carbon (SOC) and dissolved organic carbon (DOC); and (3) estimate the OC fluxes mobilized through slumping between 1972 and 2011. We identified RTSs using high- resolution satellite imagery from 2011 and geocoded aerial photographs from 1952 and 1972. To estimate the volume of eroded material, we applied spline interpolation on an airborne lidar dataset acquired in July 2013. We inferred the stocks of mobilized SOC and DOC from existing related literature. Our results show a 73% increase in the number of RTSs and 14% areal expansion between 1952 and 2011. In the study area, RTSs displaced at least 16.6 x 10(6) m(3) of material, 53% of which was ice, and mobilized 145.9 x 10(6) kg of OC. Between 1972 and 2011, 49 RTSs displaced 8.6 x 10(3) m(3) yr(-1) of material, adding 0.6% to the OC flux released by coastal retreat along the Yukon Coast. Our results show that the contribution of RTSs to the nearshore OC budget is non-negligible and should be included when estimating the quantity of OC released from the Arctic coast to the ocean.
One common approach to cope with floods is the implementation of structural flood protection measures, such as levees or flood-control reservoirs, which substantially reduce the probability of flooding at the time of implementation. Numerous scholars have problematized this approach. They have shown that increasing the levels of flood protection can attract more settlements and high-value assets in the areas protected by the new measures. Other studies have explored how structural measures can generate a sense of complacency, which can act to reduce preparedness. These paradoxical risk changes have been described as "levee effect", "safe development paradox" or "safety dilemma". In this commentary, we briefly review this phenomenon by critically analysing the intended benefits and unintended effects of structural flood protection, and then we propose an interdisciplinary research agenda to uncover these paradoxical dynamics of risk.
This publication demonstrates the abilities of a precise and straightforward microcontact printing approach for the preparation of patchy silica particles. In a broad particle size range, it is possible to finely tune the number and parameters of three-dimensional patches like diameter and thickness using only polyethyleneimine ink, poly(dimethoxysilane) as stamp material and a suitable release solvent.
We present a general analysis of the cooling produced by losses on condensates or quasi-condensates. We study how the occupations of the collective phonon modes evolve in time, assuming that the loss process is slow enough so that each mode adiabatically follows the decrease of the mean density. The theory is valid for any loss process whose rate is proportional to the jth power of the density, but otherwise spatially uniform. We cover both homogeneous gases and systems confined in a smooth potential. For a low-dimensional gas, we can take into account the modified equation of state due to the broadening of the cloud width along the tightly confined directions, which occurs for large interactions. We find that at large times, the temperature decreases proportionally to the energy scale mc(2), where m is the mass of the particles and c the sound velocity. We compute the asymptotic ratio of these two quantities for different limiting cases: a homogeneous gas in any dimension and a one-dimensional gas in a harmonic trap.
To cope with the already large, and ever increasing, amount of information stored in organizational memory, "forgetting," as an important human memory process, might be transferred to the organizational context. Especially in intentionally planned change processes (e.g., change management), forgetting is an important precondition to impede the recall of obsolete routines and adapt to new strategic objectives accompanied by new organizational routines. We first comprehensively review the literature on the need for organizational forgetting and particularly on accidental vs. intentional forgetting. We discuss the current state of the art of theory and empirical evidence on forgetting from cognitive psychology in order to infer mechanisms applicable to the organizational context. In this respect, we emphasize retrieval theories and the relevance of retrieval cues important for forgetting. Subsequently, we transfer the empirical evidence that the elimination of retrieval cues leads to faster forgetting to the forgetting of organizational routines, as routines are part of organizational memory. We then propose a classification of cues (context, sensory, business process-related cues) that are relevant in the forgetting of routines, and discuss a meta-cue called the "situational strength" cue, which is relevant if cues of an old and a new routine are present simultaneously. Based on the classification as business process-related cues (information, team, task, object cues), we propose mechanisms to accelerate forgetting by eliminating specific cues based on the empirical and theoretical state of the art. We conclude that in intentional organizational change processes, the elimination of cues to accelerate forgetting should be used in change management practices.
The stratospheric polar vortex can influence the tropospheric circulation and thereby winter weather in the mid-latitudes. Weak vortex states, often associated with sudden stratospheric warmings (SSW), have been shown to increase the risk of cold-spells especially over Eurasia, but its role for North American winters is less clear. Using cluster analysis, we show that there are two dominant patterns of increased polar cap heights in the lower stratosphere. Both patterns represent a weak polar vortex but they are associated with different wave mechanisms and different regional tropospheric impacts. The first pattern is zonally symmetric and associated with absorbed upward-propagating wave activity, leading to a negative phase of the North Atlantic Oscillation (NAO) and cold-air outbreaks over northern Eurasia. This coupling mechanism is well-documented in the literature and is consistent with the downward migration of the northern annular mode (NAM). The second pattern is zonally asymmetric and linked to downward reflected planetary waves over Canada followed by a negative phase of the Western Pacific Oscillation (WPO) and cold-spells in Central Canada and the Great Lakes region. Causal effect network (CEN) analyses confirm the atmospheric pathways associated with this asymmetric pattern. Moreover, our findings suggest the reflective mechanism to be sensitive to the exact region of upward wave-activity fluxes and to be state-dependent on the strength of the vortex. Identifying the causal pathways that operate on weekly to monthly timescales can pave the way for improved sub-seasonal to seasonal forecasting of cold spells in the mid-latitudes.
Leaf growth is a complex process that involves the action of diverse transcription factors (TFs) and their downstream gene regulatory networks. In this study, we focus on the functional characterization of the Arabidopsis thaliana TF GROWTH-REGULATING FACTOR9 (GRF9) and demonstrate that it exerts its negative effect on leaf growth by activating expression of the bZIP TF OBP3-RESPONSIVE GENE 3 (ORG3). While grf9 knockout mutants produce bigger incipient leaf primordia at the shoot apex, rosette leaves and petals than the wild type, the sizes of those organs are reduced in plants overexpressing GRF9 (GRF9ox). Cell measurements demonstrate that changes in leaf size result from alterations in cell numbers rather than cell sizes. Kinematic analysis and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay revealed that GRF9 restricts cell proliferation in the early developing leaf. Performing in vitro binding site selection, we identified the 6-base motif 5'-CTGACA-3' as the core binding site of GRF9. By global transcriptome profiling, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) we identified ORG3 as a direct downstream, and positively regulated target of GRF9. Genetic analysis of grf9 org3 and GRF9ox org3 double mutants reveals that both transcription factors act in a regulatory cascade to control the final leaf dimensions by restricting cell number in the developing leaf.
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.
Polystyrene-coated cobalt nanoparticles (NPs) were synthesized through a dual-stage thermolysis of cobalt carbonyl (Co-2(CO)(8)). The amine end-functionalized polystyrene surfactants with varying molecular weight were prepared via atom-transfer radical polymerization technique. By changing the concentration of these polymeric surfactants, Co NPs with different size, size distribution, and magnetic properties were obtained. Transmission electron microscopy characterization showed that the size of Co NPs stabilized with lower molecular weight polystyrene surfactants (M-n = 2300 g/mol) varied from 12-22 nm, while the size of Co NPs coated with polystyrene of middle (M-n = 4500 g/mol) and higher molecular weight (M-n = 10,500 g/mol) showed little change around 20 nm. Magnetic measurements revealed that the small cobalt particles were superparamagnetic, while larger particles were ferromagnetic and self-assembled into 1-D chain structures. Thermogravimetric analysis revealed that the grafting density of polystyrene with lower molecular weight is high. To the best of our knowledge, this is the first study to obtain both superparamagnetic and ferromagnetic Co NPs by changing the molecular weight and concentration of polystyrene through the dual-stage decomposition method.
Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.
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.
The synthetic yeast genome constructed by the International Synthetic Yeast Sc2.0 consortium adds thousands of loxPsym recombination sites to all 16 redesigned chromosomes, allowing the shuffling of Sc2.0 chromosome parts by the Cre-loxP recombination system thereby enabling genome evolution experiments. Here, we present L-SCRaMbLE, a lightcontrolled Cre recombinase for use in the yeast Saccharomyces cerevisiae. L-SCRaMbLE allows tight regulation of recombinase activity with up to 179-fold induction upon exposure to red light. The extent of recombination depends on induction time and concentration of the chromophore phycocyanobilin (PCB), which can be easily adjusted. The tool presented here provides improved recombination control over the previously reported estradiol-dependent SCRaMbLE induction system, mediating a larger variety of possible recombination events in SCRaMbLE-ing a reporter plasmid. Thereby, L-SCRaMbLE boosts the potential for further customization and provides a facile application for use in the S. cerevisiae genome reengineering project Sc2.0 or in other recombination-based systems.
The synthesis, structure, and photocatalytic water splitting performance of two new titania (TiO2)/gold(Au)/Bombyx mori silk hybrid materials are reported. All materials are monoliths with diameters of up to ca. 4.5 cm. The materials are macroscopically homogeneous and porous with surface areas between 170 and 210 m(2)/g. The diameter of the TiO2 nanoparticles (NPs) - mainly anatase with a minor fraction of brookite - and the Au NPs are on the order of 5 and 7-18 nm, respectively. Addition of poly(ethylene oxide) to the reaction mixture enables pore size tuning, thus providing access to different materials with different photocatalytic activities. Water splitting experiments using a sunlight simulator and a Xe lamp show that the new hybrid materials are effective water splitting catalysts and produce up to 30 mmol of hydrogen per 24 h. Overall the article demonstrates that the combination of a renewable and robust scaffold such as B. mori silk with a photoactive material provides a promising approach to new monolithic photocatalysts that can easily be recycled and show great potential for application in lightweight devices for green fuel production.