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Research article Special Issues

Imaging flow cytometry methods for quantitative analysis of label-free crystalline silica particle interactions with immune cells

  • Exposure to respirable fractions of crystalline silica quartz dust particles is associated with silicosis, cancer and the development of autoimmune conditions. Early cellular interactions are not well understood, partly due to a lack of suitable technological methods. Improved techniques are needed to better quantify and study high-level respirable crystalline silica exposure in human populations. Techniques that can be applied to complex biological matrices are pivotal to understanding particle-cell interactions and the impact of particles within real, biologically complex environments. In this study, we investigated whether imaging flow cytometry could be used to assess the interactions between cells and crystalline silica when present within complex biological matrices. Using the respirable-size fine quartz crystalline silica dust Min-u-sil® 5, we first validated previous reports that, whilst associating with cells, crystalline silica particles can be detected solely through their differential light scattering profile using conventional flow cytometry. This same property reliably identified crystalline silica in association with primary monocytic cells in vitro using an imaging flow cytometry assay, where darkfield intensity measurements were able to detect crystalline silica concentrations as low as 2.5 µg/mL. Finally, we ultilised fresh whole blood as an exemplary complex biological matrix to test the technique. Even after the increased sample processing required to analyse cells within whole blood, imaging flow cytometry was capable of detecting and assessing silica-association to cells. As expected, in fresh whole blood exposed to crystalline silica, neutrophils and cells of the monocyte/macrophage lineage phagocytosed the particles. In addition to the use of this technique in in vitro exposure models, this method has the potential to be applied directly to ex vivo diagnostic studies and research models, where the identification of crystalline silica association with cells in complex biological matrices such as bronchial lavage fluids, alongside additional functional and phenotypic cellular readouts, is required.

    Citation: Bradley Vis, Jonathan J. Powell, Rachel E. Hewitt. Imaging flow cytometry methods for quantitative analysis of label-free crystalline silica particle interactions with immune cells[J]. AIMS Biophysics, 2020, 7(3): 144-166. doi: 10.3934/biophy.2020012

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  • Exposure to respirable fractions of crystalline silica quartz dust particles is associated with silicosis, cancer and the development of autoimmune conditions. Early cellular interactions are not well understood, partly due to a lack of suitable technological methods. Improved techniques are needed to better quantify and study high-level respirable crystalline silica exposure in human populations. Techniques that can be applied to complex biological matrices are pivotal to understanding particle-cell interactions and the impact of particles within real, biologically complex environments. In this study, we investigated whether imaging flow cytometry could be used to assess the interactions between cells and crystalline silica when present within complex biological matrices. Using the respirable-size fine quartz crystalline silica dust Min-u-sil® 5, we first validated previous reports that, whilst associating with cells, crystalline silica particles can be detected solely through their differential light scattering profile using conventional flow cytometry. This same property reliably identified crystalline silica in association with primary monocytic cells in vitro using an imaging flow cytometry assay, where darkfield intensity measurements were able to detect crystalline silica concentrations as low as 2.5 µg/mL. Finally, we ultilised fresh whole blood as an exemplary complex biological matrix to test the technique. Even after the increased sample processing required to analyse cells within whole blood, imaging flow cytometry was capable of detecting and assessing silica-association to cells. As expected, in fresh whole blood exposed to crystalline silica, neutrophils and cells of the monocyte/macrophage lineage phagocytosed the particles. In addition to the use of this technique in in vitro exposure models, this method has the potential to be applied directly to ex vivo diagnostic studies and research models, where the identification of crystalline silica association with cells in complex biological matrices such as bronchial lavage fluids, alongside additional functional and phenotypic cellular readouts, is required.



    Impulsive differential equations (IDEs) are often used to simulate some evolutionary processes in the real world, such as shocks, population dynamics, harvesting. These evolutionary processes tend to have some sudden changes that are negligible compared to the whole duration of the process. The theory of IDEs has been widely used in mathematical modeling and has become an important research field in recent years. However, some dynamical behaviors of physical phenomena cannot be modeled by instantaneous IDEs, see [1,2,3,4,5].

    Thus, Hernández and O'Regan [6] introduces a non-instantaneous impulses, a special and novel type of impulses, in the form of

    {ξ(δ)=Aξ(δ)+g(δ,ξ(δ)), δ(δk,ηk+1],k=0,1,2...l;ξ(δ)=hk(δ,ξ(δ)), δ(ηk,δk],k=1,2,...l;ξ(0)=ξ0,

    where A:D(A)XX is the generator of a C0-semigroup of bounded linear operators {T(δ)}δ0 defined on a Banach space (X,), ξ0X, 0=η0=δ0<η1δ1<η2<<ηlδlηl+1=a are pre-fixed numbers, hkC((ηk,δk]×X;X) for all k=1,...,l and g:[0,a]×XX is a suitable function.

    Wang and Fěckan [7] investigates the existence of mild solutions to nonlinear operator equations with non-instantaneous impulses. Malik and Kumar [8] consider a control system represented by a second-order IDEs and obtained the existence, uniqueness and stability of mild solution. Since non-instantaneous IDEs can model some physical phenomena that remain active in fixed time intervals, this has attracted extensive attention of many researchers. For detailed results, see [9,10,11,12,13,14,15,16].

    Furthermore, the complex case with infinitely many perturbation points in a finite interval, called Zeno behavior [17], cannot be modeled by IDEs. Consequently, Pandit et al. [18] and Sharma et al. [19] established an important class of differential equations, called measure differential equations (MDEs), to deal with this complex phenomenon. Thenceforth, in [20], the existence of regulated solutions for MDEs is obtained by utilizing fixed point theorem. Federson and Mesquita [21] investigated the Lyapunov stability for abstract MDEs on time scales. For detailed results, see [18,22,23,24,25,26].

    As we know, since controllability can be described as a qualitative property of a control system, it is of great interest to researchers [1,27,28,29,30]. A common way to study controllability problems is to transform it into fixed point problems for continuous operators in Banach spaces. For instance, Ankit and Rames [31] considered the approximate controllability results in the infinite dimensional space for non-autonomous evolution system with time delay from fixed point theorem. Zhao and Liu [32] investigated the existence and controllability of solutions for semilinear fractional control systems with finite delay via differentiable resolvent operators and Banach's fixed point theorem. In [1], by utilizing the fixed point theorem and fundamental solution, the approximate controllable result for nonlinear measure evolution system with time delay and non-instantaneous impulses was obtained.

    More generally, by fixed point theorem, Cao and Sun [33] studies that the control system is exactly controllable, and its system form is

    {du(ξ)=A(ξ)u(ξ)+F(ξ,u(ξ))dμ(ξ)+Bv(ξ), ξ[0,l];u(0)+g(u)=u0.

    Subsequently, Liu et al. [34] considered fractional evolution equations with state-dependent delay as follows

    {cDαv(ι)=Av(ι)+[Bu(ι)+f(ι,vρ(ι,vι))]dμ(ι), ι[0,a];v(ι)+p(vι1,vι2,,vιm)(ι)=ϕ(ι), ι(,0],

    where cDα is Caputo derivative. By utilizing the Kuratowski measure of noncompactness and Mönch fixed point theorem, the exact controllability was investigated.

    Wang et al. [35] studied the following non-instantaneous impulsive evolution system.

    {cDαω(ξ)F(ξ,ω(ξ))+B(v(ξ)), ξ(σi,τi+1],i=0,1,,k;ω(τ+i)=gi(τi,ω(τi)),i=1,,k;ω(ξ)=gi(ξ,ω(τi)),ξ(τi,σi],i=1,,k;ω(0)=ω0.

    Using the Banach fixed point theorem, exact controllability was obtained.

    But, Wang et al. achieved controllability by using control only at the last time subinterval rather than at each impulses point. In many engineering applications, it is necessary to control the system within each impulse time interval. So, we introduce a stronger concept of exact controllability, namely total controllability. This control will be applied to each subinterval. Moveover, many physical phenomena, such as the lateral motion of stretchable beams and the vibration of hinged rods, can be modeled with partial differential equations (PDEs). These PDEs can be formulated as abstract second-order IDEs in the infinite dimensional spaces. So, it is necessary to study such systems. For detailed results, see [8,9,10,31,36].

    Inspired by the above discussion, this manuscript will focus on the controllability of second-order non-instantaneous impulsive measure evolution systems with state-dependent delay and non-autonomous conditions in a Banach space (X, ), which is of form

    {dv(η)=A(η)v(η)+[Bz(η)+F(η,vρ(η,vη),Gvρ(η,vη))]dμ(η), ηki=0(θi,ηi+1];v(η)=Hi(η,v(τi)), ηki=1(ηi,θi];v(η)=Hi(η,v(ηi)), ηki=1(ηi,θi];v(η)=ϕ(η), v(0)=ωX, η(,0], (1.1)

    where J=[0,b], ϕBh, Bh is a phase space, which will be introduced in Section 2. 0=θ0<η1<η2<<ηk<ηk+1=b, θi(ηi,ηi+1) and v+i, vi exist for i=1,2,,k with v(ηi)=v(ηi). F:J×Bh×BhX. The family of linear operators {A(η):ηJ} is closed and domain is dense in X. The function vη:(,0]X defined by vη(ν)=v(η+ν), ν(,0] which belongs to Bh. The distributional derivative of the solution v and the function μ are denoted by dv and dμ, respectively, where function μ:JR is left continuous nondecreasing. The control function z()HSL2μ(J;U), where HLS2μ(J;U) will be introduced in the next Section. ρ: J×Bh(,b] is a continuous function. The linear operator B:UX is bounded. The function Hi:(ηi,θi]×XX and their derivatives Hi:(ηi,θi]×XX represent the non-instantaneous impulses for i=1,2k. Gvρ(η,vη):=η0H(η,θ)vρ(θ,vθ)dθ is a Volterra integral operator with an integral kernel HC(Ω,R+), Ω={(η,θ):0ηθb}.

    The main contributions, significance and novelties of this article are as follows:

    ● The existence and total controllability of solution for (1.1) are obtained by employing the Mönch fixed point theorem and the theory of strongly continuous cosine family.

    ● It is well known that systems with Zeno trajectories often appear in game theory, non-smooth mechanics, etc (see [17,37]). MDEs are often used to model such systems. It may exhibit an infinite number of discontinuities within a finite interval, μ is a function of bounded variation.

    ● We point out that if μ is the sum of an absolutely continuous and a step function, then system (1.1) implies a complex situation that exhibits both non-instantaneous and instantaneous impulses. Few existing article have investigated such cases, which is an approach for solving hybrid systems separately.

    ● It is important to note that the obtained controllability results reach the desired state not only at the end of the time interval but also at each impulse point ηi+1.

    ● As [1,36] said, MDEs are more extensive than ODEs. In fact, when a system described by

    dxdt=f(t,x)

    is acted upon by perturbation, the perturbed system is generally given by

    dxdt=f(t,x)+G(t,x)

    where the perturbation term G(t,x) is assumed to be continuous or integrable and as such the state of the system changes continuously with respect to time.

    But in physical systems one cannot expect the perturbations to be well-behaved and it is therefore important to consider the case when the perturbations are impulsive. This will give rise to equations of the form

    dx=f(t,x)+G(t,x)dμ (1.2)

    where dx and dμ denote the distributional derivatives of the solution x and the function μ, respectively. If μ is a function of bounded variation, dμ can be identified with a Stieltjes measure and will have the effect of suddenly changing the state of the system at the points of discontinuity of μ. Equations (1.2) is so called measure differential equations.

    ● The derived results are involving non-instantaneous impulse and state-dependent delay; therefore, they improved and generalized the results of the paper of Cao and Sun [33]. Our findings are also generalizing the results of Liu et al. [34] for the case of control system with state-dependent delay.

    ● Finally, an example is used to verify the practical application of the conclusion.

    The structure of this paper is as follows. In Section 2, the fundamental concepts, lemma, and preliminary knowledge are given which will be required for the later sections. We obtain the controllability results for system (1.1) by using the theory of cosine families and fixed point theorem in Section 3. Finally, in Section 4, an example to verify the usefulness of our abstract results.

    In present section, we review some of the basic concepts, definitions and lemmas required.

    Definition 2.1. [20] A function F:[ξ,ζ]X is called regulated on [ξ,ζ], if the limits

    limθλF(θ)=F(λ),limθλ+F(θ)=F(λ+)

    exist and are finite for λ[ξ,ζ].

    The space G([ξ,ζ];X)={F:[ξ,ζ]X | F is regulated} is a Banach space with respect to the norm F=supη[ξ,ζ]{F(η)} (see [38]).

    Lemma 2.2. [39] Let the functions μ:[ξ,ζ]R and F:[ξ,ζ]X such that ζξFdμ exists and μ is regulated. Then, for η0[ξ,ζ], the function

    L(η)=ηη0F(θ)dμ(θ), η[ξ,ζ]

    is regulated.

    Definition 2.3. [39] For any ε>0, η0[ξ,ζ], a set AG([ξ,ζ];X) is said to be equiregulated, if there exists a δ>0 such that

    (ⅰ) if vA, η[ξ,ζ], and η0δ<η<η0, then v(η0)v(η)<ε,

    (ⅱ) if vA, η[ξ,ζ], and η0<η<η0+δ, then v(η)v(η+0)<ε.

    Lemma 2.4. [39] If a sequence {vn}n=1 is equiregulated and converges pointwise in X, then it converges uniformly in G([ξ,ζ];X).

    Definition 2.5. [20] A function F:[ξ,ζ]X is said to be Henstock-Lebesgue-Stieltjes integrable on [ξ,ζ) if there exists a map denoted by 0:[ξ,ζ]X such that for every ε>0, there is a gauge δ on [ξ,ζ) with

    ni=1F(λi)(μ(ηi)μ(ηi1))(ηi0F(θ)dμ(θ)ηi10F(θ)dμ(θ))<ε

    for every δ-fine partition {([ηi1,ηi),λi):i=1,2,,n} of [ξ,ζ).

    Let HLSpμ([ξ,ζ];X) be a p-order Henstock-Lebesgue-Stieltjes integrable regulated function space with respect to μ, with norm defined as

    FHLSpμ=(ζξF(θ)pdμ(θ))1p.

    Next, we define

    Bh={ϕ:(,0]X such that c>0, ϕ(θ) is a measurable bounded function on [c,0] with 0h(θ)supθτ0|ϕ(τ)|dθ<},

    where the function h:(,0](0,) is continuous with 0h(θ)dθ<.

    By [40], we know that Bh is a Banach space with norm

    ϕBh=0h(θ)supθτ0|ϕ(τ)|dθ, ϕBh.

    Lemma 2.6. [40] Let vBh; then, vηBh for each ηJ. In addition,

    l|v(η)|vηBhlsupθ[0,η](v(θ)+v0Bh),

    where l=0h(θ)dθ<.

    The Kuratowski measure of noncompactness α() on bounded subset S of X is defined as

    α(S)=inf{ε>0: S=ni=1Si with diameter(Si)ε , i=1,2...n,nN}.

    The Kuratowski measure of noncompactness of a bounded set in G(J;X) and X are denoted by αG(), and α(), respectively.

    Lemma 2.7. [41] Let SHLS1μ(J;X) be a countable set and function νHLS1μ(J;R+) such that r(η)ν(η) holds for all rS and ηJ. Then,

    α(JS(η)dμ(η))2Jα(S(η))dμ(η),

    where S(η)={y(η):yS, ηJ}.

    Lemma 2.8. [34] Let AG(J;X) be equiregulated and bounded on J. Then,

    α(A)=supηJ{α(A(η))}.

    Theorem 2.9. [34] (Mönch fixed point theorem) Let EX be a closed convex set where X is a Banach space. Assume that T:EE is a continuous operator and satisfies the following properties:

    DEcountable,D¯co({ϖ}T(D))impliesDisrelativelycompact.

    Therefore, T has a fixed point in E.

    Now let us consider a second-order non-autonomous control system:

    {v(η)=A(η)v(η)+g(η), 0θηb;v(θ)=x, v(θ)=y, (2.1)

    where A(η): D(A(η))XX, η[0,b] is a closed dense operator and g:[0,b]X is an appropriate function. It can be known from [31,42] that before considering the existence of the solution of (2.1), we first discuss the existence of the evolution operator of the following homogeneous equation

    v(η)=A(η)v(η), 0θηb.v(θ)=x, v(θ)=y. (2.2)

    Suppose the domain of A(η) is a dense subspace D in X and independent of η. ηA(η)v is a continuous function for each vD.

    For further study, we first review the definition of evolution operator.

    Definition 2.10 The bounded linear operator Φ(η,θ):J×JL(X) is said to be the evolution operator of (2.2) if the following properties are satisfied:

    (B1) For each vX, the operator (η,θ)Φ(η,θ)v is continuously differentiable and

    (ⅰ)

    ηΦ(η,θ)v|η=θ=v, θΦ(η,θ)v|η=θ=v, for each vX, η,θJ.

    (ⅱ) Φ(θ,θ)=0, for every θ[0,b].

    (B2) If vD(A), then Φ(η,θ)vD(A) for θ,η[0,b], the mapping (η,θ)[0,b]×[0,b]Φ(η,θ)vX is of class C2 and

    (ⅰ) 2θηΦ(η,θ)v|η=θ=0,

    (ⅱ) 2η2Φ(η,θ)v=A(η)Φ(η,θ)v,

    (ⅲ) 2θ2Φ(η,θ)v=Φ(η,θ)A(θ)v,

    (B3) For all η,θ[0,b], if vD(A), then θΦ(η,θ)vD(A). Further, there exist 2η2θΦ(η,θ)v, 2θ2ηΦ(η,θ)v and

    (ⅰ) θΦ(η,θ)vD(A), then 2η2θΦ(η,θ)v=A(η)θΦ(η,θ)v,

    (ⅱ) θΦ(η,θ)vD(A), then 2θ2ηΦ(η,θ)v=ηΦ(η,θ)A(θ)v, and the function (η,θ)[0,b]×[0,b]A(η)θΦ(η,θ)v is continuous.

    Let the evolution operator Φ(η,θ) be associated with the operator {A(η):ηJ}. For simplicity, one can also consider that

    Ψ(η,θ)=θΦ(η,θ).

    There exist constants M and N such that

    sup0η,θbΦ(η,θ)L(X)M, sup0η,θbΨ(η,θ)L(X)N.

    If function g:JX is integrable, then the solution v of the system (2.1) is given by

    v(η)=Ψ(η,θ)x+Φ(η,θ)y+ηθΦ(η,τ)g(τ)dτ. (2.3)

    Definition 2.11. The bounded linear operator parameter family {Ψ(η)}ηR that maps from Banach space X to itself is called the strongly continuous cosine family, if and only if

    (ⅰ) for all θ,ηR, Ψ(θ+η)+Ψ(θη)=2Ψ(θ)Ψ(η),

    (ⅱ) Ψ(0)=I (identity operator),

    (ⅲ) for each fixed point vX, Ψ(η)v is continuous in η on R.

    Let A:D(A)XX be the infinitesimal generator of strongly continuous cosine family {Ψ(η)}ηR, where domain D(A) is defined as

    D(A)={vX:Ψ(η)vC2(R;X)}.

    Obviously, for vD(A), it is a Banach space endowed with the norm vA=v+Av.

    In addition, the family of sine operators {Φ(η)}ηR corresponding to {Ψ(η)}ηR is defined as

    Φ(η)v=η0Ψ(θ)vdθ, vX, ηR.

    Let

    D={vX:Φ(η)vC1(R;X)},

    which is a Banach space endowed with norm vD=v+sup0η1AΦ(η)v, vD (see [43]).

    Based on the works in [36], we consider the following system

    {v(η)=(A+˜A(η))v(η), ηR;v(0)=x0, v(0)=y0, (2.4)

    where ˜A(): RL(D,X) such that for each vD, the map η˜A(η)v is a continuously differentiable function in X. Similar to Eq (2.3), we can also obtain that the mild solution of system (2.4) defined as

    v(η,θ)=Ψ(η,θ)x0+Φ(η,θ)y0+ηθΦ(η,τ)˜A(τ)v(τ,θ)dτ.

    For more theoretical results on second-order differential equations, see [31,36,42,43] and its cited references.

    Now, we are ready to introduce the concept of a mild solution of the system (1.1) as follows.

    Definition 2.12. A function vG(J,X) is said to be a mild solution of the system (1.1) if v(0)=ϕ(0), and it satisfies the following equation

    v(t)={Ψ(η,0)ϕ(0)+Φ(η,0)ω+η0Φ(η,θ)[Bz(θ)+F(θ,vρ(θ,vθ),Gvρ(θ,vθ))]dμ(θ), η[0,η1];Hi(η,v(ηi)), ηki=1(ηi,θi];Ψ(η,θi)Hi(θi,v(ηi))+Φ(η,θi)Hi(θi,v(ηi))+ηθiΦ(η,θ)[Bz(θ)+F(θ,vρ(θ,vθ),Gvρ(θ,vθ))]dμ(θ), ηki=1(θi,ηi+1]. (2.5)

    This section mainly studies the controllability of (1.1).

    Definition 3.1. System (1.1) is said to be exactly controllable on J if for the initial state v(0)Bh and any final state vbX, there is a control zHLS2μ(J;U) such that the mild solution v(η) of (1.1) satisfies v(b)=vb.

    Definition 3.2. System (1.1) is said to be totally controllable on J if for the initial state v(0)Bh and any final state vηi+1X of each sub-interval [θi,ηi+1] for i=0,1,2,...,k, there is a control zHLS2μ(J;U) such that the mild solution v(η) of (1.1) satisfies v(ηi+1)=vηi+1.

    Remark 3.3. If the total controllability of (1.1) is established, obviously it is exactly controllable. On the contrary, it does not hold.

    The following assumptions are introduced to demonstrate the main results of this paper.

    (H1) A(η) is the infinitesimal generator of a strongly continuous cosine family Ψ(η,θ).

    (H2) The function F:J×Bh×BhX satisfies that:

    (ⅰ) For each ηJ, F(η,,):Bh×BhX is a continuous function.

    (ⅱ) For ηJ, the map ηF(η,vρ(t,vη),Gvρ(η,vη)) and ηF(θ,vη) are measurable and continuous on J, respectively.

    (ⅲ) There exists a function ψrHLS2μ(J;R+), r>0 such that

    sup{F(η,ξ1,ξ2):ξ1Bhr,ξ2BhHr}ψr(η), a.e. ηJ,

    and

    γ:=lim supr+1rb0ψr(η)dμ(η)<+,

    where H:=supηJη0H(η,θ)dθ.

    (ⅳ) There exists l0HLS1μ(J,R+) such that for any bounded subsets S1,S2Bh,

    α(F(η,S1,S2))<l0(η)(α(S1)+α(S2)), ηJ.

    (H3) For each i=0,1,...,k, the linear operator Li+1:HLS2μ([θi,ηi+1];X)X defined by

    Li+1z=ηi+1θiΦ(ηi+1,θ)Bz(θ)dμ(θ)

    is such that

    (ⅰ) Li+1 has an invertible operator L1i+1, which take values in HLS2μ([θi,ηi+1];X)kerLi+1 and there exists Mi+1 such that L1i+1Mi+1.

    (ⅱ) There exists li+1HLS1μ(J,R+) such that

    α(L1i+1(S)(η))li+1(η)α(S), ηJ,

    for any countable subset SX.

    (H4) The operator Hi:[ηi,θi]×XX(i=1,2,3...,k) is continuous and there exist constants ai,bi such that

    Hi(v)ai, α(Hi(S))biα(S),

    for any countable subset SX.

    (H5) The operator Hi:[ηi,θi]×XX(i=1,2,3...,k) is continuous and there exist constants ci,di such that

    Hi(v)ci, α(Hi(S))diα(S),

    for any countable subset SX.

    Remark 3.4. It can be seen from the discussion in Section 2 that A produces a strongly continuous cosine family and corresponding strongly continuous sine family. This can represent a mild solution of system (1.1). Then, we can define an operator T. (H2) requires F to be continuously measurable, ensuring that the operator T is continuous. Assumptions (H3), we defined an invertible linear operator Li+1, which will be used to define the control function zv(η). Assumptions (H4), (H5) ensures that the operator T is continuously bounded, which helps us to discuss the controllability of the system (1.1) in a closed convex set.

    For simplicity, for r>0, one can define Er={vG(J;X):vr}. Moreover, let

    ˜M=maxi=0,1,2,...,kMi+1, ˜a=maxi=1,2,...,kai, ˜b=maxi=1,2,...,kbi, ˜c=maxi=1,2,...,kci, ˜d=maxi=1,2,...,kdi.

    Lemma 3.5. Under assumptions (H1)–(H5), the control function has estimates zQ, namely,

    Q=:˜M[vηi+1+N(˜a+ϕ(0)Bh)+M(˜c+ω)+Mb0ψr(θ)dμ(θ)],

    where r=l(ϕ(0)Bh+r).

    Proof. For any vηi+1X, one can define the control function

    zv(η)=L1i+1[vηi+1Ψ(ηi+1,θi)Hi(θi,v(ηi))Φ(ηi+1,θi)Hi(θi,v(ηi))ηi+1θiΦ(ηi+1,θ)F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)](η), vEr, η[θi,ηi+1],i=0,1,2,...,k, (3.1)

    where H0((0,v(0))=ϕ(0), H0((0,v(0))=ω.

    From Lemma 2.6, for every vEr, one can obtain that

    vθlsupθ[0,b](v(θ)+v0Bh)l(ϕ(0)Bh+r).

    Then, from (3.1), we have

    zv(η)˜M[vηi+1+NHi(θi,v(ηi))+MHi(θi,v(ηi))+Mb0F(θ,vρ(θ,vθ),Gvρ(θ,vη))dμ(θ)]˜M[vηi+1+N(˜a+ϕ(0)Bh)+M(˜c+ω)+Mb0ψr(θ)dμ(θ)]. (3.2)

    Thus, proof is done.

    Theorem 3.6. Suppose that (H1)–(H5) are satisfied. Then, system (1.1) is totally controllable on J provided that

    Mγ[1+˜MMB(μ(b)μ(0))]<1, (3.3)

    and

    Δ:=2MB[N˜b+M˜d+2(1+H)b0l0(θ)dμ(θ)]b0li+1(θ)dμ(θ)+2M(1+H)b0l0(θ)dμ(θ)+(N˜b+M˜d)<1. (3.4)

    Proof. From (3.1), the operator T is defined as follows:

    (Tv)(η)={Ψ(η,0)ϕ(0)+Φ(η,0)ξ+η0Φ(η,θ)[Bzv(θ)+F(θ,vρ(θ,vθ),Gvρ(θ,vθ))]dμ(θ), η[0,η1];Hi(η,v(ηi)), ηki=1(ηi,θi];Ψ(η,θi)Hi(θi,v(ηi))+Φ(η,θi)Hi(θi,v(ηi))+ηθiΦ(η,θ)[Bzv(θ)+F(θ,vρ(θ,vθ),Gvρ(θ,vθ))]dμ(θ), ηki=1(θi,ηi+1]. (3.5)

    Next, we divide the proof into four steps.

    Step 1. We show that there is a constant r>0 such that T(Er)Er.

    If it is not true, for any r>0, there exists vrEr such that Tvr>r.

    For η[0,η1], we get

    Tvr=supη[0,b](Tvr)(η)Ψ(η,0)ϕ(0)+Φ(η,0)ω+η0Φ(η,θ)[Bzvr(θ)+F(θ,vrρ(θ,vrθ),Gvrρ(θ,vrθ))]dμ(θ)Nϕ(0)+Mω+Mb0ψr(θ)dμ(θ)+MQBb01dμ(θ)Nϕ(0)+Mω+Mb0ψr(θ)dμ(θ)+MQB(μ(b)μ(0)). (3.6)

    For η(ηi,θi](i=1,2,3...k), then by (H4), we have

    (Tvr)(η)=Hi(η,vr(ηi))ai˜a. (3.7)

    For η(θi,ηi+1](i=1,2,3...k), Lemma 3.5 and (3.5) yield the following estimations

    Tvr=supη[0,b](Tvr)(η)Ψ(η,θi)Hi(θi,vr(ηi))+Φ(η,θi)Hi(θi,vr(ηi))+η0Φ(η,θ)[Bzvr(θ)+F(θ,vrρ(θ,vrθ),Gvrρ(θ,vrθ))]dμ(θ)N˜a+M˜c+Mb0ψr(θ)dμ(θ)+MQBb01dμ(θ)N˜a+M˜c+Mb0ψr(θ)dμ(θ)+MQB(μ(b)μ(0)). (3.8)

    Combining (3.6)–(3.8), we have

    r<TvrMb0ψr(θ)dμ(θ)+MQB(μ(b)μ(0))+N(˜a+ϕ(0))+M(˜c+ω).

    Dividing by r and taking upper limit as r, one can know that

    1Mγ[1+˜MMB(μ(b)μ(0))]<1.

    which is a contradiction to (3.3). Hence, there exists a number r such that T(Er)Er.

    Step 2. To prove that T is continuous on Er.

    For this, we take a sequence {vn}n=1Er such that

    vnv as n.

    By Lemma 2.6, for ηJ, we can easily know

    vnηvηBhlsupτJvn(τ)v(τ)=lvnv0 as n.

    In addition, for ηJ, one can obtain that

    vnρ(η,vnη)vρ(η,vnη)0 as n.

    From (3.1), we have

    zvn(θ)zv(θ)˜M(NHi(θi,vn(ηi))Hi(θi,v(ηi))+MHi(θi,vn(ηi))Hi(θi,v(ηi)))+˜MMb0F(θ,vnρ(θ,vnθ),Gvnρ(θ,vnθ))F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ). (3.9)

    By (H2), (H4), (H5), and Lemma 2.6, we get

    T(vn)T(v)Mb0F(θ,vnρ(θ,vnθ),Gvnρ(θ,vnθ))F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)+MBb0zvn(θ)zv(θ)dμ(θ), θ[0,η1], (3.10)

    and

    T(vn)T(v)(NHi(θi,vn(ηi))Hi(θi,v(ηi))+MHi(θi,vn(ηi))Hi(θi,v(ηi)))+Mb0F(θ,vnρ(θ,vnθ),Gvnρ(θ,vnθ))F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)+MBb0zvn(θ)zv(θ)dμ(θ), θki=1(θi,ηi+1]. (3.11)

    Thus, by the dominated convergence theorem, and (H2)–(H5), we conclude

    T(vn)T(v)0 as n.

    So, T is a continuous operator on Er.

    Step 3. Claim that T is equiregulated.

    For any η(θi,ηi+1), one can get that

    (Tv)(η)(Tv)(η+)Ψ(η,θi)Ψ(η+,θi)Hi(θi,v(ηi))+Φ(η,θi)Φ(η+,θi)Hi(θi,v(ηi))+η+θi[Φ(η,θ)Φ(η+,θ)]F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)+ηη+Φ(η,θ)F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)+η+θi[Φ(η,θ)Φ(η+,θ)]Bzv(θ)dμ(θ)+ηη+Φ(η,θ)Bzv(θ)dμ(θ)=A1+A2+A3+A4+A5.

    It is easy to know that A1,A2,A40 independently of v as ηη+ since Φ(η,θ) and Ψ(η,θ) are strongly continuous. Let

    K(η)=η0ψr(θ)dμ(θ).

    Then, by Lemma 2.2, K(η) is a regulated function. Then,

    A3M(K(η)K(η+))0 as ηη+.

    Similarly, A50 as ηη+.

    According to the above discussion, it is also easy to derive

    T(v)(η)T(v)(η) as ηη

    for every η(θi,ηi+1].

    For any η[0,η1], the proof is obviously similar to the aforementioned discussion, so we omit it. Therefore, T(Er) is equiregulated.

    Step 4. Claim that if CEr is countable and there exists w0Er such that

    C¯co({w0}T(C)), (3.12)

    then C is relatively compact.

    Without loss of generality, suppose C={vn}n=1Er.

    Then by (H2) and (H3), for each ηJ, we obtain

    α{zvn(θ)}n=1li+1(θ)α({vηi+1Ψ(ηi+1,θi)Hi(θi,v(ηi))Φ(ηi+1,θi)Hi(θi,v(ηi))ηi+1θiΦ(ηi+1,θ)F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)}n=1)li+1(θ)[N˜bα{vn(θ)}n=1+M˜dα{vn(θ)}n=1]+2li+1(θ)M(1+H)b0l0(θ)α{vn(θ)}n=1dμ(θ)li+1(θ)[N˜b+M˜d+2M(1+H)b0l0(θ)dμ(θ)]αG{vn}n=1. (3.13)

    By (H2), (H3), we have

    α({(Tvn)(η)}n=1)α({η0Φ(η,θ)[Bzv(θ)dμ(θ)}n=1)+α({η0Φ(η,θ)F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)}n=1)[2M(1+H)b0l0(θ)dμ(θ)]αG{vn}n=1+[2MB[N˜b+M˜d+2(1+H)b0l0(θ)dμ(θ)]b0li+1(θ)dμ(θ)]αG{vn}n=1{2MB[N˜b+M˜d+2(1+H)b0l0(θ)dμ(θ)]b0li+1(θ)dμ(θ)+2M(1+H)b0l0(θ)dμ(θ)}αG{vn}n=1, η[0,η1]. (3.14)

    For any η(θi,ηi+1](i=1,2,3...k), by using (H2)–(H5), we have

    α({(Tvn)(η)}n=1)α({Ψ(η,θi)Hi(θi,v(ηi))+Φ(η,θi)Hi(θi,v(ηi))}n=1)+α({η0Φ(η,θ)[Bzv(θ)dμ(θ)}n=1)+α({η0Φ(η,θ)F(θ,vρ(θ,vθ),Gvρ(θ,vθ))dμ(θ)}n=1)[2M(1+H)b0l0(θ)dμ(θ)]αG{vn}n=1+(N˜b+M˜d)αG{vn}n=1+[2MB[N˜b+M˜d+2(1+H)b0l0(θ)dμ(θ)]b0li+1(θ)dμ(θ)]αG{vn}n=1{2MB[N˜b+M˜d+2(1+H)b0l0(θ)dμ(θ)]b0li+1(θ)dμ(θ)+2M(1+H)b0l0(θ)dμ(θ)+(N˜b+M˜d)}αG{vn}n=1=ΔαG{vn}n=1. (3.15)

    From Lemma 2.8, one can get that

    αG({Tvn}n=1)=supηJα({Tvn(η)}n=1). (3.16)

    This together with (3.12) and (3.16) guarantees that

    αG({vn}n=1)αG({Tvn}n=1)ΔαG({vn}n=1),

    which means that C={vn}n=1 is relatively compact.

    Hence, according to Theorem 2.9, it is easy to know that the operator T has a fixed point. Then, the system (1.1) is totally controllable. So the proof is complete.

    In this section we present the application of the obtained theoretical results.

    Example: Consider the following second-order control system:

    {(v(η,x)η)=[2x2v(η,x)+A(η)xv(η,x)]dη+νz(η,x)dμ(η)+[ηe2(θη)v(θσ1(η)σ2(v(η)),x)4dθ]dμ(η)+[η0(ηθ)θe2(δθ)v(δσ1(η)σ2(v(t)),x)2dδdθ]dμ(η), η(0,13](23,1];H1(η,v)=e(η13)4|v(13,x)|1+|v(13,x)|, η(13,23];H1(η,v)=e(η13)4|v(13,x)|1+|v(13,x)|, η(13,23];v(η,0)=v(η,2π)=0, η[0,1];v(η,x)=ϕ(η,x), ηv(0,x)=ω, η(,0], x[0,2π], (4.1)

    where ηJ=[0,1], x[0,2π]. Moreover, the function σi: (0,)(0,) is continuous for i=1,2.

    Conclusion: System (4.1) is totally controllable on J.

    Proof. System (4.1) can be regarded as a system of the form (1.1), where b=1, B=ν, and

    μ(η)={112, 0η112;...11m, 11m1<η11m, for m>2 and mN;...1,t=1.

    Obviously, μ:JR is left continuous and nondecreasing.

    Define

    v(η)(x)=v(η,x),z(η)(x)=z(η,x),H1(η)(x)=H1(η,x)H1(η)(x)=H1(η,x)

    According to the research of [31] and [36], first let X=L2(L;C), where L=R2πZ is a group. We take A as the infinitesimal generator of a cosine family {Ψ(η)}ηR with associated sine family {Φ(η)}ηR. We denote A(η)=A+˜A(η), where ˜A(η):D(˜A(η))X is a closed linear operator.

    We consider the operator Af(ζ)=f(ζ) having domain H2(L;C), where H2(T;C) represents the Sobolev space of 2π periodic 2-integrable functions from R to C. Moreover, A has eigenvalues κ2(κN), with corresponding eigenfunction ϑκ(ζ)=12πeint (κZ) is an orthonormal basis. Furthermore,

    A(η)f=κ=1κ2f,ϑκϑκ, fD(A).

    The cosine function Ψ(η) is given by

    Ψ(η)f=κ=1cos(κη)f,ϑκϑκ, ηR

    with associated sine function Φ(η)

    Φ(η)f=κ=1cos(κη)κf,ϑκϑκ, ηR.

    It is clearly seen that the family {Ψ(η)}ηR is uniformly bounded by 1.

    Next, for x(0,2π), the linear operator L1 is defined as follows

    L1z=130Φ(13,θ)νz(θ,x)dμ(θ). (4.2)

    Similarly, the linear operator L2 is defined as follows

    L2z=123Φ(1,θ)νz(θ,x)dμ(θ). (4.3)

    It is easy to see that L1μ2, L2μ3. Hence, we know that ˜Mμ2.

    Since

    H1(t,v)=e(t13)4|v(13,x)|1+|v(13,x)|, H1(t,v)=e(t13)4|v(13,x)|1+|v(13,x)|,

    (H4) and (H5) are satisfied with a1=14, c1=14.

    Set, h(θ)=e2θ, θ<0, then

    l=0h(θ)dθ=12.

    The norm Bh is defined as

    ϕBh=0h(θ)supτ[θ,0]|ϕ(τ)|dθ.

    Let ρ(η,ϕ)=ησ1(η)σ2(ϕ(0)). One can get that,

    F(η,ϕ,Gϕ)=0e2θϕ4dθ+η0(ηθ)0e2τϕ2dτdθ.

    We obtain, for ϕr,

    F(t,ϕ,Gϕ)=0e2θϕ4dθ+η0(ηθ)0e2τϕ2dτdθr8+rη28.

    We take ψr(η)=r8+rη28 with γ=14, thus (H2) is satisfied.

    Finally, if ν is sufficiently small such that

    2ν2+ν<3.

    Therefore, it is easy to know from Theorem 3.6 that system (4.1) is totally controllable.

    This paper is mainly concerned with a class of non-autonomous second-order measure evolution systems involving state-dependent delay and non-instantaneous impulses. We first give the definition of Henstock-Lebesgue-Stieltjes integral and phase space. Then, the existence of the mild solution of system (1.1) is obtained by using the integral equation given by the strongly continuous family of cosines. By using the Kuratowski measure of noncompactness and Mönch fixed point theorem, we obtain some sufficient conditions to ensure the total controllability of system (1.1). Finally, an illustrative example is given to show the practical usefulness of the analytical results.

    This research was funded by National Natural Science Foundation of China: 62073202, Natural Science Foundation of Shandong Province: ZR2020MA007, Doctoral Research Funds of Shandong Management University: SDMUD202010, QiHang Research Project Funds of Shandong Management University: QH2020Z02.

    The authors declared that they have no conflict of interest in this work.


    Abbreviation PBMC: peripheral blood mononuclear cells; ISX: Imagestream X; DF: darkfield; BF: brightfield; BDI: bright detail intensity; SSC: side scatter; FS: forward scatter; AUL: area upper limit; ALL: area lower limit; gradient RMS: gradient root mean square; WB: whole blood; WEL: workplace exposure limit; NET: neutrophil extracellular trap; 7-AAD: 7-Aminoactinomycin D; PM, PM and PM: Particulate matter of less than 0.1, 2.5 or 10 µm median aerodynamic diameters;
    Acknowledgments



    This study was funded by UK Medical Research Council, Grant number MR/R005699/1. The authors wish to thank the Volunteer Studies and Clinical Services Team at MRC EWL for recruitment and written consent of volunteers and the volunteers' blood collection.

    Conflict of interest



    The authors declare no conflicts of interest.

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