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Published in final edited form as: Curr Opin Genet Dev. 2024 Feb 20;85:102159. doi: 10.1016/j.gde.2024.102159

Cohesin regulation and roles in chromosome structure and function

Natalie L Rittenhouse 1, Jill M Dowen 2,3,4,5,*
PMCID: PMC10947815  NIHMSID: NIHMS1964785  PMID: 38382406

Abstract

Chromosome structure regulates DNA-templated processes like transcription of genes. Dynamic changes to chromosome structure occur during development and in disease contexts. The cohesin complex is a molecular motor that regulates chromosome structure by generating DNA loops that bring two distal genomic sites into close spatial proximity. There are many open questions regarding the formation and dissolution of DNA loops, as well as the role(s) of DNA loops in regulating transcription of the interphase genome. This review focuses on recent discoveries that provide molecular insights into the role of cohesin and chromosome structure in gene transcription during development and disease.

Keywords: genome organization, cohesin, Cancer, development

Introduction

The three-dimensional (3D) organization of the genome influences genomic output, including the expression of genes. Chromosomes are folded into structures that are linked to gene expression and cellular identity (Bonev and Cavalli, 2016). Chromosome structure can change dynamically during development and disease as cells transition from one state to another state (Gómez-Díaz and Corces, 2014). Many proteins and DNA sequences involved in spatial genome organization have been identified and the molecular mechanisms by which they regulate genome organization and gene expression are active areas of investigation (Davidson and Peters, 2021; Gómez-Díaz and Corces, 2014). Knowledge of how DNA loops form and function in healthy cells is critical for understanding how mutations and misregulation of 3D genome regulators contribute to the pathologies of developmental disorders and diseases like cancer.

The cohesin complex is a pleiotropic regulator of genome structure and function whose activity is important for such varied biological processes as sister chromatid cohesion, cell division, DNA replication, DNA repair, and gene expression (Peters et al., 2008) (Figure 1). As a Structural Maintenance of Chromosomes (SMC) protein complex, cohesin uses ATP to fold the interphase genome of vertebrate cells into DNA loops that are important for spatial organization and gene regulation (Davidson et al., 2019). Cohesin binds and extrudes DNA until it encounters a CTCF molecule bound to the CTCF consensus motif in DNA. Many cohesin-mediated DNA loops bring together two CTCF bound sites that are located far apart in the linear genome, but are brought into close physical proximity as the left and right anchors of a DNA loop (Wutz et al., 2017). Some cohesin-mediated DNA loops lack CTCF binding at their anchors, such as enhancer-promoter loops, and it is not clear how cohesin is stabilized at these sites (Dowen et al., 2014). The biochemical and biophysical basis of cohesin-mediated genome structure is the focus of ongoing research.

Figure 1. Biological roles of cohesin.

Figure 1.

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Cohesin participates in various cellular functions including sister chromatid cohesin, homology-directed DNA repair, cell division, gene expression, and DNA replication. The molecular mechanisms by which this ATPase complex is harnessed for distinct structural and functional processes on chromosomes remain poorly understood.

3D genome structure has been mapped with sequence-level precision via chromosome conformation capture techniques, like Hi-C, which utilize millions of cells (Belton et al., 2012). Recent advances in super-resolution microscopy techniques have allowed for the analysis of 3D genome organization in live single cells over short time scales (Shaban and Seeber, 2020). Together with computational modeling and single molecule assays, these complimentary techniques have led to the view that DNA loops are infrequent within a population of cells and transient within a single cell. A major open question in the field is how such rare and dynamic DNA loops generate effects on gene expression. Furthermore, how defects in DNA loops manifest over different time scales and lead to heterogeneous developmental phenotypes is unclear. Understanding the function of DNA loops and how defects in cohesin activity lead to aberrant genome structure and gene expression is critical for knowledge of normal biology as well as the numerous disease states associated with defects in the 3D genome.

Chromosome structure and gene regulation

Regulation of cohesin engagement with chromosomes

Cohesin and CTCF control the contact dynamics of the genome. Cohesin is a multi-subunit complex made up of a core set of proteins: SMC1A, SMC3, and RAD21 (Figure 2). Different auxiliary subunits can associate with this core yielding variant cohesin complexes of distinct subunit compositions. The STAG1 and STAG2 proteins are highly conserved mutually exclusive cohesin auxiliary subunits that are required for efficient association of cohesin with DNA. Additionally, the PDS5A and PDS5B proteins also display strong sequence conservation and are mutually exclusive cohesin auxiliary subunits that function in stalling cohesin-mediated loop extrusion and release of cohesin from DNA. Other cohesin regulators are known to bind the complex, such as NIPBL and MAU2, which promote loading of cohesin onto DNA, as well as WAPL, which works with PDS5 proteins to release cohesin from chromatin. A recent Cryo-EM study identified the conformations of individual cohesin complexes when bound to DNA, including the positions of individual cohesin subunits (Shi et al., 2020). This structural information is useful for understanding the various conformations of cohesin as it engages with DNA and translocates across the genome. Evidence from biochemical and single molecule assays indicate a stepwise process by which the cohesin complex changes conformations during DNA loop extrusion in a “swing and clamp” mechanism of movement (Bauer et al., 2021; Davidson et al., 2019; Fudenberg et al., 2016). In this model NIPBL first interacts with the SMC3 hinge domain and DNA. Upon alignment of the SMC coiled-coil arms, the coiled-coils bend and NIPBL is brought to the SMC3 ATPase head (Bauer et al., 2021). When ATP binds to the ATPase heads, NIPBL clamps DNA to the SMC3 head, inducing engagement of the ATPase heads and ATP hydrolysis (Bauer et al., 2021). Subsequently, the ATPase heads disengage, thus completing the cycle of assembling and disassembling a DNA clamp with each instance of ATP binding and hydrolysis (Bauer et al., 2021). Therefore, DNA loop extrusion requires multiple conformational changes that involve swinging of the hinge domain, movements of the ATPase heads, and alignment of coiled-coils (Bauer et al., 2021).

Figure 2. Subunit composition of the cohesin complex.

Figure 2.

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The core cohesin complex in mammals consists of the structural maintenance of chromosomes subunits SMC1A and SMC3, as well as the kleisin subunit RAD21. A stromal antigen protein subunit, either STAG1 or STAG2, is bound to the RAD21 subunit. A precocious dissociation of sisters subunit, either PDS5A or PDS5B, binds to RAD21 and can be replaced by NIPBL-MAU2 during loading and translocation of cohesin along chromatin. WAPL binds to RAD21 in the presence of PDS5A or PDS5B to remove cohesin from chromatin.

The rate at which cohesin extrudes DNA can be as fast as 1 kilobase per second. Extrusion can stall at CTCF bound sites, and possibly at active enhancers and promoters through an unknown mechanism, leading to stable cohesin binding at the anchors of a DNA loop (Figure 3A). The SMC1A hinge domain and STAG subunit are critical for cohesin interaction with CTCF, and the STAG subunit specifically interacts with an interface on CTCF to stall DNA loop extrusion (Li et al., 2020; Nagasaka et al., 2023; Xiao et al., 2011). Intriguingly, the orientation of a CTCF molecule determines whether cohesin stalls at or accelerates past a CTCF site (Figure 3B) (Zhang et al., 2023). These findings provide insight into the molecular mechanisms underlying cohesin translocation and the phenomenon known as the CTCF convergence rule, in which the majority of cohesin-mediated DNA loops are anchored by a pair of CTCF bound sites with convergently oriented CTCF motifs (de Wit et al., 2015; Rao et al., 2014).

Figure 3. Regulation of DNA loop extrusion dynamics by proteins and nucleic acids.

Figure 3.

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A. Cohesin loads onto DNA and extrudes a DNA loop (left; black arrow indicates an actively growing DNA loop). DNA loop extrusion is stopped when cohesin encounters CTCF and the majority of DNA loops are anchored by a pair of CTCF bound sites (right). B. Cohesin-mediated DNA loop extrusion is stalled by encountering the N-terminal side of a CTCF molecule (left). When cohesin encounters the C-terminus of a CTCF molecule, cohesin continues DNA loop extrusion and the rate of loop extrusion increases (right). C. High DNA tension allows for more effective stalling of DNA loop extrusion by CTCF molecules in the permissive orientation (left) while low DNA tension allows for cohesin to pass over N-terminally oriented CTCF (right). D. DNA loop extrusion is stalled when RNA-DNA duplexes called R-loops are encountered. E. Transcription induced DNA supercoiling can increase the rate of DNA loop extrusion.

Given the widespread acceptance of the DNA loop extrusion model of cohesin activity, much effort has turned to identifying barriers that arrest dynamic DNA loop extrusion and understanding the significance of relatively transient DNA loops for maintaining gene expression. MCM complexes, which license eukaryotic origins of DNA replication, were recently shown to impede cohesin-mediated DNA loop extrusion during interphase. The ability of MCM complexes to pause loop extrusion is likely due to a specific protein-protein interaction since cohesin can traverse large obstacles such as a polymerase or a 200nm polystyrene bead (Dequeker et al., 2022; Pradhan et al., 2022). This evidence is consistent with the view that cohesin complexes do not topologically engage DNA during loop extrusion and, thus, many potential obstacles are sidestepped if they are not selective barriers to cohesin. Interestingly, when DNA is under high tension, the efficiency with which CTCF blocks cohesin-mediated loop extrusion increases, while low DNA tension permits cohesin to extrude past properly oriented CTCF sites in vitro (Figure 3C) (Davidson et al., 2023). RNA-DNA hybrids, known as R-loops, that form during transcription, can also stall DNA loop extrusion in vitro and are correlated with cohesin localization in vivo (Figure 3D) (Hansen et al., 2019; Saldaña-Meyer et al., 2019; Zhang et al., 2023). G-quadruplexes form in DNA at R-loops and can increase CTCF binding to proximal CTCF motifs, thus increasing DNA loop formation (Wulfridge et al., 2023). In addition to trans-acting factors regulating cohesin extrusion, transcription by RNA Polymerase creates supercoiling and torsional strain on the DNA fiber that can accelerate the rate of cohesin extrusion (Figure 3E) (Neguembor et al., 2021; Rusková and Račko, 2021; Zhang et al., 2023). These results indicate that proteins like CTCF are not simply physical roadblocks to cohesin, but that specific physical interactions with proteins or nucleotides, as well as the biochemical and biophysical properties of the DNA and RNA polymers, are direct regulators of cohesin binding and DNA loop extrusion.

Recent quantitative measurements of DNA loops and cohesin state provide answers to longstanding questions about cohesin dynamics, including the residency time of cohesin at stable DNA loops. Super-resolution live-cell imaging and single molecule assays show that cohesin-mediated DNA loops are relatively rare in the population and have short half-lives (Davidson et al., 2019; Gabriele et al., 2022; Mach et al., 2022; Pradhan et al., 2022). A typical pair of loci exists in the looped state ~5% of the time and the un-looped state ~95% of the time, with the half-life of a loop usually lasting 10–30 minutes (Gabriele et al., 2022; Mach et al., 2022). The conformational changes adopted by the cohesin complex in vivo during its various modes of DNA engagement are just beginning to be characterized. Recent work indicates that the coiled-coil domains of SMC1A and SMC3 are folded together and undergo a bend that brings the hinge domain near the ATPase heads (Petela et al., 2021). As cohesin binds DNA, DNA passes through the hinge domain and between the ATPase heads, however it is unclear if this mode of cohesin entrapment of DNA is the mode that occurs at the anchors of a DNA loop in interphase cells (Collier and Nasmyth, 2022). Intriguingly, the modes by which cohesin engages DNA and stabilizes DNA loops vary at different genomic sites. Cleavage of the core subunit RAD21 causes dissociation of cohesin and loss of DNA loops from CTCF sites, however, other cleaved cohesin molecules remain associated with chromatin at sites without CTCF (Liu and Dekker, 2022). Additionally, it has been shown that the cohesin molecules involved in chromatin looping during G1 phase of the cell cycle, can remain bound to chromatin through S phase, when cohesin complexes perform sister chromatid cohesion (J. D. P. Rhodes et al., 2017). These studies indicate that individual cohesin molecules may exist in different states and operate with different biochemical and biophysical properties, determined by their unique subunit compositions, conformation, mode of binding DNA, interaction with cohesin regulatory proteins, and the phase of the cell cycle.

Cohesin-mediated transcriptional regulation

Cohesin is implicated in regulating transcription in many different biological contexts. It is thought that cohesin-mediated gene regulation is a product of bringing cis-regulatory sites and genes together in physical proximity, such as in the formation of enhancer-promoter loops and super-enhancers. Cohesin can directly regulate transcription by increasing RNA Polymerase II occupancy at genes as well as by promoting transition of paused RNA Polymerase II to the actively elongating state (Schaaf et al., 2013). CTCF can also regulate gene transcription at promoters by binding and directing enhancer-promoter communication and gene expression in a cohesin-dependent manner (Dehingia et al., 2022; Oh et al., 2021). Loss of promoter-proximal CTCF binding can alter transcription of cell type specific genes and disrupt long-range enhancer-promoter interactions (Kubo et al., 2021). Additionally, CTCF can suppress antisense transcripts at divergently oriented promoters (Luan et al., 2022). Individual zinc fingers within CTCF were found to regulate localization of CTCF to specific binding sites in the genome and thereby regulate expression of distinct sets of genes (Hyle et al., 2023). Additionally, CTCF possesses an RNA-binding region (RBR) that is required to maintain a subset of DNA loops and gene expression profiles (Hansen et al., 2019; Saldaña-Meyer et al., 2019). The CTCF paralog BORIS, expressed in sperm and cancer cells, binds to DNA motifs similar to the CTCF motif, though BORIS lacks the domains required to stall cohesin-mediated loop extrusion and bind to RNA (Del Moral-Morales et al., 2023). BORIS regulates transcription primarily by binding to promoters of cancer testes antigens genes rather than via cohesin-mediated genome organization (Nishana et al., 2020). These results reveal insights into the previously underappreciated role of CTCF and CTCF paralogs in transcriptional control at a subset of genes.

Given the links between cohesin and transcription, it was somewhat surprising when studies employing acute degradation systems and Hi-C revealed that rapid loss of cohesin and CTCF caused a decrease in DNA loops and domains, yet nascent transcription was minimally perturbed (Nora et al., 2017; Rao et al., 2017). Techniques like Micro-C and Region Capture Micro-C allow for increased resolution of DNA interactions compared to Hi-C and have revealed more detail about fine scale genomic structures, such as enhancer-promoter loops (Goel et al., 2023; Lee et al., 2022). Intriguingly, enhancer-promoter interactions can remain intact upon loss of cohesin or CTCF, suggesting that some DNA loops are independent of loop extrusion (Goel et al., 2023; Hsieh et al., 2022). Both transcription factor residency time at chromatin sites and multivalent interactions between transcription factor activation domains contribute to gene activation. A recent study found that the phase separation propensity of transcription factor activation domains is not required for efficient transcription, therefore the function of cohesin in stimulating transcription may be independent of reported transcriptional condensates (Trojanowski et al., 2022). Additionally, transcription factors show reduced binding to target sites when cohesin is depleted, suggesting a role for cohesin in transcription factor search dynamics or steady state binding (Hsieh et al., 2022). These studies establish the roles of cohesin and CTCF in transcriptional control at some enhancers and promoters, as well as identify CTCF- and cohesin-independent enhancer-promoter loops that warrant further investigation.

The localization of cohesin to cis-regulatory elements, such as enhancers, promoters, and CTCF sites known as insulators, influences gene transcription. Cohesin induces enhancer-promoter interactions through a series of steps, termed a cohesin traffic pattern, that involve loading of cohesin at transcriptionally active enhancers, cohesin translocation until stalling at CTCF sites or transcription start sites, followed by removal of cohesin from DNA at transcription termination sites (Valton et al., 2022). Disruption of the cohesin traffic pattern leads to aberrant enhancer-promoter interactions and sensitizes cells to loss of transcription initiation factors and RNA-processing factors (Liu et al., 2020; Valton et al., 2022). Loss of cohesin also induces alternative splicing at a subset of genes, without altering the rate of transcription (Singh et al., 2023). Additionally, loss of the mediator complex induces cohesin relocalizaiton from enhancers to CTCF sites, decreases enhancer-promoter interactions, and reduces expression of the associated genes (Ramasamy et al., 2023). Intragenic cohesin in regions lacking CTCF was found to play a role in repressing transcription through inhibiting release of paused RNA polymerase II (J. Wang et al., 2022). Together, these studies provide a clearer picture of the multiple roles that cohesin plays in transcriptional regulation at individual cis-regulatory elements and genes.

Embryonic development, differentiation, and cohesinopathies

The spatial organization of chromosomes is dynamic during development. Cohesin- and CTCF-mediated DNA loops and domains are implicated in the establishment and maintenance of gene expression programs in many lineages and cell types. Total loss of cohesin is lethal at the organismal level, however, heterozygous and partial loss of function cohesin mutations are viable and associated with global developmental defects and delay (Horsfield et al., 2012). The broad collection of multisystem developmental disorders that are linked to human germline mutations in cohesin and cohesin regulators are termed cohesinopathies. The mystery of how distinct cohesin-related mutations lead to a wide array of phenotypes is beginning to be unraveled.

In Cornelia de Lange Syndrome, a prevalent cohesinopathy, most mutations occur in the cohesin regulator NIPBL, which stabilizes cohesin on chromatin and stimulates the ATP hydrolysis activity of cohesin that is important for DNA loop extrusion (Garcia et al., 2021). The number of cohesin molecules on the genome influences chromosome structure. The dose of cohesin on DNA is regulated by the balance of the cohesin loading factor NIPBL versus the cohesin unloading factor WAPL. Disruption of NIPBL causes loss of cohesin from the genome, resulting in global decreases in DNA loops and domains, as well as misexpression of thousands of genes (Schwarzer et al., 2017). Conversely, loss of WAPL increases cohesin stability, alters cohesin localization, and increases the number and size of DNA loops on chromosomes resulting in a condensed chromatin structure known as vermicelli (Tedeschi et al., 2013; Wutz et al., 2017). Interestingly, WAPL mutations have not been identified in cohesinopathy patients, yet it was recently demonstrated that the dual depletion of both WAPL and NIPBL in human HCT116 cells largely rescues the phenotypes of NIPBL loss alone (Luppino et al., 2022). Importantly, decreasing WAPL dosage in mice haploinsufficient for NIPBL partially restores transcription profiles in late-stage embryonic brain tissue, but does not resolve the perinatal lethality phenotype commonly seen in this mouse model (Kean et al., 2022). In addition to regulating the number of cohesin molecules bound to the genome, NIPBL also stimulates the ATPase activy of cohesin that promotes translocation of the complex along DNA (J. Rhodes et al., 2017). Intriguingly, NIPBL molecules can dynamically hop between cohesin complexes that are already loaded onto DNA and can bind chromatin independent of cohesin (J. Rhodes et al., 2017). NIPBL mutations frequently occur in Cornelia de Lange Syndrome and appear to disrupt cohesin-mediated DNA loop extrusion and alter gene expression by potentially reducing the processivity of loop extrusion (Panarotto et al., 2022; J. Rhodes et al., 2017). These studies further define the roles of NIPBL and WAPL in balancing cohesin activity, and suggest that cohesin dose, localization, and functions contribute to misregulation of gene expression in cohesinopathies.

Functionally diverse cell types may have different sensitivities for distinct cohesin perturbations. The STAG2 cohesin protein may play a particularly important role in the nervous system and during brain development. STAG2 loss in oligodendrocytes alters enhancer-promoter communication and expression of myelin-promoting genes, which may explain the neurological phenotypes observed in mouse models of cohesinopathies (Cheng et al., 2022). Additionally, transcriptional profiles from induced pluripotent stem cells differentiated into forebrain organoids indicate that STAG2 is highly upregulated during neuroectoderm commitment, highlighting the important role it plays in neural development (Schmidt et al., 2022). Depletion of the cohesin subunit RAD21 in mouse embryonic stem cells reduces expression of stem cell maintenance transcription factors, like OCT4, and alters transcriptional profiles allowing for preferential differentiation into neuronal and germline fates (Koh et al., 2022). Furthermore, RAD21 loss in post-mitotic neurons causes a reduction in long-range DNA interactions necessary for expression of late response neuronal genes (Calderon et al., 2022). Therefore, proper developmental regulation of cohesin appears to be critical for spatiotemporal differentiation of cell types in an organism.

Cohesin mutations and 3D genome organization in cancer

Cohesin is one of the most frequently mutated protein complexes in all cancers (Kandoth et al., 2013). Mutations in the genes of individual cohesin subunits (SMC3, RAD21, STAG2, STAG1, NIPBL) can alter the interaction of the cohesin complex with the genome. Since complete loss of cohesin leads to catastrophic chromosomal defects and eventually cell death, somatic cancer mutations are likely to be partial-loss-of-function mutations or effect the dose of cohesin molecules on the genome. Mutations of the core cohesin subunits may alter the ability of cohesin complexes to load onto chromatin, efficiently undergo conformational changes, or perform orderly DNA loop extrusion (Antony et al., 2021). Alternatively, mutations and misregulation of cohesin auxiliary subunits (STAG1, STAG2, PDS5A, PDS5B, NIPBL) may lead to more subtle phenotypes that involve transcriptional dysregulation of oncogenes and tumor suppressor genes. Indeed, investigation of individual cohesin mutations in an embryonic stem cell model found that some mutations are sufficient to cause misexpression of genes located at cohesin-mediated DNA loops (Rittenhouse et al., 2021). A point mutation in a core subunit of cohesin, SMC1A-R586W, was shown to reduce cohesin localization to enhancers and promoters, but not CTCF sites, and lead to a global loss of short-range DNA contacts across the genome (Carico et al., 2021). Cohesin mutations represent potential therapeutic targets in cancer because of the synthetic lethality observed between STAG1 and the frequently inactivated STAG2 tumor suppressor in different cellular contexts (Arruda et al., 2020; Benedetti et al., 2017; van der Lelij et al., 2017). Future functional studies of cohesin mutations will be important for determining the utility of individual cohesin mutations as biomarkers and for developing therapeutic strategies that directly target cohesin mutations or target underlying signaling pathways or transcriptional regulators in cancer.

The 3D genome organization of normal cells can be hijacked in cancer cells to promote oncogenesis. The spatial organization of chromosomes influences the susceptibility to structural rearrangements such as insertions, deletions, translocations, and copy number variation. CTCF consensus motifs are enriched for human sequence variation which can alter CTCF binding and thereby govern DNA loop propensity (Katainen et al., 2015). Exploration of cancer genomes with assays like Hi-C for detecting DNA interactions have revealed many insights into the diverse and complex genomic changes that cancer cells undergo. Detection of molecular lesions that hijack an enhancer and cause it to inappropriately activate transcription of disease-relevant genes is now possible from bulk or single cell samples (Wang et al., 2021; X. Wang et al., 2022). Oncogenic fusion proteins are common in specific types of cancer, and a recent study of the EWS/FLI fusion common in Ewing sarcoma colocalizes with cohesin, mediates new DNA loops, and regulates the expression of hundreds of genes (Showpnil et al., 2022). New epigenetic drugs targeting the 3D genome are under development. Curaxins can intercalate DNA in the CTCF motif, reducing the binding of CTCF and perturbing 3D genome structure (Kantidze et al., 2020). Further genomic profiling of diverse cancers is needed to identify pathogenic signatures that arise from altered 3D genome structure and determine their sensitivy to chemotherapeutic agents targeting different modes of action.

Concluding remarks

Many important questions about cohesin function remain to be addressed. Does cohesin interact with different proteins at different types of DNA loop anchors? How is DNA loop residency time regulated and what is the consequence for transcription? Insights to these questions and others will undoubtably be derived from studies that characterize the biochemical and biophysical properties of distinct cohesin molecules, either composed of unique subunit combinations, adopting distinct conformational states, or localized to various classes of sites in the genome. Additional mechanistic insight into chromatin folding dynamics in vivo is also important and will help define the roles of additional partner proteins and nucleic acids in regulating the modes of DNA engagement, extrusion dynamics, and other activities of cohesin. Addressing these questions will provide molecular and cellular detail into the mechanisms that shape genome structure during development and disease.

Acknowledgements

Natalie Rittenhouse received funding from NIGMS grant T32GM135128. Research in the laboratory of Jill Dowen is supported by NIH/National Institute of General Medical Sciences, USA grant R35GM124764 and R35GM152103. The authors thank all members of the Jill Dowen lab as well as the lab of Dr. Dan McKay for helpful discussions and feedback.

Footnotes

Declaration of Interest

The authors have no interests to declare.

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Data Availability

No data were used for the research described in this article.

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