Background: The gut microbiome is integral to host health, hosting complex interactions between the host and numerous microbial species in the gastrointestinal tract. Key among the molecular mechanisms employed by gut bacteria are transportomes, consisting of diverse transport proteins crucial for bacterial adaptation to the dynamic, nutrient-rich environment of the mammalian gut. These transportomes facilitate the movement of a wide array of molecules, impacting both the host and the microbial community. Summary: This communication explores the significance of transportomes in gut bacteria, focusing on their role in nutrient acquisition, competitive interactions among microbes, and potential pathogenicity. It delves into the transportomes of key gut bacterial species like E. coli, Salmonella, Bacteroides, Lactobacillus, Clostridia, and Bifidobacterium, examining the functions of predicted transport proteins. The overview synthesizes recent research efforts, highlighting how these transportomes influence host-microbe interactions and contribute to the microbial ecology of the gut. Key Messages: Transportomes are vital for the survival and adaptation of bacteria in the gut, enabling the import and export of various nutrients and molecules. The complex interplay of transport proteins not only supports bacterial growth and competition but also has implications for host health, potentially contributing to pathogenic processes. Understanding the pathogenic potential of transportomes in major gut bacterial species provides insights into gut health and disease, offering avenues for future research and therapeutic strategies.

The sum of the collective transmembrane transport proteins encoded within a bacterial genome is termed its “transportome.” These transport systems comprise ∼10% of the total proteome of a bacterial cell [1]. They play a wide array of important roles in the bacterium, ranging from uptake of nutrients, both uptake and efflux of metabolic products, and transport of signaling molecules. From the point of view of a pathogen, these proteins can export toxins and also function as drug efflux pumps. These latter activities contribute to antibacterial resistance [2]. The transportomes of bacterial genera (Escherichia, Salmonella, Bacteroides, Lactobacillus, Bifidobacterium, and others) that are predominant residents of the human gut have been studied in detail in published genomic studies [3‒6]. The genomes of the different strains in the aforementioned studies were predicted to encode numerous transport proteins/systems that contribute to or protect against pathogenesis, and in turn may damage or fortify host cells while causing or preventing disease. In this communication, we provide an overview of the most notable predicted transport proteins (belonging to different protein families) encoded within the genomes of commensal (c), probiotic (pr), and pathogenic (pa) enteric, firmicute, and actinobacterial microorganisms.

The Transporter Classification Database (TCDB; tcdb.org) is a freely accessible reference resource, which provides functional, structural, mechanistic, medical, and biotechnological information about transporters from organisms of all types [2]. It provides the background information upon which this review article was based. Currently (January 2024), the database includes almost 20,000 transport systems (many of which consist of multiple protein components), nearly 2,000 transport protein families, 106 related superfamilies, some of which include over 100 transport protein families, and about 25,000 references. It has been adopted by the International Union of Biochemistry and Molecular Biology (IUBMB) as the primary source for the classification and description of transporters. In this review, we shall use the terminology adopted by TCDB when referring to transport proteins/systems and their predicted homologs that comprise families in the bacterial strains that are present in the intestinal microbiome. For a concise overview of the major types of transporters predicted in different enteric bacterial strains, see Table 1.

Table 1.

Overview of important transport proteins predicted to be encoded by the different bacterial strains

Transporter type/functionE. coliSalmonellaBacteroidesLactobacillusBifidobacterium
Pore-forming toxins (PFTs) Yes Yes Yes Yes Yes 
ABC-type drug efflux pumps Yes Yes Yes Yes Yes 
Type III protein secretion systems (T3SS) Yes Yes No No No 
Type VI secretion systems (T6SS) Yes Yes Yes No No 
Transporter type/functionE. coliSalmonellaBacteroidesLactobacillusBifidobacterium
Pore-forming toxins (PFTs) Yes Yes Yes Yes Yes 
ABC-type drug efflux pumps Yes Yes Yes Yes Yes 
Type III protein secretion systems (T3SS) Yes Yes No No No 
Type VI secretion systems (T6SS) Yes Yes Yes No No 

Pore-forming toxins (PFTs) may target neighboring bacterial cells, thus making them important weapons for interbacterial competition [7]. They can give a species a competitive advantage in their respective ecological niche. In addition, these proteins can target host membranes while simultaneously activating a cascade of immune responses, at times resulting in bacterial and/or host cell death [8]. PFTs can be divided into two classes: α-PFTs and β-PFTs, based on the structures of the membrane-spanning regions of the toxins that can consist of either hydrophobic α-helices or amphipathic β-strands, respectively [9]. Numerous PFTs have been studied in the past, being examined from both biochemical and structural standpoints [10‒12].

In the comparative genomic study by Do et al. [3], examining different E. coli strains (c+pr+pa), homologs of PFTs belonging to families of colicins (TC#s 1.C.1 and 1.C.31) and hemolysins, HlyA (TC# 1.C.11), HlyC (TC# 1.C.126), and HlyE (TC# 1.C.10) were most common. The hemolysin, HlyA, is a member of the repeats-in-toxin family, which upon binding to different cell-types, promotes high mitochondrial Ca2+ levels, thus disrupting normal mitochondrial dynamics. This results in impairment of mitochondrial functions by loss of the membrane potential, increased production of reactive oxygen species, and ATP depletion [13]. HlyE is a member of the cytolysin A family. These proteins bind cholesterol and form oligomeric assemblies when bound to the target membrane. In addition, it has been shown that after export from the bacterial cell, the toxin is packaged into outer membrane vesicles for delivery to the host cell plasma membrane in preparation for fusion of the vesicle with the membrane, thus allowing direct entry of the toxin into the host cell cytoplasm [14].

In Salmonella species and many other related pathogenic enteric bacteria, complete bacterial type III secretory systems, T3SSs, are present that target host cells, forming pores in their plasma membranes. This type of system (consisting of a basal region, a needle-like structure and the translocon) enables the transport of effector proteins such as toxins from the bacterial cytoplasm across the inner and outer bacterial membranes and directly into the target cell cytoplasm, thus traversing three membranes in a single energy-coupled step [15]. It should, however, be noted that these systems are also capable of exporting proteins to the external medium instead of into the host cell cytoplasm, and this choice is dependent on the particular protein being transported. The ability to transport effectors across all three of these membranes in a single energy-coupled step is also a characteristic of types IV and VI protein secretion systems (see TCDB for characteristics and descriptions of these systems). It is interesting to note that these systems can also facilitate pathogenesis in plants [16‒18]. In addition, members of the Pore-Forming Amphipathic Helical Peptide (HP2-20) Family (TC# 1.C.82) and the Hemolysin III (Hly III) Family (TC# 1.C.113) may be exported via a similar mechanism. Members of the former family have antibacterial activities [19], and proteins encoded by such strains help them to establish a competitive advantage over other resident species in the intestinal bacterial flora. These proteins additionally possess several important functional characteristics, such as being bactericidal, neutrophil chemo-attractants, and/or activators of phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to produce reactive oxygen species [19]. Members of the Hly III family have strong pore-forming activities that cause lysis of target (i.e., mammalian) cells [20].

Genomic analyses of Bacteroides strains (c+pr+pa) [4] revealed that all of the seven genomes examined encode proteins belonging to the Membrane Attack Complex/Perforin (MACPF) Family, members of which have numerous biological functions [21], including toxicity towards target animal cells. The MACPF domain was originally characterized as a common pore-forming domain present in the immune systems of eukaryotes. Such systems consist of five complement components (C6, C7, C8-α, C8-β, and C9) as well as perforin [22]. Members of the Pore-Forming Amphipathic Helical Peptide (HP2-20) Family were also present in several strains of Bacteroides. Overall, the functionalities of the predicted PFTs in Bacteroides spp. led to an improved understanding of the fact that many of these strains have probiotic characteristics [4].

All of the Lactobacilli (c+pr+pa) included in a study by Zafar and Saier [5], encode proteins of the Hly III Family. This prediction is of high interest as the probiotic strains may also contain these toxins, thus pointing to unrecognized pathogenic mechanisms that may be employed by select probiotic strains. A member of the Pore-Forming Amphipathic Helical Peptide (HP2–20; TC# 1.C.82) Family was predicted in all of the Lactobacillus strains examined, suggestive of at least one mechanism of probiotic potential for these strains.

In the case of Bifidobacterium strains (c+pr+pa) analyzed by Zafar and Saier [6], all species examined had homologs of the pore-forming 6 kilodalton (kDa) early secretory antigenic target (ESAT-6; TC# 1.C.95) protein family. Members of this family function in pathogenic protein secretion. Another hemolysin of the Hly III family was also predicted to be present, thus indicative of another cause of the potential pathogenicity of these species.

Many of the bacterial strains residing in the human gut have numerous PFTs at their disposal. Through these sophisticated and potent virulence factors, pathogenic bacterial species not only gain an interbacterial advantage in their respective tissue locations in the human gut, but also cause potential damage/disease to their hosts. In addition, these toxins may help to decrease the populations of pathogenic spp. in the gut, thus making them essential components of the probiotic arsenal of their bearers.

In the past, there was a lack of knowledge about the structures and functionalities of these toxins. However, recent developments have allowed an understanding of their architectures and functions [23‒27]. Also, recent advances in the identification of the target receptors have helped to allow an understanding of the range of host cells that these toxins could potentially target [28‒31]. Collectively, these molecular insights have enabled the design of therapeutics that interfere with pore formation and can thus be used to treat infections in the future. An overview of the potential PFTs encoded by the major species within the intestinal microbiome is depicted in Figure 1.

Fig. 1.

A majority of the predicted pore-forming toxins (PFTs) in different bacterial strains are shown. A graphical representation of the pore-formation pathway is also shown. PFTs usually bind to specific receptors in the target cell envelope. Subsequently, these toxins concentrate within the membrane and initiate the oligomerization process, which can be accomplished in two ways. (i) In the pathway followed by most β-PFTs, oligomerization starts at the membrane surface, producing intermediate structures known as “pre-pores” which eventually undergo conformational rearrangements that lead to membrane insertion and pore-formation. (ii) In the pathway followed by most α-PFTs, PFT insertion into the membrane occurs in tandem with a sequential oligomerization mechanism, which can lead to the formation of either a partially formed but active pore, or a complete pore structure. The information of the mechanism of action of PFTS is adapted from [12‒14]. The protein database accession numbers (PDB #s) used to reveal the structures of the PFTs are 1CII, 1UJW, 2ZFG, 2HQS, 8ODT, 1XEF, 1QOY, 1XEZ, 2QP2, 1WA8, and 1P0G.

Fig. 1.

A majority of the predicted pore-forming toxins (PFTs) in different bacterial strains are shown. A graphical representation of the pore-formation pathway is also shown. PFTs usually bind to specific receptors in the target cell envelope. Subsequently, these toxins concentrate within the membrane and initiate the oligomerization process, which can be accomplished in two ways. (i) In the pathway followed by most β-PFTs, oligomerization starts at the membrane surface, producing intermediate structures known as “pre-pores” which eventually undergo conformational rearrangements that lead to membrane insertion and pore-formation. (ii) In the pathway followed by most α-PFTs, PFT insertion into the membrane occurs in tandem with a sequential oligomerization mechanism, which can lead to the formation of either a partially formed but active pore, or a complete pore structure. The information of the mechanism of action of PFTS is adapted from [12‒14]. The protein database accession numbers (PDB #s) used to reveal the structures of the PFTs are 1CII, 1UJW, 2ZFG, 2HQS, 8ODT, 1XEF, 1QOY, 1XEZ, 2QP2, 1WA8, and 1P0G.

Close modal

It should be noted that a particular species in any of the bacterial genuses discussed above can be both pathogenic and probiotic, depending on the tissue or site of infection and conditions [1]. However, the PFTs encoded by most of the strains have even greater pathogenic relevance when these microbes translocate to other body locations. Translocation from the gut to extraintestinal locations could be due to a variety of factors [32], but a most important factor could be disruption of the gut barrier (leaky gut) [33].

As PFTs target neighboring bacterial cells and are important for interbacterial competition, they govern the composition and functionality of the gut microbiome. PFTs can provide competitive advantages to certain bacterial species within their ecological niches. Moreover, these toxins can also target host membranes, potentially affecting host health by activating immune responses or causing cell death. Thus, PFTs can influence the gut microbiome’s composition and functionality by directly impacting the viability of different microbial members and interacting with the host’s immune system.

Bacterial spp. have various protein secretion systems (types 1–11) involved in substrate transport, protein exposition at the cell surface, pilus assembly and motility [34]; see also TCDB). In this section we shall focus on the types 1, 3, and 6 secretion systems (T1SS, T3SS, T6SS), that were predicted to be encoded in the different genomes. T1SS (ABC-types) have been found in a large number of Gram-negative and Gram-positive bacterial spp. and contribute mainly to the efflux of drugs and toxins out of the bacterial cell [35]. T1SS have three or four essential structural components: an ABC (ATP-binding cassette)-type integral membrane transporter in the inner membrane, functioning with an energy-generating ATPase (which can either be fused to the inner membrane transport protein or separate from it), a membrane fusion protein (MFP) that crosses the inner membrane and bridges it to the third (or fourth) component of the system, the outer membrane factor (OMF), located in the outer membrane [36]. These three or four protein constituents form a single pore-forming structure that allows proteins and/or drugs to be exported from the cytoplasm across both Gram-negative bacterial membranes. However, the single membrane of a Gram-positive firmicute exports a protein or drug into the external environment via an ABC system that does include a truncated MFP but not an OMF protein. This observation clearly suggests that the functions of the MFP include not only its bridging activity but also one that in conjunction with the inner membrane transporter, is essential for transport activity [37].

In E. coli (c+pr+pa) and Salmonella strains (pa), various drug efflux pumps of the ABC Superfamily (TC# 3.A.1) were predicted. Some of the E. coli strains as well as many Salmonella strains were predicted to encode components homologous to those of the system described under TC# 3.A.1.109.4. This latter system is a biofilm-inducible ABC drug (tobramycin, gentamycin, and ciprofloxacin) resistance pump. It seems to be highly active when bacterial spp. form biofilms and grow within these films [38]. The presence of this type of drug efflux system agrees with past antibiotic resistance studies in which various E. coli and Salmonella strains examined were shown to be more resistant to both aminoglycosides and quinolones [39‒41]. This type of system may be utilized specifically to promote antibiotic resistance during growth in biofilms. Interestingly, all E. coli and Salmonella strains examined contain a homolog of TC# 3.A.1.113.3, which is an efflux pump for microcins (small bacteriocins). These antibacterial peptides are produced mainly by commensal enteric bacteria, and they target and kill enteric pathogenic neighbors, mimicking siderophores that the pathogens use for iron scavenging [42]. The presence of this microcin efflux pump is in agreement with previous studies that suggested that pathogenic E. coli and Salmonella strains can counteract bacteriocins produced by commensal and probiotic neighbors [43].

Type III protein secretion systems (T3SSs) are virulence machines for Gram-negative pathogens which enable them to inject effector proteins directly into the host cell cytoplasm [44]. The effector proteins perform numerous functions in the host cell, such as (i) manipulation of host immune responses, (ii) modifications in the host cytoskeletal dynamics, (iii) hijacking of host signal transduction pathways, and (iv) interrupting vesicle transport and endocytic trafficking, all of which can promote bacterial colonization, survival, and replication [44, 45]. Both Salmonella strains and some of the pathogenic E. coli strains contain homologs of TC# 3.A.6.1.1 (a type III protein secretion complex). This T3SS induces apoptosis-like macrophage cell death through phagosome lysis and subsequent escape into host cell cytoplasm [46].

T6SSs are primarily linked to antibacterial properties; however, they may also target eukaryotic cells (e.g., mammalian cells and fungi) [47]. In this regard, T6SS-secreted effectors have important implications for virulence and infection [48]. All of the E. coli and Salmonella strains examined were predicted to encode homologs of the system with TC# 3.A.23.1.1. This type of system has been studied in Vibrio cholerae (causative agent of cholera), in which the system may target host cells to increase toxicity [49].

All Bacteroides strains (c+pr+pa) examined were predicted to encode proteins of the ABC superfamily, mostly drug exporters. Among these were two macrolide exporters (TC# 3.A.1.122.1, and TC# 3.A.1.122.16), and an enterocin exporter (TC# 3.A.1.122.3). The presence of multiple exporters for macrolides agrees with previous antibiotic resistance studies on select Bacteroides spp. (B. thetaiotaomicron, B. fragilis) [50], in which high levels of resistance were observed. However, the presence of homologs of these exporters in many of the commensal and probiotic strains is highly interesting and warrants future antibiotic resistance studies using these bacteria. As expected, none of the Bacteroides strains encode homologs of T3SSs. Similar to the E. coli and Salmonella strains, all of the Bacteroides strains were predicted to encode components of the T6SS, TC# 3.A.23.5.1.

In the lactobacilli (c+pr+pa) strains, all were predicted to encode ABC multidrug resistance efflux pumps (TC# 3.A.1.134.12), which have been shown to export nisin, gallidermin, bacitracin and β-lactam antibiotics. A few of the strains also contain homologs of TC# 3.A.1.135.8, a multidrug efflux pump that also confers resistance to fluoroquinolones. A review of past studies suggested potential resistance phenotypes in various lactobacilli against a wide range of antibiotics including the ones mentioned above [51]. Similar to the Bacteroides spp., no T3SS was predicted for any of the Lactobacillus strains considered. In the case of the Bifidobacterium strains, a majority seem to encode close homologs of TC# 3.A.1.106.3, which is a dimeric multidrug resistance exporter of nisin and polymyxin. Few of the strains were predicted to encode close homologs of TC# 3.A.1.120.3 that provide resistance to oleandomycin. Past studies have suggested antibiotic resistance patterns in Bifidobacterium species against macrolides [52].

The presence of components of T1SS in a majority of the enteric strains, especially in the pathogenic ones, indicates that many of the strains have resistance mechanisms against numerous antibiotics. By contrast, components of T3SSs were predicted only in the E. coli and Salmonella strains of those examined. The presence of T3SSs has been reported in the past in enteropathogenic and enterohemorrhagic E. coli strains, aiding the bacteria in attachment to host epithelial cells, and translocation of effector proteins into the host cytoplasm. In Salmonella spp., T3SSs have been shown to be associated with intracellular survival of the pathogen, but also in bacterial cell survival in vivo [53]. Thus, these systems seem to play important roles in the pathogenicity of their bearers. Overall, these systems collectively contribute to the ability of the bacteria to adapt to various environments, evade host defenses, and interact beneficially with other microorganisms. Understanding these multifaceted transport systems is crucial for developing strategies to combat bacterial infections. An overview of the secretion systems predicted to be present in the various strains is depicted in Figure 2.

Fig. 2.

The major protein secretion systems predicted to be parts of bacterial transportomes are shown. E. coli and Salmonella strains have members of the ABC Superfamily (TC# 3.A.1) as representatives of the type 1 secretory systems. In the same strains, proteins of the type 3 virulence-related secretory pathway (TC# 3.A.6) and members of the type 6 symbiosis/virulence secretory system (TC# 3.A.23) can be found. These and other bacterial genera (Bacteroides, Lactobacillus, Bifidobacterium) were predicted to primarily encode members of the ABC Superfamily (TC# 3.A.1).

Fig. 2.

The major protein secretion systems predicted to be parts of bacterial transportomes are shown. E. coli and Salmonella strains have members of the ABC Superfamily (TC# 3.A.1) as representatives of the type 1 secretory systems. In the same strains, proteins of the type 3 virulence-related secretory pathway (TC# 3.A.6) and members of the type 6 symbiosis/virulence secretory system (TC# 3.A.23) can be found. These and other bacterial genera (Bacteroides, Lactobacillus, Bifidobacterium) were predicted to primarily encode members of the ABC Superfamily (TC# 3.A.1).

Close modal

Autotransporters are virulence factors that insert into the outer bacterial membrane to form transmembrane β-barrels that export their extracellular protein domains. Autotransporter proteins contain three structural motifs: a signal sequence, a passenger domain, and a putative translocator domain [54]. Interesting recent reports suggest that AT1 proteins may not alone translocate their passenger domains to the outer surface of the outer membrane, but instead may use the β-barrel assembly machinery (BAM complex; TC# 1.B.33) to accomplish this task [55, 56].

Both E. coli and Salmonella strains encode TC# 1.B.12.1.3 homologs which are fibronectin binding proteins, and these systems help the microbes to adhere to host cells. Both types of strains were also predicted to encode close homologs of TC# 1.B.12.2.7, an autotransporter involved in biofilm formation as well as adhesion to collagen I and laminin. The Intimin/Invasin (Int/Inv) family of adhesins (TC# 1.B.54) consists of outer membrane proteins that mediate bacterial attachment to and/or invasion of their host cells [57]. Both E. coli and Salmonella strains were predicted to encode homologs of the aforementioned family.

Of the seven Bacteroides strains examined, five contained homologs of the OMF Family (TC# 1.B.17). The most commonly predicted homologs among these strains were most closely related to TC# 1.B.17.2.6, a putative OM macrolide efflux protein. All of the Bacteroides strains encode homologs of the Intimin/Invasin (Int/Inv) family of adhesins (TC# 1.B.54).

The transportomes of gut bacteria are collections of efficient metabolic/transport machines that can be used by their bearers for numerous physiological functions relevant to both themselves and their hosts. Moreover, transport proteins are important factors in shaping the potential roles (commensal, probiotic or pathogenic) of bacterial residents of the human gut. In this review, we have tried to identify key membrane proteins/transport systems that may have pathogenic effects with the potential to cause or prevent disease. The emergence of novel proteomic techniques with a special consideration of transportomes can certainly be helpful in the future, allowing one to identify more relevant bacterial pathogenic and probiotic transport proteins.

Future research may beneficially focus on more in-depth functional characterizations of transport proteins in intestinal bacteria. This will involve not only identifying these proteins but also understanding the specific molecules they transport and their physiological roles in the gut. It is equally important to consider how the intestinal microbiome influences the functioning of other tissues. Investigating the crosstalk between gut bacteria and the many physiological traits of the host is crucial as several recent publications have suggested [58‒60]. Future studies focusing on how bacterial transportomes contribute to or inhibit host-microbiome interactions, including the exchange of metabolites, signaling molecules, and other bioactive compounds, could lead to insights into the mechanisms underlying health and disease. Exploring the roles of transportomes in dysbiosis (imbalance in the gut microbiome) and associated diseases could become a highly relevant and novel avenue of research. Such studies could include investigating whether alterations in transportomes contribute to conditions such as inflammatory bowel disease, obesity, as well as metabolic and/or psychotic disorders.

Continued advancements in high-throughput sequencing technologies, metabolomics, and bioinformatics will likely enhance our ability to study bacterial transportomes in greater detail than has been possible to date. Of particular note would be the use of artificial intelligence/machine learning approaches which will undoubtedly lead to more comprehensive and detailed analyses of the transport processes and their physiological consequences in various gut bacteria. Understanding the transportomes of beneficial bacteria could open avenues for developing prebiotics and probiotics with enhanced functionalities and efficiencies. Targeting specific transport processes may also provide new opportunities for therapeutic interventions in pathological conditions related to tissue-specific microbiomes. Future studies should explore the possibilities of engineering the transportomes of specific bacteria to enhance their performance in therapeutics, vaccine development and/or industrial applications. This consideration could include the development of bacteria with improved capabilities for nutrient absorption, the production of beneficial metabolites and/or counteracting the harmful effects of pathogens, both bacterial and viral.

The studied transporters, constituting the transportome, have profound implications on the activity, composition, and overall functionality of the gut microbiome. Beyond their role in the export of toxic compounds, peptides, and proteins, these transport systems are likely instrumental in modulating the gut's exometabolome. By influencing the spectrum of metabolites present in the gut environment, transportomes can affect microbial viability, interspecies competition, and symbiosis, thereby shaping the microbiome landscape. This modulation extends to the host-microbe interface, impacting nutrient absorption, immune modulation, and disease susceptibility. The dynamic interaction between bacterial transportomes and the exometabolome not only dictates the microbial community structure but also underpins the metabolic harmony within the mammalian gut ecosystem. Consequently, the transportome’s influence extends beyond mere survival strategies of individual species, playing a pivotal role in the holistic functioning of the gut microbiome, with implications for host health and disease states.

Investigating the ecological consequences of bacterial transportomes, particularly in the gut microbiome ecosystems, may provide insights into how different prokaryotic species cooperate or compete for resources. Understanding these dynamics can contribute to a more holistic view of human/animal microbiomes. Integrating information from transportome studies with data from genomics, transcriptomics, and metabolomics will undoubtedly provide a more comprehensive understanding of the functional aspects of human tissue-specific microbiomes.

The authors have no conflicts of interest to declare.

This review was made possible by NIH Grant #GMO77402.

Both H.Z. and M.H.S. contributed to the conception of this project. H.Z. wrote the original draft. M.H.S. reviewed and edited the manuscript. Both authors approved the manuscript for publication.

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