β-淀粉样蛋白的聚集及其调控

doi:10.11949/0438-1157.20220063

摘要/Abstract

摘要：

β-淀粉样蛋白（amyloid β-protein，Aβ）的自发聚集形成大量毒性的寡聚体，导致脑内神经元死亡，从而引发认知障碍，即阿尔茨海默病（Alzheimer's disease，AD），严重威胁着人类的健康。Aβ聚集过程呈现复杂的多尺度自组装特性，目前尚缺乏对Aβ聚集过程多尺度寡聚体的认识，严重制约Aβ聚集抑制剂的设计开发。本文首先简述Aβ聚集的基本理论以及与介尺度科学的关系，分类介绍Aβ自组装过程中所产生的各种介尺度寡聚体及其介导的细胞毒性；之后归纳各种Aβ聚集抑制剂的设计策略、作用原理和作用效果；最后总结Aβ聚集及其调控研究中存在的主要挑战，并提出了进一步研究的重点方向。

关键词: 阿尔茨海默病, β-淀粉样蛋白, 多尺度, 聚集, 调控, 生物医学工程

Abstract:

The spontaneous aggregation of β-amyloid (amyloid β-protein, Aβ) forms a large number of toxic oligomers, which lead to the death of neurons in the brain, thereby causing cognitive impairment, namely Alzheimer's disease (AD). Serious threat to human health. At present, lack of the understanding of the multiscale Aβ oligomers has seriously restricted the design and development of Aβ modulators or inhibitors. This review is devoted to introduction of the fundamentals of the on-pathway Aβ aggregation and the relationship with mesoscience, classification of the various mesoscale Aβ oligomers generated during Aβ assembly, and the cytotoxicity mediated by the Aβ oligomers. Then, the design strategies, inhibitory mechanisms, and functions of different modulators or inhibitors developed to date are discussed. Finally, major challenges on the development of Aβ-associated AD drugs are addressed and the future research into this crucial field is proposed.

Key words: Alzheimer's disease, amyloid β-protein, multiscale, aggregation, modulation, biomedical engineering

中图分类号:

TQ 460.1

刘伟, 孙彦. β-淀粉样蛋白的聚集及其调控[J]. 化工学报, 2022, 73(6): 2381-2396.

Wei LIU, Yan SUN. Research progress on amyloid β-protein aggregation and its regulation[J]. CIESC Journal, 2022, 73(6): 2381-2396.

图/表 3

参考文献 82

1	Patterson C. World Alzheimer report 2018—the state of the art of dementia research: new frontiers[R]. London, UK: Alzheime's Disease International (ADI), 2018.
2	Heneka M T, Golenbock D T, Latz E. Innate immunity in Alzheimer's disease[J]. Nature Immunology, 2015, 16(3): 229-236.
3	Panza F, Lozupone M, Logroscino G, et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease[J]. Nature Reviews Neurology, 2019, 15(2): 73-88.
4	Cline E N, Bicca M A, Viola K L, et al. The amyloid-β oligomer hypothesis: beginning of the third decade[J]. Journal of Alzheimer's Disease: JAD, 2018, 64(s1): S567-S610.
5	Hardy J, Selkoe D J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics[J]. Science, 2002, 297(5580): 353-356.
6	Jeremic D, Jiménez-Díaz L, Navarro-López J D. Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer's disease: a systematic review[J]. Ageing Research Reviews, 2021, 72: 101496.
7	Madhu P, Mukhopadhyay S. Distinct types of amyloid-β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease[J]. Journal of Cell Biochemistry, 2021, 122(11): 1594-1608.
8	Wang J, Gu B J, Masters C L, et al. A systemic view of Alzheimer disease—insights from amyloid-β metabolism beyond the brain[J]. Nature Review Neurology, 2017, 13(10): 612-623.
9	Han X, He G F. Toward a rational design to regulate β-amyloid fibrillation for Alzheimer's disease treatment[J]. ACS Chemical Neuroscience, 2018, 9(2): 198-210
10	Banerjee S, Sun Z Q, Hayden E Y, et al. Nanoscale dynamics of amyloid β-42 oligomers as revealed by high-speed atomic force microscopy[J]. ACS Nano, 2017, 11(12): 12202-12209.
11	Lührs T, Ritter C, Adrian M, et al. 3D structure of Alzheimer's amyloid-β(1–42) fibrils[J]. PNAS, 2005, 102(48): 17342-17347.
12	Bitan G, Kirkitadze M D, Lomakin A, et al. Amyloid β-protein (Aβ) assembly: Aβ₄₀ and Aβ₄₂ oligomerize through distinct pathways[J]. PNAS, 2003, 100(1): 330-335.
13	Huang W L, Li J H, Edwards P P, Mesoscience : exploring the common principle at mesoscales[J]. National Science Review, 2018, 5(3): 321-326.
14	Oren O, Taube R, Papo N. Amyloid β structural polymorphism, associated toxicity and therapeutic strategies[J]. Cellular and Molecular Life Sciences, 2021, 78(23): 7185-7198.
15	Economou N J, Giammona M J, Do T D, et al. Amyloid β-protein assembly and Alzheimer's disease: dodecamers of Aβ₄₂, but not of Aβ₄₀, seed fibril formation[J]. Journal of the American Chemical Society, 2016, 138(6): 1772-1775.
16	Upadhaya A R, Lungrin I, Yamaguchi H, et al. High-molecular weight Aβ oligomers and protofibrils are the predominant Aβ species in the native soluble protein fraction of the AD brain[J]. Journal of Cellular and Molecular Medicine, 2012, 16(2): 287-295.
17	Lambert M P, Barlow A K, Chromy B A, et al. Diffusible, nonfibrillar ligands derived from Aβ_1–42 are potent central nervous system neurotoxins[J]. PNAS, 1998, 95(11): 6448-6453.
18	Lacor P N, Buniel M C, Chang L, et al. Synaptic targeting by Alzheimer's-related amyloid β oligomers[J]. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 2004, 24(45): 10191-10200.
19	Hoshi M, Sato M, Matsumoto S, et al. Spherical aggregates of β-amyloid (amylospheroid) show high neurotoxicity and activate Tau protein kinase I/glycogen synthase kinase-3β[J]. PNAS, 2003, 100(11): 6370-6375.
20	Ohnishi T, Yanazawa M, Sasahara T, et al. Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly[J]. PNAS, 2015, 112(32): E4465-E4474.
21	Komura H, Kakio S, Sasahara T, et al. Alzheimer Aβ assemblies accumulate in excitatory neurons upon proteasome inhibition and kill nearby NAKα3 neurons by secretion[J]. iScience, 2019, 13: 452-477.
22	Barghorn S, Nimmrich V, Striebinger A, et al. Globular amyloid β-peptide_1-42 oligomer—a homogenous and stable neuropathological protein in Alzheimer's disease[J]. Journal of Neurochemistry, 2005, 95(3): 834-847.
23	Laurén J, Gimbel D A, Nygaard H B, et al. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers[J]. Nature, 2009, 457(7233): 1128-1132.
24	Nasica-Labouze J, Nguyen P H, Sterpone F, et al. Amyloid β protein and Alzheimer's disease: when computer simulations complement experimental studies[J]. Chemical Review, 2015, 115(9): 3518-3563.
25	Nagel-Steger L, Owen M C, Strodel B. An account of amyloid oligomers: facts and figures obtained from experiments and simulations[J]. ChemBioChem, 2016, 17(8): 657-676.
26	Kreutzer A G, Hamza I L, Spencer R K, et al. X-Ray crystallographic structures of a trimer, dodecamer, and annular pore formed by an Aβ_17-36 β-hairpin[J]. Journal of the American Chemical Society, 2016, 138(13): 4634-4642.
27	Nguyen P H, Campanera J M, Ngo S T, et al. Tetrameric Aβ₄₀ and Aβ₄₂ β-barrel structures by extensive atomistic simulations (Ⅱ): In aqueous solution[J]. The Journal of Physical Chemistry B, 2019, 123(31): 6750-6756.
28	Kayed R, Head E, Thompson J L, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis[J]. Science, 2003, 300(5618): 486-489.
29	Morgado I, Wieligmann K, Bereza M, et al. Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment[J]. PNAS, 2012, 109(31): 12503-12508.
30	Pani I, Madhu P, Najiya N, et al. Differentiating conformationally distinct Alzheimer's amyloid-β oligomers using liquid crystals[J]. The Journal of Physical Chemistry Letters, 2020, 11(21): 9012-9018.
31	Lee S J, Nam E, Lee H J, et al. Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors[J]. Chemical Society Review, 2017, 46(2): 310-323.
32	Ayala S, Genevaux P, Hureau C, et al. (Bio)chemical strategies to modulate amyloid-β self-assembly[J]. ACS Chemical Neuroscience, 2019, 10(8): 3366-3374.
33	Ehrnhoefer D E, Bieschke J, Boeddrich A, et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers[J]. Nature Structural & Molecular Biology, 2008, 15(6): 558-566.
34	Palhano F L, Lee J Y, Grimster N P, et al. Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils[J]. Journal of the American Chemical Society, 2013, 135(20): 7503-7510.
35	Hyung S J, DeToma A S, Brender J R, et al. Insights into antiamyloidogenic properties of the green tea extract (–)-epigallocatechin-3-gallate toward metal-associated amyloid-β species[J]. PNAS, 2013, 110(10): 3743-3748.
36	Wang S H, Dong X Y, Sun Y. Thermodynamic analysis of the molecular interactions between amyloid β-protein fragments and (–)-epigallocatechin-3-gallate[J]. The Journal of Physical Chemistry. B, 2012, 116(20): 5803-5809.
37	Liu F F, Dong X Y, He L Z, et al. Molecular insight into conformational transition of amyloid β-peptide 42 inhibited by (–)-epigallocatechin-3-gallate probed by molecular simulations[J]. The Journal of Physical Chemistry. B, 2011, 115(41): 11879-11887.
38	Ahmed R, VanSchouwen B, Jafari N, et al. Molecular mechanism for the (–)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers[J]. Journal of the American Chemical Society, 2017, 139(39): 13720-13734.
39	Ren B P, Liu Y L, Zhang Y X, et al. Tanshinones inhibit hIAPP aggregation, disaggregate preformed hIAPP fibrils, and protect cultured cells[J]. Journal of Materials Chemistry. B, 2018, 6(1): 56-67.
40	Du W J, Guo J J, Gao M T, et al. Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity[J]. Scientific Reports, 2015, 5: 7992.
41	Li M, Dong X Y, Liu Y, et al. Brazilin inhibits prostatic acidic phosphatase fibrillogenesis and decreases its cytotoxicity[J]. Chemistry - an Asian Journal, 2017, 12(10): 1062-1068.
42	Tu Y L, Ma S, Liu F F, et al. Hematoxylin inhibits amyloid β-protein fibrillation and alleviates amyloid-induced cytotoxicity[J]. The Journal of Physical Chemistry. B, 2016, 120(44): 11360-11368.
43	Goyal D, Shuaib S, Mann S, et al. Rationally designed peptides and peptidomimetics as inhibitors of amyloid-β (Aβ) aggregation: potential therapeutics of disease[J]. ACS Combinatorial Science, 2017, 19(2): 55-80.
44	Tjernberg L O, Näslund J, Lindqvist F, et al. Arrest of β-amyloid fibril formation by a pentapeptide ligand[J]. Journal of Biological Chemistry, 1996, 271(15): 8545-8548.
45	Soto C, Sigurdsson E M, Morelli L, et al. β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy[J]. Nature Medicine, 1998, 4(7): 822-826.
46	Xiong N, Dong X Y, Zheng J, et al. Design of LVFFARK and LVFFARK-functionalized nanoparticles for inhibiting amyloid β-protein fibrillation and cytotoxicity[J]. ACS Applied Materials & Interfaces, 2015, 7(10): 5650-5662.
47	Ma S, Zhang H, Dong X Y, et al. Head-to-tail cyclization of a heptapeptide eliminates its cytotoxicity and significantly increases its inhibition effect on amyloid β-protein fibrillation and cytotoxicity[J]. Frontiers of Chemical Science and Engineering, 2018, 12(2): 283-295.
48	Zhang H, Zhang C, Dong X Y, et al. Design of nonapeptide LVFFARKHH: a bifunctional agent against Cu²⁺-mediated amyloid β-protein aggregation and cytotoxicity[J]. Journal of Molecular Recognition, 2018, 31(6): e2697.
49	Zhang H, Dong X Y, Sun Y. Carnosine-LVFFARK-NH₂ conjugate: a moderate chelator but potent inhibitor of Cu²⁺-mediated amyloid β-protein aggregation[J]. ACS Chemical Neuroscience, 2018, 9(11): 2689-2700.
50	Meng J, Zhang H, Dong X Y, et al. RTHLVFFARK-NH₂: a potent and selective modulator on Cu²⁺-mediated amyloid-β protein aggregation and cytotoxicity[J]. Journal of Inorganic Biochemistry, 2018, 181: 56-64.
51	Liu W, Dong X Y, Sun Y. D-enantiomeric RTHLVFFARK-NH₂: a potent multifunctional decapeptide inhibiting Cu²⁺-mediated amyloid β-protein aggregation and remodeling Cu²⁺-mediated amyloid β aggregates[J]. ACS Chemical Neuroscience, 2019, 10(3): 1390-1401.
52	Xu S Y, Wang W J, Dong X Y, et al. Molecular insight into Cu²⁺-induced conformational transitions of amyloid β-protein from fast kinetic analysis and molecular dynamics simulations[J]. ACS Chemical Neuroscience, 2021, 12(2): 300-310.
53	Guo J, Yu L L, Sun Y, et al. Kinetic insights into Zn²⁺-induced amyloid β-protein aggregation revealed by stopped-flow fluorescence spectroscopy[J]. The Journal of Physical Chemistry. B, 2017, 121(16): 3909-3917.
54	Hureau C. Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease (Ⅰ): An overview[J]. Coordination Chemistry Reviews, 2012, 256(19/20): 2164-2174.
55	Xie B L, Li X, Dong X Y, et al. Insight into the inhibition effect of acidulated serum albumin on amyloid β-protein fibrillogenesis and cytotoxicity[J]. Langmuir, 2014, 30(32): 9789-9796.
56	Xie B L, Liu F F, Dong X Y, et al. Modulation effect of acidulated human serum albumin on Cu²⁺-mediated amyloid β-protein aggregation and cytotoxicity under a mildly acidic condition[J]. Journal of Inorganic Biochemistry, 2017, 171: 67-75.
57	Xie B L, Dong X Y, Wang Y J, et al. Multifunctionality of acidulated serum albumin on inhibiting Zn²⁺-mediated amyloid β-protein fibrillogenesis and cytotoxicity[J]. Langmuir, 2015, 31(26): 7374-7380.
58	Xie B L, Zhang H, Li X, et al. Iminodiacetic acid-modified human serum albumin: a multifunctional agent against metal-associated amyloid β-protein aggregation and cytotoxicity[J]. ACS Chemical Neuroscience, 2017, 8(10): 2214-2224.
59	Wang W J, Dong X Y, Sun Y. Modification of serum albumin by high conversion of carboxyl to amino groups creates a potent inhibitor of amyloid β-protein fibrillogenesis[J]. Bioconjugate Chemistry, 2019, 30(5): 1477-1488.
60	Wang W J, Liu W, Xu S Y, et al. Design of multifunctional agent based on basified serum albumin for efficient in vivo β-amyloid inhibition and imaging[J]. ACS Applied Bio Materials, 2020, 3(5): 3365-3377.
61	Li X, Xie B L, Sun Y. Basified human lysozyme: a potent inhibitor against amyloid β-protein fibrillogenesis[J]. Langmuir, 2018, 34(50): 15569-15577.
62	Li X, Xie B L, Dong X Y, et al. Bifunctionality of iminodiacetic acid-modified lysozyme on inhibiting Zn²⁺-mediated amyloid β-protein aggregation[J]. Langmuir, 2018, 34(17): 5106-5115.
63	Li X, Wang W J, Dong X Y, et al. Conjugation of RTHLVFFARK to human lysozyme creates a potent multifunctional modulator for Cu²⁺-mediated amyloid β-protein aggregation and cytotoxicity[J]. Journal of Materials Chemistry. B, 2020, 8(11): 2256-2268.
64	Mukherjee S, Madamsetty V S, Bhattacharya D, et al. Recent advancements of nanomedicine in neurodegenerative disorders theranostics[J]. Advanced Functional Materials, 2020, 30(35): 2003054.
65	Ke P C, Pilkington E H, Sun Y X, et al. Mitigation of amyloidosis with nanomaterials[J]. Advanced Materials, 2020, 32(18): 1901690.
66	Feng L Y, Wang H P, Xue X. Recent progress of nanomedicine in the treatment of central nervous system diseases[J]. Advanced Therapeutic, 2020, 3(5): 1900159.
67	Wang Z Y, Tao S P, Dong X Y, et al. Para-sulfonatocalix[n]arenes inhibit amyloid β-peptide fibrillation and reduce amyloid cytotoxicity[J]. Chemistry - an Asian Journal, 2017, 12(3): 341-346.
68	Wang Z Y, Dong X Y, Sun Y. Hydrophobic modification of carboxyl-terminated polyamidoamine dendrimer surface creates a potent inhibitor of amyloid-β fibrillation[J]. Langmuir, 2018, 34(47): 14419-14427.
69	Liu H C, Xie B L, Dong X Y, et al. Negatively charged hydrophobic nanoparticles inhibit amyloid β-protein fibrillation: the presence of an optimal charge density[J]. Reactive and Functional Polymers, 2016, 103: 108-116.
70	Jiang Z Q, Dong X Y, Liu H, et al. Multifunctionality of self-assembled nanogels of curcumin-hyaluronic acid conjugates on inhibiting amyloid β-protein fibrillation and cytotoxicity[J]. Reactive and Functional Polymers, 2016, 104: 22-29.
71	Yang J N, Liu W, Sun Y, et al. LVFFARK-PEG-stabilized black phosphorus nanosheets potently inhibit amyloid-β fibrillogenesis[J]. Langmuir, 2020, 36(7): 1804-1812.
72	Xiong N, Zhao Y J, Dong X Y, et al. Design of a molecular hybrid of dual peptide inhibitors coupled on AuNPs for enhanced inhibition of amyloid β-protein aggregation and cytotoxicity[J]. Small, 2017, 13(13): 1601666.
73	Zhao G F, Dong X Y, Sun Y. Self-assembled curcumin-poly(carboxybetaine methacrylate) conjugates: potent nano-inhibitors against amyloid β-protein fibrillogenesis and cytotoxicity[J]. Langmuir, 2019, 35(5): 1846-1857.
74	Ren B P, Jiang B B, Hu R D, et al. HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity[J]. Physical Chemistry Chemical Physics, 2016, 18(30): 20476-20485.
75	Zhang H, Dong X Y, Liu F F, et al. Ac-LVFFARK-NH₂ conjugation to β-cyclodextrin exhibits significantly enhanced performance on inhibiting amyloid β-protein fibrillogenesis and cytotoxicity[J]. Biophysical Chemistry, 2018, 235: 40-47.
76	Wang Z Y, Dong X Y, Sun Y. Mixed carboxyl and hydrophobic dendrimer surface inhibits amyloid-β fibrillation: new insight from the generation number effect[J]. Langmuir, 2019, 35(45): 14681-14687.
77	Zhao G F, Qi F J, Dong X Y, et al. LVFFARK conjugation to poly(carboxybetaine methacrylate) remarkably enhances its inhibitory potency on amyloid β-protein fibrillogenesis[J]. Reactive and Functional Polymers, 2019, 140: 72-81.
78	Wang W J, Zhao G F, Dong X Y, et al. Unexpected function of a heptapeptide-conjugated zwitterionic polymer that coassembles into β-amyloid fibrils and eliminates the amyloid cytotoxicity[J]. ACS Applied Materials & Interfaces, 2021, 13(15): 18089-18099.
79	Gao W Q, Wang W J, Dong X Y, et al. Nitrogen-doped carbonized polymer dots: a potent scavenger and detector targeting β-amyloid plaques[J]. Small, 2020, 16(43): 2002804.
80	Liu W, Dong X Y, Liu Y, et al. Photoresponsive materials for intensified modulation of amyloid-β protein aggregation: a review[J]. Acta Biomaterialia, 2021, 123: 93-109.
81	Liu W, Wang W J, Dong X Y, et al. Near-infrared light-powered Janus nanomotor significantly facilitates inhibition of amyloid-β fibrillogenesis[J]. ACS Applied Materials & Interfaces, 2020, 12(11): 12618-12628.
82	Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease[J]. Nature, 2016, 537(7618): 50-56.

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