Introduction

Fungal infections refer to a range of diseases caused by fungi invading the human body. It is estimated that there are between 2. 2 and 3. 8 million different fungal species in the natural world.1 While the majority of these are beneficial to humans, a few can cause various diseases and pose severe threats to public health.2 Fungal infections are an urgent and often overlooked global health risk.3 Incomplete statistics suggest that approximately one billion people globally are affected by fungal infections, resulting in more than 1. 6 million deaths each year,4 with the incidence rising annually.5 Invasive fungal infections are the predominant cause of these fatalities,6 exhibiting mortality rates as high as 90%,7 especially among individuals with weakened immune systems. These infections are primarily linked to pathogens such as Candida, Cryptococcus, and Aspergillus.8 Currently, there are five principal categories of antifungal drugs:9 (1) azoles, (2) echinocandins, (3) polyenes, (4) allylamines, and (5) pyrimidine analogs. Despite these medications can improve symptoms in some patients, they are limited by several factors, including adverse reactions, narrow therapeutic scope, limited targets, and resistance issues among fungi. Particularly, the issue of drug resistance is recognized as an urgent public health crisis that needs immediate attention.10 There is a crucial need for the development of rapid and sustainable treatment options, necessitating a focused effort on the research and development of new medications that offer broader potential applications, especially to combat the escalating problem of resistance.

However, developing safe and effective antifungal drugs poses a formidable challenge. This involves addressing widespread epidemics caused by fungal infections, managing the emergence and spread of drug-resistant strains due to medication misuse, and tackling complications arising from host immune deficiencies.11,12 Natural compounds and bioactive products, especially those derived from plants, have garnered significant attention in the treatment of infectious diseases, due to their stability, efficiency, broad-spectrum activity, and harmlessness to health.13,14 This focus has opened up new perspectives for the development of antifungal drugs.

Garlic (Allium sativum L)., widely utilized in traditional medicine, is frequently selected as a primary treatment for preventing and managing various epidemic diseases.15 It demonstrates broad-spectrum antibacterial and antifungal properties.16 Contemporary research indicates that extracts from garlic are effective in inhibiting the growth of a range of fungi, including species from the genera Candida, Torulopsis, Trichophyton, Cryptococcus, Aspergillus, Microsporum, and Rhodotorula.17 Additionally, when combined with other antifungal agents, garlic can significantly enhance the antimicrobial effectiveness of these treatments.18 The antifungal effects of garlic are primarily attributed to its multiple actions, including inhibiting fungal growth, preventing biofilm formation, boosting immunity, and combating drug resistance, particularly its notable effectiveness against resistant strains.19 However, the specific mechanisms through which garlic counters fungal resistance and its potential for treating fungal infections still require further research and clarification.

Quorum Sensing (QS), a widely studied microbial communication mechanism, plays a pivotal role in both fungal ecology and the resistance to antifungal drugs. This process affects various aspects of fungal behavior, such as growth, biofilm formation, the expression of virulence factors, and the production of secondary metabolites.20–22 It is important to note that reducing gene expression regulated by Quorum Sensing can suppress the formation of fungal biofilms, thereby addressing drug resistance issues. This approach is known as Quorum Sensing Inhibition (QSI).23 Increasingly, scholars believe that targeting QS is an effective strategy for treating fungal infections.24,25 However, synthetic QSIs are limited in clinical application due to their issues with selectivity, cytotoxicity, and instability, prompting more researchers to consider natural products as potential sources for robust and non-toxic new QSIs.26 For example, a study by Vadakkan et al27 showed that while desmodium gangeticum root extract does not have direct antimicrobial activity, it effectively reduces the virulence of chromobacterium violaceum by inhibiting QS, confirming that natural products can effectively target QS to suppress microbial infections.

Among various natural products, garlic has attracted significant attention due to its broad-spectrum antifungal effects and potential QS inhibition. A study by Rasmussen et al28 suggested that garlic extract is an “ideal” QSI, as it not only downregulates the expression of virulence factors but also enhances the sensitivity of biofilms to conventional antibiotics. Moreover, garlic’s widespread availability, low toxicity, and cost-effectiveness further enhance its clinical applicability.29 The QS inhibitory effect of garlic could be a key mechanism underlying its antifungal activity, however, no studies have explored this perspective in depth. This study initially discusses the antimicrobial components and pharmacological effects of garlic, as well as its effects on the QS system, before delving deeper into the antifungal mechanisms of garlic and its potential clinical applications. We discovered that garlic, a natural plant, not only inhibits fungal growth effectively but also boosts the body’s immune response. Importantly, it significantly suppresses fungal resistance, a property likely closely linked to garlic’s modulation of the QS system. Therefore, focusing on the QS system to investigate garlic’s therapeutic effects against fungal infections is crucial. Targeting QS offers fresh perspectives on addressing fungal drug resistance, opening new avenues for the treatment of fungal infections.

Heading Chemical Composition and Antimicrobial Activity of Garlic

Garlic, a shallow-rooted vegetable plant from the Allium genus of the Amaryllidaceae family,30 is extensively utilized in both culinary and medicinal contexts,17 often described as a panacea.31 Pharmacological studies have revealed that garlic is rich in multiple bioactive compounds,32 including allicin (diallyl thiosulfinate), garlic phenols, diallyl sulfide, diallyl disulfide, diallyl trisulfide, ajoene, and S-allyl cysteine (Figure 1). These compounds exhibit a range of biological activities such as antifungal, antioxidant, anti-inflammatory, antiproliferative, antiviral, immunomodulatory, lipid-lowering, and anti-tumor effects.33,34

Figure 1 The chemical composition of garlic.

Garlic is hailed as a “natural broad-spectrum antimicrobial”,16 with its antimicrobial activity primarily attributed to allicin.35 The chemical structure of allicin is CH2=CH-CH2-S(=O)-S-CH2-CH=CH2. Allicin is an active component formed by the decomposition of alliin under the catalysis of alliinase36 (Figure 2). It displays considerable antibacterial, antifungal, antiparasitic, and antiviral properties,37 and also has the capability to effectively alleviate inflammatory responses.38

Figure 2 The conversion of alliin to allicin in garlic starts with a sulfur-containing amino acid called alliin. When garlic is minced or crushed, alliin interacts with an enzyme present in garlic known as alliinase. This interaction initiates a chemical reaction that transforms alliin into allicin, a compound that not only suppresses fungal growth but also demonstrates antibacterial and anti-inflammatory properties.

Studies have shown that fungi are highly susceptible to allicin.39 Both allicin and garlic extracts have been demonstrated to effectively kill various fungi, including Trichophyton rubrum,40 Aspergillus versicolor,41 Candida albicans,42 Sporothrix schenckii,43 Phytophthora capsici,31 Phytophthora nicotianae,44 Penicillium funiculosum45 and Meyerozyma guilliermondii46 (Table 1). Garlic is now extensively employed in the management of a variety of fungal-related diseases such as skin fungal infections,47 denture stomatitis (DS),48 Fusarium keratitis,49 and fungal pulmonary diseases.50

Table 1 Inhibitory Effects of Active Ingredients of Garlic on Different Fungi (Partial Overview)

A New Strategy for Treating Fungal Infections: QS in Fungal Species

QS was first introduced and defined by Fuqua and others in 1994 in bacteria,54 QS is a widespread cell-to-cell communication mechanism that is prevalent among various microbes, characterized by the release of signaling molecules known as Quorum Sensing Molecules (QSMs). These molecules coordinate microbial metabolism and gene expression in a synchronous manner.55 QS is involved in a variety of biological behaviors, including virulence factor production, motility, symbiosis, adhesion, the development of antibiotic resistance, sporulation, and biofilm creation.56,57 The role of QS in bacteria is widely acknowledged by researchers,58 and it has been recognized as a potential therapeutic target for bacterial infections such as Pseudomonas aeruginosa59 and Staphylococcus aureus.60 However, its role in fungi remains poorly understood.

Already in 1955, Allen61 observed that in the Puccinia graminis, the density of the population affects the fungal morphology and suppresses spore germination. Kügler and et al62 were the first to associate fungi with the term “quorum sensing”, unveiling the QS phenomenon in fungi. The signaling mechanism is remarkably similar to that of bacteria and primarily involves four steps:63 (1) the generation of signaling molecules; (2) secretion of signal molecules; (3) recognition by receptors when the concentration of signal molecules reaches a threshold; (4) initiation of target gene expression. Studies have demonstrated that a range of fungi, including Candida albicans,64 Cryptococcus neoformans,55 Saccharomyces cerevisiae,65 Neurospora crassa,66 and Ophiostoma floccosum,67 are influenced by quorum sensing mechanisms.

Fungi regulate various crucial biological processes such as pathogenicity, resistance, morphological development, and secondary metabolism through the production of QSMs, which are influenced by community density.68 At present, the quorum sensing system in fungi has confirmed several QSMs such as farnesol,69 aromatic alcohols,70 tyrosol,64 tryptophol,23 and phenylethanol.71 These molecules are pivotal in regulating the formation of fungal mycelia, morphogenesis, and biofilms,72,73 with farnesol being the earliest identified74 (Figure 3). According to research by Wongsuk et al, QSMs not only influence spore germination but also initiate programmed cell death or apoptosis, playing a role in fungal pathogenicity.24

Figure 3 The production of quorum-sensing molecules and quorum-sensing inhibitors and their roles in different cell types.

Albuquerque et al72 argue that targeting QS could enhance the development of antifungal therapies. Quorum quenching (QQ) disrupts the QS systems among microbes, significantly reducing or even completely suppressing the production of microbial virulence factors, including biofilm formation.75 QSIs that exhibit QQ properties are increasingly being discovered and have emerged as a key area in microbial management.76 QSIs offer an effective solution to alleviate microbial resistance compared to traditional antimicrobial drugs. QSIs operate through three main mechanisms:77 First, blocking the synthesis of QS signaling molecules; Second, inhibiting the intercellular exchange and transport of QS signals; and third, suppressing the detection and response to QS signals. Although extensive research has been conducted on QSIs, the stability and effectiveness of artificially synthesized QSIs are suboptimal. Moreover, their potential toxicity restricts their application. Therefore, seeking potent, natural, and non-toxic new QSIs from natural products appears to be a promising direction for future efforts.

Potential Mechanisms of Garlic in Treating Fungal Infections

QS is a mechanism by which microbes coordinate behavior through the production and detection of signaling molecules. It plays a role in many critical biological processes, including biofilm maturation, immune evasion, and drug tolerance, providing microbial populations with enhanced survival rates.20 Garlic, a natural compound with dual roles in food and medicine, is recognized as an ideal QSI.28 It combats various fungal species by inhibiting fungal growth, exhibiting anti-biofilm properties, boosting immune responses, and reducing the development of resistance, thus effectively curbing fungal infections (Figure 4). The crucial aspect of garlic’s anti-resistance properties is its QSI effect.

Figure 4 Potential Mechanisms of Garlic in the Treatment of Fungal Infections.

Anti-Fungal Growth

Garlic has demonstrated antifungal properties against a range of fungal genera. Research by Yamada et al has shown that allicin, a compound in garlic, is effective in vitro against genera such as Candida, Cryptococcus, Trichophyton, Epidermophyton, and Microsporum, with inhibitory concentrations ranging from approximately 1. 57 to 6. 25 μg/mL.51 Allicin, the primary antimicrobial agent found in garlic, displays biological activity across microbial, plant, and mammalian cells. It acts in a dose-dependent fashion to inhibit fungal growth or directly kill cells.78

Allicin is highly hydrophobic, allowing it to rapidly diffuse across various phospholipid membranes.79 This property allows allicin to easily traverse cell membranes, be taken up by exposed cells, and directly interact with molecules within the organism.80 When pathogenic microorganisms come into contact with allicin, it alters their cell membrane permeability, which disrupts the structural integrity of the cells and ultimately leads to cell death.81 Allicin’s primary mechanism for inhibiting microbial growth involves its molecules penetrating the cell membrane, where its oxygen atoms react with the thiol groups in cysteine or deactivate thiol-based enzymes within the pathogens.82 Furthermore, allicin’s S-(O)-S groups react with -SH group-containing proteins in pathogens, forming mixed disulfides that inhibit microbial growth.83

Moreover, allicin allicin inhibits spore germination and mycelial growth under both in vivo and in vitro conditions.39 Extracts from fresh garlic reduce the expression of SIR2 in Candida albicans,84,85 a gene essential for its mycelial growth.86 Allicin’s ability to inhibit the development of Candida albicans mycelia matches or surpasses that of fluconazole.85 Studies have shown that Trichophyton rubrum treated with allicin or garlic extract exhibits cytoplasmic disintegration/degradation, with damage to the cell walls and membranes, leading to mycelial fragmentation.87

Anti-Biofilm Activity

Garlic’s anti-biofilm activity is widely acknowledged, with its effectiveness likely stemming from the disruption of quorum sensing mechanisms. Biofilms are resilient communities of microbes88 that strongly adhere to microbial surfaces and each other, shielding the microbes from antibiotics and the immune system.89,90 They are a principal factor in the development of antibiotic resistance during microbial infection treatments91 and contribute to persistent92 and recurrent infections.93 Interrupting any phase of the biofilm formation process, whether attachment, maturation, or dispersal, can significantly diminish microbial virulence.94

Biofilms are primarily composed of microbial cells and the extracellular polymeric substances (EPS) they secrete.95 EPS includes extracellular polysaccharides that provide cohesion and adhesion sites, proteins that serve as carbon and energy sources, and extracellular DNA (eDNA) that facilitates the dissemination of resistance genes.96 The secretion of EPS encourages individual bacteria to exhibit behaviors that either aid or harm nearby cells, and influences the evolutionary dynamics of the biofilm to balance individual and community interests.97 EPS forms the biofilm matrix, which protects microorganisms from the host’s immune system and antifungal agents, playing a crucial role in the development of resistance.98 According to the research by Xavier et al,99 EPS secretion typically increases in mixed bacterial populations, strengthening the biofilm’s structure and stability. Therefore, inhibiting EPS secretion can effectively prevent the formation of biofilms.100

The secretion of EPS is regulated by QS, which enables microorganisms to toggle EPS production on or off.101 QS is pivotal in biofilm formation,102,103 and pathogenic bacteria within biofilms can leverage QS to activate virulence factors, both of which contribute to the development of resistance.104 QQ can inhibit microbial biofilm formation by disrupting QS signals, thereby decreasing the potential for resistance development.105 As a quorum-sensing inhibitor, garlic not only effectively diminishes microbial pathogenicity28 but also inhibits biofilm formation to combat microbial resistance.106 The anti-biofilm efficacy of garlic has been demonstrated in several microorganisms, including Candida albicans,107 Escherichia coli,108 and Proteus mirabilis.109 Garlic has shown positive antibacterial effects through QSI in vitro, in animal models, and in clinical trials.20 This points to a promising new therapeutic approach for tackling antibiotic resistance. Research by Li et al110 has demonstrated that garlic can increase the sensitivity of multiple drug-resistant strains, including Candida albicans and methicillin-resistant Staphylococcus aureus (MRSA), to antibiotics.

Additionally, allicin, a compound in garlic, can exert anti-biofilm effects by downregulating genes associated with biofilm formation. Research by Xiong et al111 demonstrated that allicin reduces the expression of key biofilm-related genes in Candida albicans, including HWP1, ALS1, ALS3, MP65, and SUN41, effectively inhibiting biofilm formation. Furthermore, the earlier allicin is introduced, the more significant its biofilm-inhibiting effects. In conclusion, garlic exhibits significant anti-biofilm effects through its QSI activity and gene regulatory mechanisms. This effectiveness has been validated in fungi, indicating substantial potential for the clinical treatment of fungal infections.

Enhancing Immune Response

Immunity plays a vital role in protecting humans against fungal diseases.112 When the immune system is significantly compromised, fungi, as opportunistic pathogens, can cause severe infections, especially invasive fungal infections.113 Enhancing immune responses is critical in the treatment of fungal infections.114,115 Garlic, recognized for stabilizing the immune system, typically exerts beneficial effects on immune functions.116,117 It primarily boosts immunity by activating various immune cells, including macrophages, lymphocytes, natural killer (NK) cells, dendritic cells, and eosinophils.118

The existing research indicates that Aged Garlic Extract (AGE) promotes the proliferation of γδ-T cells and NK cells, thereby improving the host’s immune cell function;119 specifically, the protein component F4 within AGE has been identified as an effective immune booster;117 other chemical components in garlic also help enhance the functions of macrophages and T lymphocytes.120 Additionally, experimental research by Zamani et al has demonstrated that a water-soluble extract of garlic enhances the proliferation of lymphocytes in the thymus and spleen of rats.121 This further confirms the potential of garlic to modulate immune responses.

Suppressing Resistance

In recent years, the extensive use of antifungal drugs has significantly heightened resistance among fungi.122 This resistance manifests as increased minimum inhibitory concentrations (MICs), which results in reduced drug efficacy and an inability to effectively suppress infections.123 It represents one of the primary causes of persistent fungal infections124 and has emerged as a major medical challenge.125

Choo et al18 have identified that using allicin in combination with other antimicrobial drugs offers a potent strategy to combat increasing antimicrobial resistance. When allicin is paired with azole compounds such as fluconazole or ketoconazole, it generates a synergistic effect that lowers the MICs of fungal strains, thereby reducing their resistance.126 This demonstrates that the active ingredients in garlic are effective in curbing fungal resistance. The inhibitory effect is multifaceted (Figure 4): 1. Allicin can directly influence fungal growth, reducing their exposure and selective pressure, thus lowering the likelihood of resistance development. 2. Allicin boosts the body’s immune response, which in turn aids in more effective combat against infections, indirectly mitigating the emergence of resistance. According to Bicer et al,127 exosomes that possess immunomodulatory characteristics can counteract fungal resistance. 3. Most importantly, allicin significantly inhibits fungal biofilms. The effectiveness of garlic in inhibiting biofilm formation is now widely recognized and is likely achieved through QQ mechanisms. Biofilm formation alters the sensitivity of fungi to antifungal drugs128 and is considered an ideal target for antifungal therapy, offering a promising solution to the problem of drug resistance.129,130 EPS, a major component of biofilms, is considered crucial in the development of drug resistance.131 Notably, QS, an intercellular communication system, regulates EPS secretion and activates virulence, thereby contributing to resistance.101,104 Thus, garlic’s ability to inhibit QS may be key to overcoming fungal drug resistance.

From Bench to Bedside: The Antifungal Effects of Garlic

Garlic and its derivatives have demonstrated impressive antifungal effects in both laboratory research and clinical applications. These effects not only inhibit fungal growth but also aid in preventing the development of fungal resistance.

Laboratory studies have shown that the active compounds in garlic can inhibit fungal infections at multiple levels, including spore germination, biofilm growth, cell wall synthesis, metabolism, and oxidative stress. Additionally, these compounds exhibit synergistic effects when combined with antifungal drugs. For example, Schier et al132 found that both allicin solution and vapor can inhibit the germination of Mucorales fungi, with half-maximal effective concentrations (EC50) being 25–72 times lower than those for fungal spores. Allicin also demonstrated synergistic effects with amphotericin B (ampB), and in direct contact, allicin was even more effective than ampB at inhibiting spore germination. Research by Yang et al133 demonstrated that allicin effectively inhibits the growth of T. asahii planktonic cells and biofilm cells significantly; In vivo, allicin increased the average survival time of mice with systemic trichosporonosis and decreased the fungal burden in their tissues; Electron microscopy revealed that allicin causes significant morphological damage to T. asahii cells, including structural disorganization and irregular plasma membranes. These findings indicate that allicin disrupts fungal processes on multiple levels, including the cell membrane, cell wall, glucose metabolism, and oxidative stress response.

Recently, an increasing number of researchers have explored the potential application of garlic in treating various fungal infections in clinical studies. For example, Schier et al50 simulated airflow conditions in the human lung in vitro and discovered that allicin can inhibit fungal spore germination through direct contact or vapor transmission. These findings suggest that allicin could be a promising candidate for treating fungal infections in the lungs and upper respiratory tract. Watson et al134 have used garlic tablets to treat vulvovaginal candidiasis (VVC), with some patients experiencing significant improvement. Their in-depth research revealed that treatment with fresh garlic extract and pure allicin led to the downregulation of the SIR2 gene expression in all strains, and pure allicin treatment also inhibited ECE1 expression. These findings suggest that garlic and its derivatives may alleviate VVC symptoms by downregulating key virulence genes.135

Summary and Discussion

Over the past few decades, the risk of fungal infections has significantly increased due to the widespread use of antimicrobial drugs, the routine application of immunosuppressive therapy following organ transplants, and cancer treatments involving radiation and chemotherapy.136 Furthermore, fungal resistance has significantly escalated on a global scale.137 However, current antifungal therapies are limited and have not effectively tackled the issue of resistance.138 This poses severe challenges to antifungal treatment, making it a critical clinical problem that urgently needs to be addressed.

Targeting quorum sensing is considered a highly promising therapeutic strategy. QS is a communication mechanism among microorganisms, where a single microbe can possess multiple QS systems and produce various QS signal molecules to coordinate or regulate their biological functions.139 QS regulates the production and expression of fungal virulence factors, biofilm formation, and drug resistance.21,140,141 Disrupting QS can inhibit hyphal formation, reduce the expression of fungal virulence factors, and prevent biofilm formation, effectively decreasing resistance.142 However, the development of QSI drugs still faces significant challenges.

Garlic is considered an “ideal” natural QSI drug and has been widely used to treat infectious diseases for centuries due to its medicinal properties. Both laboratory and clinical studies have demonstrated garlic’s significant antifungal efficacy. This antimicrobial effect is achieved through various mechanisms, including inhibiting fungal growth, exhibiting anti-biofilm activity, enhancing immune responses, and reducing resistance. Most notably, garlic’s ability to combat resistance offers an effective solution to this issue, with the core mechanism being the inhibition of the QS system.

Additionally, garlic’s chemical composition is complex, and its processing methods can influence the efficacy and safety of its active components.143,144 Therefore, finding effective ways to preserve garlic’s antifungal properties has become a crucial area of research. Currently, scientists are actively investigating how to combine garlic’s active components with modern technology to enhance its antimicrobial efficacy. Silver nanoparticles (AgNPs) are a rapid, environmentally friendly, and sustainable synthesis method that exhibits exceptional antibacterial properties.145 Notably, when used in combination with garlic extract.146 For example, A study by Vijayakumar et al147 revealed that using garlic clove extract with silver nanoparticles (G-AgNPs) significantly enhanced antibacterial and anti-biofilm activities against key clinical pathogens, including MRSA and Pseudomonas aeruginosa. Robles-Martínez et al40 discovered that the combination of allicin and G-AgNPs effectively inhibited the growth of Trichophyton rubrum. Remarkably, even at a low concentration of 0. 4 μg/mL, allicin was able to completely inhibit the growth of this fungus. Additionally, Tomsik et al148 utilized spray congealing technology to encapsulate wild garlic extract, significantly enhancing the solubility, bioavailability, and stability of garlic’s active components without compromising their antimicrobial properties. These findings underscore the potential of garlic in the antimicrobial field, particularly when combined with modern technology, which can greatly enhance its effects. Building on the research of Vijayakumar,147 Tomsik,148 and others, developing more straightforward and cost-effective methods to improve garlic’s bioavailability seems to be a promising direction for future efforts.

In conclusion, QS is a critical target in fungal infections, closely related to biofilm formation and the development of drug resistance. Targeting QS can effectively address the challenge of fungal resistance. Garlic, a natural QSI, has been widely recognized for its therapeutic effects on fungal infections. It effectively inhibits fungal resistance, and its mechanism of action is closely related to QS. These discoveries provide novel and valuable insights into the treatment and prognosis of fungal infections. However, the clinical application of garlic still faces some challenges. Firstly, there may be variability in the potency of bioactive compounds, the composition of garlic extracts can differ significantly between batches, and different application methods may influence their clinical efficacy. In addition, although natural QSIs are generally considered to have low toxicity, their potential toxicity with long-term use remains to be further assessed. Therefore, optimizing the activity, stability, and safety of natural QSIs, as well as ensuring their consistency in clinical applications, are critical issues that need to be addressed in future research. Future studies should focus on the following directions: 1) Investigating the specific mechanisms through which garlic modulates QS; 2) Conducting clinical trials to evaluate the effectiveness and safety of garlic in treating various refractory fungal infections; 3) Optimizing garlic-derived formulations by utilizing modern technologies such as AgNPs and spray-drying techniques to improve drug release efficiency and enhance antifungal activity; 4) Promoting interdisciplinary collaboration across fields such as biology, chemistry, and medicine to explore and develop more efficient QSIs, providing new strategies and broader applications for antifungal therapy.

Consent for Publication

All authors have consented to the publication.

Funding

The present study was financially supported by the National Natural Science Foundation of China (No. 81973840), Sichuan Provincial Administration of Traditional Chinese Medicine Major Science and Technology project (2021XYCZ004).

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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