New inhibitors of the Tat-TAR RNA interaction found with a "fuzzy" pharmacophore model

TAR RNA is a potential target for AIDS therapy. Ligand-based virtual screening was performed to retrieve novel scaffolds for RNA-binding molecules capable of inhibiting the Tat-TAR interaction, which is essential for HIV replication. We used a "fuzzy" pharmacophore approach (SQUID) and an alignment-free pharmacophore method (CATS3D) to carry out virtual screening of a vendor database of small molecules and to perform "scaffold-hopping". A small subset of 19 candidate molecules were experimentally tested for TAR RNA binding in a fluorescence resonance energy transfer (FRET) assay. Both methods retrieved molecules that exhibited activities comparable to those of the reference molecules acetylpromazine and chlorpromazine, with the best molecule showing ten times better binding behavior (IC50 = 46 microM). The hits had molecular scaffolds different from those of the reference molecules.     

Luminescent Amphiphilic Aminoglycoside Probes to Study Transfection

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.     

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, 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.     

Influence of processing parameters on quality factors of one-shot hybrid structures made by RTM

This paper is dealing with the influence of processing parameters for manufacturing of steel–carbon-fiber-reinforced-plastic (CFRP) hybrid plates by using the one-shot-hybrid resin-transfer-moulding (OSH-RTM) process. A design of experiments study was carried out. The quality of the manufactured parts was quantified by the bending modulus, the apparent interlaminar shear strength (ILSS), the maximum deflection and the density of the CFRP. The following changeable processing parameters were chosen: mould temperature, resin temperature, change in mass flow and maximum injection pressure. It is shown that the mould temperature and the change in mass flow show significant impact on the flexural modulus, density and maximum deflection of the plate while there is no significant impact on the apparent ILSS. Furthermore, the interaction between the mould temperature and resin temperature is having an influence on the flexural modulus and density.     

Vitamin D Reverses Disruption of Gut Epithelial Barrier Function Caused by Campylobacter jejuni

Infections by the zoonotic foodborne bacterium Campylobacter jejuni (C. jejuni) are among the most frequent causes of bacterial gastroenteritis worldwide. The aim was to evaluate the relationship between epithelial barrier disruption, mucosal immune activation, and vitamin D (VD) treatment during C. jejuni infection, using intestinal epithelial cells and mouse models focused on the interaction of C. jejuni with the VD signaling pathway and VD treatment to improve C. jejuni-induced barrier dysfunction. Our RNA-Seq data from campylobacteriosis patients demonstrate inhibition of VD receptor (VDR) downstream targets, consistent with suppression of immune function. Barrier-preserving effects of VD addition were identified in C. jejuni-infected epithelial cells and IL-10^−/− mice. Furthermore, interference of C. jejuni with the VDR pathway was shown via VDR/retinoid X receptor (RXR) interaction. Paracellular leakiness of infected epithelia correlated with tight junction (TJ) protein redistribution off the TJ domain and apoptosis induction. Supplementation with VD reversed barrier impairment and prevented inhibition of the VDR pathway, as shown by restoration of transepithelial electrical resistance and fluorescein (332 Da) permeability. We conclude that VD treatment restores gut epithelial barrier functionality and decreases bacterial transmigration and might, therefore, be a promising compound for C. jejuni treatment in humans and animals.     

Tetrabutyl-tetraphenyl-diindenoperylene derivatives as alternative green donor in bulk heterojunction organic solar cells

We present the material 2,3,10,11-tetrabutyl-1,4,9,12-tetraphenyl-diindeno[1,2,3-cd:1′,2′,3′-lm] perylene (Bu4-Ph4-DIP) as alternative green donor for bulk heterojunction small molecule organic solar cells (SMOSC). It is shown that Bu4-Ph4-DIP exhibits suitable absorption characteristics to be a potential material to fill the absorption gap between the commonly used standard absorbers ZnPc and C₆₀.Devices with bulk heterojunctions of Bu4-Ph4-DIP:C₆₀ display very high open circuit voltages of 0.99 V, high fill factors of up to 57%, and experiments yield promising efficiencies of η>2%. Such green-blue absorbing SMOSC are characterized by current voltage and external quantum efficiency measurements, and material properties are studied. It is shown that the devices are responsive to substrate heating, and that different donor-acceptor mixing ratios can increase device performance. Possible influences of mixing ratio and heating on device morphology and electrical properties are discussed.     

Filtration performance at high temperatures and analysis of ceramic filter elements during biomass gasification

During the CHRISGAS project, various experimental campaigns were performed with the aim to study the hot gas filtration process during steam-O₂ biomass gasification at Delft University of Technology. The test-rig consists of a 100 kW thermal atmospheric circulating fluidized-bed gasifier and a high temperature filter unit which contains 3 rigid ceramic candles with an outer diameter of 60 mm, 10 mm wall thickness and a length of 1520 mm. This paper gives an overview of tests performed with different fuels (A-wood, B-wood, miscanthus) and with sand and magnesite used as bed materials. Dia-Schumalith¹ candles were operated in the temperature range between 600 °C and 800 °C for more than 50 h. The filtration performance was studied through continuous observation of the increasing differential pressure while the filter cake formed on the surface of the candles. Gas face velocities ranged between 3 cm s^?1 and 5 cm s^?1. Stable filtration was achieved during some tests. Dust cake analysis indicated formation of calcium phosphates and silicates and potassium silicates.     

Status,causes and controls of cyanobacterial blooms in Lake Erie

The Laurentian Great Lakes are among the most prominent sources of fresh water in the world. Lake Erie's infamous cyanobacterial blooms have, however, threatened the health of this valuable freshwater resource for decades. Toxic blooms dominated by the cyanobacterium Microcystis aeruginosa have most recently been one of primary ecological concerns for the lake. These toxic blooms impact the availability of potable water, as well as public health and revenues from the tourism and fishery industries. The socioeconomic effects of these blooms have spurred research efforts to pinpoint factors that drive bloom events. Despite decades of research and mitigation efforts, these blooms have expanded both in size and duration in recent years. However, through continued joint efforts between the Canadian and United States governments, scientists, and environmental managers, identification of the factors that drive bloom events is within reach. This review provides a summary of historical and contemporary research efforts in the realm of Lake Erie's harmful cyanobacterial blooms, both in terms of experimental and management achievements and insufficiencies, as well as future directions on the horizon for the lake's research community.