Search

Orai family are a calcium channel of cell membrane extracellular Ca

Thymic stromal lymphopoietin presents in two distinct isoforms: short-form (sfTSLP) and long-form (lfTSLP). lfTSLP promotes inflammation, whereas sfTSLP inhibits inflammation, in allergic asthma. However, little is known about the regulation of lfTSLP and sfTSLP during allergic attack in the asthma airway epithelium. Here, we report that small ubiquitin-like modifier (SUMOylation) was enhanced in house dust mite-induced allergic asthma airway epithelium. Inhibition of SUMOylation significantly alleviated airway T-helper cell type 2 inflammation and lfTSLP expression. Mechanistically, chromobox 4 (CBX4), a SUMOylation E3 ligase, enhanced lfTSLP mRNA translation, but not sfTSLP, through the RNA-binding protein muscle excess (MEX)-3B. MEX-3B promoted lfTSLP translation by binding the lfTSLP mRNA through its K homology domains. Furthermore, CBX4 regulated MEX-3B transcription in human bronchial epithelial cells through enhancing SUMOylation concentrations of the transcription factor TFII-I. In conclusion, we demonstrate an important mechanism whereby CBX4 promotes MEX-3B transcription through enhancing TFII-I SUMOylation and MEX-3B enhances the expression of lfTSLP through binding to the lfTSLP mRNA and promoting its translation. Our findings uncover a novel target of CBX4 for therapeutic agents for lfTSLP-mediated asthma.

The Variational Principle (VP) is designed to generate non-folding grids (diffeomorphisms) with prescribed Jacobian determinant (JD) and curl. The solution pool of the original VP is based on an additive formulation and, consequently, is not invariant in the diffeomorphic Lie algebra. The original VP works well when the prescribed pair of JD and curl is calculated from a diffeomorphism, but not necessarily when the prescribed JD and curl are unknown to come from a diffeomorphism. In spite of that, the original VP works effectively in 2D grid generations. To resolve this issue, in this paper, we describe a new version of VP (revised VP), which is based on the composition of transformations and, therefore, is invariant in the Lie algebra. The revised VP seems to have overcome the inaccuracy of the original VP in 3D grid generations. In the following sections, the mathematical derivations are presented. It is shown that the revised VP can calculate the inverse transformation of a known diffeomorphism. Its inverse consistency and transitivity of transformations are also demonstrated numerically. Finally, a new definition of averaging diffeomorphisms based on the revised VP is proposed.

We find that the excluded volume interaction (EVI) can accelerate an abrupt transition in extension for an intrinsically curved two-dimensional semiflexible biopolymer. It makes the transition much sharper, reduces the critical force remarkably, and the larger the persistent length or the intrinsic curvature, the larger the reduction in critical force. The transition is caused by a collective change in bending angles associated with removing cusps owing to thermal fluctuation. Our results reveal that EVI can excite a cooperative behavior, straighten more bonds simultaneously so cause a sharper transition. The transition is dominated by the mechanical force because the specific heat does not divergence. Our findings suggest that an intrinsically curved biopolymer can act as a switch or sensor in some biological processes.

Background: Thymic stromal lymphopoietin (TSLP) is present in two distinct isoforms, short-form (sfTSLP) and long-form (lfTSLP). lfTSLP promotes inflammation while sfTSLP inhibits inflammation in allergic asthma. However, little is known about the regulation of lfTSLP and sfTSLP during allergic attack in asthma airway epithelium. Methods and Results: Here, we report that SUMOylation was enhanced in HDM-induced allergic asthma airway epithelium. Inhibition of SUMOylation significantly alleviated airway Th2 inflammation and lfTSLP expression. Mechanistically, CBX4, a SUMOylation E3 ligase, enhanced lfTSLP, but not sfTSLP, mRNA translation through the RNA binding protein, MEX-3B. MEX-3B promoted lfTSLP translation through binding of its KH domains to the lfTSLP mRNA. Furthermore, CBX4 regulated MEX-3B transcription in HBE through enhancing SUMOylation levels of the transcription factor, TFII-I. Conclusion: We demonstrate an important mechanism whereby CBX4 promotes MEX-3B transcription through enhancing TFII-I SUMOylation, and MEX-3B enhances the expression of lfTSLP through binding to the lfTSLP mRNA and promoting its translation. Our findings uncover a novel target of CBX4 for therapeutic agents to lfTSLP-mediated asthma.

The natural configuration of an intrinsically curved and twisted filament is uniquely a helix so that it can be referred to as a helical filament. We find that confining a helical filament on a cylinder can create a bistable state. When c_{0}R=0.5, where c_{0} is the intrinsic curvature of filament and R is the radius of cylinder, the phase diagram for the stability of a helix contains three regimes. Regime I has a small intrinsic twisting rate (ITR) and exhibits a bistable state which consists of two isoenergic helices. In regime II, the filament has a moderate ITR and the bistable state consists of a metastable low-pitch helix and a stable nonhelix. In regime III, the helix is unstable, owing to a large ITR. A similar phenomenon occurs when c_{0}R∼0.5. Monte Carlo simulation confirms these conclusions and indicates further that there are bistable nonhelices in regime III. This bistable system offers a prospective green material since the wide range of parameters and distinctive configurations for bistable states favor its realization and application.

Avasimibe (Ava) is an acetyl-CoA acetyltransferase 1 (ACAT1) specific inhibitor and an established medicine for atherosclerosis, owing to its excellent and safe anti-inflammation effects in humans. However, its efficacy in asthma has not yet been reported. We first administered varying concentrations of avasimibe to house dust mite (HDM)-induced asthmatic mice; results showed that 20 mg/kg avasimibe most significantly reduced IL-4 and IL-5 production in bronchoalveolar lavage fluid (BALF) and total IgE in serum, and the avasimibe treatment also exhibited lower mucus secretion, decreased goblet and basal cells but increased ciliated cells compared to the HDM group. And the redistribution of adherens junction (AJ) proteins induced by HDM was far more less upon avasimibe administration. However, avasimibe did not reduce the cholesterol ester ratio in lung tissues or intracellular cholesterol ester, which is avasimibe’s main effect. Further analysis confirmed that avasimibe impaired epithelial basal cell proliferation independent of regulating cholesterol metabolism and we analyzed datasets using the Gene Expression Omnibus (GEO) database and then found that the KRT5 gene (basal cell marker) expression is correlated with the β-catenin gene. Moreover, we found that β-catenin localized in cytomembrane upon avasimibe treatment. Avasimibe also reduced β-catenin phosphorylation in the cytoplasm and inactivated the Wnt/β-catenin signaling pathway induced by HDMs, thereby alleviating the airway epithelial barrier disruption. Taken together, these findings indicated that avasimibe has potential as a new therapeutic option for allergic asthma.

Epithelial barrier dysfunction is involved in the pathogenesis of asthma. Previous studies show that SUMOylation can regulate epithelial junction molecule localization. However, the role of SUMOylation in epithelial barrier dysfunction in asthma remains unclear. This study found that inhibition of SUMOylation attenuates house dust mite (HDM)-induced epithelial barrier dysfunction. The SUMOylation levels of junction molecules were determined by co-immunoprecipitation (CO-IP) and proximity ligation assay (PLA). HDM treatment significantly enhanced SUMOylation levels of β-catenin, while no effect was seen on ZO-1, Occludin, and E-cadherin SUMOylation levels. Inhibition of β-catenin SUMOylation through 2-D08 treatment or SUMOylation modification site mutant (K233A) promoted its membrane localization and repressed Wnt/β-catenin signaling. Further, we identified that CBX4, an E3 ligase, mediated SUMOylation of β-catenin. Knockdown of CBX4 promoted β-catenin membrane localization and improved epithelial barrier function. In vivo analysis showed that AAV6-shCBX4-mediated knockdown of CBX4 attenuated HDM-induced allergic airway inflammation and epithelial barrier dysfunction. The findings showed that inhibiting β-catenin SUMOylation by targeting CBX4 mitigated HDM-induced epithelial barrier dysfunction in asthma.

RationaleThymic stromal lymphopoietin (TSLP) is present in two distinct isoforms, short-form (sfTSLP) and long-form (lfTSLP). lfTSLP promotes inflammation while sfTSLP inhibits inflammation in allergic asthma. However, little is known about the regulation of lfTSLP and sfTSLP during allergic attack in asthma airway epithelium.Methods and ResultsHere, we report that SUMOylation was enhanced in HDM-induced allergic asthma airway epithelium. Inhibition of SUMOylation significantly alleviated airway Th2 inflammation and lfTSLP expression. Mechanistically, CBX4, a SUMOylation E3 ligase, enhanced lfTSLP, but not sfTSLP, mRNA translation through the RNA binding protein, MEX-3B. MEX-3B promoted lfTSLP translation through binding of its KH domains to the lfTSLP mRNA. Furthermore, CBX4 regulated MEX-3B transcription in HBE through enhancing SUMOylation levels of the transcription factor, TFII-I.ConclusionWe demonstrate an important mechanism whereby CBX4 promotes MEX-3B transcription through enhancing TFII-I SUMOylation, and MEX-3B enhances the expression of lfTSLP through binding to the lfTSLP mRNA and promoting its translation. Our findings uncover a novel target of CBX4 for therapeutic agents to lfTSLP-mediated asthma.

Background: Asthma is a complex and heterogeneous disease. Autophagy, process of self-protection in cells, is an intracellular process when cells are being attacked by certain stress. Our team focused upon the disruption of airways epithelial barrier in asthma, and we interested in whether autophagy played a key role in asthma. Methods: 400U HDM was used to treat HBECs and established asthmatic mice model. Western blotting, RT-PCR and immunofluorescence were mainly used to detect autophagy process in vivo and in vitro. One way ANOVA and Mann Whitney test were used for statistic. Results: After treated with HDM, expression of LC3ab increased in vivo and in vitro. Using Rapamycin, 3-MA and Chloroquine to treat HBECs, then we surprisingly found that HDM disrupts epithelial barrier through incomplete autophagy. To find out the connection between asthma and autophagy, we chose known autophagy related genes to determine the association between autophagy and disruption of airway epithelial barrier. Atg5 and atg12 were chosen because these two genes varied upon the time dependent manner. Knocked down the expression of atg5 or atg12 by siRNA, the expression of TSLP, which can induce the disruption of airway epithelial barrier, remarkably reduced. Conclusions: These results demonstrated that HDM induced inflammatory in airway epithelium through autophagy, and then knocked down autophagy related genes alleviated the inflammatory in HBECs.

We find that a moderate intrinsic twisting rate (ITR) can induce a bistable state for a force-free two-dimensional intrinsically curved filament. There are two different configurations of equal energy in a bistable state so that the filament is clearly different from its three-dimensional counterpart. The smaller the ITR or the larger the intrinsic curvature (IC), the clearer the distinction between two isoenergetic configurations and the longer the filament. In bistable states, the relationship between length and ITR is approximately a hyperbola and relationship between IC and critical ITR is approximately linear. Thermal fluctuation can result in a shift between two isoenergetic configurations, but large bending and twisting rigidities can prevent the shift and maintain the filament in one of these two configurations. Moreover, a filament can have a metastable state and at a finite temperature such a filament has the similar property as that of a filament with bistable state.

We study the effects of the intrinsic curvature (IC), intrinsic twist rate (ITR), anisotropic bending rigidities, sequence disorder, and temperature (T) on the persistence length (l_{p}) of a two- or three-dimensional semiflexible biopolymer. We develop some general expressions to evaluate exactly these effects. We find that a moderate IC alone reduces l_{p} considerably. Our results indicate that the centerline of the filament keeps as a helix in a rather large range of T when ITR is small. However, a large ITR can counterbalance the effect of IC and the result is insensitive to the twist rigidity. Moreover, a weak randomness in IC and ITR can result in an "overexpanded" state. Meanwhile, when ITR is small, l_{p} is not a monotonic function of T but can have either minimum or maximum at some T, and in the two-dimensional case the maximum is more obvious than that in the three-dimensional case. These results reveal that to obtain a proper size at a finite T for an intrinsically curved semiflexible biopolymer, proper values of bending rigidities and ITR are necessary but a large twist rigidity may be only a by-product. Our findings are instructive in controlling the size of a semiflexible biopolymer in organic synthesis since the mean end-to-end distance and radius of gyration of a long semiflexible biopolymer are proportional to l_{p}.

We explore the effects of two typical torques on the mechanical property of the helical configuration for an intrinsically straight filament or biopolymer either in three-dimensional space or on a cylinder. One torque is parallel to the direction of a uniaxial applied force, and is coupled to the cross section of the filament. We obtain some algebraic equations for the helical configuration and find that the boundary conditions are crucial. In three-dimensional space, we show that the extension is always a monotonic function of the applied force. On the other hand, for a filament confined on a cylinder, the twisting rigidity and torque coupled to the cross section are irrelevant in forming a helix if the filament is isotropic and under free boundary condition. However, the twisting rigidity and the torque coupled to the cross section become crucial when the Euler angle at two ends of the filament are fixed. Particularly, the extension of a helix can subject to a first-order transition so that in such a condition a biopolymer can act as a switch or sensor in some biological processes. We also present several phase diagrams to provide the conditions to form a helix.

We study the mechanical property of a two-dimensional free rotating chain (FRC). We find that at low force and with a scaled bond length, the relation between extension and applied force of a FRC obeys the same linear law as that of a free jointed chain (FJC), agreeing with the conclusion that free of applied force the end-to-end distances of two models have the same power law. But beginning from a moderate force, the two models become very different even with a scaled bond length. Especially, when the bond angle is small, the relative extension of a FRC is always smaller than that of a FJC; but with a large bond angle the relative extension of a FRC becomes larger than that of a FJC. Moreover, the extension of FJC is a smooth function of applied force, but the extension of a long FRC can subject to a first order transition when the bond angle is large.

This work explores the ground-state of an elastic model for an intrinsically curved semiflexible biopolymer. We find that the two- and three-dimensional systems have exactly the same mechanical property and show that the signed curvature of the model is nowhere continuous so that the standard variational technique fails in continuous model. Moreover, we show that the ground-state configuration of the model is a sawtooth line, and find that the relative extension of the corresponding discrete model is z r = cos [ 2 c 0 / ( 4 + f ) ] when c0

Monte Carlo (MC) simulations based on lattice model were performed to study the phase diagram (anisotropy, uniaxiality and biaxiality) of liquid crystals formed by bent-cored molecules with a strong transverse dipole moment deviating from their angular bisector. It is shown that the asymmetric strong dipolar interaction enhances biaxiality slightly but encourages uniaxiality greatly and as a result suppresses the system’s isotropic order, which is different from a system free from external field in that dipole moment increases biaxiality by suppressing the uniaxial and the isotropic orders simultaneously. It is also found that an external electric field encourages the biaxiality slightly but considerably enhances the uniaxiality of bent-cored liquid crystal.

Free rotating chain (FRC) is a well-known model of polymer but the knowledge to its mechanical property is yet incomplete. This work uses Monte Carlo simulation to evaluate the relation between force and extension, the specific heat, the stretching strength and the fourth-order cumulants of the order parameter of a three-dimensional (3D) FRC. We simplify some expressions to calculate the thermodynamical quantities. Our results reveal that at low force, the behavior of the mechanical property of the model is the same as that of a free jointed chain (FJC) in both two-dimensional (2D) and 3D cases. But beginning from a moderate force, the two models have different mechanical properties. Moreover, we find that a 3D FRC has essential different mechanical property from its 2D counterpart, because the extension of a stretched 2D FRC can subject to a first order transition when the bond angle is large enough, but there is no such a transition for a 3D chain despite its stretching strength exhibits a peaks at large bond angle. Our findings reveal that the space constraint on a stretched polymer favors a sharp change in its size.

Background: Up-regulation of aerobic glycolysis has been reported as a characterization of asthma and facilitates airway inflammation. Thymic stromal lymphopoietin (TSLP) has been previously reported to have dual immunoregulatory roles due to long and short isoform (lTSLP and sTSLP) in asthma. However, their role in aerobic glycolysis in asthma airway epithelial was poorly defined. Methods: Asthmatic model was established in challenging Male BALB/c mice and 16-HBE (human bronchial epithelial) cell line with house dust mite (HDM). Indicators of glycolysis were assessed to measure whether involve in lTSLP and sTSLP regulating airway epithelial inflammation in asthmatic model in vivo and in vitro. Results: lTSLP promoted the enhancement of aerobic glycolysis as well as HDM in 16-HBE. HIF-1α was increased significantly in 16-HBE growing with lTSLP which suppressed VHL expression by promoting miR-223 expression. Inhibition of aerobic glycolysis restrained HDM- and lTSLP-induced inflammatory cytokines production. sTSLP had almost no potential to alter aerobic glycolysis of 16-HBE alone but might have prevented effects of lTSLP in 16-HBE, decreased LDH and LD in BALF, and HIF-1α and LDHA in airway epithelial of asthma mouse model. lTSLP and sTSLP both induced formation of TSLPR and IL-7R receptor complex, and lTSLP obviously facilitated phosphorylation of JAK1, JAK2 and STAT5, while sTSLP induced a little phosphorylation of JAK1 and STAT5. Conclusion: We identified a novel mechanism that lTSLP could promote inflammatory cytokines production by miR-223/VHL/HIF-1α pathway to upregulate aerobic glycolysis in airway epithelial in asthma. This pathway is suppressed by sTSLP through occupying binding site of lTSLP in TSLPR and IL-7R receptor complex. Funding Statement: This study was supported by the National Natural Science Foundation of China (81700034， 81670026, 81470228，81770033, 81500023), Natural Science Foundation of Guangdong Province (2017A030310106, 2015A030313236, 2017A030313849), the Precision Medicine Research of The National Key Research and Development Plan of China (2016YFC0905803), and China Postdoctoral Science Foundation (2017M620377, 2018T110885). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The asthmatic models experiment were approved by the Animal Subjects Committee of South Medical University.

By the Fourier filtering method, we generate one-dimensional binary sequences from coarse-grained continuous sequences with preset exponents α 0 . Using the spectrum analysis, we find that the corresponding binary sequences have pure 1 / f α power spectrum and spectrum exponents α ∈ [ 0.0 , 2.0 ] , where f is the frequency. We evaluate numerically the relation between α and α 0 . Using the autocorrelation function analysis, the detrended fluctuation analysis, the duration time analysis and the entropy analysis, we investigate extensively the statistical properties of such binary sequences. We find that the statistical properties are basically different for α 1 and α > 1 , and binary sequences become more and more ordered as α increases.

We derive the shape equations in terms of Euler angles for a uniform elastic rod with isotropic bending rigidity and spontaneous curvature, and study within this model the elasticity and stability of a helical filament under uniaxial force and torque. We find that due to the special requirements on the boundary conditions, a static slightly distorted helix cannot exist in this system except in some special cases. We show analytically that the extension of a helix may undergo a one-step sharp transition. This agrees quantitatively with experimental observations for a stretched helix in a chemically-defined lipid concentrate (CDLC). We predict further that under twisting, the extension of a helix in CDLC may also exhibit similar behavior. We find that a negative twist tends to destabilize a helix.

We present an analytical-based proof for the consistency of two asymmetric elastic models of the double-stranded DNA in the regime around the B-form. We derive the shape equations in terms of Euler angles for a uniform ribbon with noncircular cross section and spontaneous torsion. We study the conditions to form a helical ribbon for the model and find that the Euler angle ψ must be either 0 or π / 2 . We find that the helix is always stable or at least metastable for the model, and there is either a continuous or discontinuous transition of extension, from a twisted straight ribbon to a helical ribbon. An “over-collapse” phenomena of extension is observed for the ribbon under twisting. The stability of the helix and the intrinsic asymmetric elasticity under twisting are also studied.

We derive the general shape equations in terms of Euler angles for an elastic model of uniform ribbon with noncircular cross section and vanishing spontaneous curvatures. We show that it has in general not a planar solution for a closed ribbon free of external force and torque. We study the conditions to form a helix with the axis along the direction of the applied force for a ribbon under external force and twisting. We find that if the bending rigidity is greater than the twisting rigidity, then no such helical rod can exist. Our stability analysis shows that a helical ribbon is in general stable or at least metastable under arbitrary force and torque. We find that the extension of the ribbon may undergo a discontinuous transition from a twisted straight rod to a helical ribbon. The intrinsic asymmetric elasticity of a helical ribbon under external torque is also studied.

Using density-functional theory within the generalized gradient approximation the interaction between atomic Si and the Cu(1 1 0) surface is investigated. Various structures of on-surface adsorption as well as surface-substitutional adsorption for a wide range of Si coverage are considered. Our results shows that the Cu(1 1 0) surface is active towards adsorption of Si. The energetically most preferred structure is the c(2 × 2)-Si/Cu(1 1 0) surface alloy. The reason that (2 × 2) Si chain can form on c(2 × 2)-Si/Cu(1 1 0) surface is due to the particular stability of c(2 × 2)-Si/Cu(1 1 0) surface.