Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

For the design of next-generation tuberculosis chemotherapy, insight into bacterial defence against drugs is required. Currently, targeting respiration has attracted strong attention for combatting drug-resistant mycobacteria. Q203 (telacebec), an inhibitor of the cytochrome bcc complex in the mycobacterial respiratory chain, is currently evaluated in phase-2 clinical trials. Q203 has bacteriostatic activity against M. tuberculosis, which can be converted to bactericidal activity by concurrently inhibiting an alternative branch of the mycobacterial respiratory chain, cytochrome bd. In contrast, non-tuberculous mycobacteria, such as Mycobacterium smegmatis, show only very little sensitivity to Q203. In this report, we investigated factors that M. smegmatis employs to adapt to Q203 in the presence or absence of a functional cytochrome bd, especially regarding its terminal oxidases. In the presence of a functional cytochrome bd, M. smegmatis responds to Q203 by increasing the expression of cytochrome bcc as well as of cytochrome bd, whereas a M. smegmatis bd-KO strain adapted to Q203 by increasing the expression of cytochrome bcc. Interestingly, single-cell studies revealed cell-to-cell variability in drug adaptation. We also investigated the role of a putative second cytochrome bd isoform postulated for M. smegmatis. Although this putative isoform showed differential expression in response to Q203 in the M. smegmatis bd-KO strain, it did not display functional features similar to the characterised cytochrome bd variant.     

Synthesis and Characterization of an Epidermal Growth Factor Receptor-Selective RuII Polypyridyl–Nanobody Conjugate as a Photosensitizer for Photodynamic Therapy

There is a current surge of interest in the development of novel photosensitizers (PSs) for photodynamic therapy (PDT), as those currently approved are not completely ideal. Among the tested compounds, we have previously investigated the use of Ru^II polypyridyl complexes with a [Ru(bipy)₂(dppz)]²⁺ and [Ru(phen)₂(dppz)]²⁺ scaffold (bipy=2,2′-bipyridine; dppz=dipyrido[3,2-a:2′,3′-c]phenazine; phen=1,10-phenanthroline). These complexes selectively target DNA. However, because DNA is ubiquitous, it would be of great interest to increase the selectivity of our PDT PSs by linking them to a targeting vector in view of targeted PDT. Herein, we present the synthesis, characterization, and in-depth photophysical evaluation of a nanobody-containing Ru^II polypyridyl conjugate selective for the epidermal growth factor receptor (EGFR) in view of targeted PDT. Using ICP-MS and confocal microscopy, we could demonstrate that our conjugate has high selectivity for the EGFR receptor, which is a crucial oncological target because it is overexpressed and/or deregulated in a variety of solid tumors. However, in contrast to expectations, this conjugate was found to not produce reactive oxygen species (ROS) in cancer cells and is therefore not phototoxic.     

Enhancing the exergetic performance of a pilot-scale convective dryer by exhaust air recirculation

Abstract

In this study, an air recirculating pilot-scale convective dryer operating at various exhaust air recycle fractions was exergetically investigated in detail. Two drying air temperatures (55–70?°C), two air volume flow rates (360–450?m³/h), and six exhaust air recycle fractions (0–100%) were considered for drying of poplar wood chips. The effects of drying variables were studied on the exergetic efficiencies of drying system and drying chamber. The total exergy of air exhausting from drying chamber was also fractionated into thermophysical and wet exergies for further evaluating the effect of recycle fraction. The universal exergetic efficiency of drying chamber ranged from 41.84% to 98.07%, while the average overall functional exergetic efficiency of drying system varied from 1.32% to 4.01%. Exhaust air recirculation profoundly improved the overall functional exergetic efficiency of drying system as a decision-making parameter up to over two times. Although the recycle fraction of 100% showed the highest improvement in the overall functional exergetic efficiency of drying system, the drying time drastically increased at this condition as expected. Overall, a compromise should be made between drying time and exergetic improvement in order to select a proper recycle fraction for recovering exergy from outflow air.     

Disassembly 4.0: A Review on Using Robotics in Disassembly Tasks as a Way of Automation

To successfully implement circular economy processes into present value chains, economic feasibility of disassembly processes is essential. Current developments in science and technology, such as artificial intelligence and Internet of Things, foster steep progression in the field of robotics. In this review, the current research on robotics in disassembly is investigated by a systematic literature review. The results were clustered in a framework system distinguishing between applied and basic research on the two main streams of disassembly automation research, namely, predefined processes and adaptable, flexible automation.     

Structural Integration of Sensors/Actuators by Laser Beam Melting for Tailored Smart Components

Laser beam melting (LBM), an additive laser powder bed fusion technology, enables the structural integration of temperature-sensitive sensors and actuators in complex monolithic metallic structures. The objective is to embed a functional component inside a metal part without losing its functionality by overheating. The first part of this paper addresses the development of a new process chain for bonded embedding of temperature-sensitive sensor/actuator systems by LBM. These systems are modularly built and coated by a multi-material/multi-layer thermal protection system of ceramic and metallic compounds. The characteristic of low global heat input in LBM is utilized for the functional embedding. In the second part, the specific functional design and optimization for tailored smart components with embedded functionalities are addressed. Numerical and experimental validated results are demonstrated on a smart femoral hip stem.     

Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics**

Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure-based design of a new class of alanine-containing 3-arylindoles as potent and selective PRMT4 inhibitors, and describe key structure–activity relationships for this class of compounds.     

Inferring Bias and Uncertainty in Camera Calibration

International Journal of Computer Vision - Accurate camera calibration is a precondition for many computer vision applications. Calibration errors, such as wrong model assumptions or imprecise...     

A Simple and Non-Trivial Ramsey Test

Journal of Logic, Language and Information - This paper expounds a simple and non-trivial Ramsey Test. Drawing on the work of Peter Gärdenfors, it aims to help establish an epistemic...     

Fluorophore-Labeled Cyclic Nucleotides as Potent Agonists of Cyclic Nucleotide-Regulated Ion Channels

High-affinity fluorescent derivatives of cyclic adenosine and guanosine monophosphate are powerful tools for investigating their natural targets. Cyclic nucleotide-regulated ion channels belong to these targets and are vital for many signal transduction processes, such as vision and olfaction. The relation of ligand binding to activation gating is still challenging, and there is a need for fluorescent probes that enable the process to be broken down to the single-molecule level. This inspired us to prepare fluorophore-labeled cyclic nucleotides, which are composed of a bright dye and a nucleotide derivative with a thiophenol motif at position 8 that has already been shown to enable superior binding affinity. These bioconjugates were prepared by a novel cross-linking strategy that involves substitution of the nucleobase with a modified thiophenolate in good yield. Both fluorescent nucleotides are potent activators of different cyclic nucleotide-regulated ion channels with respect to the natural ligand and previously reported substances. Molecular docking of the probes excluding the fluorophore reveals that the high potency can be attributed to additional hydrophobic and cation-π interactions between the ligand and the protein. Moreover, the introduced substances have the potential to investigate related target proteins, such as cAMP- and cGMP-dependent protein kinases, exchange proteins directly activated by cAMP or phosphodiesterases.     

Influence of Mixing on the Precipitation of Organic Nanoparticles: A Lagrangian Perspective on Scale‐up Based on Self‐Similar Distributions

Precipitation of nanoparticles is applied in various fields with a rising interest in the formulation of poorly soluble drugs. The impact of fluid mixing on the precipitation of organic nanoparticles is analyzed. Direct numerical simulations are applied to determine the spatiotemporal evolution of the liquid phase composition and to estimate the particle evolution along Langragian trajectories. The simulation results are compared with laboratory experiments of mixing and particle size evolution, which use a recently developed approach to rapidly stabilize the precipitated nanoparticles. The impact of mixing on precipitation is revealed, thereby enabling a parameter‐free estimation of the mean particle sizes and the particle size distributions. The distributions of residence time, supersaturation time, and particle size are self‐similar for Reynolds numbers in the turbulent regime and allow the derivation of scale‐up rules.