Abstract

Glycosylation, the enzymatic process by which glycans are attached to proteins and lipids, is the most abundant and functionally important type of post-translational modification associated with brain development, neurodegenerative disorders, psychopathologies and brain cancers. Glycan structures are diverse and complex; however, they have been detected and targeted in the central nervous system (CNS) by various immunohistochemical detection methods using glycan-binding proteins such as anti-glycan antibodies or lectins and/or characterized with analytical techniques such as chromatography and mass spectrometry. The glycan structures on glycoproteins and glycolipids expressed in neural stem cells play key roles in neural development, biological processes and CNS maintenance, such as cell adhesion, signal transduction, molecular trafficking and differentiation. This brief review will highlight some of the important findings on differential glycan expression across stages of CNS cell differentiation and in pathological disorders and diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia and brain cancer.

Introduction

In the central nervous system (CNS), neurons transmit electrical and chemical impulses to promote cellular communication while glia (astrocytes, microglia, oligodendrocytes and ependymal cells) function to provide protection, immune defense and support for neurons. All eukaryotic cells, including neurons and glia of the CNS, are coated with glycans and rely on their presence and function for carrying out normal communication and biological processes [1]. Glycans consisting of individual monosaccharides are linked together via glycosidic bonds and can be covalently bound to proteins and lipids. The resulting glycoconjugates are of several classes (Figure 1) [2]. In neural development, the glycan structures on glycoproteins and glycolipids are widely associated with cellular changes in cell adhesion, signal transduction, molecular trafficking and differentiation. Due to the important functional roles of glycosylation in the CNS, aberrant glycosylation including chemical modification, trimming or elongation of glycan structures on the cellular surface, and on critical receptors and neurotransmitter transporters, is associated with many neurological problems, immune responses, disorders and cancers [3,4].

The types of mammalian glycan structures.

Figure 1.
The types of mammalian glycan structures.

Glycan structures of the six classes relevant to the CNS (N-glycans, O-glycans, glycosaminoglycans, hyaluronic acid, glycosphingolipids, glycosylphosphatidylinositol (GPI) anchor) as well as intracellular glycan O-linked β-N-acetylglucosamine (O-GlcNAc) are shown. Representative examples of each class are indicated using symbol nomenclature for monosaccharides (see key). Reprinted with permission from Moremen et al. [2].

Figure 1.
The types of mammalian glycan structures.

Glycan structures of the six classes relevant to the CNS (N-glycans, O-glycans, glycosaminoglycans, hyaluronic acid, glycosphingolipids, glycosylphosphatidylinositol (GPI) anchor) as well as intracellular glycan O-linked β-N-acetylglucosamine (O-GlcNAc) are shown. Representative examples of each class are indicated using symbol nomenclature for monosaccharides (see key). Reprinted with permission from Moremen et al. [2].

Tools for detection and targeting of glycans in CNS

For visualization and targeting of glycan structures in the CNS, glycan-binding proteins such as lectins and antibodies have been generally used. The abundance of lectins from many plant sources has enabled their detailed characterization for research on the glycans expressed in CNS disease [5]. Some of the most widely used lectins can identify major biological glycan residues such as sialic acids (wheat germ agglutinin (WGA)), mannose (Concanavalin A; Lens culinaris agglutinin), fucose (Aleuria aurantia lectin) and galactose (peanut agglutinin (PNA); Ricinus communis Agglutinin; Griffonia simplificola lectin I). The binding of lectin proteins to glycan moieties initiates cellular endocytosis of synaptic and/or somatic membrane glycolipids. The lectins are subsequently trafficked to intracellular organelles such as endosomes and the endoplasmic reticulum. The affinity of some lectin proteins towards glycan moieties has been exploited extensively in the CNS for the purpose of neuronal tracing [6]. For example, the lectin-based neuronal tracers WGA and cholera toxin B (CTB) are readily endocytosed by CNS cells after binding to cell surface glycolipids, such as GM1 ganglioside for CTB [7], making them useful for understanding complex functional neuronal network connections in an anterograde or retrograde manner [811]. WGA can bind to cell surface carbohydrate constituents of the neuronal membrane such as N-acetylglucosamine and sialic acid residues and therefore has been used to study neuronal synapses [12]. WGA has also been used in the CNS for transneuronal tracing in multiple animal species including Drosophila [13] and rodent brains [14]. Although lectins have greatly contributed to our understanding of CNS cell glycosylation profiles and neural networks, they are not without limitations for biomarker detection purposes as they generally have low affinities for their targets and often require multivalency for high-avidity binding. Concanavalin A for instance is specific to glycan structures with the trisaccharide core mannoses of all N-glycans [15]; however, it binds oligomannose-type N-glycans with much higher affinity than complex-type bi-antennary N-glycans, and it does not recognize more highly branched complex-type N-glycans [16].

Antibodies against protein antigens for specific CNS cell types have been well developed and characterized in the past [17]; however, good monoclonal anti-glycan antibodies remain scarce due to the challenges faced during their selection and development [18]. The currently available anti-glycan antibodies are mostly of the IgM and IgG subtypes, with high-affinity and specific binding achieved for O-glycans, N-glycans, glycolipids/glycosphingolipids, Lewis and blood group antigens and glycosaminoglycans [16]. Among these, a few have been used extensively for CNS studies to determine myelination, differentiation, migration and synaptic plasticity. One example of this is the mAb A2B5 antibody that binds to polysialoganglioside antigens, which is used routinely for cell separation and isolation of oligodendrocyte precursor cells [19]. This developmental process has also widely been studied by immunofluorescence staining using the mAb735 antibody that binds to the α2–8-linked sialic acid long chain glycan, polysialic acid (polySia), where it has been used to demonstrate that polySia down-regulation is required for efficient myelin formation and maintenance [20,21].

Bioorthogonal chemical reporter strategies allow analogs of sialic acid, or its biosynthetic precursor N-acetylmannosasmine (ManNAc), containing chemical reporters (e.g. azide) to be used as metabolic tracers for labeling and targeting sialoglycans in living animals [22]. Some recent efforts have been made on these glycan manipulation methods, in particular, for in vivo brain imaging [2326]. Tracing sialoglycans in the brain is difficult, presumably due to the inaccessibility of labeled sugars through the blood–brain barrier. To address this, for example, modified ManNAc has been conjugated to neuroactive carriers such as choline forming a carbohydrate-neuroactive hybrid molecule that can exploit carrier-mediated transport systems readily available at the blood–brain barrier to access the brain via intravenous injection in mice [24].

For intricate structural determination and configuration of glycosidic linkages, analysis is typically subcategorized at glycoprotein, glycopeptide and cleaved-glycan levels, requiring isolation and enrichment from their complex biological samples and then typically detection using chromatography and mass spectrometry (MS)-based techniques [2731]. MS imaging (MSI) is an emerging MS tool that allows label-free mapping of the analyte abundance, distribution and regional heterogeneity directly from an intact thin section of tissue therefore overcoming some of the challenges of histological staining with lectins and antibodies. Using MSI, a global snapshot of major N-linked glycans has been identified from intact mouse brain tissues thereby demonstrating tissue localization, distribution structure and relative abundance of glycan subtypes [32]. Ion mobility (IM) spectrometry coupled to MS (IM–MS) has also gained considerable interest for use in glycan and glycoconjugate analysis in the brain. In this way, Sarbu et al. [33] have used IM–MS on a highly complex mixture extracted from the frontal lobe of a human brain to demonstrate the high degree of sialylation on gangliosides and substantial ceramide heterogeneity in such tissues for the first time. They were also able to characterize a novel tetrasialylated O-GalNAc modified species as a biomarker for brain development. Everest Dass et al. [27,34], have recently extensively reviewed these and other major current advances in glycan characterization techniques.

Glycan expression in neural development

Each CNS cell type arises from highly proliferative neural stem cells with self-renewal characteristics, which ultimately determine their fate as being neurons or glia. Some of the major glycan-rich molecules expressed in neural stem cells play a key role in neural development and CNS maintenance. For example, glycan antigen conjugates such as stage-specific embryonic antigen-1 (SSEA-1; [Galβ1-4(Fucα1-3)GlcNAcβ]) and tumor-rejection antigens (TRA1–60, 1–81; [Galβ1-3GlcNAcβ1-3Galβ1-4GlcNAc]) undergo dynamic changes over the period of differentiation into mature neurons and glia making glycans on the cell surface of neural stem cells ideal targets for identifying and sorting cell types with immunohistochemistry or flow cytometry during different developmental stages [3539].

A major class of glycoconjugates predominantly observed in CNS are glycosphingolipids that are complex lipids containing a diverse family of glycans attached to a ceramide lipid core structure. Gangliosides are sialic acid-containing glycosphingolipids that are ubiquitously found in tissues and body fluids but are most abundant in the CNS. The heterogeneity and diversity of their structures in their carbohydrate chains are characteristic hallmarks of these glycolipids. Gangliosides drastically change in their expression profiles throughout development from embryonic to adult brains. For example, simple gangliosides such as GD2, GM3 and GD3 are predominant in neural stem cells and embryonic brains while complex gangliosides such as GM1, GD1a GD1b and GT1b are most common in adult brains [40,41]. The expression of GD3, which accounts for more than 80% of the total gangliosides in neural stem cells, is prominent on neuroepithelial cells in early development and in brain regions rich in neural stem cells such as the subventricular zone of postnatal and adult rodents [40]. GD3-synthase knockout mice show decreased neural stem cell self-renewal ability compared with wild-type mice due to the interaction of GD3 with epidermal growth factor receptor and the endosomal–lysosomal degradative pathway [42]. GD3 is therefore an ideal ganglioside biomarker for targeting and imaging neural stem cells and has known critical functional implications in CNS signaling. The most abundant type of glycolipid on the surface of the neuronal membrane is GM1 and GD1a. GD1a serves as a reserve pool for the synthesis and maintenance of GM1. Thus, GM1 and GD1a are considered as a functional unit involved with sialidase that converts GD1a to GM1 [43]. The abundance of GM1/GD1a is consonant with the numerous functional roles of GM1. The involvement of glycosphingolipids in neuronal function and cell signaling modulation has been reviewed in detail elsewhere [44].

The human natural killer-1 glycan antigen (HNK-1; [HSO3-3GlcAβ1-3Galβ1-4GlcNAc]), is highly abundant in CNS regions associated with neogenesis and synaptic plasticity. This includes expression in the dentate gyrus of the hippocampus, perineuronal nets and in neural stem cells, where HNK-1 antigen has a direct impact on synaptic plasticity and higher brain functions such as spatial learning and memory formation via significant effects on long-term potentiation [4548]. Specifically, HNK-1 glycan antigen expression is key to normal hippocampal dendritic spine maturation and post-synaptic function via the AMPA-type (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type) glutamate receptor subunit GluR2 and post-synaptic protein PSD-95 [49]. The expression of HNK-1 glycan antigen is also closely associated with immature oligodendrocyte differentiation and may be a viable biomarker for breakdowns in re-myelination in the brain and spinal cord of human patients with multiple sclerosis [50].

Synaptic plasticity, cell differentiation and migration are also dependent on polySia glycans, which are known for their widespread expression during embryonic and postnatal brain development stages [51]. Due to its highly negative charge and hydrophilic nature, during development polySia facilitates cell motility by increasing intercellular space [51], enhances cell migration and axon finding [5153] and promotes repair or regeneration in lesioned peripheral and CNS tissues [54,55]. The most prominent polySia expression is found on interneuron precursor cells that migrate from the subventricular zone of the lateral ventricle to the olfactory bulb during differentiation into mature neurons [56]. The removal of polySia glycans with endo-neuraminidase (EndoN) enzyme results in premature differentiation and migration deficits of these precursor interneurons [57]. Migrating precursor cells of cortical interneurons [58,59] and cerebellar granule cells [60] prominently express polySia glycans during the course of brain development and polySia glycans are present during synapse formation of hippocampal neurons [61]. Recently it has also been shown using in vitro medial prefrontal cortex cultures that depletion of polySia glycans causes an imbalance of excitatory and inhibitory synaptic inputs and affects the structural plasticity of interneurons [62]. Collectively, these reports indicate the diverse roles of polySia at all stages of neurogenesis and suggest polySia as a particularly useful biomarker for targeting and imaging CNS neurons functionally implicated in regulating migration and synaptic plasticity.

Glycan expression in CNS cancer and disease

In the CNS, glycans are prominently expressed on cell surface glycoprotein and glycolipid receptors which are important for CNS cell functions. For example, the glycosylated G-protein coupled receptors can be absolutely critical for receptor trafficking and function, as is the case for the angiotensin II AT1a receptor glycoprotein that regulates blood pressure [63]. Membrane transporter expression and activity like the crucial solute carrier family of glycoproteins that transport serotonin, dopamine, noradrenaline, gamma-aminobutyric acid (GABA) and glycine are also highly affected by glycan expression [64]. For example, a mutant model lacking N-glycosylation site N370 of the AMPA glutamate receptor protein subunit GluA2 strongly suppressed its intracellular trafficking from the endoplasmic reticulum, suggesting that the cell surface expression of this receptor is predominantly regulated by site-specific N-glycans [65].

Glycan biomarker identification and major alterations in glycan expression have been observed in multiple CNS disorders [6674] including Alzheimer's disease [75], Parkinson's disease [76], Huntington's disease [77], amyotrophic lateral sclerosis (ALS) [78], multiple sclerosis [79], schizophrenia [80] as well as in the brain cancers glioblastoma multiforme [81] and neuroblastoma [82,83] (Table 1). Cellular glycan expression is closely associated with the innate immune response [84] as well as in neuroinflammation driven by microglia [79]. Microglia normally function to detect and destroy pathogens by phagocytosis or with the secretion of neurotoxins such as cytokines in response to CNS cell inflammation [85]. Disruptions to this process, where they may misidentify CNS cells as pathogens and target them for damage, or fail to act in response to threats, are the case in most neurodegenerative and autoimmune inflammatory diseases [85]. In Alzheimer's disease, which is predominantly characterized pathologically by amyloid plaques and tau proteins that contain functionally important N-glycans and O-glycans, decreases in sialic acid glycan residues are apparent in patient cerebrospinal fluid (CSF) samples compared with healthy controls [75]. In addition to decreased sialic acids, reduced polysialylated neural cell adhesion molecule (polySia-NCAM) in the entorhinal cortex region of the brain, also correlates with tau load in Alzheimer's disease [86] (Table 1). The degree of sialylation on the N-glycans of amyloid precursor proteins is directly related to the secretion of these proteins and their metabolites [75]. Interestingly, there is a notable increase in expression in the sialic acid binding lectin CD33 on brain microglial cells of human patients with Alzheimer's disease [87] suggesting altered expression, recognition or handling of sialic acids may be contributing to the development or maintenance of this disease. Recognition of sialic acid as a biomarker for targeting and imaging of CNS abnormalities in Alzheimer's disease is further supported by previously reported decreases in staining using the sialic acid targeting lectin WGA but not Concanavalin A and L. culinaris agglutinin (mannose binding) or Ricinus communis Agglutinin (galactose and lactose binding) in human CSF samples [88]. Paired helical filament tangles containing tau proteins are glycosylated with high mannose and sialylated bi- and triantennary-type glycans in Alzheimer's patient brains in contrast with the non-glycosylated normal tau proteins, and glycosylation is also responsible for maintaining these abnormal tau protein structures [89,90]. Evidently, changes in glycosylation are highly linked to the etiology of Alzheimer's disease for both amyloid plaques and tau proteins. Ganglioside metabolism is also closely associated with the pathological process of Alzheimer's disease [91]. Amyloid plaques undergo a conformational transition after the binding of GM1 ganglioside to amyloid-beta protein, where the initial random coil of the protein transforms to an ordered structure of beta-sheets [92]. The assembly of amyloid-beta protein with GM1 is an endogenous seed for the fundamental event of amyloid fibril formation in the Alzheimer's diseased brain. This assembly of hereditary amyloid-beta proteins is accelerated by GM3 and GD3. In addition, GD3 is up-regulated in astrocytes and endothelial cells, which form cerebrovascular basement membrane, the site of amyloid-beta protein deposition [93].

Table 1
Changes in glycosylation and potential biomarkers for several CNS diseases
graphic
 
graphic
 

GM1 gangliosides are also involved in the pathogenesis of Parkinson's disease, they have been recommended as potential therapeutics for the disease as they influence dopamine transporter binding [94,95] and inhibit fibrillation by interacting with α-synuclein (a ganglioside-binding protein in the brain) [76,96]. Immunoblotting, peptide antigen (HP2A) immunoprecipitation, mass spectrometric analysis and enzymatic digestions with N-glycosidase, O-glycosidase and sialidase A of α-synuclein in human Parkinson's disease patients revealed O-linked glycosylation of α-synuclein (α-Sp22) that is accumulated in the diseased brain [97] (Table 1). Additionally, immunohistochemical analysis of sections from Parkinson's disease patients showed a significant GM1 deficiency in nigral dopaminergic neurons, and animal models of GM1 deficiency displayed Parkinson-like symptoms that were alleviated by administration of LIGA-20 (blood–brain barrier-permeable analog of GM1) [98].

Total glycan analysis using MS in brain tissues and sera from a transgenic mouse model of the neurodegenerative Huntington's disease demonstrated increased core-fucosylated N-glycans, sialylated bi-antennary type glycans and bisecting GlcNAc type glycans [99] (Table 1). Another important class of glycans, the cytoplasmic O-linked GlcNAc, has also been implicated in neurodegenerative diseases but is beyond the scope of this review. An example of the importance of O-GlcNAc in neurodegenerative disease is shown in the work of Grima et al. [100] in which, using the anti-O-linked N-acetylglucosamine antibody [RL2], they showed that the regulation of O-GlcNAc expression is crucial to the pathogenesis of Huntington's disease.

In ALS, a disease characterized by the death of motor neurons controlling voluntary muscular movements, there is an increase in sialylated glycan expression occurring on IgG that could serve as a biomarker in patient sera [78]. These glycan epitopes, which are recognized by CD16 (FcgammaIIIR) proteins expressed on the surface of microglia, may be involved in initiating neuronal damage as they activate pro-inflammatory microglia signaling. Interestingly, CD16 was also reported to be overexpressed in brain and spinal cord microglia cells in a mouse model of ALS [78,101].

In pathological conditions of the CNS that results in demyelination, oligodendrocyte precursor cells proliferate and are recruited to demyelinated areas where they differentiate into mature re-myelinating cells [102]. Kanekiyo et al. [103] reported in a study using the Cat-315 antibody, that branch-type β1,6-linked O-mannosyl glycans in the brain are key components that inhibit the re-myelination process in CNS injury models (Table 1). In line with this, by genetic and environmental factors, the dysregulation of total N-glycan expression and branching has been found to promote multiple sclerosis [104]. The induced changes were characterized by inflamed lesions that damaged the insulation surrounding nerve fibers via the improper functioning of the interface between immune cells, CNS neurons and oligodendrocytes. Decreased N-glycan branching, stimulated by IL-2 and IL-7 signaling in infiltrating human CD4+ T phenotype cells, was cytotoxic to oligodendrocytes and drove the progression of multiple sclerosis [105,106] and was detected using flow cytometry with L-PHA (Phaseolus vulgaris, leukoagglutinin), a plant lectin that binds specifically to β1,6GlcNAc-branched N-glycans [104]. In addition, immunohistochemistry analysis of multiple sclerosis lesions revealed that re-expression of polySia-NCAM accounts for the failure of re-myelination and participates in disease progression in multiple sclerosis [107].

Abnormal glycan branching is also apparent in up to 95% of schizophrenia patient CSF samples, with decreased levels of both bisecting and sialylated glycans detected by fluorescent labeling with a 2-AB GlycoProfile kit and subsequent HPLC analysis [108] (Table 1). PolySia-NCAM is also reduced in the hippocampus region of schizophrenic brains [109]. In human cortex samples from schizophrenia patients, there are also multiple reports of N-glycan dysfunction in patient glutamatergic handling, with decreased glycan expression on excitatory amino acid transporters that could hinder glutamate reuptake [110] as well as altered N-glycosylation on all of the ionotropic glutamate receptor subtypes: AMPA receptor subunits [111] and N-methyl-d-aspartate and kainate receptor subunits [112]. Additionally, alterations in GABAergic signaling due to immature N-glycan expression in multiple GABAA receptor subunits was apparent in other human schizophrenia patient samples taken from the superior temporal gyrus [113].

Glycan biomarkers could also be useful in cell targeting for diagnosis and drug delivery applications in brain cancers such as glioblastoma [114] and neuroblastoma [115]. Generally, in abnormal cell proliferation instances like metastatic cancers, cell division and migration of malignant cells are driven by cell–cell signaling pathways. As described previously, cell surface glycans play important roles in such cell functions; hence glycosylation is commonly altered in brain cancer cells [116]. For example, in glioblastoma patients, immunohistochemistry analysis of biopsies revealed polySia-NCAM as an adverse prognosis factor and thus a potential biomarker for the disease [117]. Disease associated N-glycans including oligomannose as well as fucosylated and non-fucosylated complex-type glycans were identified to be spatially specific in different regions of the brain of healthy and glioblastoma mouse models using matrix-assisted laser desorption/ionization (MALDI)-MSI, with 13 glycoforms that were differentially expressed in tumor versus normal brain tissues [118] (Table 1). Fucose containing cell surface N-glycans are up-regulated in glioblastoma multiforme (occurring in astrocytes), the most aggressive form of brain cancer as detected by Ulex europaeus agglutinin I (UEA-1) [119] or HPLC columns and fluorescent detection [120] while other findings suggest that bisecting GlcNAc (as detected by E-PHA lectin staining) may be a viable glycan biomarker for pediatric brain cancers such as astrocytomas and ependymomas [121] (Table 1). The lectins Dolichos biflorus agglutinin (DBA), Griffonia simplificola lectin I (GSL I) and PNA, which are specific to α-N-acetylgalactosamine (GalNAc) and/or galactose, have been used as markers to detect glycocalyx differences in undifferentiated versus glioma-derived stem cells [122] reinforcing findings that lectins could potentially be used as biomarkers for the identification of primary brain tumors [123,124]. Furthermore, in neuroblastoma, the most common cancer in children, the expression of GD2 is substantially up-regulated in patient serum and neuroblastoma cell surfaces; therefore, the use of anti-GD2 monoclonal antibodies is the primary immunotherapy target for neuroblastoma cancer treatment [82,115] (Table 1).

Conclusions

In summary, glycan modifications on the glycoproteins and glycolipids in the CNS are key to normal neural development, biological processes and maintenance of cellular functions. Alterations to glycan expression are widely believed to negatively impact brain development and can result in pathological CNS conditions such as neurodegenerative disorders, psychopathologies and brain cancers. A variety of glycan biomarkers associated with these pathologies has been identified and has huge potential to be used for targeting and imaging of CNS cell developmental stages and disease.

Abbreviations

     
  • ALS

    amyotrophic lateral sclerosis

  •  
  • AMPA

    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

  •  
  • CNS

    central nervous system

  •  
  • CSF

    cerebrospinal fluid

  •  
  • DBA

    Dolichos biflorus agglutinin

  •  
  • GABA

    gamma-aminobutyric acid

  •  
  • GalNAc

    N-acetylgalactosamine

  •  
  • GD

    ganglioside

  •  
  • GlcNAc

    N-acetylglucosamine

  •  
  • GluR2

    glutamate receptor subunit 2

  •  
  • GSL-1

    Griffonia simplificola lectin I

  •  
  • HNK-1

    human natural Killer-1

  •  
  • IM

    ion mobility

  •  
  • L-PHA

    Phaseolus vulgaris, leukoagglutinin

  •  
  • MALDI

    matrix-assisted laser desorption/ionization

  •  
  • MS

    mass spectrometry

  •  
  • MSI

    mass spectrometry imaging

  •  
  • PNA

    peanut agglutinin

  •  
  • PolySia

    polysialic Acid

  •  
  • PSD

    post-synaptic protein

  •  
  • SSEA-1

    stage-specific embryonic antigen-1

  •  
  • TRA1

    tumor-rejection antigens

Author Contribution

S.I. and M.G.F. wrote the manuscript. L.M.P., A.E.D. and N.H.P. critically revised the article for important intellectual content.

Funding

This work is primarily supported by the Australian Research Council (ARC) Centre of Excellence Scheme through the Centre of Excellence for Nanoscale BioPhotonics [CE140100003]. L.M.P. is also supported by an Australian Research Council Discovery Early Career Research Award [Project Number: DE180100206].

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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Author notes

*

These authors have contributed equally to this paper.