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The media is considered to be the fourth pillar in a democratic country. It acts as an effective control mechanism to check the other branches of the government. But this is only consequential when the media functions in an independent and transparent fashion with trained and neutral professionals who are aware of the accountability and consequences of their work. All these factors together would further the country as a democratic institution. Traditionally, it was legacy media responsible for a one-to-many communication process. Their goal was to provide information to the citizens. But this changed with development in technology and the use of social media in daily life. The internet brought with it new media formats which are easily accessible but also unstructured. These lowered barriers of entry in the media enabled citizens to become active participants in the communication process. As a result, these citizens developed a different relationship with the already existing media wherein they were not only the receivers to information but also co-producers. Real-time information allows users to communicate with each other and in turn widely generate public opinion on internet platforms. A many-to-many communication style emerged. While on the one hand, this type of discourse could be an opportunity for citizens to exercise their fundamental freedom of speech and expression, it is on the other hand, proving to have a detrimental effect in two parts: Lack of neutrality, polarized views and pre-existing misconceptions on the part of citizens as well as algorithms and formation of echo-chambers on the part of technology. Some questions arise in this scenario about the capability of citizen journalists, the duties they should adhere to along with the enjoyment of their rights and freedoms, the risks involved in an unchecked method of communication and the effect of citizen journalism in the democratic process.
The application of Raman and infrared (IR) microspectroscopy is leading to hyperspectral data containing complementary information concerning the molecular composition of a sample. The classification of hyperspectral data from the individual spectroscopic approaches is already state-of-the-art in several fields of research. However, more complex structured samples and difficult measuring conditions might affect the accuracy of classification results negatively and could make a successful classification of the sample components challenging. This contribution presents a comprehensive comparison in supervised pixel classification of hyperspectral microscopic images, proving that a combined approach of Raman and IR microspectroscopy has a high potential to improve classification rates by a meaningful extension of the feature space. It shows that the complementary information in spatially co-registered hyperspectral images of polymer samples can be accessed using different feature extraction methods and, once fused on the feature-level, is in general more accurately classifiable in a pattern recognition task than the corresponding classification results for data derived from the individual spectroscopic approaches.
For protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter taste substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca2+](i) in BC and subsequent ACh-release. ACh-release is regulated in an autocrine manner. While the muscarinic ACh-receptors M3R and M1R are activating, M2R is inhibitory. Paracrine effects of ACh released in response to denatonium included increased [Ca2+](i) in ciliated cells. Stimulation by denatonium or with Pseudomonas quinolone signaling molecules led to an increase in mucociliary clearance in explanted tracheae that was Trpm5- and M3R-mediated. We show that ACh-release from BC via the bitter taste cascade leads to immediate paracrine protective responses that can be boosted in an autocrine manner. This mechanism represents the initial step for the activation of innate immune responses against pathogens in the airways.
Plant sap-feeding insects are widespread, having evolved to occupy diverse environmental niches despite exclusive feeding on an impoverished diet lacking in essential amino acids and vitamins. Success depends exquisitely on their symbiotic relationships with microbial symbionts housed within specialized eukaryotic bacteriocyte cells. Each bacteriocyte is packed with symbionts that are individually surrounded by a host-derived symbiosomal membrane representing the absolute host-symbiont interface. The symbiosomal membrane must be a dynamic and selectively permeable structure to enable bidirectional and differential movement of essential nutrients, metabolites, and biosynthetic intermediates, vital for growth and survival of host and symbiont. However, despite this crucial role, the molecular basis of membrane transport across the symbiosomal membrane remains unresolved in all bacteriocyte-containing insects. A transport protein was immuno-localized to the symbiosomal membrane separating the pea aphid Acyrthosiphon pisum from its intracellular symbiont Buchnera aphidicola. The transporter, A. pisum nonessential amino acid transporter 1, or ApNEAAT1 (gene: ACYPI008971), was characterized functionally following heterologous expression in Xenopus oocytes, and mediates both inward and outward transport of small dipolar amino acids (serine, proline, cysteine, alanine, glycine). Electroneutral ApNEAAT1 transport is driven by amino acid concentration gradients and is not coupled to transmembrane ion gradients. Previous metabolite profiling of hemolymph and bacteriocyte, alongside metabolic pathway analysis in host and symbiont, enable prediction of a physiological role for ApNEAAT1 in bidirectional host-symbiont amino acid transfer, supplying both host and symbiont with indispensable nutrients and biosynthetic precursors to facilitate metabolic complementarity.
The limited sodium availability of freshwater and terrestrial environments was a major physiological challenge during vertebrate evolution. The epithelial sodium channel (ENaC) is present in the apical membrane of sodium-absorbing vertebrate epithelia and evolved as part of a machinery for efficient sodium conservation. ENaC belongs to the degenerin/ENaC protein family and is the only member that opens without an external stimulus. We hypothesized that ENaC evolved from a proton-activated sodium channel present in ionocytes of freshwater vertebrates and therefore investigated whether such ancestral traits are present in ENaC isoforms of the aquatic pipid frog Xenopus laevis. Using whole-cell and single-channel electrophysiology of Xenopus oocytes expressing ENaC isoforms assembled from alpha beta gamma- or delta beta gamma-subunit combinations, we demonstrate that Xenopus delta beta gamma-ENaC is profoundly activated by extracellular acidification within biologically relevant ranges (pH 8.0-6.0). This effect was not observed in Xenopus alpha beta gamma-ENaC or human ENaC orthologs. We show that protons interfere with allosteric ENaC inhibition by extracellular sodium ions, thereby increasing the probability of channel opening. Using homology modeling of ENaC structure and site-directed mutagenesis, we identified a cleft region within the extracellular loop of the delta-subunit that contains several acidic amino acid residues that confer proton-sensitivity and enable allosteric inhibition by extracellular sodium ions. We propose that Xenopus delta beta gamma-ENaC can serve as a model for investigating ENaC transformation from a proton-activated toward a constitutively-active ion channel. Such transformation might have occurred during the evolution of tetrapod vertebrates to enable bulk sodium absorption during the water-to-land transition.
Der Unfallversicherungsträger kann bei der Ausgestaltung des Beitragsausgleichsverfahrens nach § 162 Abs. 1 SGB VII die dort genannten Berechnungselemente (Zahl, Schwere oder Aufwendungen der Versicherungsfälle) alternativ oder in Kombination miteinander verwenden und eine geänderte Satzungsregelung auch auf Unfälle anwenden, deren Folgen erst im Beitragsjahr die maßgeblichen Merkmale erfüllen.
Herein we report an update to ACPYPE, a Python3 tool that now properly converts AMBER to GROMACS topologies for force fields that utilize nondefault and nonuniform 1–4 electrostatic and nonbonded scaling factors or negative dihedral force constants. Prior to this work, ACPYPE only converted AMBER topologies that used uniform, default 1–4 scaling factors and positive dihedral force constants. We demonstrate that the updated ACPYPE accurately transfers the GLYCAM06 force field from AMBER to GROMACS topology files, which employs non-uniform 1–4 scaling factors as well as negative dihedral force constants. Validation was performed using β-d-GlcNAc through gas-phase analysis of dihedral energy curves and probability density functions. The updated ACPYPE retains all of its original functionality, but now allows the simulation of complex glycomolecular systems in GROMACS using AMBER-originated force fields. ACPYPE is available for download at https://github.com/alanwilter/acpype.
Ereignet sich ein Unfall auf dem Heimweg vom Arbeitsplatz, während die betroffene Arbeitnehmerin mit einem Mobiltelefon telefoniert (sogenannte „gemischte Tätigkeit“), so scheidet ein Wegeunfall dann aus, wenn die Unfallentstehung überwiegend dem Telefonieren zuzurechnen ist und dieses damit für die Unfallentstehung wesentlich war.
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.
This paper proposes an approach to an ANN-based temperature controller design for a plastic injection moulding system. This design approach is applied to the development of a controller based on a combination of a classical ANN and integrator. The controller provides a fast temperature response and zero steady-state error for three typical heaters (bar, nozzle, and cartridge) for a plastic moulding system. The simulation results in Matlab Simulink software and in comparison to an industrial PID regulator have shown the advantages of the controller, such as significantly less overshoot and faster transient (compared to PID with autotuning) for all examined heaters. In order to verify the proposed approach, the designed ANN controller was implemented and tested using an experimental setup based on an STM32 board.