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Research article

MiR-608 rs4919510 C>G polymorphism increased the risk of bladder cancer in an Iranian population

  • Received: 21 September 2016 Accepted: 08 November 2016 Published: 10 November 2016
  • MicroRNAs (miRNAs) participate in diverse biological pathways and may act as oncogenes or tumor suppressors. The single nucleotide polymorphisms (SNPs) in miRNAs potentially can alter miRNA-binding sites on target genes as well as affecting miRNAs expression. The present study aimed to evaluate the impact of miR-608 rs4919510 C>G variant on bladder cancer risk. This case-control study conducted on 233 bladder cancer patients and 252 healthy subjects. Genotyping of miR-608 rs4919510 was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings showed that CG as well as CG+GG genotypes significantly increased the risk of bladder cancer (OR = 1.94, 95% CI = 1.28–2.94, p = 0.002, and OR = 1.90, 95% CI = 1.26–2.86, p = 0.002, respectively) compared to CC genotype. The G allele significantly increased the risk of bladder cancer compared to C allele (OR = 1.69, 95% CI = 1.17–2.45, p = 0.005). Our findings proposed that miR-608 polymorphism might be associated with increased risk of bladder cancer in a sample of Iranian population. Further large-scale studies with different ethnicities are needed to verify our findings

    Citation: Mohammad Hashemi, Fatemeh Bizhani, Hiva Danesh, Behzad Narouie, Mehdi Sotoudeh, Mohammad Hadi Radfar, Mehdi Honarkar Ramezani, Gholamreza Bahari, Mohsen Taheri, Saeid Ghavami. MiR-608 rs4919510 C>G polymorphism increased the risk of bladder cancer in an Iranian population[J]. AIMS Genetics, 2016, 3(4): 212-218. doi: 10.3934/genet.2016.4.212

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  • MicroRNAs (miRNAs) participate in diverse biological pathways and may act as oncogenes or tumor suppressors. The single nucleotide polymorphisms (SNPs) in miRNAs potentially can alter miRNA-binding sites on target genes as well as affecting miRNAs expression. The present study aimed to evaluate the impact of miR-608 rs4919510 C>G variant on bladder cancer risk. This case-control study conducted on 233 bladder cancer patients and 252 healthy subjects. Genotyping of miR-608 rs4919510 was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings showed that CG as well as CG+GG genotypes significantly increased the risk of bladder cancer (OR = 1.94, 95% CI = 1.28–2.94, p = 0.002, and OR = 1.90, 95% CI = 1.26–2.86, p = 0.002, respectively) compared to CC genotype. The G allele significantly increased the risk of bladder cancer compared to C allele (OR = 1.69, 95% CI = 1.17–2.45, p = 0.005). Our findings proposed that miR-608 polymorphism might be associated with increased risk of bladder cancer in a sample of Iranian population. Further large-scale studies with different ethnicities are needed to verify our findings


    In this paper, we investigate the existence of a least energy sign-changing solution for the following fractional p-Laplacian problem:

    (Δ)sN/su+V(x)|u|Ns2u=f(u)  in RN, (1.1)

    where s(0,1), 2<Ns:=p, (Δ)sp is the fractional p-Laplacian operator which, up to a normalizing constant, may be defined by setting

    (Δ)spu(x)=2limε0+RNBε(x)|u(x)u(y)|p2(u(x)u(y))|xy|N+psdy, xRN

    along functions uC0(RN), where Bε(x) denotes the ball of RN centered at xRN and radius ε>0. In addition, the potential VC(RN,R), the nonlinear f has exponential critical growth, and such nonlinear behavior is motivated by the Trudinger-Moser inequality (Lemma 2.2).

    Recently, the study of nonlocal problems driven by fractional operators has piqued the mathematical community's interest, both because of their intriguing theoretical structure and due to concrete applications such as obstacle problems, optimization, finance, phase transition, and so on. We refer to [18] for more details. In fact, when p=2, problem (1.1) appears in the study of standing wave solutions, i.e., solutions of the form ψ(x,t)=u(x)eiωt, to the following fractional Schrödinger equation:

    iψt=2(Δ)sψ+W(x)ψf(|ψ|) in RN×R, (1.2)

    where is the Planck constant, W:RNR is an external potential, and f is a suitable nonlinearity. Laskin [25,26] first introduced the fractional Schrödinger equation due to its fundamental importance in the study of particles on stochastic fields modeled by Lévy processes.

    After that, remarkable attention has been devoted to the study of fractional Schrödinger equations, and a lot of interesting results were obtained. For the existence, multiplicity and behavior of standing wave solutions to problem (1.2), we refer to [1,9,10,14,19,33] and the references therein.

    For general p with 2<p<Ns, problem (1.1) becomes the following fractional Laplacian problem:

    (Δ)spu+V(x)|u|p2u=f(u) in RN. (1.3)

    We emphasize that the fractional p-Laplacian is appealing because it contains two phenomena: the operator's nonlinearity and its nonlocal character. In fact, for the fractional p-Laplacian operator (Δ)sp with p2, one cannot obtain a similar equivalent definition of (Δ)sp by the harmonic extension method in [10]. For those reasons, the study of (1.3) becomes attractive. In [13], the authors obtained infinitely many sign-changing solutions of (1.3) by using the invariant sets of descent flow. Moreover, they also proved (1.3) possesses a least energy sign-changing solution via deformation Lemma and Brouwer degree. We stress that, by using a similar method, Wang and Zhou [35], Ambrosio and Isernia [3] obtained the least energy sign-changing solutions of (1.3) with p=2. For more results involving the fractional p-Laplacian, we refer to [2,17,20,21,32] and the references therein.

    Another motivation to investigate problem (1.1) comes from the fractional Schrödinger equations involving exponential critical growth. Indeed, we shall study the case where the nonlinearity f(t) has the maximum growth that allows us to treat problem (1.1) variationally in Ws,Ns(RN) (see the definition in (1.5)). If p<Ns, Sobolev embedding (Theorem 6.9 in [18]) states Ws,p(RN)Lps(RN), where ps=NpNsp, and ps is called the critical Sobolev exponent. Moreover, the same result ensures that Ws,Ns(RN)Lλ(RN) for any λ[Ns,+). However, Ws,Ns(RN) is not continuously embedded in L(RN) (for more details, we refer to [18]). On the other hand, in the case p=Ns, the maximum growth that allows us to treat problem (1.1) variationally in Sobolev space Ws,Ns(RN), which is motivated by the fractional Trudinger-Moser inequality proved by Ozawa [30] and improved by Kozono et al. [23] (see Lemma 2.2). More precisely, inspired by [23], we say that f(t) has exponential critical growth if there exists α0>0 such that

    lim|t|f(t)exp(α|t|NNs)={0,  for α>α0,+,  for α<α0.

    On the basis of this notation of critical, many authors pay their attention to investigating elliptic problems involving the fractional Laplacian operator and nonlinearities with exponential growth. When N=1,s=12, p=2 and replacing R by (a,b), problem (1.1) becomes the following fractional Laplacian equation:

    {(Δ)12u=f(u) in (a,b),u=0 in R(a,b). (1.4)

    When f is o(|t|) at the origin and behaves like exp(αt2) as |t|, by virtue of the Mountain Pass theorem, Iannizzotto and Squassina [22] proved the existence and multiplicity of solutions for (1.4). Utilizing the constrained variational methods and quantitative deformation lemma, Souza et al. [16] considered the least energy sign-changing solution of problem (1.4) involving exponential critical growth.

    For problem (1.1) with exponential critical growth nonlinearity f, we would like to mention references [8,27,34]. In [27], by applying variational methods together with a suitable Trudinger-Moser inequality for fractional space, the authors obtained at least two positive solutions of (1.1). In [8], the authors considered problem (1.1) with a Choquard logarithmic term and exponential critical growth nonlinearity f. They proved the existence of infinite many solutions via genus theory. In [34], by using Ljusternik-Schnirelmann theory, Thin obtained the existence, multiplicity and concentration of nontrivial nonnegative solutions for problem (1.1). For more recent results on fractional equations involving exponential critical growth, see [8,15,16,22,27,31,34] and the references therein. We also refer the interested readers to [11,29] for general problems with Trudinger-Moser-type behavior.

    Inspired by the works mentioned above, it is natural to ask whether problem (1.1) has sign-changing solutions when the nonlinearity f has exponential critical growth. To our knowledge, there are few works on it except [16]. Souza et al. [16] considered the case when N=1,p=2 and s=12. However, compared with [16], the situation when p>2 is quite different. In particular, the decomposition of functional I (see the definition in (1.8)) is more difficult than that in [16]. Therefore, some difficulties arise in studying the existence of a least energy sign-changing solution for problem (1.1), and this makes the study interesting.

    In order to study problem (1.1), from now on, we fix p=Ns, p=pp1=NNs and consider the following assumptions on V and f :

    (V) V(x)C(RN) and there exists V0>0 such that V(x)V0 in RN. Moreover, lim|x|V(x)=+;

    (f1) The function fC1(R) with exponential critical growth at infinity, that is, there exists a constant α0>0 such that

    lim|t||f(t)|exp(α|t|p)=0  for α>α0andlim|t||f(t)|exp(α|t|p)=  for α<α0;

    (f2) limt0|f(t)||t|p1=0;

    (f3) There exists θ>p such that

    0<θF(t)tf(t) for tR{0},

    where F(t)=t0f(s)ds; (f4)

    There are two constants q>p and γ>1 such that

    sgn(t)f(t)γ|t|q1 for tR;

    (f5) f(t)|t|p1 is an increasing function of tR{0}.

    Before stating our results, we recall some useful notations. The fractional Sobolev space Ws,p(RN), where p=Ns, is defined by

    Ws,p(RN):={uLp(RN):[u]s,p<}, (1.5)

    where [u]s,p denotes Gagliardo seminorm, that is,

    [u]s,p:=( R2N|u(x)u(y)|p|xy|N+psdxdy)1p.

    Ws,p(RN) is a uniformly convex Banach space (see [18]) with norm

    uWs,p=(upLp(RN)+[u]ps,p)1p.

    Let us consider the work space

    X:={uWs,p(RN):RNV(x)|u|pdx<+}, (1.6)

    with the norm

    uX:=([u]ps,p+RNV(x)|u|pdx)1p.

    X is a uniformly convex Banach space, and thus X is a reflexive space. By the condition (V), we have that the embedding from X into Ws,p(RN) is continuous.

    Definition 1.1. We say that uX is a weak solution of problem (1.1) if

    R2N|u(x)u(y)|p2(u(x)u(y))(φ(x)φ(y))|xy|N+psdxdy+RNV(x)|u(x)|p2u(x)φ(x)dx=RNf(u(x))φ(x)dx (1.7)

    for all φX.

    Define the energy functional I:XR associated with problem (1.1) by

    I(u)=1pR2N|u(x)u(y)|p|xy|N+psdxdy+1pRNV(x)|u|pdxRNF(u)dx. (1.8)

    By the Trudinger-Moser type inequality in [23] (see Lemma 2.2), we prove that I(u)C1(X,R), and the critical point of functional I is a weak solution of problem (1.1) (see Remark 2.2 in Section 2).

    For convenience, we consider the operator A:XX given by

    A(u),vX,X=R2N|u(x)u(y)|p2(u(x)u(y))(v(x)v(y))|xy|N+psdxdy+RNV(x)|u|p2uvdx, u,vX, (1.9)

    where X is the dual space of X. In the sequel, for simplicity, we denote ,X,X by ,. Moreover, we denote the Nehari set N associated with I by

    N={uX{0}:I(u),u=0}. (1.10)

    Clearly, N contains all the nontrivial solutions of (1.1). Define u+(x):=max{u(x),0} and u(x):=min{u(x),0}, and then the sign-changing solution of (1.1) stays on the following set:

    M={uX{0}:u±0, I(u),u+=0, I(u),u=0}. (1.11)

    Set

    c:=infuNI(u), (1.12)

    and

    m:=infuMI(u). (1.13)

    Now, we can state our main results.

    Theorem 1.1. Assume that (V) and (f1) to (f5) hold, and then problem (1.1) possesses a least energy sign-changing solution uX, provided that

    γ>γ:=[θpmqθp(α0α)p1]qpp>0,

    where α is a constant defined in Lemma 2.2,

    mq=infuMqIq(u), Mq={uX:u±0,Iq(u),u±=0},

    and

    Iq(u)=1pupX1qRN|u|qdx.

    The proof of Theorem 1.1 is based on the arguments presented in [7]. We first check that the minimum of functional I restricted on set M can be achieved. Then, by using a suitable variant of the quantitative deformation Lemma, we show that it is a critical point of I. However, due to the nonlocal term

    1pR2N|u(x)u(y)|p|xy|N+psdxdy,

    the functional I no longer satisfies the decompositions

    I(u)=I(u+)+I(u)andI(u),u±=I(u±),u±, (1.14)

    which are very useful to get sign-changing solutions of problem (1.1) (see for instance [4,5,6,7,12]). In fact, due to the fractional p-Laplacian operator (Δ)sp with s(0,1) and p2, one cannot obtain a similar equivalent definition of (Δ)sp by the harmonic extension method (see [10]). In addition, compared with [16], problem (1.1) contains nonlocal operator (Δ)sp with p>2, which brings some difficulties while studying problem (1.1). In particular, for problem (1.4), one has the following decomposition:

    J(u)=J(u+)+J(u)+R2Nu+(x)u(y)u(x)u+(y)|xy|N+2sdxdy,J(u),u+=J(u+),u++R2Nu+(x)u(y)u(x)u+(y)|xy|N+2sdxdy, (1.15)

    where J is the energy functional of (1.4). However, for the energy functional I, it is impossible to obtain a similar decomposition like (1.15) due to the nonlinearity of the operator (Δ)sp. In order to overcome this difficulty, we divide R2N into several regions (see Lemma 2.6) and decompose functional I on each region carefully. Furthermore, another difficulty arises in verifying the compactness of the minimizing sequence in X since problem (1.1) involves the exponential critical nonlinearity term. Fortunately, thanks to the Trudinger-Moser inequality in [23], we overcome this difficulty by choosing γ in assumption (f4) appropriately large to ensure the compactness of the minimizing sequence. To achieve this, a more meticulous calculation is needed in estimating m.

    On the other hand, by a similar argument in [13], we also consider the energy behavior of I(u) in the following theorem, where u is the least energy sign-changing solution obtained in Theorem 1.1.

    Theorem 1.2. Assume that (V) and (f1) to (f4) are satisfied. Then, c>0 is achieved, and

    I(u)>2c,

    where u is the least energy sign-changing solution obtained in Theorem 1.1.

    The paper is organized as follows: Section 2 contains the variational setting of problem (1.1), and it establishes a version of the Trudinger-Moser inequality for (1.1). In Section 3, we give some technical lemmas which will be crucial in proving the main result. Finally, in Section 4, we combine the minimizing arguments with a variant of the Deformation Lemma and Brouwer degree theory to prove the main result.

    Throughout this paper, we will use the following notations: Lλ(RN) denotes the usual Lebesgue space with norm ||λ; C,C1,C2, will denote different positive constants whose exact values are not essential to the exposition of arguments.

    In this section, we outline the variational framework for problem (1.1) and give some preliminary Lemmas. For convenience, we assume that V0=1 throughout this paper. Recalling the definition of fractional Sobolev space X in (1.6), we have the following compactness results.

    Lemma 2.1. Suppose that (V) holds. Then, for all λ[p,), the embedding XLλ(RN) is compact.

    Proof. Define Y=Lλ(RN) and BR={xRN:|x|<R},BcR=RN¯BR. Let X(Ω) and Y(Ω) be the spaces of functions uX,uY restricted onto ΩRN respectively. Then, it follows from Theorems 6.9, 6.10 and 7.1 in [18] that X(BR)Y(BR) is compact for any R>0. Define VR=infxBcRV(x). By (V), we deduce that VR as R. Therefore, when λ=Ns=p, we have

    BcR|u|pdx1VRBcRV(x)|u|pdx1VRupX,

    which implies

    limR+supuX{0}uLp(BcR)uX=0.

    By virtue of Theorem 7.9 in [24], we can see that XLp(RN) is compact.

    When λ>p, by the interpolation inequality, one can also obtain that XLλ(RN) is compact. This completes the proof.

    To study problems involving exponential critical growth in the fractional Sobolev space, the main tool is the following fractional Trudinger-Moser inequality, and its proof can be found in Zhang [37]. First, to make the notation concise, we set, for α>0 and tR,

    Φ(α,t)=exp(α|t|p)Skp2(α,t), (2.1)

    where Skp2(α,t)=kp2k=0αkk!|t|pk with kp=min{kN;kp}.

    Lemma 2.2. Let s(0,1) and sp = N. Then, there exists a positive constant α>0 such that

    RNΦ(α,u)dx<+, α(0,α), (2.2)

    for all uWs,p(RN) with uWs,p(RN)1.

    For Φ(α,u), we also have the following properties, which have been proved in [8,27]. For the reader's convenience, we sketch the proof here.

    Lemma 2.3. [27] Let α>0 and r>1. Then, for every β>r, there exists a constant C= C(β)>0 such that

    (exp(α|t|p)Skp2(α,t))rC(β)(exp(βα|t|p)Skp2(βα,t)).

    Proof. Noticing that

    (exp(α|t|p)Skp2(α,t))rexp(βα|t|p)Skp2(βα,t)=(j=kp1αj|t|jpj!)rj=kp1(βα)j|t|jpj!=|t|r(p1)p(j=kp1αj|t|(jp+1)pj!)r|t|(p1)pj=kp1(βα)j|t|(jp+1)pj!,

    we deduce

    limt0(exp(α|t|p)Skp2(α,t))rexp(βα|t|p)Skp2(βα,t)=0.

    On the other hand, it holds that

    lim|t|(exp(α|t|p)Sp2(α,t))rexp(βα|t|p)Sp2(βα,t)=lim|t|exp(αr|t|p)(1Sp2(α,t)(exp(α|t|))p)rexp(βα|t|p)(1Sp2(βα,t)exp(βα|t|p))=0, (2.3)

    and the lemma follows.

    Lemma 2.4. [8] Let α>0. Then, Φ(α,u)L1(RN) for all uX.

    Proof. Let uX{0} and ε>0. Since C0(RN) is dense in X, there exists ϕC0(RN) such that 0<uϕX<ε. Observe that for each kkp1,

    |u|pk2pkεpk|uϕuϕX|pk+2pk|ϕ|pk.

    Consequently,

    Φ(α,u)Φ(α2pεp,|uϕuϕX|p)+Φ(α2p,|ϕ|p).

    From Lemma 2.2, choosing ε>0 sufficiently small such that α2pεp<α, we have

    RNΦ(α2pεp,|uϕuϕX|p)dx<+.

    On the other side, since exp(α2p|ϕ|p)=+k=0αkk!2pk|ϕ|pk, there exists k0N such that +k=k0αkk!2pk|ϕ|pk<ε. This fact, combined with the fact that pk>0 for all kp1kk0, gives us

    RNΦ(α2p,|ϕ|p)dx=suppϕΦ(α2p,|ϕ|p)dx<+.

    Therefore, Φ(α,u)L1(RN) for all uX.

    Remark 2.1. From Lemmas 2.2–2.4, we deduce that Φ(α,u)lL1(RN) for all uX, α>0 and l1.

    The next lemma shows the growth behavior of the nonlinearity f.

    Lemma 2.5. Given ε>0, α>α0 and ζ>p, for all uX, it holds that

    |f(u)|ε|u|p1+C1(ε)|u|ζ1Φ(α,u),

    and

    |F(u)|εp|u|p+C2(ε)|u|ζΦ(α,u).

    Proof. We will only prove the first result. Since the second inequality is a direct consequence of the first one due to assumption (f3), we omit it here.

    In fact, by (f2), for given ε>0, there exists δ>0 such that |f(u)|ε|u|p1 for all |u|<δ. Now, as ζ>p, there exists r>0 such that ζ=p+r. Hence, once zζ1,zqk for all kkp1 and zr are increasing functions, if |u|>δ, it follows from (f1) that

    |f(u)|ε|u|p1+CεΦ(α,u)ε|u|p1|u|rΦ(α,u)δrΦ(α,δ)+Cε|u|ζ1δζ1Φ(α,u)=C1(ε)|u|ζ1Φ(α,u).

    This completes the proof.

    Remark 2.2. It follows from Lemmas 2.1–2.3 that I is well-defined on X. Moreover, IC1(X,RN), and

    I(u),v=R2N|u(x)u(y)|p2(u(x)u(y))(v(x)v(y))|xy|N+psdxdy+RNV(x)|u|p2uvdxRNf(u)vdx

    for all vX. Consequently, the critical point of I is the weak solution of problem (1.1).

    We seek the sign-changing solution of problem (1.1). As we saw in Section 1, one of the difficulties is the fact that the functional I does not possess a decomposition like (1.14). Inspired by [13,35], we have the following:

    Lemma 2.6. Let uX with u±0. Then,

    (i) I(u)>I(u+)+I(u),

    (ii) I(u),u±>I(u±),u±.

    Proof. Observe that

    I(u)=1pupXRNF(u)dx=1pA(u),uRNF(u)dx=1pA(u),u+RNF(u+)dx+1pA(u),uRNF(u)dx. (2.4)

    By density (see Di Nezza et al. Theorem 2.4 [18]), we can assume that u is continuous. Define

    (RN)+={xRN;u+(x)0} and (RN)={xRN;u(x)0}.

    Then, for uX with u±0, by a straightforward computation, one can see that

    A(u),u+=R2N|u(x)u(y)|p2(u(x)u(y))(u+(x)u+(y))|xy|N+psdxdy+RNV(x)|u+|pdx =(RN)+×(RN)+|u+(x)u+(y)|p|xy|N+psdxdy+(RN)+×(RN)|u+(x)u(y)|p1u+(x)|xy|N+psdxdy +(RN)×(RN)+|u(x)u+(y)|p1u+(y)|xy|N+psdxdy+RNV(x)|u+|pdx =A(u+),u++(RN)+×(RN)|u+(x)u(y)|p1u+(x)|u+(x)|p|xy|N+psdxdy +(RN)×(RN)+|u(x)u+(y)|p1u+(y)|u+(y)|p|xy|N+psdxdy>A(u+),u+. (2.5)

    Similarly, we also have

    A(u),u>A(u),u. (2.6)

    Taking into account (2.4)–(2.6), we deduce that I(u)>I(u+)+I(u). Analogously, one can prove (ii).

    In the last part of this section, we prove the following inequality, which will play an important role in estimating the upper bound for m:=infuMI(u).

    Lemma 2.7. For all uX with u±0 and constants σ,τ>0, it holds that

    σu++τupXσpA(u),u++τpA(u),u. (2.7)

    Furthermore, the inequality in (2.7) is an equality if and only if σ=τ.

    Proof. First, we claim the following elementary inequality holds true:

    (σa+τb)p(a+b)p1(σpa+τpb), (2.8)

    where a,b0, σ,τ>0 and p=Ns>2.

    Indeed, if a=0 or b=0, one can easily check (2.8). Thus, we can assume that a,b>0. Setting κ=aa+b and t=στ, (2.8) becomes

    (κt+(1κ))pκtp+(1κ). (2.9)

    Let us define g(t):=κtp+(1κ)(κt+(1κ))p, and then g(t)=κp[tp1(κt+(1κ))p1]. Noting that 0<κ<1, we can observe that g(1)=0, g(t)<0 for 0<t<1, and g(t)>0 for t>1. Therefore, g(t)>g(1)=0 for all t>0 and t1, which implies (2.9). Consequently, (2.8) holds true.

    Now, let us consider the inequality (2.7). By a straightforward computation, one can see from (2.8) that

    σu++τupXσpA(u),u+τpA(u),u=(RN)+×(RN)|σu+(x)τu(y)|p|u+(x)u(y)|p1(σpu+(x)τpu(y))|xy|N+psdxdy+(RN)×(RN)+|τu(x)σu+(y)|p|u(x)u+(y)|p1(τp(u(x))+σpu+(y))|xy|N+psdxdy0,

    which implies (2.7), and Lemma 2.7 follows.

    The aim of this section is to prove some technical lemmas related to the existence of a least energy nodal solution. Firstly, we collect some preliminary lemmas which will be fundamental to prove our main result.

    Lemma 3.1. Under the assumptions of Theorem 1.1, we have

    (i) For all uN such that uX, I(u);

    (ii) There exist ρ,μ>0 such that u±Xρ for all uM and uX>μ for all uN.

    Proof. (i) Since uN and (f3) holds, we see that

    I(u)=I(u)1θI(u),u(1p1θ)upX. (3.1)

    Hence, the above inequality ensures that I(u) as uX.

    (ii) We claim that there exists μ>0, such that uX>μ for all uN. By contradiction, we suppose that there exists a sequence {un}N such that unX0 in X.

    Then, it follows from Lemmas 2.1, 2.3, 2.5 and Hölder's inequality that

    unpX=RNf(un)undxεRN|un|pdx+C1(ε)RN|un|ζΦ(α,un)dxεunpX+C1(ε)(RN|un|ζrdx)1r(RNΦ(α,un)rdx)1r=εunpX+C2(ε)(RNΦ(α,un)rdx)1runζX, (3.2)

    where α>α0, ζ>p and r>1 with 1r+1r=1.

    On the other hand, since unX0, there exists N0N and ϑ>0 such that unpX<ϑ<αα0 for all n>N0. Choosing α>α0, r>1 and β>r satisfying αϑ<α and βαϑ<α, for all n>N0, we deduce from Lemmas 2.2 and 2.3 that

    RNΦ(α,un)rdx=RN(exp(α|un|p)Skp2(α,un))rdx=RN(exp(αunpX(ununX)p)Skp2(αunpX,ununX))rdxCRN(exp(βαϑ(ununX)p)Skp2(βαϑ,ununX))dxC. (3.3)

    Combining (3.3) with (3.2), and choosing ε=12 in (3.2), we can see that

    unpXCunζX, (3.4)

    where C is a constant independent of n. Obviously, (3.4) contradicts with unX0, and we have proved the claim.

    For unM, we have I(un),u±n=0. Hence, it follows from Lemma 2.6 that

    I(u±n),u±n<0,

    which implies

    u±npX<RNf(u±n)u±ndx.

    By arguments as with (3.2) and (3.3), we deduce that there exist ρ1,ρ2>0 such that u+nX>ρ1 and unX>ρ2. Select ρ=min(ρ1,ρ2), and then u±nX>ρ, and this completes the proof.

    Lemma 3.2. Under the assumptions of Theorem 1.1, for any uX{0}, there exists a unique νuR+ such that νuuN. Moreover, for any uN, we have

    I(u)=maxν[0,)I(νuu). (3.5)

    Proof. Given uX{0}, we define g(ν)=I(νu) for all ν0, i.e.,

    g(ν)=1pνpupXRNF(νu)dx.

    It follows from (f2) and (f4) that the function g(ν) possesses a global maximum point νu, and g(νu)=0, i.e.,

    νp1uupX=RNf(νuu)udx, (3.6)

    which implies νuuN. Now, we claim the uniqueness of νu. Suppose, on the contrary, there exists ˜νuνu such that ˜νuuN. Then, it holds that

    ˜νp1uupX=RNf(˜νuu)udx. (3.7)

    Without loss of generality, we may assume ˜νu>νu. Combining (3.6), (3.7) and (f5), we deduce that

    0={xRN: u(x)0}(f(˜νuu)|˜νuu|p1f(νuu)|νuu|p1)|u|p1udx>0,

    which leads to a contradiction. Thus, νu is unique. Obviously, for any uN, νu=1, and (3.5) follows. This completes our proof.

    Since we are considering the constrained minimization problem on M, in the following, we will show that the set M is nonempty.

    Lemma 3.3. If uX with u±0, then there exists a unique pair (σu,τu) of positive numbers such that

    (I(σuu++τuu),u+,I(σuu++τuu),u)=(0,0).

    Consequently, σuu++τuuM.

    Proof. Let G:(0,+)×(0,+)R2 be a continuous vector field given by

    G(σ,τ)=(I(σu++τu),σu+,I(σu++τu),τu)

    for every (σ,τ)(0,+)×(0,+). By virtue of Lemmas 2.5 and 2.6, we deduce that

    I(σu++τu),σu+I(σu+),σu+=σpu+pXRNf(σu+)σu+dxσpu+pXεσpRN|u+|pdxCεRN|σu+|ζΦ(α,σu+)dx, (3.8)

    where α>α0 and ζ>q. Choose ε=12, σ small enough such that σu+pX<αα0. Taking into account (3.8) and arguing as with (3.3) in Lemma 3.1, one can see that

    I(σu++τu),σu+12σpu+pXC1σζu+ζX, (3.9)

    and similarly

    I(σu++τu),τu12τpupXC2τζuζX. (3.10)

    Hence, it follows from (3.9) and (3.10) that there exists R1>0 small enough such that

    I(R1u++τu),R1u+>0 for all τ>0, (3.11)

    and

    I(σu++R1u),R1u>0 for all σ>0. (3.12)

    On the other hand, by (f3), there exist constants D1,D2>0 such that

    F(t)D1tθD2 for all t>0. (3.13)

    Then, we have

    I(σu++τu),σu+σp(RN)+×(RN)+|u+(x)u+(y)|p|xy|N+psdxdy+(RN)+×(RN)|σu+(x)τu(y)|p1σu+(x)|xy|N+psdxdy+(RN)×(RN)+|τu(x)σu+(y)|p1σu+(y)|xy|N+psdxdy+σpRNV(x)|u+|pdxD1σθA+|u+|θdx+D2|A+|, (3.14)

    where A+supp(u+) is a measurable set with finite and positive measure |A+|. Due to the fact that θ>p, for R2 sufficiently large, we get

    I(R2u++τu),R2u+<0 for all τ[R1,R2]. (3.15)

    Similarly, we get

    I(σu++R2u),R2u<0 for all σ[R1,R2]. (3.16)

    Hence, taking into account (3.6), (3.7), (3.15), (3.16) and thanks to the Miranda theorem [28], there exists (σu,τu)[R1,R2]×[R1,R2] such that G(σu,τu)=0, which implies σuu++τuuM.

    Now, we are in the position to prove the uniqueness of the pair (σu,τu). First, we assume that u=u++uM and (σu,τu)(0,+)×(0,) is another pair such that σuu++τuuM. In this case, we just need to prove that (σu,τu)=(1,1). Notice that

    A(u),u+=RNf(u+)u+dx, A(u),u=RNf(u)udx, (3.17)

    and

    A(σuu++τuu),σuu+=RNf(σuu+)σuu+dx, A(σuu++τuu),τuu=RNf(τuu)τuudx. (3.18)

    Without loss of generality, we may assume σuτu. Then, by a direct computation, one has

    A(σuu++τuu),σuu+=(RN)+×(RN)+|σuu+(x)σuu+(y)|p|xy|N+psdxdy+(RN)+×(RN)|σuu+(x)τuu(y)|p1σuu+(x)|xy|N+psdxdy+(RN)×(RN)+|τuu(x)σuu+(y)|p1σuu+(y)|xy|N+psdxdyA(σuu++σuu),σuu+=σpuA(u),u+, (3.19)

    which together with (3.18) implies

    σpuA(u),u+RNf(σuu+)σuu+dx. (3.20)

    Combining (3.20) with (3.17), we deduce that

    {xRN:u+(x)0}(f(σuu+)(σuu+)p1f(u+)(u+)p1)(u+)pdx0.

    Hence, by (f5) and since u+0, we obtain σu1. Moreover, using similar arguments as in (3.19), we can deduce that

    A(σuu++τuu),τuuA(τuu++τuu),τuu. (3.21)

    Therefore, it follows from (3.17), (3.18) and (3.21) that

    {xRN: u(x)0}(f(τuu)(τuu)p1f(u)(u)p1)(u)pdx0,

    which together with (f5) implies τu1. Thus, we conclude the proof of the uniqueness of the pair (1,1).

    For the general case, we suppose that u does not necessarily belong to M. Let (σu,τu), (σu,τu)(0,+)×(0,). We define v=v++v with v+=σuu+ and v=τuu. Therefore, we have vM and σuσuv++τuτuvM, which implies (σu,τu)=(σu,τu), and this completes the proof.

    The following two lemmas will be useful in proving Theorem 1.1.

    Lemma 3.4. Under the assumptions of Theorem 1.1, and let uX with u±0 such that I(u),u±0. Then, the unique pair of positive numbers obtained in Lemma 3.3 satisfies 0<σu,τu1.

    Proof. Here we will only prove 0<σu1. The proof of 0<τu1 is analogous, and we omit it here. Since I(u),u+0, it holds that

    A(u),u+RNf(u+)u+dx. (3.22)

    Without loss of generality, we can assume that σuτu>0, and σuu++τuuM. Therefore, utilizing a similar argument as in (3.19), we deduce that

    σpuA(u),u+=A(σuu++σuu),σuu+A(σuu++τuu),σuu+=RNf(σuu+)σuu+dx. (3.23)

    Taking into account (3.22) and (3.23), we obtain

    RN(f(σuu+)(σuu+)p1f(u+)(u+)p1)(u+)pdx0,

    which together with assumption (f5) and the fact u+0 shows that σu1. Hence, we finish the proof.

    Lemma 3.5. Under the assumptions of Theorem 1.1, let uX with u±0 and (σu,τu) be the unique pair of positive numbers obtained in Lemma 3.3. Then, (σu,τu) is the unique maximum point of the function hu:[0,+)×[0,+)R given by

    hu(σ,τ):=I(σu++τu).

    Proof. In the demonstration of Lemma 3.3, we saw that (σu,τu) is the unique critical point of hu in (0,+)×(0,+). In addition, by the definition of hu and (3.13), we have

    hu(σ,τ)=I(σu++τu)1pσu++τupXD1σθA+|u+|θdxD1τθA|τu|θdx+D2(|A+|+|A|),

    where A+supp(u+) and Asupp(u) are measurable sets with finite and positive measures |A+| and |A|. Since θ>p, we conclude that hu(σ,τ) as |(σ,τ)|. In particular, one can easily check that there exists R>0 such that hu(a,b)<hu(σu,τu) for all (a,b) (0,)×(0,)¯BR(0), where ¯BR(0) is a closure of the ball of radius R in R2.

    To end the proof, we just need to verify that the maximum of hu does not occur in the boundary of [0,+)×[0,+). Suppose, by contradiction, that (0,b) is a maximum point of hu. Then, for a>0 small enough, one can see from (3.9) that hu(a,0)=I(au+)>0. Hence, it follows from Lemma 2.6 that

    hu(a,b)=I(au++bu)>I(au+)+I(bu)>hu(0,b),

    for a>0 small enough. However, this contradicts with the assumption that (0,b) is a maximum point of hu. The case (a,0) is similar, and we complete the proof.

    Since Lemma 3.3 shows M is nonempty, and Lemma 3.1 implies that I(u)>0 for all uM, I is bounded below in M, which means that m:=infuMI(u) is well-defined. Now, we shall prove an upper bound for m to recover the compactness, which urges us to prove that m can be achieved.

    Lemma 3.6. Under the assumptions of Theorem 1.1 and that θ is the constant given by (f3),

    0<m<θpθp(αα0)p1. (3.24)

    Proof. Due to MN, we have mc:=infuNI(u). Moreover, for all uN, by Lemma 3.1 it holds that

    I(u)(1p1θ)upXθpθpμp>0. (3.25)

    On the other hand, by the similar procedure used in [13], there exists wMq with w±0, such that Iq(w)=mq and Iq(w),w±=0. Therefore, it holds that

    1pwpX1q|w|qq=mq  and  A(w),w±=|w±|qq. (3.26)

    In addition, by virtue of Lemma 3.3, there exist σ,τ>0 such that σw++τwM. Therefore, it holds that

    mI(σw++τw)=1pσw++τwpXRNF(σw++τw)dx,

    which together with (f4) implies that

    m1pσw++τwpXγqσq|w+|qqγqτq|w|qq.

    Now, from (3.26) and thanks to Lemma 2.7, we conclude that

    m1pσpA(w),w++1pτpA(w),wγqσq|w+|qqγqτq|w|qq+1p(σw++τwpXσpA(w),w+τpA(w),w)(1pσpγqσq)|w+|qq+(1pτpγqτq)|w|qqmaxξ0(1pξpγqξq)|w|qq=(1p1q)γppq|w|qq=γppqmq.

    Therefore, by the definition of γ in Theorem 1.1, we obtain (3.24).

    Lemma 3.7. Under the assumptions of Theorem 1.1, let {un}M be a minimizing sequence for m, and then

    RNf(u±n)u±ndxRNf(u±)u±dx as n, (3.27)

    and

    RNF(u±n)dxRNF(u±)dx as n (3.28)

    hold for some uX.

    Proof. We will only prove the first result, since the second limit is a direct consequence of the first one. Since {un}M is a minimizing sequence for m, I(un)m, and it follows from (3.25) that

    unpXθpθpI(un), (3.29)

    which implies {un} is bounded in X. Then, by virtue of Lemma 2.1, up to a subsequence, there exists uX such that

    unu in X,unu in Lλ(RN) for λ[p,+),unu  a.e. in RN. (3.30)

    Hence,

    u±nu± in X,u±nu± in Lλ(RN) for λ[p,+),u±nu±  a.e. in RN. (3.31)

    Moreover, utilizing (3.29) again, we deduce that there exist n0N and ϑ>0 such that unpX<ϑ<αα0 for n>n0. Choose α>α0, r>1 and close to 1, and β>r satisfying αϑ<α and βαϑ<α, and then for all n>n0, it follows from Lemmas 2.2 and (3) that

    RNΦ(α,un)rdx=RN(exp(α|un|p)Skp2(α,un))rdx=RN(exp(αunpX(ununX)p)Skp2(αunpX,ununX))rdxCRN(exp(βαϑ(ununX)p)Skp2(βαϑ,ununX))C, (3.32)

    where C is a constant independent of n. Thus, by virtue of Lemma 2.5 and Hölder's inequality, for every Lebesgue measurable set ARN and n>n0, it holds that

    |Af(un)undx|C1A|un|pdx+C2A|un|ζΦ(α,un)dxC1A|un|pdx+C2(A|un|ζrdx)1r(AΦ(α,un)rdx)1r=C1A|un|pdx+C2C1r(A|un|ζrdx)1r. (3.33)

    Due to (3.33) and the fact that u±nu± in Lp(RN) and Lζr(RN), we conclude that for any ε>0 and n>n0, there exists δ>0 such that for every Lebesgue measurable set ARN with meas(A)δ, it holds that

    |Af(u±n)u±ndx|<ε. (3.34)

    Similarly, for any ε>0 and n>n0, there exists R>0 such that

    | RNBR(0)f(u±n)u±ndx|<ε. (3.35)

    Therefore, by (3.31), (3.34), (3.35) and thanks to Vitali's convergence theorem, one can prove

    RNf(u±n)u±ndxRNf(u±)u±dx as n. (3.36)

    Thus, we finish the proof.

    In this section, we will prove Theorems 1.1 and 1.2. To this end, we consider the minimization problem

    m:=infuMI(u).

    Firstly, let us start with the existence of a minimizer uM of I.

    Lemma 4.1. Under the assumptions of Theorem 1.1, the infimum m is achieved.

    Proof. By using Lemma 3.1, we know that there exists a minimizing sequence {un}nM bounded in X, such that

    I(un)m  as n. (4.1)

    Without loss of generality, we may assume up to a subsequence that there exists u such that

    u±n(u)± in X,u±n(u)± in Lλ(RN) for all λ[p,+),u±n(u)± a.e. in RN.

    Then, by Lemmas 2.6, 3.1 and 3.7, we conclude that

    ρplim infnu±npXlim infnA(un),u±n=lim infnRNf(u±n)u±ndx=RNf((u)±)(u)±dx,

    which implies (u)±0, and consequently u=(u)++(u) is sign-changing. Hence, by Lemma 3.3, there exist σ,τ>0 such that

    I(σ(u)++τ(u)),(u)+=0,I(σ(u)++τ(u)),(u)=0. (4.2)

    Now, we claim that σ=τ=1. Indeed, since unM, I(un),u±n=0, i.e.,

    u+npX+(RN)+n×(RN)n(|u+n(x)un(y)|p1u+n(x)|xy|N+ps|u+n(x)|p|xy|N+ps)dxdy+(RN)n×(RN)+n(|un(x)u+n(y)|p1u+n(y)|xy|N+ps|u+n(y)|p|xy|N+ps)dxdy=RNf(u+n)u+ndx, (4.3)

    and

    unpX+(RN)n×(RN)+n(|un(x)u+n(y)|p1(un(x))|xy|N+ps|un(x)|p|xy|N+ps)dxdy+(RN)+n×(RN)n(|u+n(x)un(y)|p1(un(y))|xy|N+ps|un(y)|p|xy|N+ps)dxdy=RNf(un)undx, (4.4)

    where (RN)+n:={xRN:un(x)0} and (RN)n:={xRN:un(x)0}. Notice the functional upX is weakly lower semicontinuous on X, and we see that

    (u)±pXlim infnu±npX. (4.5)

    Moreover, it follows from Lemma 3.7 that

    RNf(u±n)u±ndxRNf((u)±)(u)±dx as n. (4.6)

    Taking into account (4.3)–(4.6) and thanks to Fatou's lemma, we deduce that

    I(u),(u)+0 and I(u),(u)0, (4.7)

    which together with Lemma 3.4 implies that 0<σ,τ1. In the following, we will show that σ=τ=1, and I(u)=m. In fact, by (4.2), (f5), Fatou's lemma and the definition of M, one has

    mI(σ(u)++τ(u))=I(σ(u)++τ(u))1pI(σ(u)++τ(u)),(σ(u)++τ(u))=RN[1pf(σ(u)+)σ(u)+F(σ(u)+)]dx+RN[1pf(τ(u))τ(u)F(τ(u))]dxRN[1pf((u)+)(u)+F((u)+)]dx+RN[1pf((u))(u)F((u))]dxlim infn[I(un)1pI(un),un]=limnI(un)=m. (4.8)

    Let us observe that by the above calculation we can infer that σ=τ=1. Thus, uM, and I(u)=m.

    Now we are ready to prove Theorem 1.1. The proof is based on the quantitative deformation lemma and Brouwer degree theory. For more details, we refer to the arguments used in [7].

    Proof of Theorem 1.1. We assume by contradiction that I(u)0. Then, there exist δ,κ>0 such that

    |I(v)|κ, for all vuX3δ.

    Define D:=[1δ1,1+δ1]×[1δ1,1+δ1] and a map ξ:DX by

    ξ(σ,τ):=σ(u)++τ(u),

    where δ1(0,12) small enough such that ξ(σ,τ)uX3δ for all (σ,τ)ˉD. Thus, by virtue of Lemma 4.1, we can see that

    I(ξ(1,1))=m, I(ξ(σ,τ))<m for all (σ,τ)D{(1,1)}.

    Therefore,

    β:=max(σ,τ)DI(ξ(σ,τ))<m.

    By using [36,Theorem 2.3] with

    Sδ:={vX:vuXδ}

    and c:=m. By choosing ε:=min{mβ4,κδ8}, we deduce that there exists a deformation ηC([0,1]×X,X) such that:

    (i) η(t,v)=v if vI1([m2ε,m+2ε]); (ii) I(η(1,v))mε for each vX with vuXδ and I(v)m+ε; (iii) I(η(1,v))I(v) for all uX.

    By (ii) and (iii) we conclude that

    max(σ,τ)¯DI(η(1,ξ(σ,τ)))<m. (4.9)

    Therefore, to complete the proof of this Lemma, it suffices to prove that

    η(1,ξ(¯D))M. (4.10)

    Indeed, if (4.10) holds true, then by the definition of m and (4.9), we get a contradiction.

    In the following, we will prove (4.10). To this end, let us define Ψu:[0,+)×[0,+)R2 by

    Ψu(σ,τ):=(Ψu1(σ,τ),Ψu2(σ,τ))=(I(σ(u)++τ(u)),(u)+,I(σ(u)++τ(u)),(u)).

    Furthermore, for (σ,τ)¯D, we define

    ˜Ψ(σ,τ):=(1σI(η(1,ξ(σ,τ))),η+(1,ξ(σ,τ)),1τI(η(1,ξ(σ,τ))),η(1,ξ(σ,τ))).

    Since η(1,ξ(σ,τ))=ξ(σ,τ) on D, by the Brouwer degree theory (see Theorem D.9 [36]), we have

    deg(˜Ψ,D,0)=deg(Ψu,D,0). (4.11)

    Now, we assert that deg(Ψu,D,0)=1. If this assertion holds true, then ˜Ψ(σ0,τ0)=0 for some (σ0,τ0)D. Thus, there exists u0:=η(1,ξ(σ0,τ0))M and (4.10) follows.

    In fact, let us first define

    Ap:=R2N|u(x)u(y)|p2|(u)+(x)(u)+(y)|2|xy|N+psdxdy+RNV(x)|(u)+|pdx,Bp:=R2N|u(x)u(y)|p2|(u)(x)(u)(y)|2|xy|N+psdxdy+RNV(x)|(u)|pdx,Cp:=R2N|u(x)u(y)|p2((u)(x)(u)(y))((u)+(x)(u)+(y))|xy|N+psdxdy,Dp:=R2N|u(x)u(y)|p2((u)+(x)(u)+(y))((u)(x)(u)(y))|xy|N+psdxdy,a1:=RNf((u)+)|(u)+|2dx, a2:=RNf((u)+)(u)+dx,b1:=RNf((u))|(u)|2dx, b2:=RNf((u))(u)dx.

    Clearly, Cp=Dp>0, Ap,Bp>0. Notice that uM, and we can see that

    Ap+Cp=a2,Bp+Dp=b2. (4.12)

    Moreover, (f5) guarantees

    a1>(p1)a2,b1>(p1)b2. (4.13)

    Then, by a direct computation, we have

    Ψu1σ(1,1)=(p1)Apa1<0, (4.14)

    and

    Ψu2τ(1,1)=(p1)Bpb1<0. (4.15)

    In addition,

    Ψu1τ(1,1)=Ψu2σ(1,1)=(p1)Cp=(p1)Dp. (4.16)

    Taking advantage of (4.12)–(4.16), we deduce that

    det(Ψu)(1,1)=[(p1)Apa1][(p1)Bpb1](p1)2CpDp>[(p1)a2(p1)Ap][(p1)b2(p1)Bp](p1)2CpDp=(p1)2CpDp(p1)2CpDp=0. (4.17)

    Notice that uM, and thanks to Lemmas 3.3 and 3.5, it holds that

    deg(Ψu,D,0)=sgn(det(Ψu)(1,1))=1,

    which together with (4.11) implies deg(Ψu,D,0)=1. This completes our proof.

    Lemma 4.2. For any vM, there exist ˜σv,˜τv(0,1) such that ˜σvv+,˜τvvN.

    Proof. We just prove ˜σv(0,1). The other case can be obtained by similar arguments. Since vM, i.e., I(v),v+=0, by Lemma 2.6, we obtain

    v+pX<RNf(v+)v+dx. (4.18)

    On the other hand, by Lemma 3.2, there exists ˜σv>0 such that ˜σvv+N, which implies that

    ˜σpvv+pX=RNf(˜σvv+)˜σvv+dx. (4.19)

    Taking into account (4.9) and (4.10), we deduce that

    RN[f(v+)(v+)p1f(˜σvv+)(˜σvv+)p1](˜σvv+)pdx>0.

    Thus, it follows from (f4) that ˜σv<1.

    Proof of Theorem 1.2. Using a similar idea from the proof of Lemma 4.1, we find ˉuN such that I(ˉu)=c>0, where c:=infuNI(u). Furthermore, utilizing the same steps of the proof of Theorem 1.1, we show that I(ˉu)=0. Thus, ˉu is a ground state solution of problem (1.1). Hence, to complete the proof of Theorem 1.2, we need to study the energy behavior of I(u), where u is the sign-changing solution of (1.1) obtained in Theorem 1.1.

    In fact, by Lemma 4.2, there exist 0<˜σu,˜τu<1 such that ˜σu(u)+,˜τu(u)N. Therefore, we deduce from (f5) and Lemma 3.2 that

    m=I(u)=I(u)1pI(u),u=RN(1pf(u)uF(u))dx>RN(1pf(˜σu(u)+)˜σu(u)+F(˜σu(u)+))dx+RN(1pf(˜τu(u))˜τu(u)F(˜τu(u)))dx=I(˜σu(u)+)1pI(˜σu(u)+),˜σu(u)++I(˜τu(u))1pI(˜τu(u)),˜τu(u)=I(˜σu(u)+)+I(˜τu(u))2c,

    which completes the proof of Theorem 1.2.

    This manuscript has employed the variational method to study the fractional p-Laplacian equation involving Trudinger-Moser nonlinearity. By using the constrained variational methods, quantitative Deformation Lemma and Brouwer degree theory, we prove the existence of least energy sign-changing solutions for the problem.

    K. Cheng was supported by the Jiangxi Provincial Natural Science Foundation (20202BABL211005), W. Huang was supported by the Jiangxi Provincial Natural Science Foundation (20202BABL211004), and L. Wang was supported by the National Natural Science Foundation of China (No. 12161038) and the Science and Technology project of Jiangxi provincial Department of Education (Grant No. GJJ212204).

    The authors declare that there is no conflict of interest.

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