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81.
82.
Jan H. Dring Julian Schrter Jerome Jüngling Saskia Biskup Kerstin A. Klotz Thomas Bast Tobias Dietel G. Christoph Korenke Sophie Christoph Heiko Brennenstuhl Guido Rubboli Rikke S. Mller Gaetan Lesca Yves Chaix Stefan Klker Georg F. Hoffmann Johannes R. Lemke Steffen Syrbe 《International journal of molecular sciences》2021,22(6)
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants. 相似文献
83.
Dr. Armin Welker Dr. Christian Kersten Dr. Christin Müller Dr. Ramakanth Madhugiri Collin Zimmer Patrick Müller Robert Zimmermann Stefan Hammerschmidt Hannah Maus Prof. John Ziebuhr Prof. Christoph Sotriffer Prof. Tanja Schirmeister 《ChemMedChem》2021,16(2):340-354
Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide ( 2 b ), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors. 相似文献
84.
Oliver Schmutzler Sebastian Graf Nils Behm Wael Y. Mansour Florian Blumendorf Theresa Staufer Christian Krnig Dina Salah Yanan Kang Jan N. Peters Yang Liu Neus Feliu Wolfgang J. Parak Anja Burkhardt Elisabetta Gargioni Sabrina Gennis Sharah Chandralingam Finn Heg Wolfgang Maison Kai Rothkamm Florian Schulz Florian Grüner 《International journal of molecular sciences》2021,22(7)
Quantitative cellular in vitro nanoparticle uptake measurements are possible with a large number of different techniques, however, all have their respective restrictions. Here, we demonstrate the application of synchrotron-based X-ray fluorescence imaging (XFI) on prostate tumor cells, which have internalized differently functionalized gold nanoparticles. Total nanoparticle uptake on the order of a few hundred picograms could be conveniently observed with microsamples consisting of only a few hundreds of cells. A comparison with mass spectroscopy quantification is provided, experimental results are both supported and sensitivity limits of this XFI approach extrapolated by Monte-Carlo simulations, yielding a minimum detectable nanoparticle mass of just 5 pg. This study demonstrates the high sensitivity level of XFI, allowing non-destructive uptake measurements with very small microsamples within just seconds of irradiation time. 相似文献
85.
Alon M. Douek Mitra Amiri Khabooshan Jason Henry Sebastian-Alexander Stamatis Florian Kreuder Georg Ramm Minna-Liisa nk Donald Wlodkowic Jan Kaslin 《International journal of molecular sciences》2021,22(11)
Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA represents a significant proportion of childhood dementias. This condition generally leads to patient death in the teenage years, yet no effective therapy exists for MPS IIIA and a complete understanding of the mechanisms of MPS IIIA pathogenesis is lacking. Here, we employ targeted CRISPR/Cas9 mutagenesis to generate a model of MPS IIIA in the zebrafish, a model organism with strong genetic tractability and amenity for high-throughput screening. The sgshΔex5−6 zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgshΔex5−6 zebrafish faithfully recapitulate diverse CNS-specific features of MPS IIIA, including neuronal lysosomal overabundance, complex behavioural phenotypes, and profound, lifelong neuroinflammation. We further demonstrate that neuroinflammation in sgshΔex5−6 zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in sgshΔex5−6 mutant larvae in a context-dependent manner. We expect the sgshΔex5−6 zebrafish mutant to be a valuable resource in gaining a better understanding of MPS IIIA pathobiology towards the development of timely and effective therapeutic interventions. 相似文献
86.
Alexander Zimmermann Qais Z. Jaber Dr. Johannes Koch Steffen Riebe Dr. Cecilia Vallet Dr. Kateryna Loza Matthias Hayduk Dr. Kfir B. Steinbuch Prof. Shirley K. Knauer Prof. Micha Fridman Jun.-Prof. Jens Voskuhl 《Chembiochem : a European journal of chemical biology》2021,22(9):1563-1567
We report the characterization of amphiphilic aminoglycoside conjugates containing luminophores with aggregation-induced emission properties as transfection reagents. These inherently luminescent transfection vectors are capable of binding plasmid DNA through electrostatic interactions; this binding results in an emission “on” signal due to restriction of intramolecular motion of the luminophore core. The luminescent cationic amphiphiles effectively transferred plasmid DNA into mammalian cells (HeLa, HEK 293T), as proven by expression of a red fluorescent protein marker. The morphologies of the aggregates were investigated by microscopy as well as ζ-potential and dynamic light-scattering measurements. The transfection efficiencies using luminescent cationic amphiphiles were similar to that of the gold-standard transfection reagent Lipofectamine® 2000. 相似文献
87.
Peter Meszmer Karla Hiller Steffen Hartmann Alexey Shaporin Daniel May Raul David Rodriguez Jörg Arnold Gianina Schondelmaier Jan Mehner Dietrich R. T. Zahn Bernhard Wunderle 《Microsystem Technologies》2014,20(6):1041-1050
In this paper, a novel concept of a thermo-mechanical MEMS actuator using aluminum thin-film heaters on a thermal oxide for electrical insulation is presented. The actuator is part of an universal tensile testing platform for thermo-mechanical material characterization of one dimensional materials on a micro- and nano-scopic scale under different environmental conditions, as varying temperatures, pressure, moisture or even vacuum and is realised in BDRIE technology. It is shown, that the actuator concept fulfills the requirements for the use in a tensile loading stage along with heterogeneously integrated nanofunctional elements, following a specimen centered approach in line with bottom-up self-assembly processes. Simulation and experiment agree very well in the thermal and mechanical domain and allow subsequent optimisation of the actuator performance. 相似文献
88.
Fides Aarts Harco Kuppens Jan Tretmans Frits Vaandrager Sicco Verwer 《Machine Learning》2014,96(1-2):189-224
Using a well-known industrial case study from the verification literature, the bounded retransmission protocol, we show how active learning can be used to establish the correctness of protocol implementation I relative to a given reference implementation R. Using active learning, we learn a model M R of reference implementation R, which serves as input for a model-based testing tool that checks conformance of implementation I to M R . In addition, we also explore an alternative approach in which we learn a model M I of implementation I, which is compared to model M R using an equivalence checker. Our work uses a unique combination of software tools for model construction (Uppaal), active learning (LearnLib, Tomte), model-based testing (JTorX, TorXakis) and verification (CADP, MRMC). We show how these tools can be used for learning models of and revealing errors in implementations, present the new notion of a conformance oracle, and demonstrate how conformance oracles can be used to speed up conformance checking. 相似文献
89.
Pavel Krömer Jan Platoš Václav Snášel 《International journal of parallel programming》2014,42(5):681-709
Graphic processing units (GPUs) emerged recently as an exciting new hardware environment for a truly parallel implementation and execution of Nature and Bio-inspired Algorithms with excellent price-to-power ratio. In contrast to common multicore CPUs that contain up to tens of independent cores, the GPUs represent a massively parallel single-instruction multiple-data devices that can nowadays reach peak performance of hundreds and thousands of giga floating-point operations per second. Nature and Bio-inspired Algorithms implement parallel optimization strategies in which a single candidate solution, a group of candidate solutions (population), or multiple populations seek for optimal solution or set of solutions of given problem. Genetic algorithms (GA) constitute a family of traditional and very well-known nature-inspired populational meta-heuristic algorithms that have proved its usefulness on a plethora of tasks through the years. Differential evolution (DE) is another efficient populational meta-heuristic algorithm for real-parameter optimization. Particle swarm optimization (PSO) can be seen as nature-inspired multiagent method in which the interaction of simple independent agents yields intelligent collective behavior. Simulated annealing (SA) is global optimization algorithm which combines statistical mechanics and combinatorial optimization with inspiration in metallurgy. This survey provides a brief overview of the latest state-of-the-art research on the design, implementation, and applications of parallel GA, DE, PSO, and SA-based methods on the GPUs. 相似文献
90.
Aqueous photoresists that are capable of higher resolutions than are currently employed by the cathode ray tube (CRT) industry were developed by combining photoactivators, which activate at shorter UV wavelengths with polyvinylpyrrolidone (PVP). Two photoactivators were synthesized: 4,4′‐diazido‐2,2′‐biphenyl disodium disulfonate (DABP), which has a maximum absorbance at 264 nm, and 4,4′‐diazido‐2,2′‐biphenylethane disodium disulfonate (DABPE), which has a maximum absorbance at 258 nm. The PVP/DABP and PVP/DABPE photoresists successfully imaged a pattern with resolution as small as 4.4 μm with photoactivator concentrations greater than 20% of the PVP concentration. Addition of silane and emulgen greatly improved the performance of the photoresists with more uniform coatings of thicknesses of up to 1.4 μm. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 1637–1644, 2006 相似文献