Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis.

Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide-cysteamine combination treatment as a novel dual-target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.

PROTACs- a game-changing technology.

Introduction: Proteolysis - targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.

Analytical Study of Fuel Switching from Heavy Fuel Oil to Natural Gas in clay brick factories at Arab Abu Saed, Greater Cairo.

Arab Abu Saed area in Giza governorate, south to Cairo contains more than 228 clay brick kilns represent the largest cluster of brickworks in Egypt. Burning of Heavy Fuel Oil (HFO) in such kilns is the main source of air pollution in the surrounding locations. In this study, investigation of switching the fuel used in brick kilns from (HFO) to Natural Gas (NG) is carried out and the pollution loads are assessed in both cases. In addition, two Gaussian dispersion plume models are employed to estimate the concentration of primary pollutants; PM10, SO2, and NO2 at seven locations in the vicinity of Arab Abu Saed to determine the most adversely affected locations. Statistical analysis is applied to evaluate the correlation and conformity of the results of both models. Results show that using of NG leads to a significant reduction of pollution loads of PM10, SO2 and NO2 reaches 96%, 72%, and 24% respectively. In addition, the reduction of naturally occurring radionuclides in air is analyzed. Activity concentrations of Ra-226, Th-232 and K-40 in Bq/l for HFO were measured using HPGe detector for six HFO samples. Exposure due to air submersion of naturally occurring radionuclides in the study area leads to annual equivalent dose ranged between 2.16 mSv/y (received by Uterus) and 14 mSv/y (received by skin), and average effective dose 2.65 mSv/y which represent valuable exposure.

Calculating isotope concentrations using different schemes of dispersion parameters.

The investigated work aims to calculate the concentration of different isotopes through short downwind distances. A theoretical model was designed to calculate the isotope concentration in the wind. The mathematical calculation depends on wind speed, decay distance and the dilution factor to get the concentration of isotopes ((131)I, (133)I, (135)I and (137)Cs) detected in wind at different distances from a nuclear power station. There is a good agreement between the calculated and observed concentrations of (131)I, (133)I, (135)I and (137)Cs.