Conwayfitzpatrick3246

Cyclooxygenase (Cox) inhibitors are known to have severe side effects during renal development. These consist of reduced renal function, underdeveloped subcapsular glomeruli, interstitial fibrosis, and thinner cortical tissue. Global genetic deletion of Cox-2 mimics the phenotype observed after application of Cox inhibitors. This study aimed to investigate which cell types express Cox-2 and prostaglandin E2 receptors and what functions are mediated through this pathway during renal development. Expression of EP2 and EP4 mRNA was detected by RNAscope mainly in descendants of FoxD1+ stromal progenitors; EP1 and EP3, on the other hand, were expressed in tubules. Cox-2 mRNA was detected in medullary interstitial cells and macula densa cells. Functional investigations were performed with a cell-specific approach to delete Cox-2, EP2, and EP4 in FoxD1+ stromal progenitor cells. Our data show that Cox-2 expression in macula densa cells is sufficient to drive renal development. Deletion of EP2 or EP4 in FoxD1+ cells in neonatal mouse kidneys. Furthermore, it shows that stromal progenitor cells may require intact prostaglandin E2 signaling through EP2 and EP4 receptors for normal renal development.There is an increasing interest in using zebrafish (Danio rerio) larva as a vertebrate screening model to study drug disposition. As the pronephric kidney of zebrafish larvae shares high similarity with the anatomy of nephrons in higher vertebrates including humans, we explored in this study whether 3- to 4-day-old zebrafish larvae have a fully functional pronephron. Intravenous injection of fluorescent polyethylene glycol and dextran derivatives of different molecular weight revealed a cutoff of 4.4-7.6 nm in hydrodynamic diameter for passive glomerular filtration, which is in agreement with corresponding values in rodents and humans. Distal tubular reabsorption of a FITC-folate conjugate, covalently modified with PEG2000, via folate receptor 1 was shown. Transport experiments of fluorescent substrates were assessed in the presence and absence of specific inhibitors in the blood systems. Thereby, functional expression in the proximal tubule of organic anion transporter oat (slc22) multidrug resistance-associtations, our proof-of-concept study demonstrates that the zebrafish larva is a translational in vivo test model that allows for mechanistic investigations to study renal function.Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. There is accumulating evidence suggesting that there are shared cellular mechanisms responsible for cystogenesis in human and murine PKD and that reprogramming of metabolism is a key disease feature. In this study, we used a targeted metabolomics approach in an orthologous mouse model of PKD (Pkd1RC/RC) to investigate the metabolic modifications a cystic kidney undergoes during disease progression. Using the Kyoto Encyclopedia of Genes and Genomes pathway database, we identified several biologically relevant metabolic pathways that were altered early in this disease (in 3-mo-old Pkd1RC/RC mice), the most highly represented being arginine biosynthesis and metabolism and tryptophan and phenylalanine metabolism. During the next 6 mo of disease progression, multiple uremic solutes accumulated in the kidney of cystic mice, including several established markers of oxidative stress andhologous or rapidly-progressive PKD models. Importantly, we identified novel alterations, including augmentation of kynurenines, polyamines, and indoles, suggesting increased inflammation and microbial dysbiosis that provide insights into PKD pathomechanisms and may prove helpful for diagnosing, monitoring, and treating ADPKD.Bromoform (CHBr3) belongs to very-short-lived substances (VSLSs), which are important precursors of reactive bromine species (BrOx) contributing to tropospheric and stratospheric chemistry. To date, most models calculating bromine product emissions to the atmosphere only consider the natural production of CHBr3 from marine organisms such as macroalgae and phytoplankton. However, CHBr3 has many other anthropogenic sources (coastal industrial sites, desalination and wastewater plants, ballast waters, and seawater toilets) that may drastically increase the amounts emitted in the atmosphere. Here, we report the levels of CHBr3 released in water and air (according to real-time and offline measurements by proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS) and gas chromatography with electron capture detection (GC-ECD)) in a highly industrialized area where 3 million cubic meters of chlorinated seawater is released each day, which were measured during six field campaigns (at sea and on land) distributed over 3 years. The highest levels found during this survey (which were correlated to the physical-chemical characteristics of the water, meteorological and hydrological conditions, salinity, and temperature gradients along the water column) reached 34.6 μg L-1 in water (100-10 000 times higher than reported natural levels) and 3.9 ppbv in the air (100 times higher than the maximum reported value to date). These findings suggest the need to undertake sampling and analysis campaigns as close as possible to chlorinated discharges, as anthropogenic CHBr3 sources from industrial discharges may be a missing factor in global flux estimates or organic bromine to the atmosphere.The removal of Cr(VI) has attracted extensive attention since it causes serious harm to public health. Herein, we report a two-step method to synthesize N-doped MoS2 nanoflowers (NFs) with controllable sizes, which are first utilized for Cr(VI) removal and display outstanding removal performance. The N-MoS2 NFs with an average size of 40 nm (N-MoS2 NFs-40 nm) can rapidly remove Cr(VI) in 15 min under optimal conditions. The maximum adsorption capacity of N-MoS2 NFs-40 nm can reach 787.41 mg·g-1, which is significantly larger than that of N-MoS2 NFs-150 and -400 nm (314.46 and 229.88 mg·g-1). Meanwhile, N-MoS2 NFs-400 nm have a higher maximum adsorption capacity than pure MoS2 NFs-400 nm (172.12 mg·g-1). In this adsorption/reduction process, N-MoS2 NFs have abundant adsorption sites due to a high surface area. N doping can generate more sulfur vacancy defects in the MoS2 NF structure to accelerate electron transfer and enhance the reduction of Cr(VI) to low-toxicity Cr(III). This study provides a facile approach to fabricating N-MoS2 nanoflowers and demonstrates their superior removal ability for Cr(VI).In the western United States, the number and severity of large wildfires have been growing for decades. Biomass burning (BB) is a major source of volatile organic compounds (VOCs) to the atmosphere both globally and regionally. Following emission, BB VOCs are oxidized while being transported downwind, producing ozone, secondary organic aerosols, and secondary hazardous VOCs. In this research, we measured VOCs using proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) in an urban area 55-65 km downwind of the October 2017 Northern California wildfires. Nonaromatic oxygenated compounds were the dominant component of BB VOCs measured. In the smoke plumes, the VOCs account for 70-75% of the total observed organic carbon, with the remainder being particulate matter (with a diameter of less then 2.5 μm, PM2.5). We show that the correlation of VOCs with furan (primary BB VOC) and maleic anhydride (secondary BB VOC) can indicate the origin of the VOCs. This was further confirmed by the diurnal variations of the VOCs and their concentration-weighted trajectories. Oxidation during transport consumed highly reactive compounds including benzenoids, furanoids, and terpenoids and produced more oxygenated VOCs. Furthermore, wildfire VOCs altered the ozone formation regime and raised the O3 levels in the San Francisco Bay Area.Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab.Four combinations of type-I olefins isoeugenol and 4-hydroxy-3-methoxystyrene with type-II olefins acrolein and crotonaldehyde were investigated in cross-metathesis (CM) reactions. find more While both type-I olefins are suitable CM partners for this transformation, we observed synthetically useful conversions only with type-II olefin crotonaldehyde. For economic reasons, isoeugenol, a cheap xylochemical available from renewable lignocellulose or from clove oil, is the preferred type-I CM partner. Nearly quantitative conversions to coniferyl aldehyde by the CM reaction of isoeugenol and crotonaldehyde can be obtained at ambient temperature without a solvent or at high substrate concentrations of 2 mol·L-1 with the second-generation Hoveyda-Grubbs catalyst. Under these conditions, the ratio of reactants can be reduced to 11.5 and catalyst loadings as low as 0.25 mol % are possible. The high reactivity of the isoeugenol/crotonaldehyde combination in olefin metathesis reactions was demonstrated by a short synthesis of the natural product 7-methoxywutaifuranal, which was obtained from isoeugenol in a 44% yield over five steps. We suggest that the superior performance of crotonaldehyde in the CM reactions investigated can be rationalized by "methylene capping", i.e., the steric stabilization of the propagating Ru-alkylidene species.Circulating tumor cells in body fluids are important biomarkers in cancer diagnosis. The culture of tumor cells isolated from body fluids can provide intrinsic information about tumors and can be used to screen for the best anticancer drugs. However, the culture of primary tumor cells has been hindered by their low viability and difficulties in recapitulating the phenotype of primary tumors in in vitro culture. The culture of tumor cells under serum-free conditions is one of the methodologies to maintain the phenotype and genotype of primary tumors. Poly(2-methoxyethyl acrylate) (PMEA)-coated substrates have been investigated to prolong the proliferation of tumor cells under serum-free conditions. In this study, we investigated the detailed behavior and the mechanism of the increase in tumor cell viability after adherence to PMEA substrates. The blebbing formation of tumor cells on PMEA was attributed not to apoptosis but to the low adhesion strength of cells on PMEA. Moreover, blebbing tumor cells showed amoeboid movement and formed clusters with other cells via N-cadherin, leading to an increase in tumor cell viability.