Weaverberger5019

Thus, our study provides insights into the complexity of GJB2 genetics. Our data indicate that GJB2 c.109G>A heterozygotes had poorer hearing than did homozygotes. The mechanism underlying the more severe phenotype in heterozygotes and whether the phenotype is caused by GJB2 heterozygotes or compound heterozygotes warrant future investigation.In a sustained search for novel α-amylase inhibitors for the treatment of type 2 diabetes mellitus (T2DM), we report herein the synthesis of a series of nineteen novel rhodanine-fused spiro[pyrrolidine-2,3'-oxindoles]. They were obtained by one-pot three component [3 + 2] cycloaddition of stabilized azomethine ylides, generated in situ by condensation of glycine methyl ester and the cyclic ketones 1H-indole-2,3-dione (isatin), with (Z)-5-arylidine-2-thioxothiazolidin-4-ones. The highlight of this protocol is the efficient high-yield construction of structurally diverse rhodanine-fused spiro[pyrrolidine-2,3'-oxindoles] scaffolds, including four contiguous stereocenters, along with excellent regio- and diastereoselectivities. The stereochemistry of all compounds was confirmed by NMR and corroborated by an X-ray diffraction study performed on one derivative. All cycloadducts were evaluated in vitro for their α-amylase inhibitory activity and showed good α-amylase inhibition with IC50 values ranging between 1.49 ± 0.10 and 3.06 ± 0.17 µM, with respect to the control drug acarbose (IC50 = 1.56 µM). Structural activity relationships (SARs) were also established for all synthesized compounds and the binding interactions of the most active spiropyrrolidine derivatives were modelledby means of molecular insilico docking studies. The most potent compounds 5 g, 5 k, 5 s and 5 l were further screened in vivo for their hypoglycemic activity in alloxan-induced diabetic rats, showing a reduction of the blood glucose level. Therefore, these spiropyrrolidine derivatives may be considered as promising candidates for the development of new classes of antidiabetic drugs.A series of new thieno[2,3-d]pyrimidin-4(3H)-one derivatives were synthesized and evaluated for their activity against four gram-positive and four gram-negative bacterial and eight fungal species. The majority of the compounds exhibited excellent antimicrobial and antifungal activity, being more potent than the control compounds. Compound 22, bearing a m-methoxyphenyl group and an ethylenediamine side chain anchored at C-2 of the thienopyrimidinone core, is the most potent antibacterial compound with broad antimicrobial activity with MIC values in the range of 0.05-0.13 mM, being 6 to 15 fold more potent than the controls, streptomycin and ampicillin. Furthermore, compounds 14 and 15 which bear a p-chlorophenyl and m-methoxyphenyl group, respectively, and share a 2-(2-mercaptoethoxy)ethan-1-ol side chain showed the best antifungal activity, being 10-15 times more potent than ketoconazole or bifonazole with MIC values 0.013-0.026 and 0.027 mM, respectively. Especially in the case of compound 15 the low MIC values were accompanied by excellent MFC values ranging from 0.056 to 0.058 mM. Evaluation of toxicity in vitro on HFL-1 human embryonic primary cells and in vivo in the nematode C. elegans revealed no toxic effects for both compounds 15 and 22 tested at the MIC concentrations. Ligand-based similarity search and molecular docking predicted that the antibacterial activity of analogue 22 is related to inhibition of the topoisomerase II DNA gyrase enzyme and the antifungal activity of compound 15 to CYP51 lanosterol demethylase enzyme. R-Group analysis as a means of computational structure activity relationship tool, highlighted the compounds' crucial pharmacophore features and their impact on the antibacterial and antifungal activity. The presence of a N-methyl piperidine ring fused to the thienopyrimidinone core plays an important role in both activities.Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC50 = 0.12 ± 0.05 μM), but also low toxicity against normal cell line L02 (IC50 = 12.46 ± 0.10 μM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca2+ levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer.Celebrex (1), commonly used as an anti-inflammatory drug, was functionalized (compounds 2-9) to identify new α-glucosidase inhibitors. Initially, all the synthesized derivatives were evaluated for anti-inflammatory activity but none was found to be active. Subsequently a random biological screening was carried out. Interestingly many of them were found to be potent α-glucosidase inhibitors in vitro. All the structures of synthesized derivatives were deduced through 1H NMR, FAB-MS, HR-MS, FT-IR analysis. The single-crystal X-ray structures of compounds 1, and 5 further confirmed the assigned structures. Compounds exhibited a potent α-glucosidase inhibitory activity (IC50 = 92.32 ± 1.530-445.20 ± 1.04 µM) against tested standard acarbose (IC50 = 875.75 ± 2.08 µM), except compounds 2 and 4, which appeared as inactive. Among them, compound 9 (IC50 = 92.32 ± 1.530 µM) was the most potent inhibitor of α-glucosidase enzyme. Molecular docking studies revealed that compounds 6, and 9 interacted with the key amino acid residues of α-glucosidase via H-bonding, and π-π stacking interactions. α-Glucosidase is a key target for the anti-diabetic drug development, and its inhibitors are known to exert anti hyperglycemic effect and help in lowering of post-prandial blood glucose levels.Disused Sealed Radioactive Sources (DSRS) borehole disposal is an innovative concept recommended by international atomic energy agency (IAEA) to improve the safety and security of the management end point for these sources. A green application of Palm Oil Fuel Ash (POFA) as a supplementary material for cementitious backfill barrier in DSRS borehole disposal facility is proposed. Samples with up to 50% POFA replacement complied with the mechanical and hydraulic performance requirements for backfill barriers in retrievable radioactive waste disposal facilities. The structures of one year old OPC and optimum OPC-POFA cement backfills were evaluated using FESEM, XRD, EDXRF, BET, and TGA and their 226 Ra confinement performances were assessed. 30% POFA replacement improved the geochemical conditions by reducing competitive Ca2+ release into the disposal environment. It enhanced 226Ra confinement performance independently on the amount of water intrusion or releases below 2% of 1 Ci source. The improved performance is attributed to the higher fraction of active sites of OPC-POFA backfill compared to that of OPC backfill. 226Ra sorption onto C-S-H is irreversible, spontaneous, endothermic, and independent on the degree of the surface filling. The provided experimental data and theoretical analysis proved the feasibility of this green use of POFA in reducing the radiological hazard of 226Ra.Hazardous waste disposal via incineration generates a substantial amount of ashes and slags which pose an environmental risk due to their toxicity. Currently, these residues are deposited in landfills with loss of potentially recyclable raw material. In this study, the use of acidophilic bioleaching bacteria (Acidithiobacillus ferrooxidans, Acidithiobacillus thiooxidans, and Leptospirillum ferrooxidans) as an environmentally friendly, efficient strategy for the recovery of valuable metals from incineration residues was investigated. Zinc, Cobalt, Copper, and Manganese from three different incineration residues were bio-extracted up to 100% using A. ferrooxidans under ferrous iron oxidation. The other metals showed lower leaching efficiencies based on the type of culture used. Sulfur-oxidizing cultures A. Polyinosinic acid-polycytidylic acid solubility dmso ferrooxidans and A. thiooxidans, containing sulfur as the sole substrate, expressed a significantly lower leaching efficiency (up to 50%). According to ICP-MS, ashes and slags contained Fe, Zn, Cu, Mn, Cr, Cd, and Ni in economically attractive concentrations between 0.2 and 75 mg g-1. Compared to conventional hydrometallurgical and pyrometallurgical processes, our biological approach provides many advantages such as the use of a limited amount of used strong acids (H2SO4 or HCl), recycling operations at lower temperatures (~30 °C) and no emission of toxic gases during combustion (i.e., dioxins and furans).Flood disasters have appeared more frequently in recent years because of climate change and urbanization, and Integrated Flood Risk Management (IFRM) has emerged as an effective method to reduce damage from these floods. This research studies IFRM methods in three aspects flood risk identification of high-risk areas, flood risk assessment to quantify economic losses, and flood risk management to identify structural measures with the greatest engineering benefits. These methods were applied to Beijing as a case study, and the results showed that the Zuoan-Road area was a high-risk area with economic losses ranging from 0.7 million to 35.9 million euros over different return periods. There are five structural measures in Zuoan-Road area, with engineering benefits ranging from 0.97 to 1.60 over different return periods, and the one with the greatest engineering benefits had a fifty-year return period. The results of this research can be used to support urban flood risk management in Beijing.There is an ongoing paradigm shift; wastewater is often not considered a waste any more, but a source of valuable resources nutrients (N nitrogen, P phosphorus, and K potassium), energy and water. The recovery of phosphorus from municipal wastewater has gained a lot of attention because of limited phosphate rock reserves and associated geopolitics, and pollution of phosphate rock. At the WWTP of Leuven, Aquafin operates a full scale installation to recover phosphorus as struvite from digested sludge. This paper discusses the performance of the struvite plant, pollutants in the struvite, struvite use, and economics.The variation in the speed and intensity of SARS-CoV-2 transmission and severity of the resulting COVID-19 disease are still imperfectly understood. We postulate a dose-response relationship in COVID-19, and that "the dose of virus in the initial inoculum" is an important missing link in understanding several incompletely explained observations in COVID-19 as a factor in transmission dynamics and severity of disease. We hypothesize that (1) Viral dose in inoculum is related to severity of disease, (2) Severity of disease is related to transmission potential, and (3) In certain contexts, chains of severe cases can build up to severe local outbreaks, and large-scale intensive epidemics. Considerable evidence from other infectious diseases substantiates this hypothesis and recent evidence from COVID-19 points in the same direction. We suggest research avenues to validate the hypothesis. If proven, our hypothesis could strengthen the scientific basis for deciding priority containment measures in various contexts in particular the importance of avoiding super-spreading events and the benefits of mass masking.