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Analysis of related factors of radiation pneumonia caused by precise radiotherapy of esophageal cancer based on random forest algorithm


  • The precise radiotherapy of esophageal cancer may cause different degrees of radiation damage for lung tissues and cause radioactive pneumonia. However, the occurrence of radioactive pneumonia is related to many factors. To further clarify the correlation between the occurrence of radioactive pneumonia and related factors, a random forest model was used to build a risk prediction model for patients with esophageal cancer undergoing radiotherapy. In this study, we retrospectively reviewed 118 patients with esophageal cancer confirmed by pathology in our hospital. The health characteristics and related parameters of all patients were analyzed, and the predictive effect of radiation pneumonia was discussed using the random forest algorithm. After treatment, 71 patients developed radioactive pneumonia (60.17%). In univariate analyses, age, planning target volume length, Karnofsky performance score (KPS), pulmonary emphysema, with or without chemotherapy, and the ratio of planning target volume to planning gross tumor volume (PTV/PGTV) in mediastinum were significantly associated with radioactive pneumonia (P < 0.05 for each comparison). Multivariate analysis revealed that with or without pulmonary emphysema (OR = 7.491, P = 0.001), PTV/PGTV (OR = 0.205, P = 0.007), and KPS (OR = 0.251, P = 0.011) were independent predictors for radiation pneumonia. The results concluded that the analysis of radiation pneumonia-related factors based on the random forest algorithm could build a mathematical prediction model for the easily obtained data. This algorithm also could effectively analyze the risk factors of radiation pneumonia and formulate the appropriate treatment plan for esophageal cancer.

    Citation: Na Li, Peng Luo, Chunyang Li, Yanyan Hong, Mingjun Zhang, Zhendong Chen. Analysis of related factors of radiation pneumonia caused by precise radiotherapy of esophageal cancer based on random forest algorithm[J]. Mathematical Biosciences and Engineering, 2021, 18(4): 4477-4490. doi: 10.3934/mbe.2021227

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  • The precise radiotherapy of esophageal cancer may cause different degrees of radiation damage for lung tissues and cause radioactive pneumonia. However, the occurrence of radioactive pneumonia is related to many factors. To further clarify the correlation between the occurrence of radioactive pneumonia and related factors, a random forest model was used to build a risk prediction model for patients with esophageal cancer undergoing radiotherapy. In this study, we retrospectively reviewed 118 patients with esophageal cancer confirmed by pathology in our hospital. The health characteristics and related parameters of all patients were analyzed, and the predictive effect of radiation pneumonia was discussed using the random forest algorithm. After treatment, 71 patients developed radioactive pneumonia (60.17%). In univariate analyses, age, planning target volume length, Karnofsky performance score (KPS), pulmonary emphysema, with or without chemotherapy, and the ratio of planning target volume to planning gross tumor volume (PTV/PGTV) in mediastinum were significantly associated with radioactive pneumonia (P < 0.05 for each comparison). Multivariate analysis revealed that with or without pulmonary emphysema (OR = 7.491, P = 0.001), PTV/PGTV (OR = 0.205, P = 0.007), and KPS (OR = 0.251, P = 0.011) were independent predictors for radiation pneumonia. The results concluded that the analysis of radiation pneumonia-related factors based on the random forest algorithm could build a mathematical prediction model for the easily obtained data. This algorithm also could effectively analyze the risk factors of radiation pneumonia and formulate the appropriate treatment plan for esophageal cancer.



    Nowadays predator-prey models have been widely applied in biological and ecological phenomena. The most general prey-predator population model is represented by

    {˙x(t)=xG(x)yP(x,y),˙y(t)=yH(x,y),

    where x(t) and y(t) denote the density of the prey and predator at time t, respectively. G(x) is the per capita growth rate of the prey in the absence of predator, P(x,y) represents the functional response of predators and H(x,y) measures the growth rate of predators.

    A prototype of G(x) is the logistic growth pattern of G(x)=r(1xN), where r>0 denotes the prey intrinsic growth rate and N means the carrying capacity in the absence of predator [1]. One of known growth rate of predators is the Leslie-Gower type: H(x,y)=α(1kyx) [2,3], where α is the intrinsic growth rates of predator and k is the conversion factor of prey into predators.

    Lotka-Volterra response was used by Lotka [4] in studying a hypothetical chemical reaction and by Volterra [5] in modeling a predator-prey interaction. Lotka-Volterra response function is a straight line through the origin and is unbounded. The solutions of Lotka-Volterra model are not structural stable, thus a small perturbation can have a very marked effect [6]. The Holling-type Ⅱ functional responses function is P(x,y)=cxa+bx, where c is the maximum number of prey consumed per predator per unit time [7,8]. When a=1 and b=0, the functional response is of Lotka-Volterra type. In 1975, Beddington [9] and DeAngelis et al. [10] developed a predator-prey model of the mutual interference effects, in which the relationship between predators' searching efficiency and both prey and predator is presented. The Beddington-DeAngelis (B-D) functional response is defined by

    P(x,y)=sx1+ax+by,

    where s,a,b>0, s is the consumption rate, a means the saturation constant for an alternative prey and b stands for the predator interference. The predator-prey models with the B-D functional response have been well-studied in the literature, for example, see [11,12,13,14] and references therein.

    From the view of human needs, the exploitation of biological resources and harvest of population are commonly practised in the fields of fishery, wildlife, and forestry management. Many mathematical models have been proposed and developed to better describe the relationship between predator and prey populations by taking into account the harvesting, for instance, see [14,15,16,17,18]. In a very general way, harvesting for predator-prey models can be divided into three types. If the harvesting function h(t) is a constant, it is called constant-rate or constant yield harvesting. It arises when a quota is specified (for example, through permits, as in deer hunting seasons in many areas, or by agreement as sometimes occurring in whaling) [19,20]. If the function h(t) is a linear function of population size, it is called proportional or constant-effort harvesting [16,17,18]. The harvesting function h(t) can be of nonlinear form, for example, one of which is the so-called Michaelis-Menten type harvesting used in ecology and economics [21,22].

    Movements of some individuals usually cannot be restricted to a small area, and they are often free, so integral operators have been widely applied to model the long-distance dispersal problem [23]. That is, the diffusion process depends on the distance between two niches of population, such as the model:

    ut(x,t)=RJ(xy)(u(y,t)u(x,t))dy+f(u),

    where RJ(xy)(u(y,t)u(x,t))dy represents the nonlocal dispersal process [24,25]. Such model arises not only in biological phenomena, but also in many other fields, such as phase transition modelling [25,26,27,28].

    There is, however, considerable evidence that time delay should not be neglected in biological and ecological phenomena. The growth rate of population of species and the response of one species to the interactions with other species are mediated by some time delay. Other causes of response delays include differences in resource consumption with respect to age structure, migration and diffusion of populations, gestation and maturation periods, delays in behavioral response to environmental changes, and dependence of a population on a food supply that requires time to recover from grazing [15,25]. Hence, in order to make the modeling of interactions between predator and prey more realistic, time delay is often necessarily incorporated into predator-prey models [22,28,29,30,31].

    The purpose of this paper is to study the existence and nonexistence of traveling wave solution of a nonlocal dispersal delayed predator-prey model with the B-D functional response and harvesting:

    {ut=d1((Ju)(x,t)u(x,t))+ru(x,t)(1u(x,t)K)su(x,t)v(x,tτ)1+au(x,t)+bv(x,tτ)qu(x,t),vt=d2((Jv)(x,t)v(x,t))+v(x,t)(αβv(x,t)u(x,tτ)), (1.1)

    where

    (Jw)(x,t)=RJ(y)w(xy,t)dy,

    q represents the prey harvesting, τ denotes the time delay, and a,b,r,d1,d2,s,K,α and β are positive real constants. To reduce the number of parameters in system (1.1), we make the following transformations:

    ˉt=rt, ˉτ=rτ, ˉu=uK, ˉv=svr, ¯d1=d1r, ¯d2=d2r,
    ˉa=aK, ˉb=rbs, ˉα=αr, ˉβ=βsK, ˉq=qr.

    For the sake of convenience, we ignore the bars on u,v and other parameters, then system (1.1) can be re-expressed as

    {ut=d1(Juu)+u(1u)uv(x,tτ)1+au+bv(x,tτ)qu,vt=d2(Jvv)+v(αβvu(x,tτ)). (1.2)

    Biologically, we require 0<q<1. It is easy to see that system (1.2) has two spatially constant equilibria (1q,0) and (u,v), where u=(1q)κβα+(κβα)2+4βκ2κ, v=αuβ and κ=(aβ+bα)(1q).

    In biology and ecology, traveling wave solutions are often used to describe the spatial-temporal process where the predator invades the territory of prey and they eventually coexist [25]. A solution of system (1.2) is called a traveling wave with the speed c>0 if there exist positive function ϕ1 and ϕ2 defined on R such that

    u(x,t)=ϕ1(z),v(x,t)=ϕ2(z),z=x+ct.

    Here ϕ1 and ϕ2 represent the wave profiles and (ϕ1, ϕ2) satisfies the resultant system:

    {cϕ1(z)=d1(Jϕ1(z)ϕ1(z))+ϕ1(z)(1ϕ1(z))ϕ1(z)ϕ2(zcτ)1+aϕ1(z)+bϕ2(zcτ)qϕ1(z),cϕ2(z)=d2(Jϕ2(z)ϕ2(z))+ϕ2(z)(αβϕ2(z)ϕ1(zcτ)), (1.3)

    and

    Jϕ(z)=RJ(y)ϕ(zy)dy.

    Our primary interest lies in the traveling wave solution of system (1.3) connecting (1q, 0) and (u, v) with the asymptotic behavior:

    limz(ϕ1(z),ϕ2(z))=(1q,0),   limz+(ϕ1(z),ϕ2(z))=(u,v). (1.4)

    The asymptotic behavior of traveling wave solution plays an important role in dispersion models of biological populations, because it describes the propagation processes of different species and enables us to understand how some species migrate from one area into another area until the density attains a certain value.

    Recently, the existence of traveling wave solution for the nonlocal dispersal systems with the time delay has been extensively studied [28,29,30,31,32,33]. We can see that system (1.3) is non-monotone system and Schauder's fixed point theorem is a quiet powerful technique for constructing a suitable invariant set (see, for example [31,33,34,35,36]). To explore the existence of traveling wave solution of nonlocal dispersal systems with c>c, we need to construct an invariant cone in a large bounded domain with the initial functions [33,34,35], where the nonlocal dispersal kernel function J is assumed to be compactly supported. For the existence of traveling wave solution at the critical point c=c, Corduneanu's theorem and the limiting method are useful techniques [33,36].

    Throughout this paper, for the nonlocal dispersal kernel function J of system (1.3), we make the following assumptions:

    (G1) J is a smooth function in R, Lebesgue measurable with JC1(R) and

    J(x)=J(x)0,  RJ(x)dx=1.

    (G2) RJ(x)eλxdx<+, λR.

    For convenience, we assume the parameters of system (1.3) satisfying

    0<d1d2,0<q<1,b>1,a>1q,0<bαβ.

    The rest of this paper is structured as follows. We construct an appropriate pair of upper-lower solutions of system (1.3) for c>c in Section 2. We apply Schauder's fixed point theorem to investigate the existence of traveling wave solution for c>c and develop the contracting rectangles method to study the asymptotic behavior of system (1.3) in Section 3. The existence of traveling wave solution for c=c is discussed by means of Corduneanu's theorem and Lebesgue's dominated convergence theorem in Section 4. Section 5 is dedicated to the nonexistence of traveling wave for 0<c<c. A brief conclusion is given in Section 6.

    Definition 2.1. Assume that Z:={z1,z2,,zm}R contains finite points of R. We say that the functions (¯ϕ1, ¯ϕ2) and (ϕ_1, ϕ_2) are a pair of upper-lower solutions of system (1.3), if for any zRZ, ¯ϕi(z) and ϕ_i(z) (i=1,2) are bounded and continuous such that

    {F(¯ϕ1,ϕ_2)(z)=d1(J¯ϕ1(z)¯ϕ1(z))c¯ϕ1(z)+¯ϕ1(z)(1¯ϕ1(z)) ¯ϕ1(z)ϕ_2(zcτ)1+a¯ϕ1(z)+bϕ_2(zcτ)q¯ϕ1(z)0,F(ϕ_1,¯ϕ2)(z)=d1(Jϕ_1(z)ϕ_1(z))cϕ_1(z)+ϕ_1(z)(1ϕ_1(z)) ϕ_1(z)¯ϕ2(zcτ)1+aϕ_1(z)+b¯ϕ2(zcτ)qϕ_1(z)0,F(¯ϕ1,¯ϕ2)(z)=d2(J¯ϕ2(z)¯ϕ2(z))c¯ϕ2(z)+¯ϕ2(z)(αβ¯ϕ2(z)¯ϕ1(zcτ))0,F(ϕ_1,ϕ_2)(z)=d2(Jϕ_2(z)ϕ_2(z))cϕ_2(z)+ϕ_2(z)(αβϕ_2(z)ϕ_1(zcτ))0. (2.1)

    Define

    fσ(d,c,λ)=d(RJ(y)eλydy1)cλ+σ,

    where σ0. By a direct calculation, for c>0 and λ>0 we have

    (F1) f0(d1,c,0)=0 and fα(d2,c,0)>0;

    (F2) fσc=λ<0, fσλ|λ=0=c<0 and fσd=RJ(y)eλydy1>0;

    (F3) 2fσλ2>0.

    From (F1)–(F3), it follows that there exist c>0 and λ>0 such that [35]

    fα(d2,c,λ)=0andfα(d2,c,λ)λ|(c,λ)=0.

    Lemma 2.1. There exist c>c and positive constants 0<λ2<λ<λ3<λ1 such that

    f0(d1,c,λ){=0λ=0, λ=λ1>0λ(λ1,+)<0λ(0,λ1),fα(d2,c,λ){=0λ=λ2, λ=λ3>0λ(0,λ2)(λ3,+)<0λ(λ2,λ3).

    Proof. We only need to show λ1>λ3. It is easy to see fα(d2,c,λ3)=f0(d1,c,λ1)=0 and f0(d1,c,λ1)<fα(d1,c,λ1). Due to d2d1 and (F2), we have fα(d1,c,λ1)fα(d2,c,λ1). It indicates fα(d2,c,λ3)<fα(d2,c,λ1), i.e., λ1>λ3.

    Now, we will construct an appropriate pair of upper-lower solutions for system (1.3). We fix c>c. For any given constant m>1, it is easy to check that the function

    g(z)=eλ2zmeθz

    has a unique zero point at z0=lnmθλ2 where θ(λ2,min{2λ2,λ3}), and a unique maximum point at zM=lnmλ2(θλ2)<z0. Clearly, g is continuous on R and positive on (,z0). For any given yR we let

    Θ(z)=zJ(yx)g(x)dxg(z)2

    with z[zM,z0]. Since Θ(z) is nondecreasing for z[zM,z0] and Θ(z0)>0, we can find a sufficiently small δ(0,α(b1)β) and z2(zM,z0) such that

    δ=g(z2),Θ(z2)>0.

    Let p and m satisfy the following conditions:

    (A1) p>1f0(d1,c,λ2).

    (A2) m>β(b1)fα(d2,c,θ).

    Then, we introduce ¯ϕ1(z),¯ϕ2(z),ϕ_1(z),ϕ_2(z) as follows:

    ¯ϕ1(z)=1q  zR, (2.2)
    ϕ_1(z)={(1q)(11b)zz1,(1q)(11b(eλ1z+peλ2z))zz1, (2.3)
    ¯ϕ2(z)={1qb z0,1qbeλ2z z0, (2.4)
    ϕ_2(z)={1qbδzz2,1qb(eλ2zmeθz)zz2, (2.5)

    where z1<0 is defined by eλ1z1+peλ2z1=1.

    Lemma 2.2. Assume c>c. Then (¯ϕ1, ¯ϕ2) and (ϕ_1, ϕ_2) defined by (2.2)–(2.5) are a pair of upper-lower solutions of system (1.3).

    Proof. Firstly, we show that

    F(¯ϕ1,ϕ_2)(z)0

    holds for zR. For any zR, we have ¯ϕ1(z)=1qE and

    F(¯ϕ1,ϕ_2)(z)=(1q)q(1q)ϕ_2(zcτ)1+a(1q)+bϕ_2(zcτ)q(1q)=(1q)ϕ_2(zcτ)1+a(1q)+bϕ_2(zcτ)0.

    For zz1, we would like to show that

    F(ϕ_1,¯ϕ2)(z)0.

    When z>z1, we have ϕ_1(z)=(1q)(11b),¯ϕ2(z)1qb and

    F(ϕ_1,¯ϕ2)(z)(1q)b1b[1(1q)b1b1qb+a(1q)(b1)+b(1q)q]0.

    In view of f0(d1,c,λ2)<f0(d2,c,λ2)<fα(d2,c,λ2)=0 and (A1), for z<z1<0 we have ϕ_1=(1q)[11b(eλ1z+peλ2z)], ¯ϕ2=1qbeλ2z and

    F(ϕ_1,¯ϕ2)(z)d1(RJ(y)(1q)[11b(eλ1(zy)+peλ2(zy))]dy(1q)[11b(eλ1z+peλ2z)])+(1q)cb(λ1eλ1z+pλ2eλ2z)+(1q)2[11b(eλ1z+peλ2z)](1q)2[11b(eλ1z+peλ2z)]2ϕ_1¯ϕ2(zcτ)1+aϕ_1+b¯ϕ2=1qbeλ1z[d1(RJ(y)eλ1ydy1)cλ1]1qbpeλ2z[d1(RJ(y)eλ2ydy1)cλ2]+(1q)2b(eλ1z+peλ2z)[11b(eλ1z+peλ2z)]ϕ_1¯ϕ2(zcτ)1+aϕ_1+b¯ϕ2(zcτ)>1qbpeλ2z[d1(RJ(y)eλ2ydy1)cλ2]¯ϕ2(zcτ)=1qbpeλ2z[d1(RJ(y)eλ2ydy1)cλ2]1qbeλ2(zcτ)=1qbeλ2z[(p)(d1(RJ(y)eλ2ydy1)cλ2)eλ2cτ]>1qbeλ2z[(p)f0(d1,c,λ2)1]>0. (2.6)

    Now, we show

    F(¯ϕ1,¯ϕ2)(z)0

    for z0. In the case of z>0, we have ¯ϕ1=1q and ¯ϕ2=1qb. Then

    F(¯ϕ1,¯ϕ2)(z)1qb[αβ1qb1q]=1qb[αβb]0.

    For z<0, we obtain ¯ϕ2=1qbeλ2z and

    F(¯ϕ1,¯ϕ2)(z)d2(RJ(y)1qbeλ2(zy)dy1qbeλ2z)1qbcλ2eλ2z+1qbeλ2z[αβbeλ2z]=1qbeλ2z[d2(RJ(y)eλ2ydy1)cλ2+α]β(1q)b2e2λ2z=β(1q)b2e2λ2z0.

    Finally, to show

    F(ϕ_1,ϕ_2)(z)0

    for zz2, we use the inequality ϕ_1(1q)(11b) and ϕ_2=1qbδ if z>z2. Then

    F(ϕ_1,ϕ_2)(z)d2(1q)b[+zz2J(y)(eλ2(zy)meθ(zy))dy+zz2J(y)δdyδ]+1qbδ[αβ(1q)(11b)1qbδ]d2(1q)b(z2J(zy)(eλ2zmeθz)dyδ2)+1qbδ[αβδb1]=d2(1q)bΘ(z2)+1qbδ[αβδb1]1qbδ[αβδb1]0,

    due to 0<δ<α(b1)β.

    On the other hand, if z<z2, we have ϕ_2=1qb(eλ2zmeθz) and thus

    F(ϕ_1,ϕ_2)(z)d2(1q)b[RJ(y)(eλ2(zy)meθ(zy))dy(eλ2zmeθz)]c(1q)b(λ2eλ2zmθeθz)+1qb(eλ2zmeθz)[αβ(1q)(11b)1qb(eλ2zmeθz)]=1qbeλ2z[d2(RJ(y)eλ2ydy1)cλ2+α]m1qbeθz[d2(RJ(y)eθzdy1)cθ+α]β(1q)b(b1)(eλ2zmeθz)2>m1qbeθz[d2(RJ(y)eθzdy1)cθ+α]β(1q)b(b1)e2λ2z=1qbeθz[(m)(d2(RJ(y)eθzdy1)cθ+α)βb1e(2λ2θ)z]>1qbeθz[(m)(d2(RJ(y)eθzdy1)cθ+α)βb1]>1qbeθz[(m)fα(d2,c,θ)βb1]>0.

    The last inequality holds due to θ(λ2,min{2λ2,λ3}) and condition (A2).

    In this section, we start with discussing the existence of traveling wave solution for system (1.3) with condition (1.4) by using the upper-lower solutions of system (1.3), which is defined in the preceding section, to construct an invariant set.

    Let C be a set of bounded and uniformly continuous functions from R to R2 and

    Γ={(ϕ1,ϕ2)C:ϕ_i(z)ϕi¯ϕi(z), zR, i=1,2},

    where ¯ϕi(z) and ϕ_i(z) (i = 1, 2) are defined by (2.2)–(2.5). Thus for any (ϕ1,ϕ2)Γ, we have (1q)b1bϕ1(z)1q and  0ϕ2(z)1qb.

    For Φ=(ϕ1,ϕ2)Γ, we define

    {H1(ϕ1,ϕ2)(z):=d1Jϕ1(z)+F1(ϕ1(z),ϕ2(zcτ)),H2(ϕ1,ϕ2)(z):=d2Jϕ2(z)+F2(ϕ1(zcτ),ϕ2(z)),

    where

    {F1(y1,y2)=(γd1)y1+y1(1y1y21+ay1+by2q),F2(y1,y2)=(γd2)y2+y2(αβy2y1),

    for some constant γ. For any fixed γ>max{d1+(1q)(1+1b),d2+2βb1α}, it follows that F1 is nondecreasing in y1 and is decreasing in y2 for y1[(1q)b1b, 1q] and y2[0, 1qb]. Also, F2 is nondecreasing with respect to y1 and y2 for y1[(1q)b1b, 1q] and y2[0, 1qb].

    Define an operator P=(P1,P2):ΓC by

    {P1(ϕ1,ϕ2)(z)=1czeγ(zy)cH1(ϕ1,ϕ2)(y)dy,P2(ϕ1,ϕ2)(z)=1czeγ(zy)cH2(ϕ1,ϕ2)(y)dy.

    Apparently, a fixed point of P is a solution of system (1.3). Let ρ(0,γc) and |||| denote the Euclidean norm in R2. We define

    Bρ(R,R2)={ΦC:supzR||Φ(z)||eρ|z|<}

    and

    |Φ|ρ:=supzR||Φ(z)||eρ|z|.

    It is easy to see that (Bρ(R,R2)),||ρ) is a Banach space. Clearly, Γ is nonempty, bounded, convex and closed in Bρ(R,R2).

    Lemma 3.1. P:ΓΓ.

    Proof. For any Φ(z)=(ϕ1,ϕ2)(z)Γ, owing to the monotonicity of F1 and F2 we have

    {H1(ϕ1,ϕ2)(z)d1Jϕ_1(z)+F_1(z)=:H_1(z), zR,H1(ϕ1,ϕ2)(z)d1J¯ϕ1(z)+¯F1(z)=:¯H1(z), zR,

    and

    {H2(ϕ1,ϕ2)(z)d2Jϕ_2(z)+F_2(z)=:H_2(z), zR,H2(ϕ1,ϕ2)(z)d2J¯ϕ2(z)+¯F2(z)=:¯H2(z), zR,

    in which ¯F1, F_1, ¯F2 and F_2 are defined by

    {¯F1(z)=(γd1)¯ϕ1(z)+¯ϕ1(z)(1q¯ϕ1(z)ϕ_2(zcτ)1+a¯ϕ1(z)+bϕ_2(zcτ)),F_1(z)=(γd1)ϕ_1(z)+ϕ_1(z)(1qϕ_1(z)¯ϕ2(zcτ)1+aϕ_1(z)+b¯ϕ2(zcτ)),

    and

    {¯F2(z)=(γd2)¯ϕ2(z)+¯ϕ2(z)(αβ¯ϕ2(z)¯ϕ1(zcτ)),F_2(z)=(γd2)ϕ_2(z)+ϕ_2(z)(αβϕ_2(z)ϕ_1(zcτ)).

    Let

    P_1(z)=1czeγ(zy)cH_1(y)dy,  ¯P1(z)=1czeγ(zy)c¯H1(y)dy, zR,
    P_2(z)=1czeγ(zy)cH_2(y)dy,  ¯P2(z)=1czeγ(zy)c¯H2(y)dy, zR.

    Obviously, P_i(z)Pi(z)¯Pi(z) (i=1,2). It suffices to prove that

    ϕ_i(z)P_i(z),¯Pi(z)¯ϕi(z), zR, i=1,2.

    We denote z0= and zm+1=. For any zRZ, there exists a k{0,1,2,...,m} such that z(zk,zk+1), and

    ¯P1(z)=1czeγ(zy)c¯H1(y)dy=(ki=11czizi1+1czzk)eγ(zy)c¯H1(y)dy(ki=11czizi1+1czzk)eγ(zy)c[c¯ϕ1(y)dy+γ¯ϕ1(y)]=¯ϕ1(z).

    Due to the continuity of both ¯P1(z) and ¯ϕ1(z), we get

    ¯P1(z)¯ϕ1(z), zR.

    Similarly, we have

    ϕ_1(z)P_1(z), zR,

    and

    ϕ_2(z)P2(ϕ)(z)¯ϕ2(z), zR.

    Consequently, we obtain P(Γ)Γ.

    Lemma 3.2. P: ΓΓ is continuous with respect to ||ρ.

    Proof. For any Φ=(ϕ1,ϕ2) and Ψ=(ψ1,ψ2)Γ, we have

    |H1(ϕ1,ϕ2)(z)H1(ψ1,ψ2)(z)|d1RJ(zy)|ϕ1(y)ψ1(y)|dy+(γd1+1q)|ϕ1(z)ψ1(z)|+|ϕ1(z)+ψ1(z)||ϕ1(z)ψ1(z)|+|ϕ1(z)ϕ2(zcτ)1+aϕ1(z)+bϕ2(zcτ)ψ1(z)ψ2(zcτ)1+aψ1(z)+bψ2(zcτ)|

    and

    |ϕ1(z)ϕ2(zcτ)1+aϕ1(z)+bϕ2(zcτ)ψ1(z)ψ2(zcτ)1+aψ1(z)+bψ2(zcτ)|<1qb(2q)(1+a(1q)b1b)2|ϕ1(z)ψ1(z)|+(1q)(1+a(1q))(1+a(1q)b1b)2|ϕ2(zcτ)ψ2(zcτ)|<1qb(2q)|ϕ1(z)ψ1(z)|+(1q)(1+a(1q))|ϕ2(zcτ)ψ2(zcτ)|<1b(1q)(2q)|ϕ1(z)ψ1(z)|+a(1q)(2q)|ϕ2(zcτ)ψ2(zcτ)|.

    A straightforward calculation yields

    |P1(ϕ1,ϕ2)(z)P1(ψ1,ψ2)(z)|eρ|z|d1eρ|z|czeγ(zs)c(RJ(sy)|ϕ1(y)ψ1(y)|dy)ds+(γd1+1q)eρ|z|czeγ(zy)c|ϕ1(y)ψ1(y)|dy+2(1q)eρ|z|czeγ(zy)c|ϕ1(y)ψ1(y)|dy+(1q)(2q)eρ|z|cbzeγ(zy)c|ϕ1(y)ψ1(y)|dy+a(1q)(2q)eρ|z|czeγ(zy)c|ϕ2(ycτ)ψ2(ycτ)|dy=d1eρ|z|czeγ(zs)c(RJ(sy)|ϕ1(y)ψ1(y)|dy)ds+[γd1+(1q)(3+2qb)]eρ|z|czeγ(zy)c|ϕ1(y)ψ1(y)|dy+a(1q)(2q)eρ|z|czeγ(zy)c|ϕ2(ycτ)ψ2(ycτ)|dy.

    We further have

    eρ|z|czeγ(zs)c(RJ(sy)|ϕ1(y)ψ1(y)|dy)ds=eρ|z|czeγ(zs)c(RJ(sy)eρ|y||ϕ1(y)ψ1(y)|eρ|y|dy)ds|ΦΨ|ρcze(γcρ)(zs)(RJ(y)eρ|y|dy)ds2RJ(y)eρydyγcρ|ΦΨ|ρ

    and

    eρ|z|czeγ(zy)c|ϕ1(y)ψ1(y)|dy=eρ|z|czeγ(zy)ceρ|y||ϕ1(y)ψ1(y)|eρ|y|dy|ΦΨ|ρcze(γcρ)(zy)dy1γcρ|ΦΨ|ρ.

    Processing in an analogous manner, we can derive

    eρ|z|czeγ(zy)c|ϕ2(ycτ)ψ2(ycτ)|dyeρcτγcρ|ΦΨ|α.

    We now choose

    L1=2d1RJ(y)eρydy+γd1+(1q)[3+(1b+aeρcτ)(2q)]γcρ

    such that

    |P1(ϕ1,ϕ2)(z)P1(ψ1,ψ2)(z)|eρ|z|L1|ΦΨ|α. (3.1)

    On the other hand, we have

    |P2(ϕ1,ϕ2)(z)P2(ψ1,ψ2)(z)|eρ|z|d2eρ|z|czeγ(zs)c(RJ(ys)|ϕ2(y)ψ2(y)|dy)ds+(γd2+α+2bβ(b1)2)eρ|z|czeγ(zy)c|ϕ2(y)ψ2(y)|dy+βeα|z|(b1)2czeγ(zy)c|ϕ1(ycτ)ψ1(ycτ)|dyL2|ΦΨ|ρ, (3.2)

    where

    L2=2d2RJ(y)eρydy+γd2+α+β(2b+eρcτ)(b1)2γcρ.

    In view of (3.1)–(3.2), there exists some constant L>0 such that

    |P(ϕ)P(Ψ)|ρL|ΦΨ|ρ.

    Hence, P is a continuous operator from Γ to Γ.

    For any given NR, let RN:=(,N] and consider the domain of the functions of the space Bρ on RN:

    Bρ(RN,R2)={ΦC|RN: supzRN||Φ(z)||e|ρ|z<}.

    Then (Bρ(RN,R2),||Nρ) is a Banach space equipped with the norm ||Nρ defined by

    |Φ|Nα:=supzRN||Φ(z)||e|ρ|z.

    Let us recall Corduneanu's Theorem [37,§2.12].

    Lemma 3.3. Let FBα(RN,R2) be a set satisfying the following conditions:

    (1) F is bounded in Bα(RN,R2));

    (2) the functions belonging to F are equicontinuous on any compact interval of RN;

    (3) the functions in F are equiconvergent, i.e., for any given ε>0, there is a corresponding Z(ε)<0 such that Φ(z)Φ()e|ρ|z<ε for zZ(ε) and ΦF.

    Then F is compact in Bα(RN,R2).

    Lemma 3.4. P(Γ) is compact in Bρ.

    Proof. For any Φ=(ϕ1,ϕ2)Γ and nN, we define

    Pn(Φ)(z)={P(Φ)(n)z>n,P(Φ)(z)z(,n]. (3.3)

    Clearly, Pn(Γ) is compact if P(Γ)(z)|Rn is compact. We will show that the functions belonging to P(Γ)(z)|Rn satisfy all three conditions (1)–(3) in Lemma 3.3. Since P(Γ)Γ, it is easy to see that P(Γ)(z)|Rn is bounded. Indeed, for any z1,z2(,n] we deduce

    |P1(ϕ1,ϕ2)(z1)eρ|z1|P1(ϕ1,ϕ2)(z2)eρ|z2||=1c|eρ|z1|z1eγ(z1y)cH1(ϕ1,ϕ2)(y)dyeα|z2|z2eγ(z2y)cH1(ϕ1,ϕ2)(y)dy|=1c|e(ρ|z1|+γcz1)z1eγcyH1(ϕ1,ϕ2)(y)dye(ρ|z2|+γcz2)z2eγcyH1(ϕ1,ϕ2)(y)dy|1ceγcz1|z2z1eγcyH1(ϕ1,ϕ2)(y)dy|+1c(eρ|z2||eγcz1eγcz2|+eγcz1|eρ|z1|eρ|z2||)|z2eγcyH1(ϕ1,ϕ2)(y)dy|(1q)eγc|z2z1|[(1+γc)|z2z1|+1].

    Similarly, we have

    |P2(ϕ1,ϕ2)(z1)eρ|z1|P2(ϕ1,ϕ2)(z2)eρ|z2||1qbγ(γ+αβb)eγc|z2z1|[(1+γc)|z2z1|+1].

    This implies that P(Γ)(z)|Rn is equicontinuous on any compact interval of Rn.

    For any Φ(z)=(ϕ1(z),ϕ2(z))Γ, we find

    (1q)(11b(eλ1z+peλ2z))ϕ1(z)1q,  1qb(eλ2zmeθz)ϕ1(z)1qbeλ2z

    for z<min{z1, z2}. That is,

    limzϕ1(z)=1q,limzϕ2(z)=0.

    Then

    |ϕ1(z)(1q)|eρ|z|<1qb(e(λ1+ρ)z+pe(λ2+ρ)z),  |ϕ2(z)0|eρ|z|<1qbe(λ2+ρ)z

    for z<min{z1, z2}. That is, condition (3) is satisfied. According to Lemma 3.3, Pn(Γ)(z) is compact in the sense of the norm ||ρ. Note that

    |Pn(Φ)(z)P(Φ)(z)|eρ|z|2(1q)1+(γ+αβbbγ)2eρn0, as n.

    Hence, Pn(Φ)(z) converge to P(Φ)(z) with respect to the norm ||ρ, and P(Γ) is compact.

    From Lemmas 3.1–3.4 and Schauder's fixed point theorem, we can see that P has a fixed point ΦΓ such that P(Φ)=Φ, which is a solution of system (1.3). Hence, we obtain the following theorem immediately.

    Theorem 3.5. Assume that conditions (G1)–(G2) hold. Then for any fixed c>c, system (1.3) has a positive solution (ϕ1(z),ϕ2(z))Γ. That is, ϕ_i(z)ϕi(z)¯ϕi(z) (i=1,2), where ¯ϕi and ϕ_i (i=1,2) are defined by (2.2)–(2.5).

    We now discuss the asymptotic behavior of traveling wave solution described in Theorem 3.5. For z, it is easy to see that

    limzϕ1(z)=1q,limzϕ2(z)=0.

    By applying the contracting rectangles method, we analyze the asymptotic behavior of traveling wave solution as z. We define

    {E1(ξ,η):=ξ(1qEξη1+aξ+bη),E2(ξ,η):=η(αβηξ), (3.4)

    and

    u1(θ):=uθ,u2(θ):=(1+βaαb(1ϵ)(1θ))u,v1(θ):={vθ2(1ϵ)θ<2ϵvθϵ1ϵθ2ϵ, v2(θ):=v+abu(1θ), (3.5)

    for θ[0,1], where (u,v) is the equilibrium point of system (1.3) and 0<ϵ<min{14,bv1+au,11a}.

    Theorem 3.6. The following three statements are true.

    (C1) u1(θ) and v1(θ) are continuous and strictly increasing while u2(θ) and v2(θ) are continuous and strictly decreasing for θ[0,1].

    (C2) For θ[0,1], we have

    {u1(0)u1(θ)u1(1)=u=u2(1)u2(θ)u2(0),v1(0)v1(θ)v1(1)=v=v2(1)v2(θ)v2(0).

    (C3) If ξ1=u1(θ0), η1=v1(θ0) for any θ0(0,1) and

    u1(θ0))ξu2(θ0),  v1(θ0)ηv2(θ0),

    then E1(ξ1,η)>0 and E2(ξ,η1)>0.

    If ξ2=u2(θ0), η2=v2(θ0) for any θ0(0,1) and

    u1(θ0))ξu2(θ0),  v1(θ0)ηv2(θ0),

    then E1(ξ2,η)<0 and E2(ξ,η2)<0.

    Proof. It is easy to see that (C1)–(C2) are true.

    To prove (C3), we claim that for any θ0(0,1), there holds E1(ξ1,η)>0 with ξ1=u1(θ0)=uθ0 and v1(θ0)ηv2(θ0). As E1(ξ,η) is decreasing in η, we only need to show that E1(uθ0,v2(θ0))>0.

    Let

    ˜v(θ)=abuθ+abb2+ab(1q)abb21b(1q)+buθ.

    Then E1(uθ,˜v(θ))0 for θ[0,1]. In view of a>1q, it follows that

    v2(θ0)=v+abu(1θ0)=abuθ0+abb2+ab(1q)abb21b(1q)+bu<abuθ0+abb2+ab(1q)abb21b(1q)+buθ0=˜v(θ0).

    Thus, E1(uθ0,v2(θ0))>E1(uθ0,˜v(θ0))=0.

    To show E2(ξ,η1)>0 for any θ0(0,1), η1=v1(θ0) and u1(θ0))ξu2(θ0), we know that E2(ξ,η) is nondecreasing in ξ. So it is equivalent to prove E2(u1(θ0),v1(θ0))>0. When 2ϵθ0<1, in view of v1(θ0)=vθ0ϵ1ϵ we have

    E2(u1(θ0),v1(θ0))=v1(θ0)[αβvθ0ϵ1ϵuθ0]=αv1(θ0)ϵ(1θ0)θ0(1ϵ)>0.

    For 0<θ0<2ϵ, using v1(θ0)=vθ02(1ϵ) we have

    E2(u1(θ0),v1(θ0))=v1(θ0)[αβvθ02(1ϵ)uθ0]=αv1(θ0)12ϵ2(1ϵ)>0.

    For any θ0(0,1), to show E1(ξ2,η)<0, where ξ2=u2(θ0) and v1(θ0)ηv2(θ0), it suffices to prove that E1(u2(θ0),v1(θ0))<0. Let φ(θ):=E1(u2(θ),v1(θ))/u2(θ). Then φ(1)=0. We proceed by considering two cases.

    Case 1_: for 2ϵθ<1, from (3.5) we have v1(θ)=vθϵ1ϵ, u2(θ)=(1+βaαb(1ϵ)(1θ))u for θ[2ϵ,1), and then

    dφdθ=ddθ(1qu2(θ)v1(θ)1+au2(θ)+bv1(θ))=ρ1(θ)(1+au2(θ)+bv1(θ))2,

    where

    ρ1(θ)=du2dθ(1+au2(θ)+bv1(θ))2dv1dθ(1+au2(θ))+av1(θ)du2dθ=βaαb(1ϵ)u(1+au2(θ)+bv1(θ))2v1ϵ(1+au)βa2αbuv(1ϵ).

    Since αbβ and 0<ϵ<11a, we get

    ddθ(1+au2(θ)+bv1(θ))=bv1ϵβa2αbu(1ϵ)=bv1ϵ[1(βaαb)2(1ϵ)2]<0.

    It is easy to see that infθ[2ϵ,1)ρ1(θ)=ρ1(1). In view of 0<ϵ<min{14,bv1+au,11a}, we have

    ρ1(1)=βaαb(1ϵ)u[(1+au+bv)2av]v1ϵ(1+au)>u[(1+au+bv)2av1+au(1ϵ)]>u[1+2au+2bvav(1+2ϵ)(1+au)]>2u[bvϵ(1+au)]>0.

    This implies that for θ[2ϵ,1), ρ1(θ)>0 holds and φ(θ) is nondecreasing. That is, φ(θ)<0. Moreover, E1(u2(θ),v1(θ))=φ(θ)u2(θ)<0 for θ[2ϵ,1).

    Case 2_: for 0<θ<2ϵ, from (3.5) we have v1(θ)=vθ2(1ϵ) and u2(θ)=(1+βaαb(1ϵ)(1θ))u for θ(0,2ϵ). Then we get

    dφdθ=ρ2(θ)(1+au2(θ)+bv1(θ))2,

    where

    ρ2(θ)=βaαb(1ϵ)u(1+au2(θ)+bv1(θ))2v2(1ϵ)(1+au)βa22αbuv,

    and infθ(0,2ϵ)ρ2(θ)=ρ2(2ϵ). In view of 0<ϵ<min{14,bv1+au,11a}, there holds

    ρ2(2ϵ)>u[1+au(1+βaαb(1ϵ)(12ϵ))+ϵbv2(1ϵ)]2v2(1ϵ)(1+au)βa22αbuv>u[1+2au+2uβa2αb(13ϵ)1+2ϵ2(1+au)βa22αbu]=u[(11+2ϵ2)+(21+2ϵ2)au+(2(13ϵ)12)βa2αbu]>0.

    Since φ(2ϵ)<0, for θ(0,2ϵ) we have ρ2(θ)>0 and φ(θ)<0. This leads to E1(u2(θ),v1(θ))=φ(θ)u2(θ)<0 for θ(0,2ϵ). Hence, E1(u2(θ),v1(θ))<0 for θ(0,1).

    To prove E2(ξ,η2)<0 for θ0(0,1), η2=v2(θ0) and u1(θ0))ξu2(θ0), from (3.5) we deduce

    E2(u2(θ0),v2(θ0))=v2(θ0)[αβv+abu(1θ0)u+βaαb(1ϵ)(1θ0)u]<v2(θ0)[αβv+abu(1θ0)u+βaαbu(1θ0)]=v2(θ0)[αβv+abu(1θ0)βα(v+abu(1θ0))]=0.

    Hence, E2(u2(θ),v2(θ))<0 for any θ(0,1).

    Theorem 3.7. Assume that conditions (G1)–(G2) hold and Φ=(ϕ1,ϕ2)Γ is a solution of system (1.3). Then we have

    limz(ϕ1(z),ϕ2(z))=(u,v). (3.6)

    Proof. From (3.5), we observe

    u1(0)=0,u2(0)=u+βaαb(1ϵ)u>2u>1q,v1(0)=0,v2(0)=v+abu>v+ub>1qb.

    In view of (ϕ1,ϕ2)Γ for z>>0, it follows that

    (1q)(11b)ϕ1(z)1q,1qbδϕ2(z)1qb.

    So we have

    u1(θ0))lim infzϕ1(z)lim supzϕ1(z)u2(θ0),v1(θ0)lim infξϕ2(z)lim supzϕ2(z)v2(θ0), (3.7)

    for some θ0(0,1).

    Denote

    θ:=sup{θ[θ0,1)| (3.7) hold}.

    Then, θ=1. Otherwise, we have θ<1 in (3.7). Namely, at least one of the following equalities is true:

    u1(θ)=lim infzϕ1(z), u2(θ)=lim supzϕ1(z),
    v1(θ)=lim infzϕ2(z), v2(θ)=lim supzϕ2(z).

    Without loss of generality, we assume that

    u1(θ)=lim infzϕ1(z).

    It follows from Lebesgue's dominated convergence theorem that

    lim infzϕ1(z)=lim infz1γ[γϕ1(z)+E1(ϕ1(z),ϕ2(zcτ))]lim infzϕ1(z)+1γE1(lim infzϕ1(z),lim supzϕ2(z)).

    That is,

    E1(lim infzϕ1(z), lim supzϕ2(z))0.

    This implies that E1(u1(θ), η)0 with v1(θ)ηv2(θ), which yields a contradiction to (C3) of Theorem 3.6. The other three cases can be proceeded in an analogous manner.

    Let zRN with NR. We define

    Cl(RN,R2)={(ϕ1,ϕ2)C|RN: limzϕ1(z)=ϕ1(),limzϕ2(z)=ϕ2()}.

    It is not difficult to see that Cl(RN,R2) is isomorphic to C([NN1,1],R2). Indeed, if x(s)C([NN1,1],R2), then y(t)=x(s) for t=ss1, s[NN1,1), and y(t)Cl(RN,R2). That is, Cl(RN,R2) is a Banach space equipped with the superemum norm.

    Theorem 4.1. When c=c, system (1.3) has a positive traveling wave solution satisfying (1.4).

    Proof. Let {cn} be a decreasing sequence with cn<c+1 and limncn=c. Then for each cn, system (1.3) has a positive traveling wave solution (ϕ1n(z),ϕ2n(z)) satisfying (1.4) and

    (1q)b1bϕ1n(z)1q,  0ϕ2n(z)1qb.

    Since a traveling wave solution is invariant in the sense of phase shift, we can assume that

    ϕ1n(0)=(1q)ι1, ϕ1n(z)>(1q)ι1 for z<0 and ϕ2n(0)=ι2, ϕ2n(z)<ι2 for z<0,

    with b1b<ι1<1 and 0<ι2<1qb. From (1.4), we know that the above expressions are admissible.

    For nN, it is evident that (ϕ1n(z),ϕ2n(z)) are equipcontinuous, bounded and equipconvergent in Cl(RN,R2). According to Lemma 3.3, {(ϕ1n(z),ϕ2n(z))} has a subsequence, still denoted by {(ϕ1n(z),ϕ2n(z))}, such that

    ϕ1n(z)ϕ1(z), ϕ2n(z)ϕ2(z), as n

    and

    limzϕ1(z)=1q,limzϕ2(z)=0.

    Here, (ϕ1(z),ϕ2(z))Cl(RN,R2) is continuous and the above limits converge uniformly on RN. It follows from Lebesgue's dominated convergence theorem that

    limnJϕin(z)=ϕi(z),i=1,2

    on zRN. Thus, (ϕ1(z),ϕ2(z)) is a solution to system (1.3) which satisfies

    ϕ1(0)=(1q)ι1, ϕ1(z)>(1q)ι1 for z<0 and ϕ2(0)=ι2, ϕ2(z)<ι2 for z<0,

    and

    (1q)b1bϕ1(z)1q,  0ϕ2(z)1qb.

    From ϕ2(0)=ι2>0, lim infzϕ2(z)>0 holds. By virtue of Theorem 3.7, we obtain

    limz+ϕ1(z)=u,  limz+ϕ2(z)=v.

    Consider the Cauchy problem:

    {u(x,t)t=d(Ju(x,t)u(x,t))+u(x,t)(1ru(x,t)),u(x,0)=u0(x), xR, (5.1)

    where J satisfies condition (G1), r>0 is constant and the initial value u0(x) is uniformly continuous and bounded for xR.

    Lemma 5.1. [32] Assume that 0u0(x)1r. Then system (5.1) admits a solution for xR and t>0. If ω(x,0) is uniformly continuous and bounded, and ω(x,0) satisfies

    {ω(x,t)t()d(Jω(x,t)ω(x,t))+ω(x,t)(1rω(x,t)),ω(x,0)()u0(x), xR,

    then we have

    ω(x,t)()u(x,t), xR, t>0.

    Lemma 5.2. [32] Assume that u0(x)>0. Then for any 0<c<c there holds

    lim inftinf|x|<ctu(x,t, u0(x))=lim suptsup|x|<ctu(x,t, u0(x))=1r.

    Theorem 5.3. For any speed 0<c<c, there is no nontrivial positive solution (ϕ1(z),ϕ2(z)) of system (1.3) satisfying condition (1.4).

    Proof. Suppose on the contrary that there exists some 0<c1<c, such that system (1.3) has a positive solution (ϕ1(z),ϕ2(z)) satisfying condition (1.4). Then ϕ1(z) is bounded on R and we can find a positive constant K such that ψ(x,t)=ϕ2(x+ct) satisfies

    {ψ(x,t)td2(Jψ(x,t)ψ(x,t))+αψ(x,t)(1Kψ(x,t)),ψ(x,0)=ϕ2(x)>0.

    Let x(t)=c1+c2t. From Lemmas 5.1 and 5.2 it follows that

    lim inftinf2|x|=(c1+c)tψ(x,t)1K.

    Meanwhile, in view of x(t)+c1t=c1c2t, we see z=x(t)+c1t as t+, and

    lim suptψ(x(t),t)=limzϕ2(z)=0.

    This yields a contradiction.

    In this paper, we have studied the existence and nonexistence of traveling wave solution of a nonlocal delayed predator-prey model with the B-D functional response and harvesting. As we see, model (1.3) is nonmonotone or not quasimonotone. We employed Schauder's fixed point theorem and the upper-lower solutions method to discuss the existence of traveling wave solution for the speed c>c. Then, we investigated the asymptotic behavior of traveling wave solution by construction of the upper-lower solutions at and by developing the contacting rectangles technique at +. For the special case of c=c, one usually can not establish the existence of traveling wave solution directly by constructing a pair of upper-lower solutions. One of available methods is the limiting argument together with the Arzela-Ascoli Theorem [33,36,39]. In this study we have presented not only the existence of traveling wave solution but also the asymptotic behavior of traveling wave solution at by Corduneanu's theorem. The nonexistence of traveling wave solution of system (1.3) with condition (1.4) was investigated by applying the comparison principle of nonlocal dispersal equations.

    It is remarkable that for the parameters of system (1.3), we only need b>1 and 0<bαβ to prove Theorem 3.5. These conditions were used to construct a pair of suitable upper-lower solutions of system (1.3). For a>1 and 0<aαβ, we could also construct the appropriate upper-lower solutions of system (1.3) in a similar way. To obtain the asymptotic behavior of traveling wave solution as z, we additionally needed a>1q.

    When q=0 in model (1.3), it means that there does not have any prey harvesting. By assuming b>1, 0<bαβ and a>bαβ, we can derive the same results as Theorems 3.5 and 3.7 in an analogous manner.

    We are grateful to the anonymous referees for their valuable comments. This work is supported by National Science Foundation of China under 11601029. All authors declare no conflicts of interest in this paper.

    The authors declare there is no conflicts of interest.



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