| 1. |
- Chen, Zhen, et al.
(författare)
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Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton
- 2019
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 62:7, s. 3336-3353
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Tidskriftsartikel (refereegranskat)abstract
- Monoacylglycerol lipase (MAGL) is a senile hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with C-11 or F-18. [C-11]8 ([C-11]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [C-11]17 ([C-11]PAD) and [F-18]37 ([F-18]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
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| 2. |
- Cheng, Ran, et al.
(författare)
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In Vitro and in Vivo Evaluation of C-11-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:6, s. 2278-2291
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Tidskriftsartikel (refereegranskat)abstract
- Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including C-11-carbonylation and spirocyclic iodonium ylide (SCIDY) radio fluorination. The lead compound [C-11]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.
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| 3. |
- Chong, Hui, et al.
(författare)
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Organo-ptii complexes for potent photodynamic inactivation of multi-drug resistant bacteria and the influence of configuration
- 2024
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Ingår i: Advanced Science. - : John Wiley & Sons. - 2198-3844. ; 11:14
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Tidskriftsartikel (refereegranskat)abstract
- PtII based organometallic photosensitizers (PSs) have emerged as novel potent photodynamic inactivation (PDI) reagents through their enhanced intersystem crossing (ISC) processes. Currently, few PtII PSs have been investigated as antibacterial materials, with relatively poor performances reported and with structure-activity relationships not well described. Herein, a pair of configurational isomers are reported of Bis-BODIPY (4,4-difluoro-boradizaindacene) embedded PtII PSs. The cis-isomer (cis-BBP) displayed enhanced 1O2 generation and better bacterial membrane anchoring capability as compared to the trans-isomer (trans-BBP). The effective PDI concentrations (efficiency > 99.9%) for cis-BBP in Acinetobacter baumannii (multi-drug resistant (MDR)) and Staphylococcus aureus are 400 nM (12 J cm−2) and 100 nM (18 J cm−2), respectively; corresponding concentrations and light doses for trans-BBP in the two bacteria are 2.50 µM (30 J cm−2) and 1.50 µM (18 J cm−2), respectively. The 50% and 90% minimum inhibitory concentration (MIC50 and MIC90) ratio of trans-BBP to cis-BBP is 22.22 and 24.02 in A. baumannii (MDR); 21.29 and 22.36 in methicillin resistant S. aureus (MRSA), respectively. Furthermore, cis-BBP displays superior in vivo antibacterial performance, with acceptable dark and photoinduced cytotoxicity. These results demonstrate cis-BBP is a robust light-assisted antibacterial reagent at sub-micromolecular concentrations. More importantly, configuration of PtII PSs should be an important issue to be considered in further PDI reagents design.
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| 4. |
- Cui, Manying, et al.
(författare)
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Regulation of Lithium-Ion Flux by Nanotopology Lithiophilic Boron-Oxygen Dipole in Solid Polymer Electrolytes for Lithium-Metal Batteries
- 2023
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Ingår i: Energy & Environmental Materials. - 2575-0356.
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Tidskriftsartikel (refereegranskat)abstract
- Inhomogeneous lithium-ion (Li+) deposition is one of the most crucial problems, which severely deteriorates the performance of solid-state lithium metal batteries (LMBs). Herein, we discovered that covalent organic framework (COF-1) with periodically arranged boron-oxygen dipole lithiophilic sites could directionally guide Li+ even deposition in asymmetric solid polymer electrolytes. This in situ prepared 3D cross-linked network Poly(ACMO-MBA) hybrid electrolyte simultaneously delivers outstanding ionic conductivity (1.02 × 10−3 S cm−1 at 30 °C) and excellent mechanical property (3.5 MPa). The defined nanosized channel in COF-1 selectively conducts Li+ increasing Li+ transference number to 0.67. Besides, The COF-1 layer and Poly(ACMO-MBA) also participate in forming a boron-rich and nitrogen-rich solid electrolyte interface to further improve the interfacial stability. The Li‖Li symmetric cell exhibits remarkable cyclic stability over 1000 h. The Li‖NCM523 full cell also delivers an outstanding lifespan over 400 cycles. Moreover, the Li‖LiFePO4 full cell stably cycles with a capacity retention of 85% after 500 cycles. the Li‖LiFePO4 pouch full exhibits excellent safety performance under pierced and cut conditions. This work thereby further broadens and complements the application of COF materials in polymer electrolyte for dendrite-free and high-energy-density solid-state LMBs.
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| 5. |
- Wang, Zhang, et al.
(författare)
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Testing contrasting models of the formation of the upper Yellow River usingheavy-mineral data from the Yinchuan Basin drill cores
- 2019
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Ingår i: Geophysical Research Letters. - : John Wiley & Sons. - 0094-8276 .- 1944-8007. ; 46:17-18, s. 10338-10345
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Tidskriftsartikel (refereegranskat)abstract
- The upper Yellow River drains the central and northeastern Tibetan Plateau. Understanding the origin of this river is essential for unraveling the interplay between fluvial incision, basement uplift, and climate change. However, the formation age of the upper Yellow River is highly debated, with estimates ranging from Eocene to late Pleistocene. In order to clarify the history of the upper Yellow River, we present a heavy-mineral dataset from drill core in the Yinchuan Basin, a depositional sink at the end of the upper Yellow River course. Our results reveal that the drainage area of the upper Yellow River (i.e., northeastern Tibetan Plateau) has been serving as a major sediment source region for the Yinchuan Basin since at least 3.3 Ma. A late Pleistocene formation of the upper Yellow River, and erosion of neighboring deserts or bounding mountains as an explanation for thick sediment accumulations in this area, is thus ruled out.
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| 6. |
- Zhang, Yichen, et al.
(författare)
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A GPU-based computational framework that bridges neuron simulation and artificial intelligence
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Biophysically detailed multi-compartment models are powerful tools to explore computational principles of the brain and also serve as a theoretical framework to generate algorithms for artificial intelligence (AI) systems. However, the expensive computational cost severely limits the applications in both the neuroscience and AI fields. The major bottleneck during simulating detailed compartment models is the ability of a simulator to solve large systems of linear equations. Here, we present a novel Dendritic Hierarchical Scheduling (DHS) method to markedly accelerate such a process. We theoretically prove that the DHS implementation is computationally optimal and accurate. This GPU-based method performs with 2-3 orders of magnitude higher speed than that of the classic serial Hines method in the conventional CPU platform. We build a DeepDendrite framework, which integrates the DHS method and the GPU computing engine of the NEURON simulator and demonstrate applications of DeepDendrite in neuroscience tasks. We investigate how spatial patterns of spine inputs affect neuronal excitability in a detailed human pyramidal neuron model with 25,000 spines. Furthermore, we provide a brief discussion on the potential of DeepDendrite for AI, specifically highlighting its ability to enable the efficient training of biophysically detailed models in typical image classification tasks.
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| 7. |
- Geng, Xiaofei, et al.
(författare)
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Year-Round Measurements of Dissolved Black Carbon in Coastal Southeast Asia Aerosols : Rethinking Its Atmospheric Deposition in the Ocean
- 2021
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Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 126:18
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Tidskriftsartikel (refereegranskat)abstract
- Dissolved black carbon (DBC) is an important recalcitrant fraction of marine dissolved organic matter. Riverine discharge is the largest known source of oceanic DBC; however, the significance of atmospheric deposition as a source of oceanic DBC remains poorly understood. In this study, year-round aerosol sampling was carried out at a rural coastal site in Southeast Asia for DBC analysis using the benzene polycarboxylic acid (BPCA) method. The results revealed the uncertainty of an earlier estimate of the atmospheric deposition flux of DBC to the global ocean (FDBC), which assumed a linear correlation between DBC and water-soluble organic carbon (WSOC). The correlation between DBC and WSOC depended on the sources of carbonaceous aerosols. The DBC/WSOC ratios were higher for the biomass burning aerosols. DBC was linearly correlated with black carbon (BC) for biomass or fossil fuel combustion aerosols. However, the DBC/BC ratios were higher for biomass burning aerosols (0.41 ± 0.22), whereas lower for fossil fuel combustion aerosols (0.04 ± 0.03). FDBC was revisited based on the relationship between DBC and BC. FDBC is primarily contributed by biomass burning aerosols and maybe previously underestimated. In this study, the DBC in aerosols had less condensed aromatic structures than the DBC present in the major rivers of the world, as shown by the BPCA compositions. This indicated that oceanic DBC sourced from atmospheric deposition was less likely to be removed by photodegradation and sedimentation, as compared to the DBC sourced from riverine discharge.
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| 8. |
- Li, Yuanzi, et al.
(författare)
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Optimization of the l-tyrosine metabolic pathway in Saccharomyces cerevisiae by analyzing p-coumaric acid production
- 2020
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Ingår i: 3 Biotech. - : Springer Science and Business Media LLC. - 2190-572X .- 2190-5738. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we applied a series of genetic modifications to wild-type S. cerevisiae strain BY4741 to address the bottlenecks in the l-tyrosine pathway. A tyrosine ammonia-lyase (TAL) gene from Rhodobacter capsulatus, which can catalyze conversion of l-tyrosine into p-coumaric acid, was overexpressed to facilitate the analysis of l-tyrosine and test the strain's capability to synthesize heterologous derivatives. First, we enhanced the supply of precursors by overexpressing transaldolase gene TAL1, enolase II gene ENO2, and pentafunctional enzyme gene ARO1 resulting in a 1.55-fold increase in p-coumaric acid production. Second, feedback inhibition of 3-deoxy-d-arabino-heptulosonate-7-phosphate synthase and chorismate mutase was relieved by overexpressing the mutated feedback-resistant ARO4(K229L) and ARO7(G141S), and a 3.61-fold improvement of p-coumaric acid production was obtained. Finally, formation of byproducts was decreased by deleting pyruvate decarboxylase gene PDC5 and phenylpyruvate decarboxylase gene ARO10, and p-coumaric acid production was increased 2.52-fold. The best producer-when TAL1, ENO2, ARO1, ARO4(K229L), ARO7(G141S), and TAL were overexpressed, and PDC5 and ARO10 were deleted-increased p-coumaric acid production by 14.08-fold (from 1.4 to 19.71 mg L-1). Our study provided a valuable insight into the optimization of l-tyrosine metabolic pathway.
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| 9. |
- Liu, Junwen, et al.
(författare)
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Isotope constraints of the strong influence of biomass burning to climate-forcing Black Carbon aerosols over Southeast Asia
- 2020
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 744
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Tidskriftsartikel (refereegranskat)abstract
- Black Carbon (BC) deteriorates air quality and contributes to climate warming, yet its regionally- and seasonally-varying emission sources are poorly constrained. Here we employ natural abundance radiocarbon (C-14) measurements of BC intercepted at a northern Malaysia regional receptor site, Bachok, to quantify the relative biomass vs. fossil source contributions of atmospheric BC, in a first year-round study for SE Asia (December 2015-December 2016). The annual average C-14 signature suggests as large contributions from biomass burning as from fossil fuel combustion. This is similar to findings from analogous measurements at S Asian receptors sites (similar to 50% biomass burning), while E Asia sites are dominated by fossil emission (similar to 20% biomass burning). The C-14-based source fingerprinting of BC in the dry spring season in SE Asia signals an even more elevated biomass burning contribution (similar to 70% or even higher), presumably from forest, shrub and agricultural fires. This is consistent with this period showing also elevated ratio of organic carbon to BC (up from similar to 5 to 30) and estimates of BC emissions from satellite fire data. Hence, the present study emphasizes the importance of mitigating dry season vegetation fires in SE Asia.
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| 10. |
- Ma, Zhuo, et al.
(författare)
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Deciphering early human pancreas development at the single-cell level
- 2023
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Ingår i: Nature Communications. - : NATURE PORTFOLIO. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Understanding pancreas development can provide clues for better treatments of pancreatic diseases. However, the molecular heterogeneity and developmental trajectory of the early human pancreas are poorly explored. Here, we performed large-scale single-cell RNA sequencing and single-cell assay for transposase accessible chromatin sequencing of human embryonic pancreas tissue obtained from first-trimester embryos. We unraveled the molecular heterogeneity, developmental trajectories and regulatory networks of the major cell types. The results reveal that dorsal pancreatic multipotent cells in humans exhibit different gene expression patterns than ventral multipotent cells. Pancreato-biliary progenitors that generate ventral multipotent cells in humans were identified. Notch and MAPK signals from mesenchymal cells regulate the differentiation of multipotent cells into trunk and duct cells. Notably, we identified endocrine progenitor subclusters with different differentiation potentials. Although the developmental trajectories are largely conserved between humans and mice, some distinct gene expression patterns have also been identified. Overall, we provide a comprehensive landscape of early human pancreas development to understand its lineage transitions and molecular complexity. Here, the authors revealed molecular heterogeneity, developmental trajectory and regulatory network of early human pancreas development, and depict the whole progression of pancreatic organogenesis during the first trimester at the single-cell level.
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