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Article ; Online: Molecular determinants of response kinetics of mouse M1 intrinsically-photosensitive retinal ganglion cells.

Sheng, Yanghui / Chen, Lujing / Ren, Xiaozhi / Jiang, Zheng / Yau, King-Wai

2021 Volume 11, Issue 1, Page(s) 23424

Abstract: Intrinsically-photosensitive retinal ganglion cells (ipRGCs) are non-rod/non-cone retinal photoreceptors expressing the visual pigment, melanopsin, to detect ambient irradiance for various non-image-forming visual functions. The M1-subtype, amongst the ... ...

Abstract	Intrinsically-photosensitive retinal ganglion cells (ipRGCs) are non-rod/non-cone retinal photoreceptors expressing the visual pigment, melanopsin, to detect ambient irradiance for various non-image-forming visual functions. The M1-subtype, amongst the best studied, mediates primarily circadian photoentrainment and pupillary light reflex. Their intrinsic light responses are more prolonged than those of rods and cones even at the single-photon level, in accordance with the typically slower time course of non-image-forming vision. The short (OPN4S) and long (OPN4L) alternatively-spliced forms of melanopsin proteins are both present in M1-ipRGCs, but their functional difference is unclear. We have examined this point by genetically removing the Opn4 gene (Opn4
MeSH term(s)	Animals ; Circadian Rhythm/physiology ; Dependovirus ; Intravitreal Injections ; Kinetics ; Light ; Light Signal Transduction ; Mice ; Mice, Transgenic ; Mutation ; Neurosciences ; Phosphorylation ; Retinal Cone Photoreceptor Cells/metabolism ; Retinal Ganglion Cells/metabolism ; Rod Opsins/chemistry ; Signal Transduction ; Vision, Ocular ; beta-Arrestins/chemistry
Chemical Substances	Rod Opsins ; beta-Arrestins ; melanopsin
Language	English
Publishing date	2021-12-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-02832-9
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Article ; Online: Low signaling efficiency from receptor to effector in olfactory transduction: A quantified ligand-triggered GPCR pathway.

Li, Rong-Chang / Molday, Laurie L / Lin, Chih-Chun / Ren, Xiaozhi / Fleischmann, Alexander / Molday, Robert S / Yau, King-Wai

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 32, Page(s) e2121225119

Abstract: G protein-coupled receptor (GPCR) signaling is ubiquitous. As an archetype of this signaling motif, rod phototransduction has provided many fundamental, quantitative details, including a dogma that one active GPCR molecule activates a substantial number ... ...

Abstract	G protein-coupled receptor (GPCR) signaling is ubiquitous. As an archetype of this signaling motif, rod phototransduction has provided many fundamental, quantitative details, including a dogma that one active GPCR molecule activates a substantial number of downstream G protein/enzyme effector complexes. However, rod phototransduction is light-activated, whereas GPCR pathways are predominantly ligand-activated. Here, we report a detailed study of the ligand-triggered GPCR pathway in mammalian olfactory transduction, finding that an odorant-receptor molecule when (one-time) complexed with its most effective odorants produces on average much less than one downstream effector. Further experiments gave a nominal success probability of tentatively ∼10
MeSH term(s)	Animals ; Ligands ; Light Signal Transduction ; Mammals/metabolism ; Odorants ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Odorant/metabolism ; Retinal Rod Photoreceptor Cells ; Signal Transduction ; Smell
Chemical Substances	Ligands ; Receptors, G-Protein-Coupled ; Receptors, Odorant
Language	English
Publishing date	2022-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2121225119
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Article ; Online: An aligned porous electrospun fibrous membrane with controlled drug delivery - An efficient strategy to accelerate diabetic wound healing with improved angiogenesis.

Ren, Xiaozhi / Han, Yiming / Wang, Jie / Jiang, Yuqi / Yi, Zhengfang / Xu, He / Ke, Qinfei

Acta biomaterialia

2018 Volume 70, Page(s) 140–153

Abstract: A chronic wound in diabetic patients is usually characterized by poor angiogenesis and delayed wound closure. The exploration of efficient strategy to significantly improve angiogenesis in the diabetic wound bed and thereby accelerate wound healing is ... ...

Abstract	A chronic wound in diabetic patients is usually characterized by poor angiogenesis and delayed wound closure. The exploration of efficient strategy to significantly improve angiogenesis in the diabetic wound bed and thereby accelerate wound healing is still a significant challenge. Herein, we reported a kind of aligned porous poly (l-lactic acid) (PlLA) electrospun fibrous membranes containing dimethyloxalylglycine (DMOG)-loaded mesoporous silica nanoparticles (DS) for diabetic wound healing. The PlLA electrospun fibers aligned in a single direction and there were ellipse-shaped nano-pores in situ generated onto the surface of fibers, while the DS were well distributed in the fibers and the DMOG as well as Si ion could be controlled released from the nanopores on the fibers. The in vitro results revealed that the aligned porous composite membranes (DS-PL) could stimulate the proliferation, migration and angiogenesis-related gene expression of human umbilical vein endothelial cells (HUVECs) compared with the pure PlLA membranes. The in vivo study further demonstrated that the prepared DS-PL membranes significantly improved neo-vascularization, re-epithelialization and collagen formation as well as inhibited inflammatory reaction in the diabetic wound bed, which eventually stimulated the healing of the diabetic wound. Collectively, these results suggest that the combination of hierarchical structures (nanopores on the aligned fibers) with the controllable released DMOG drugs as well as Si ions from the membranes, which could create a synergetic effect on the rapid stimulation of angiogenesis in the diabetic wound bed, is a potential novel therapeutic strategy for highly efficient diabetic wound healing. Statement of significance: A chronic wound in diabetic patients is usually characterized by the poor angiogenesis and the delayed wound closure. The main innovation of this study is to design a new kind of skin tissue engineered scaffold, aligned porous poly (l-lactic acid) (PlLA) electrospun membranes containing dimethyloxalylglycine (DMOG)-loaded mesoporous silica nanoparticles (DS), which could significantly improve angiogenesis in the diabetic wound bed and thereby accelerate diabetic wound healing. The results revealed that the electrospun fibers with ellipse-shaped nano-pores on the surface were aligned in a single direction, while there were DS particles distributed in the fibers and the DMOG as well as Si ions could be controllably released from the nanopores on the fibers. The in vitro studies demonstrated that the hierarchical nanostructures (nanopores on the aligned fibers) and the controllable released chemical active agents (DMOG drugs and Si ions) from the DS-PL membranes could exert a synergistic effect on inducing the endothelial cell proliferation, migration and differentiation. Above all, the scaffolds distinctly induced the angiogenesis, collagen deposition and re-epithelialization as well as inhibited inflammation reaction in the wound sites, which eventually stimulated the healing of diabetic wounds in vivo. The significance of the current study is that the combination of the hierarchical aligned porous nanofibrous structure with DMOG-loaded MSNs incorporated in electrospun fibers may suggest a high-efficiency strategy for chronic wound healing.
MeSH term(s)	Amino Acids, Dicarboxylic/chemistry ; Amino Acids, Dicarboxylic/pharmacokinetics ; Amino Acids, Dicarboxylic/pharmacology ; Animals ; Delayed-Action Preparations/chemistry ; Delayed-Action Preparations/pharmacokinetics ; Delayed-Action Preparations/pharmacology ; Diabetic Angiopathies/drug therapy ; Diabetic Angiopathies/metabolism ; Diabetic Angiopathies/pathology ; Human Umbilical Vein Endothelial Cells ; Humans ; Male ; Membranes, Artificial ; Mice ; Nanoparticles/chemistry ; Neovascularization, Physiologic/drug effects ; Polyesters/chemistry ; Polyesters/pharmacokinetics ; Polyesters/pharmacology ; Porosity ; Silicon Dioxide/chemistry ; Silicon Dioxide/pharmacokinetics ; Silicon Dioxide/pharmacology ; Wound Healing/drug effects
Chemical Substances	Amino Acids, Dicarboxylic ; Delayed-Action Preparations ; Membranes, Artificial ; Polyesters ; poly(lactide) (459TN2L5F5) ; Silicon Dioxide (7631-86-9) ; oxalylglycine (VVW38EB8YS)
Language	English
Publishing date	2018-02-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2018.02.010
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Article ; Online: Ca

Li, Rong-Chang / Lin, Chih-Chun / Ren, Xiaozhi / Wu, Jingjing Sherry / Molday, Laurie L / Molday, Robert S / Yau, King-Wai

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 21, Page(s) 5570–5575

Abstract: In mammalian olfactory transduction, odorants activate a cAMP-mediated signaling pathway that leads to the opening of cyclic nucleotide-gated (CNG), nonselective cation channels and depolarization. The ... ...

Abstract	In mammalian olfactory transduction, odorants activate a cAMP-mediated signaling pathway that leads to the opening of cyclic nucleotide-gated (CNG), nonselective cation channels and depolarization. The Ca
MeSH term(s)	Animals ; Anoctamins/physiology ; Brain/cytology ; Brain/physiology ; Calcium/pharmacology ; Chlorides/metabolism ; Cyclic AMP/pharmacology ; Cyclic Nucleotide-Gated Cation Channels/drug effects ; Cyclic Nucleotide-Gated Cation Channels/physiology ; Membrane Potentials/drug effects ; Mice ; Mice, Knockout ; Olfactory Receptor Neurons/cytology ; Olfactory Receptor Neurons/drug effects ; Olfactory Receptor Neurons/physiology ; Patch-Clamp Techniques ; Signal Transduction/drug effects ; Smell/drug effects
Chemical Substances	ANO2 protein, mouse ; Anoctamins ; Chlorides ; Cyclic Nucleotide-Gated Cation Channels ; Cyclic AMP (E0399OZS9N) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2018-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1803443115
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Article ; Online: Butyrated ManNAc analog improves protein expression in Chinese hamster ovary cells.

Yin, Bojiao / Wang, Qiong / Chung, Cheng-Yu / Ren, Xiaozhi / Bhattacharya, Rahul / Yarema, Kevin J / Betenbaugh, Michael J

Biotechnology and bioengineering

2018 Volume 115, Issue 6, Page(s) 1531–1541

Abstract: The chemical additive sodium butyrate (NaBu) has been applied in cell culture media as a direct and convenient method to increase the protein expression in Chinese hamster ovary (CHO) and other mammalian cells. In this study, we examined an alternative ... ...

Abstract	The chemical additive sodium butyrate (NaBu) has been applied in cell culture media as a direct and convenient method to increase the protein expression in Chinese hamster ovary (CHO) and other mammalian cells. In this study, we examined an alternative chemical additive, 1,3,4-O-Bu
MeSH term(s)	Animals ; Butyric Acid/metabolism ; CHO Cells/metabolism ; Cell Culture Techniques/methods ; Cricetulus ; Culture Media/chemistry ; Erythropoietin/biosynthesis ; Gene Expression ; Hexosamines/metabolism ; Humans ; Immunoglobulin G/biosynthesis ; Recombinant Proteins/biosynthesis
Chemical Substances	Culture Media ; Hexosamines ; Immunoglobulin G ; Recombinant Proteins ; Butyric Acid (107-92-6) ; Erythropoietin (11096-26-7) ; N-acetylmannosamine (X80PR7P73R)
Language	English
Publishing date	2018-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	280318-5
ISSN	1097-0290 ; 0006-3592
ISSN (online)	1097-0290
ISSN	0006-3592
DOI	10.1002/bit.26560
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Article ; Online: Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes.

Sato, Mari / Tsuji, Tadataka / Yang, Kunyan / Ren, Xiaozhi / Dreyfuss, Jonathan M / Huang, Tian Lian / Wang, Chih-Hao / Shamsi, Farnaz / Leiria, Luiz O / Lynes, Matthew D / Yau, King-Wai / Tseng, Yu-Hua

PLoS biology

2020 Volume 18, Issue 2, Page(s) e3000630

Abstract: Opsin3 (Opn3) is a transmembrane heptahelical G protein-coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. ... ...

Abstract	Opsin3 (Opn3) is a transmembrane heptahelical G protein-coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin resistance. At the cellular level, Opn3-KO brown adipocytes cultured in darkness had decreased glucose uptake and lower nutrient-induced mitochondrial respiration than wild-type (WT) cells. Light exposure promoted mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3's putative G protein-binding domain also exhibited a reduction in glucose uptake and mitochondrial respiration in darkness. Using RNA-sequencing, we identified several novel light-sensitive and Opn3-dependent molecular signatures in brown adipocytes. Importantly, direct exposure of brown adipose tissue (BAT) to light in living mice significantly enhanced thermogenic capacity of BAT, and this effect was diminished in Opn3-KO animals. These results uncover a previously unrecognized cell-autonomous, light-sensing mechanism in brown adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and mitochondrial respiration. Our work also provides a molecular basis for developing light-based treatments for obesity and its related metabolic disorders.
MeSH term(s)	Adipocytes, Brown/metabolism ; Adipose Tissue, Brown/innervation ; Animals ; Diet, High-Fat/adverse effects ; Energy Metabolism ; Gene Expression Regulation ; Glucose/metabolism ; Insulin Resistance ; Light ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Mutation ; Obesity/genetics ; Obesity/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Rod Opsins/genetics ; Rod Opsins/metabolism ; Signal Transduction ; Thermogenesis
Chemical Substances	OPN3 protein, mouse ; Receptors, G-Protein-Coupled ; Rod Opsins ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000630
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Article ; Online: Spontaneous activation of visual pigments in relation to openness/closedness of chromophore-binding pocket.

Yue, Wendy Wing Sze / Frederiksen, Rikard / Ren, Xiaozhi / Luo, Dong-Gen / Yamashita, Takahiro / Shichida, Yoshinori / Cornwall, M Carter / Yau, King-Wai

eLife

2017 Volume 6

Abstract: Visual pigments can be spontaneously activated by internal thermal energy, generating noise that interferes with real-light detection. Recently, we developed a physicochemical theory that successfully predicts the rate of spontaneous activity of ... ...

Abstract	Visual pigments can be spontaneously activated by internal thermal energy, generating noise that interferes with real-light detection. Recently, we developed a physicochemical theory that successfully predicts the rate of spontaneous activity of representative rod and cone pigments from their peak-absorption wavelength (λ
MeSH term(s)	Animals ; Binding Sites ; Chemical Phenomena ; Mice ; Retinal Cone Photoreceptor Cells/physiology ; Retinal Pigments/chemistry ; Retinal Pigments/metabolism ; Retinal Rod Photoreceptor Cells/physiology
Chemical Substances	Retinal Pigments
Language	English
Publishing date	2017--10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.18492
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Article ; Online: A novel sugar analog enhances sialic acid production and biotherapeutic sialylation in CHO cells.

Yin, Bojiao / Wang, Qiong / Chung, Cheng-Yu / Bhattacharya, Rahul / Ren, Xiaozhi / Tang, Juechun / Yarema, Kevin J / Betenbaugh, Michael J

Biotechnology and bioengineering

2017 Volume 114, Issue 8, Page(s) 1899–1902

Abstract: A desirable feature of many therapeutic glycoprotein production processes is to maximize the final sialic acid content. In this study, the effect of applying a novel chemical analog of the sialic acid precursor N-acetylmannosamine (ManNAc) on the sialic ... ...

Abstract	A desirable feature of many therapeutic glycoprotein production processes is to maximize the final sialic acid content. In this study, the effect of applying a novel chemical analog of the sialic acid precursor N-acetylmannosamine (ManNAc) on the sialic acid content of cellular proteins and a model recombinant glycoprotein, erythropoietin (EPO), was investigated in CHO-K1 cells. By introducing the 1,3,4-O-Bu
MeSH term(s)	Animals ; CHO Cells ; Cricetulus ; Culture Media/chemistry ; Culture Media/metabolism ; Erythropoietin/biosynthesis ; Erythropoietin/genetics ; Hexosamines/metabolism ; N-Acetylneuraminic Acid/biosynthesis ; N-Acetylneuraminic Acid/isolation & purification ; Oligosaccharides ; Protein Engineering/methods ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/genetics
Chemical Substances	Culture Media ; Hexosamines ; Oligosaccharides ; Recombinant Proteins ; Erythropoietin (11096-26-7) ; N-Acetylneuraminic Acid (GZP2782OP0) ; N-acetylmannosamine (X80PR7P73R)
Language	English
Publishing date	2017-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	280318-5
ISSN	1097-0290 ; 0006-3592
ISSN (online)	1097-0290
ISSN	0006-3592
DOI	10.1002/bit.26291
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Article ; Online: Elementary response triggered by transducin in retinal rods.

Yue, Wendy W S / Silverman, Daniel / Ren, Xiaozhi / Frederiksen, Rikard / Sakai, Kazumi / Yamashita, Takahiro / Shichida, Yoshinori / Cornwall, M Carter / Chen, Jeannie / Yau, King-Wai

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 11, Page(s) 5144–5153

Abstract: G protein-coupled receptor (GPCR) signaling is crucial for many physiological processes. A signature of such pathways is high amplification, a concept originating from retinal rod phototransduction, whereby one photoactivated rhodopsin molecule (Rho*) ... ...

Abstract	G protein-coupled receptor (GPCR) signaling is crucial for many physiological processes. A signature of such pathways is high amplification, a concept originating from retinal rod phototransduction, whereby one photoactivated rhodopsin molecule (Rho*) was long reported to activate several hundred transducins (G
MeSH term(s)	Amino Acid Motifs ; Animals ; Cyclic GMP/metabolism ; GTP-Binding Protein alpha Subunits/metabolism ; Light Signal Transduction ; Mice, Transgenic ; Mutation/genetics ; Phosphoric Diester Hydrolases/metabolism ; Photons ; Retinal Rod Photoreceptor Cells/metabolism ; Rhodopsin/chemistry ; Rhodopsin/metabolism ; Transducin/metabolism
Chemical Substances	GTP-Binding Protein alpha Subunits ; Gnat1 protein, mouse ; Rhodopsin (9009-81-8) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Transducin (EC 3.6.5.1) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2019-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1817781116
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Article ; Online: Melanopsin-expressing ganglion cells on macaque and human retinas form two morphologically distinct populations.

Liao, Hsi-Wen / Ren, Xiaozhi / Peterson, Beth B / Marshak, David W / Yau, King-Wai / Gamlin, Paul D / Dacey, Dennis M

The Journal of comparative neurology

2016 Volume 524, Issue 14, Page(s) 2845–2872

Abstract: The long-term goal of this research is to understand how retinal ganglion cells that express the photopigment melanopsin, also known as OPN4, contribute to vision in humans and other primates. Here we report the results of anatomical studies using our ... ...

Abstract	The long-term goal of this research is to understand how retinal ganglion cells that express the photopigment melanopsin, also known as OPN4, contribute to vision in humans and other primates. Here we report the results of anatomical studies using our polyclonal antibody specifically against human melanopsin that confirm and extend previous descriptions of melanopsin cells in primates. In macaque and human retina, two distinct populations of melanopsin cells were identified based on dendritic stratification in either the inner or the outer portion of the inner plexiform layer (IPL). Variation in dendritic field size and cell density with eccentricity was confirmed, and dendritic spines, a new feature of melanopsin cells, were described. The spines were the sites of input from DB6 diffuse bipolar cell axon terminals to the inner stratifying type of melanopsin cells. The outer stratifying melanopsin type received inputs from DB6 bipolar cells via a sparse outer axonal arbor. Outer stratifying melanopsin cells also received inputs from axon terminals of dopaminergic amacrine cells. On the outer stratifying melanopsin cells, ribbon synapses from bipolar cells and conventional synapses from amacrine cells were identified in electron microscopic immunolabeling experiments. Both inner and outer stratifying melanopsin cell types were retrogradely labeled following tracer injection in the lateral geniculate nucleus (LGN). In addition, a method for targeting melanopsin cells for intracellular injection using their intrinsic fluorescence was developed. This technique was used to demonstrate that melanopsin cells were tracer coupled to amacrine cells and would be applicable to electrophysiological experiments in the future. J. Comp. Neurol. 524:2845-2872, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Count/methods ; Humans ; Macaca ; Macaca fascicularis ; Macaca nemestrina ; Middle Aged ; Retina/cytology ; Retina/metabolism ; Retinal Ganglion Cells/metabolism ; Rod Opsins/biosynthesis ; Rod Opsins/genetics ; Species Specificity
Chemical Substances	Rod Opsins ; melanopsin
Language	English
Publishing date	2016-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.23995
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