The authors provide an epidemiologic analysis of the first 425 confirmed cases of infection with the novel coronavirus in Wuhan, China. This analysis provides estimates of the epidemic doubling time ...and the basic reproductive number and shows clear evidence of sustained human-to-human transmission.
Previously thought of as a nonselective digestion process, autophagy is now known to specifically degrade aggregated proteins and damaged cellular organelles through the action of autophagy ...receptors, which provides cellular quality control and maintains homeostasis. Autophagy receptors recognize and recruit specific cargoes to the autophagosome–lysosome pathway for degradation in ubiquitin-dependent and -independent manners, and their functions (in selective autophagy) are regulated by protein modifications, for example, phosphorylation and ubiquitination. Growing evidence has linked the genetic variants of autophagy receptors to neurodegenerative diseases and multiple experimental systems have validated their roles in modulating the disease process. Here, we review the recent advances in understanding the physiology and pathophysiology of autophagy receptors in selective autophagy, and discuss their potentials as therapeutic targets for neurodegenerative diseases.
This paper investigated effects of Digital Elevation Model (DEM) resolution on flow simulation by applying the HSPF watershed model to three U.S. watersheds with different topographic conditions. ...Each watershed was delineated automatically and manually with four DEMs of the resolution ranging from 3.5 to 100 m. Results indicated that the simulated flow decreased with lowering DEM resolutions due to the reduction in the delineated drainage area particularly in low gradient watersheds. The DEM resolution impact was minimal when the manual method for watershed delineation was applied. The parameter uncertainty was found to be substantially greater than the resolution uncertainty in two out of three tested watersheds, indicating that the calibration of water balance parameters can alleviate the adverse effects of coarse DEM resolution for watersheds with high to moderate gradients. The findings are important to reducing the uncertainty, caused by DEM resolutions, in watershed modelling results, serving as guidelines for watershed modelling-based water resources management.
A Pd-catalyzed amide-directed enantioselective hydrocarbofunctionalization of unactivated alkenes with C–H nucleophiles has been developed using a chiral monodentate oxazoline (MOXin) ligand. Various ...indoles react at C3 position with aminoquinoline-coupled 3-alkenamides to give γ addition products in good to excellent yield and enantioselectivity. This study represents an important advance of the development of chiral monodentate oxazoline ligands, which have been underexplored for asymmetric catalysis.
This paper presents a hybrid model for predicting oyster norovirus outbreaks by combining the Artificial Neural Networks (ANNs) and Principal Component Analysis (PCA) methods and using the Moderate ...Resolution Imaging Spectroradiometer (MODIS) satellite remote-sensing data. Specifically, 10 years (2007-2016) of cloud-free MODIS Aqua data for water leaving reflectance and environmental data were extracted from the center of each oyster harvest area. Then, the PCA was utilized to compress the size of the MODIS Aqua data. An ANN model was trained using the first 4 years of the data from 2007 to 2010 and validated using the additional 6 years of independent datasets collected from 2011 to 2016. Results indicated that the hybrid PCA-ANN model was capable of reproducing the 10 years of historical oyster norovirus outbreaks along the Northern Gulf of Mexico coast with a sensitivity of 72.7% and specificity of 99.9%, respectively, demonstrating the efficacy of the hybrid model.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that share genetic risk factors and pathological hallmarks. Intriguingly, these shared factors ...result in a high rate of comorbidity of these diseases in patients. Intracellular protein aggregates are a common pathological hallmark of both diseases. Emerging evidence suggests that impaired RNA processing and disrupted protein homeostasis are two major pathogenic pathways for these diseases. Indeed, recent evidence from genetic and cellular studies of the etiology and pathogenesis of ALS-FTD has suggested that defects in autophagy may underlie various aspects of these diseases. In this review, we discuss the link between genetic mutations, autophagy dysfunction, and the pathogenesis of ALS-FTD. Although dysfunction in a variety of cellular pathways can lead to these diseases, we provide evidence that ALS-FTD is, in many cases, an autophagy disease.
A new approach, called hydrograph-based approach, is proposed for predicting bacterial concentrations in rivers. The new approach is relatively simple and efficient in terms of data requirements. It ...uses widely available hydrographs as the main input data for estimating flow and sediment transport parameters responsible for bacterial transport under varying flow conditions. The major component of the hydrograph-based approach is a new model, called VARTBacT model which is an extension of the Variable Residence Time (VART) model by including effects of unsteady flow, sediment transport, and bacterial decay/growth processes on bacterial transport and fate in rivers. The applicability of the new hydrograph-based approach is demonstrated through three case studies, each with distinct sediment and flow conditions: (1) steady low flow without sediment transport, (2) flood events with significant sediment transport due to watershed inputs, and (3) sediment resuspension from the streambed. While the sediment resuspension from streambed may be an important process for bacterial transport during high flows, results from this study indicate that the most important mechanism responsible for bacterial transport in streams is watershed loading during flood events and hyporheic exchange during low flow periods.
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► A hydrograph-based approach is developed to modeling bacterial transport in rivers. ► The new approach is able to simulate bacterial concentrations in diverse flows. ► Watershed loading is an important factor for bacterial transport during floods. ► The new approach is demonstrated through three case studies.
Autophagy is a bulk degradation pathway for long-lived proteins, protein aggregates, and damaged organelles. ULK1 protein kinase and Vps34 lipid kinase are two key autophagy regulators that are ...critical for autophagosome biogenesis. However, it isn't fully understood how ULK1 regulates Vps34, especially in the context of disease. Polyglutamine expansion in huntingtin (Htt) causes aberrant accumulation of the aggregated protein and disrupts various cellular pathways including autophagy, a lysosomal degradation pathway, underlying the pathogenesis of Huntington's disease (HD). Although autophagic clearance of Htt aggregates is under investigation as therapeutic strategy for HD, the precise mechanism of autophagy impairment remains poorly understood. Moreover, in-vivo assays of autophagy have been particularly challenging due to lack of reliable and robust molecular biomarkers.
We generated anti-phosphorylated ATG14 antibody to determine ATG14-mediated autophagy regulation; we employed Huntington's disease (HD) genetic cell models and animal models as well as autophagy reporter animal model to understand autophagy signaling and regulation in vivo. We applied biochemical analysis and molecular biology approaches to dissect the alteration of autophagy kinase activity and regulation.
Here, we demonstrate that ULK1 phosphorylates ATG14 at serine 29 in an mTOR-dependent manner. This phosphorylation critically regulates ATG14-Vps34 lipid kinase activity to control autophagy level. We also show that ATG14-associated Vps34 activity and ULK1-mediated phosphorylation of ATG14 and Beclin 1 are compromised in the Q175 mouse model of Huntington's disease. Finally, we show that ATG14 phosphorylation is decreased during general proteotoxic stress caused by proteasomal inhibition. This reduction of the specific phosphorylation of ATG14 and Beclin 1 is mediated, in part, by p62-induced sequestration of ULK1 to an insoluble cellular fraction. We show that increased ULK1 levels and phosphor-mimetic mutant ATG14 facilitate the clearance of polyQ mutant in cells.
Our study identifies a new regulatory mechanism for ATG14-Vps34 kinase activity by ULK1, which can be used as valuable molecular markers for in-vivo autophagic activity as well as potential therapeutic target for the clearance of polyglutamine disease protein.
Palladium-catalyzed enantioselective C(sp3)–H functionalization could provide valuable reactions for organic synthesis. While significant progress has been made on monodentate ...directing-group-mediated (DG-mediated) enantioselective C–H functionalization using amino acid or N-heterocycle-based chiral ligands, methods for enantioselective C(sp3)–H functionalization mediated by bidentate DGs have lagged far behind. For Pd-catalyzed C(sp3)–H functionalization reactions, 8-aminoquinoline (AQ) is a powerful N,N-bidentate auxiliary. The bidentate binding mode of AQ can stabilize high-valent Pd intermediates, enabling challenging transformations through a PdII/IV catalytic manifold. Recently, Duan reported an enantioselective Pd-catalyzed AQ-directed benzylic C–H arylation of 3-arylpropanamides using PdII catalyst and the BINOL phosphoramide (PV) ligand. Herein, we report a protocol for Pd-catalyzed AQ-mediated enantioselective benzylic C–H arylation of 3-arylpropanamides using Pd0 catalyst and the BINOL-phosphoramidite (PIII) ligand. These reactions give good to high yield and improved enantioselectivity (up to 95% ee). Mechanistic studies indicate that the reactions proceed via a Pd0/II catalytic cycle, unprecedented for AQ-directed reactions. DFT calculations suggest that both the phosphoramidite ligand and cesium carbonate base are involved in the enantiodetermining C–H palladation step, and that the AQ directing group converts between binding modes to accommodate the C–H palladation and reductive elimination steps.
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