Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl⁻ currents and intracellular Ca²⁺ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca²⁺ activated Cl⁻ channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca²⁺ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.     

Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. People with ME/CFS often report a prodrome consistent with infections. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls. Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013). Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873. Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle. These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease.     

Biomass Smoke Exposure Enhances Rhinovirus-Induced Inflammation in Primary Lung Fibroblasts

Biomass smoke is one of the major air pollutants and contributors of household air pollution worldwide. More than 3 billion people use biomass fuels for cooking and heating, while other sources of exposure are from the occurrence of bushfires and occupational conditions. Persistent biomass smoke exposure has been associated with acute lower respiratory infection (ALRI) as a major environmental risk factor. Children under the age of five years are the most susceptible in developing severe ALRI, which accounts for 940,000 deaths globally. Around 90% of cases are attributed to viral infections, such as influenza, adenovirus, and rhinovirus. Although several epidemiological studies have generated substantial evidence of the association of biomass smoke and respiratory infections, the underlying mechanism is still unknown. Using an in vitro model, primary human lung fibroblasts were stimulated with biomass smoke extract (BME), specifically investigating hardwood and softwood types, and human rhinovirus-16 for 24 h. Production of pro-inflammatory mediators, such as IL-6 and IL-8, were measured via ELISA. Firstly, we found that hardwood and softwood smoke extract (1%) up-regulate IL-6 and IL-8 release (p ≤ 0.05). In addition, human rhinovirus-16 further increased biomass smoke-induced IL-8 in fibroblasts, in comparison to the two stimulatory agents alone. We also investigated the effect of biomass smoke on viral susceptibility by measuring viral load, and found no significant changes between BME exposed and non-exposed infected fibroblasts. Activated signaling pathways for IL-6 and IL-8 production by BME stimulation were examined using signaling pathway inhibitors. p38 MAPK inhibitor SB239063 significantly attenuated IL-6 and IL-8 release the most (p ≤ 0.05). This study demonstrated that biomass smoke can modulate rhinovirus-induced inflammation during infection, which can alter the severity of the disease. The mechanism by which biomass smoke exposure increases inflammation in the lungs can be targeted and inhibited via p38 MAP kinase pathway.     

Logic circuits based on individual semiconducting and metallic carbon-nanotube devices

Nanoscale transistors employing an individual semiconducting carbon nanotube as the channel hold great potential for logic circuits with large integration densities that can be manufactured on glass or plastic substrates. Carbon nanotubes are usually produced as a mixture of semiconducting and metallic nanotubes. Since only semiconducting nanotubes yield transistors, the metallic nanotubes are typically not utilized. However, integrated circuits often require not only transistors, but also resistive load devices. Here we show that many of the metallic carbon nanotubes that are deposited on the substrate along with the semiconducting nanotubes can be conveniently utilized as load resistors with favorable characteristics for the design of integrated circuits. We also demonstrate the fabrication of arrays of transistors and resistors, each based on an individual semiconducting or metallic carbon nanotube, and their integration on glass substrates into logic circuits with switching frequencies of up to 500 kHz using a custom-designed metal interconnect layer.     

Effect of terbium gallium garnet crystal orientation on the isolation ratio of a Faraday isolator at high average power

We present a comprehensive and systematic investigation of the fundamental physical limitations of Faraday isolation performance at high average powers that are due to thermally induced birefringence. First, the operation of various Faraday isolator designs by use of arbitrary orientation of cubic magneto-optic crystals is studied theoretically. It is shown that, for different Faraday isolator designs, different crystal orientations can optimize the isolation ratio. Second, thermo-optic and photoelastic constants for terbium gallium garnet crystals grown by different manufacturers were measured. Measurements of self-induced depolarization are made for various orientations of crystallographic axes. The measurements are in good agreement with our theoretical predictions. Based on our results, it is possible to select a crystal orientation that optimizes isolation performance at high average powers, resulting in a 5-dB enhancement over nonoptimized orientations.     

Schraubpfähle: Herstellung,Tragfähigkeit und numerische Modellierung

Screw piles: construction methods, bearing capacity and numerical modeling. In the last years the technology of screw‐piling has been developed to overcome the shortcomings of the non‐displacement piles (e.g. bored or flight auger piles) that are always accompanied by soil disturbance, which affect negatively the pile bearing capacity. On the contrary, the screw piles can be considered more or less as full displacement piles, which are comparable with the conventional displacement driven piles. Due to vibration free installation and minimal noise disturbance of the environment they can be applied in urban areas, where driven piles are not appropriate. The full displacement screw piles offer meaningful advantages in terms of environmental engineering. This relatively new piling technology is used successfully as an efficient foundation system that fulfils both stability and serviceability requirements. The use of standard compact machines with high productivity simplifies site operations and contributes to economical performance of the system at the same time. A general overview of the pile system ‐installation techniques, process and bearing capacity – will be described and discussed. First numerical analyses, calibrated on pile load tests to check the validity of the numerical model were applied.     

Regen‐Wind‐induzierte Schwingungen – ein State‐of‐the‐Art Report

Rain‐wind induced vibrations can occur, when rain and wind simultaneously act, for instance, on the cables of cable‐stayed bridges, on inclined steel hangers of arch bridges or on the backstays of guyed masts. As a result of wind and gravity, the rainwater forms small rivulets, which flow down on the surface of these structural members. The rivulets disturb the wind flow around the dry cross section and cause a modified unsymmetrical distribution of the surrounding wind pressure, which leads to periodic exciting forces. Due to the movement of the cable and the wind forces, the position of the rivulets varies on the cable surface. This constellation can lead to aeroelastic excitation with large amplitudes. Rain‐wind induced vibrations can reduce the life cycle of a structure seriously, because the initialising wind velocity of rain‐wind induced vibrations is significantly lower than the design wind velocity and thus has a high probability of occurrence. In this paper, the further researches and investigations up to now dealing with rain‐wind induced vibrations are summed and commented.