Functionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell.

G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in a broad range of physiological responses and disease states. Activated GPCRs can undergo agonist-induced phosphorylation by G protein receptor kinases (GRKs) and second messenger-dependent protein kinases such as protein kinase A (PKA). Here, we characterize spatially segregated subpopulations of β2-adrenergic receptor (β2AR) undergoing selective phosphorylation by GRKs or PKA in a single cell. GRKs primarily label monomeric β2ARs that undergo endocytosis, whereas PKA modifies dimeric β2ARs that remain at the cell surface. In hippocampal neurons, PKA-phosphorylated β2ARs are enriched in dendrites, whereas GRK-phosphorylated β2ARs accumulate in soma, being excluded from dendrites in a neuron maturation-dependent manner. Moreover, we show that PKA-phosphorylated β2ARs are necessary to augment the activity of L-type calcium channel. Collectively, these findings provide evidence that functionally distinct subpopulations of this prototypical GPCR exist in a single cell

Dynamic Modeling of Inland Flooding and Storm Surge on Coastal Cities Under Climate Change Scenarios: Transportation Infrastructure Impacts in Norfolk, Virginia USA as a Case Study

Low-lying coastal cities across the world are vulnerable to the combined impact of rainfall and storm tide. However, existing approaches lack the ability to model the combined effect of these flood mechanisms, especially under climate change and sea level rise (SLR). Thus, to increase flood resilience of coastal cities, modeling techniques to improve the understanding and prediction of the combined effect of these flood hazards are critical. To address this need, this study presents a modeling system for assessing the combined flood impact on coastal cities under selected future climate scenarios that leverages ocean modeling with land surface modeling capable of resolving urban drainage infrastructure within the city. The modeling approach is demonstrated in quantifying the impact of possible future climate scenarios on transportation infrastructure within Norfolk, Virginia, USA. A series of combined storm events are modeled for current (2020) and projected future (2070) climate scenarios. The results show that pluvial flooding causes a larger interruption to the transportation network compared to tidal flooding under current climate conditions. By 2070, however, tidal flooding will be the dominant flooding mechanism with even nuisance flooding expected to happen daily due to SLR. In 2070, nuisance flooding is expected to cause a 4.6% total link close time (TLC), which is more than two times that of a 50-year storm surge (1.8% TLC) in 2020. The coupled flood model was compared with a widely used but physically simplistic bathtub method to assess the difference resulting from the more complex modeling presented in this study. The results show that the bathtub method overestimated the flooded area near the shoreline by 9.5% and 3.1% for a 10-year storm surge event in 2020 and 2070, respectively, but underestimated the flooded area in the inland region by 9.0% and 4.0% for the same events. The findings demonstrate the benefit of sophisticated modeling methods compared to more simplistic bathtub approaches, in climate adaptive planning and policy in coastal communities

Anti-platelet aggregation activities of different grades of Angelica sinensis and their therapeutic mechanisms in rats with blood deficiency: insights from metabolomics and lipidomics analyses

In traditional Chinese medicine, the radix of Angelica sinensis (Oliv.) Diels (RAS) is mainly used to replenish and invigorate the blood circulation. This study investigated anti-platelet aggregation activities were used by New Zealand rabbits, and high-performance liquid chromatography data were obtained to determine the spectrum–effect relationship for different commercial grades of RAS. Plasma and urine metabolites were examined using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry-based metabolomics to elucidate the mechanisms underlying the role of these metabolites in a rat model of blood deficiency (BD). Plasma and spleen metabolites were additionally examined using ultra-performance liquid chromatography plus Q-Exactive tandem mass spectrometry-based lipidomics to clarify the mechanisms of RAS in treating BD. The third grade of RAS exhibited the best activity in replenishing and invigorating blood in vitro and in vivo. Ferulic acid, ligustilide, senkyunolide I, uridine, and guanine are quality markers of anti-platelet aggregation activity. Based on the metabolomics results, 19 potential biomarkers were screened in plasma, and 12 potential metabolites were detected in urine. In lipidomics analyses, 73 potential biomarkers were screened in plasma, and 112 potential biomarkers were screened in the spleen. RAS may restore lipid metabolism by regulating disorders of glycerophospholipid and sphingolipid metabolism, the tricarboxylic acid cycle, amino acid metabolism (thereby improving energy metabolism), and arachidonic acid metabolism (thereby promoting blood circulation). These results provide a deeper understanding of the effects of different grades of RAS and a scientific reference for the establishment of grading standards and for the clinical use of RAS

Structural basis for energy transfer in a huge diatom PSI-FCPI supercomplex

Diatom is an important group of marine algae and contributes to around 20% of the global photosynthetic carbon fixation. Photosystem I (PSI) of diatoms is associated with a large number of fucoxanthin-chlorophyll a/c proteins (FCPIs). We report the structure of PSI-FCPI from a diatom Chaetoceros gracilis at 2.38 Å resolution by single-particle cryo-electron microscopy. PSI-FCPI is a monomeric supercomplex consisting of 12 core and 24 antenna subunits (FCPIs), and 326 chlorophylls a, 34 chlorophylls c, 102 fucoxanthins, 35 diadinoxanthins, 18 β-carotenes and some electron transfer cofactors. Two subunits designated PsaR and PsaS were found in the core, whereas several subunits were lost. The large number of pigments constitute a unique and huge network ensuring efficient energy harvesting, transfer and dissipation. These results provide a firm structural basis for unraveling the mechanisms of light-energy harvesting, transfer and quenching in the diatom PSI-FCPI, and also important clues to evolutionary changes of PSI-LHCI

Photoluminescent and superparamagnetic reduced graphene oxide-iron oxide quantum dots for dual-modality imaging, drug delivery and photothermal therapy

Reduced graphene oxide–iron oxide quantum dots (QDs) with intrinsic photoluminescent and superparamagnetic properties were synthesized through a green, hydrothermal method that simultaneously reduced and shattered graphene nanosheets to form the dots. The structure, morphology, properties and cell viability of these QDs were investigated. The QDs emitted violet light when excited at 320 nm, possessed no residual magnetization upon magnetic hysteresis tests, and had low cytotoxicity to healthy cells at low concentrations. The suitability of the QDs for fluorescent and magnetic resonance dual-modality imaging was shown by in vitro imaging with dermal fibroblast cells and T2 relaxation time. A drug could be loaded onto the surface of the QDs, with a loading ratio of drug to QD of 0.31:1. The drug achieved a steady but full release from the QDs over 8 h: these drug-loaded QDs could be manipulated by an external magnetic stimulation for targeted drug delivery. The potential for use as a cancer photothermal therapy was demonstrated by both a rapid, ∼50 °C temperature increase by a suspension of 100 μg ml−1 of QDs and the photothermal ablation of HeLa cells in vitro under near infrared irradiation. The stability of the MGQDs in fetal calf serum was shown to improve when an ionic drug was coated on the surface

Physics-guided multi-objective mixture optimization for functional cementitious composites containing microencapsulated phase changing materials

A physics-guided multi-objective optimization procedure is developed for the mixture design of functional cementitious materials containing microencapsulated phase change materials (MEPCM). The mixture design procedure combines physics-based models with multi-objective optimization and decision-making methods to meet user’s demands on material’s mechanical and thermal properties, as well as the requirements for sustainability, functionalities, and cost. Physics-based models were utilized to draw the linkage between design variables and objective functions, including a hydration model to capture the hydration kinetics of slag-blended cement and a multiscale sub-stepping homogenization model to obtain the properties of cementitious composite. The multi-objective feasible enhanced particle swarm optimization (MOFEPSO) algorithm and the technique for preference by similarity to an ideal solution (TOPSIS) algorithm are used for mixture optimization and decision-making. The material design method is demonstrated through the design of functional cementitious composite materials containing two MEPCMs – i.e., a polymer encapsulated paraffin wax (PolyPCM) and a recently developed fly-ash cenosphere encapsulated PCM (CenoPCM). The design decision-making charts show the trade-offs among mechanical, thermal, and economic performances of cementitious composites containing MEPCMs. The mixture optimization and decision-making method can be used to assist the design of a variety types of functional cementitious composite and concrete