Bifurcation analysis of a free boundary model of vascular tumor growth with a necrotic core and chemotaxis.

A considerable number of research works has been devoted to the study of tumor models. Several biophysical factors, such as cell proliferation, apoptosis, chemotaxis, angiogenesis and necrosis, have been discovered to have an impact on the complicated biological system of tumors. An indicator of the aggressiveness of tumor development is the instability of the shape of the tumor boundary. Complex patterns of tumor morphology have been explored in Lu et al. (J Comput Phys 459:111153, 2022). In this paper, we continue to carry out a bifurcation analysis on such a vascular tumor model with a controlled necrotic core and chemotaxis. This bifurcation analysis, to the parameter of cell proliferation, is built on the explicit formulas of radially symmetric steady-state solutions. By perturbing the tumor free boundary and establishing rigorous estimates of the free boundary system, we prove the existence of the bifurcation branches with Crandall-Rabinowitz theorem. The parameter of chemotaxis is found to influence the monotonicity of the bifurcation point as the mode l increases both theoretically and numerically.

Phase field modeling and computation of vesicle growth or shrinkage.

We present a phase field model for vesicle growth or shrinkage induced by an osmotic pressure due to a chemical potential gradient. The model consists of an Allen-Cahn equation describing the evolution of the phase field parameter that describes the shape of the vesicle and a Cahn-Hilliard-type equation describing the evolution of the ionic fluid. We establish conditions for vesicle growth or shrinkage via a common tangent construction using free energy curves. During the membrane deformation, the model ensures total mass conservation of the ionic fluid, and we weakly enforce a surface area constraint of the vesicle. We develop a stable numerical scheme and an efficient nonlinear multigrid solver to evolve the phase and concentration fields, and we use this to evolve the fields to near equilibrium for 2D vesicles. Convergence tests confirm an [Formula: see text] accuracy for our scheme and near-optimal convergence for our multigrid solver. Numerical results reveal that the diffuse interface model captures the main features of cell shape dynamics: for a growing vesicle, there exist circle-like equilibrium shapes if the concentration difference across the membrane and the initial osmotic pressure are large enough; while for a shrinking vesicle, there exists a rich collection of finger-like equilibrium morphologies.

Complex Far-Field Geometries Determine the Stability of Solid Tumor Growth with Chemotaxis.

In this paper, we develop a sharp interface tumor growth model to study the effect of the tumor microenvironment using a complex far-field geometry that mimics a heterogeneous distribution of vasculature. Together with different nutrient uptake rates inside and outside the tumor, this introduces variability in spatial diffusion gradients. Linear stability analysis suggests that the uptake rate in the tumor microenvironment, together with chemotaxis, may induce unstable growth, especially when the nutrient gradients are large. We investigate the fully nonlinear dynamics using a spectrally accurate boundary integral method. Our nonlinear simulations reveal that vascular heterogeneity plays an important role in the development of morphological instabilities that range from fingering and chain-like morphologies to compact, plate-like shapes in two dimensions.

Nonlinear studies of tumor morphological stability using a two-fluid flow model.

We consider the nonlinear dynamics of an avascular tumor at the tissue scale using a two-fluid flow Stokes model, where the viscosity of the tumor and host microenvironment may be different. The viscosities reflect the combined properties of cell and extracellular matrix mixtures. We perform a linear morphological stability analysis of the tumors, and we investigate the role of nonlinearity using boundary-integral simulations in two dimensions. The tumor is non-necrotic, although cell death may occur through apoptosis. We demonstrate that tumor evolution is regulated by a reduced set of nondimensional parameters that characterize apoptosis, cell-cell/cell-extracellular matrix adhesion, vascularization and the ratio of tumor and host viscosities. A novel reformulation of the equations enables the use of standard boundary integral techniques to solve the equations numerically. Nonlinear simulation results are consistent with linear predictions for nearly circular tumors. As perturbations develop and grow, the linear and nonlinear results deviate and linear theory tends to underpredict the growth of perturbations. Simulations reveal two basic types of tumor shapes, depending on the viscosities of the tumor and microenvironment. When the tumor is more viscous than its environment, the tumors tend to develop invasive fingers and a branched-like structure. As the relative ratio of the tumor and host viscosities decreases, the tumors tend to grow with a more compact shape and develop complex invaginations of healthy regions that may become encapsulated in the tumor interior. Although our model utilizes a simplified description of the tumor and host biomechanics, our results are consistent with experiments in a variety of tumor types that suggest that there is a positive correlation between tumor stiffness and tumor aggressiveness.

Dynamics of a multicomponent vesicle in shear flow.

We study the fully nonlinear, nonlocal dynamics of two-dimensional multicomponent vesicles in a shear flow with matched viscosity of the inner and outer fluids. Using a nonstiff, pseudo-spectral boundary integral method, we investigate dynamical patterns induced by inhomogeneous bending for a two phase system. Numerical results reveal that there exist novel phase-treading and tumbling mechanisms that cannot be observed for a homogeneous vesicle. In particular, unlike the well-known steady tank-treading dynamics characterized by a fixed inclination angle, here the phase-treading mechanism leads to unsteady periodic dynamics with an oscillatory inclination angle. When the average phase concentration is around 1/2, we observe tumbling dynamics even for very low shear rate, and the excess length required for tumbling is significantly smaller than the value for the single phase case. We summarize our results in phase diagrams in terms of the excess length, shear rate, and concentration of the soft phase. These findings go beyond the well known dynamical regimes of a homogeneous vesicle and highlight the level of complexity of vesicle dynamics in a fluid due to heterogeneous material properties.

Analysis and mitigation of the carrier phase delay effect of the digital phase generated carrier algorithm.

We present an improved digital phase generated carrier algorithm based on the synchronous carrier restoration (SCR) method to mitigate the carrier phase delay effect. The most distinguishing feature of this method is that it directly picks up the carrier signal information (frequency and phase) from the interference signal and synchronically accomplishes the processing of carrier signal restoration. In comparison to the traditional method, which adopts the initial carrier signal, total-harmonic-distortion with SCR is only 0.091%, lower than the traditional SCR of 18.38%, and the signal-to-noise ratio increases by 29 dB. Further, we derived the analytic expression of the distortion component and verified it by experiments. This technique may be potentially applied to a long-distance large-scale distributed fiber-optic interferometric sensor array.

Wrinkling dynamics of fluctuating vesicles in time-dependent viscous flow.

We study the fully nonlinear, nonlocal dynamics of two-dimensional vesicles in a time-dependent, incompressible viscous flow at finite temperature. We focus on a transient instability that can be observed when the direction of applied flow is suddenly reversed, which induces compressive forces on the vesicle interface, and small-scale interface perturbations known as wrinkles develop. These wrinkles are driven by regions of negative elastic tension on the membrane. Using a stochastic immersed boundary method with a biophysically motivated choice of thermal fluctuations, we investigate the wrinkling dynamics numerically. Different from deterministic wrinkling dynamics, thermal fluctuations lead to symmetry-breaking wrinkling patterns by exciting higher order modes. This leads to more rapid and more realistic wrinkling dynamics. Our results are in excellent agreement with the experimental data by Kantsler et al. [Kantsler et al., Phys. Rev. Lett., 2007, 99, 17802]. We compare the nonlinear simulation results with perturbation theory, modified to account for thermal fluctuations. The strength of the applied flow strongly influences the most unstable wavelength characterizing the wrinkles, and there are significant differences between the results from perturbation theory and the fully nonlinear simulations, which suggests that the perturbation theory misses important nonlinear interactions. Strikingly, we find that thermal fluctuations actually have the ability to attenuate variability of the characteristic wavelength of wrinkling by exciting a wider range of modes than the deterministic case, which makes the evolution less constrained and enables the most unstable wavelength to emerge more readily. We further find that thermal noise helps prevent the vesicle from rotating if it is misaligned with the direction of the applied extensional flow.

Pinch force sense test-retest reliability evaluation using contralateral force matching task.

A high test-retest reliability in measurement of pinch force sense is required to assess a clinical parameter accurately over a longitudinal study. Ipsilateral reproduction (IR) task and contralateral matching (CM) task have commonly been used for the assessment of force sense. To date, there has been little research on the test-retest reliability of pinch force sense utilizing the contralateral force matching task. This research aimed to explore this phenomenon across a spectrum of reference force levels (10, 30, and 50 percent maximum voluntary isometric contraction (MVIC)) using a contralateral matching task. Every participant in the study was tested twice by the same skilled experts, with each session separated by one week. Although normalized variable error indicated a poor level of reliability (intraclass correlation coefficient (ICC) = - 0.25 to 0.05) for these force sense tests, normalized constant error (ICC = 0.76-0.85) and normalized absolute error (ICC = 0.61-0.81) results indicated a fair to good of reliability. The lower bound of 95% CI of ICC for NAE and NCE indicated fair test-retest reliability (0.41-0.69). These findings suggest that investigators can reasonably obtain a fair to good test-retest reliability when investigating pinch force sense using the contralateral matching task. The Bland-Altman plots, SEM, and MDD95% were lower at these lower reference force level (10% MVIC) compared to the level of higher reference forces (30% and 50% MVIC). Therefore, when the reference force level increases, the participant needs a larger NAE or NCE decrease to show that their pinch force sense has indeed improved.

Grip force makes wrist joint position sense worse.

Background: The purpose of this study was to investigate how grip force affects wrist joint position sense. Methods: Twenty-two healthy participants (11 men and 11 women) underwent an ipsilateral wrist joint reposition test at 2 distinct grip forces [0 and 15% of maximal voluntary isometric contraction (MVIC)] and 6 different wrist positions (pronation 24°, supination 24°, radial deviation 16°, ulnar deviation 16°, extension 32°, and flexion 32°). Results: The findings demonstrated significantly elevated absolute error values at 15% MVIC (3.8 ± 0.3°) than at 0% MVIC grip force [3.1 ± 0.2°, t(20) = 2.303, P = 0.032]. Conclusion: These findings demonstrated that there was significantly worse proprioceptive accuracy at 15% MVIC than at 0% MVIC grip force. These results may contribute to a better comprehension of the mechanisms underlying wrist joint injuries, the development of preventative measures to lower the risk of injuries, and the best possible design of engineering or rehabilitation devices.

Three-dimensional numerical study on wrinkling of vesicles in elongation flow based on the immersed boundary method.

We study the wrinkling dynamics of three-dimensional vesicles in a time-dependent elongation flow by utilizing an immersed boundary method. For a quasispherical vesicle, our numerical results well match the predictions of perturbation analysis, where similar exponential relationships between wrinkles' characteristic wavelength and the flow strength are observed. Using the same parameters as in the experiments by Kantsler et al. [V. Kantsler et al., Phys. Rev. Lett. 99, 178102 (2007)0031-900710.1103/PhysRevLett.99.178102], our simulations of an elongated vesicle are in good agreement with their results. In addition, we get rich three-dimensional morphological details, which are favorable to comprehend the two-dimensional snapshots. This morphological information helps identify wrinkle patterns. We analyze the morphological evolution of wrinkles using spherical harmonics. We find discrepancies in elongated vesicle dynamics between simulations and perturbation analysis, highlighting the importance of the nonlinear effects. Finally, we investigate the unevenly distributed local surface tension, which largely determines the position of wrinkles excited on the vesicle membrane.

Role of CD68 in tumor immunity and prognosis prediction in pan-cancer.

CD68 plays a critical role in promoting phagocytosis; however, the function of CD68 in tumor immunity and prognosis remains unknown. We analyzed CD68 expression among 33 tumor and normal tissues from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. The relationship between CD68 expression and cancer prognosis, immune infiltration, checkpoint markers, and drug response was explored. Upregulated CD68 levels were observed in various cancer types, which were verified through tumor tissue chips using immunohistochemistry. High levels of CD68 in tumor samples correlated with an adverse prognosis in glioblastoma, kidney renal clear cell carcinoma, lower-grade glioma, liver hepatocellular carcinoma, lung squamous cell carcinoma, thyroid carcinoma, and thymoma and a favorable prognosis in kidney chromophobe. The top three negatively enriched Kyoto Encyclopedia of Genes and Genomes terms in the high CD68 subgroup were chemokine signaling pathway, cytokine-cytokine receptor interaction, and cell adhesion molecule cams. The top negatively enriched HALLMARK terms included complement, allograft rejection, and inflammatory response. A series of targeted drugs and small-molecule drugs with promising therapeutic effects were predicted. The clinical prognosis and immune infiltration of high expression levels of CD68 differ across tumor types. Inhibiting CD68-dependent signaling could be a promising therapeutic strategy for immunotherapy in many tumor types.

The role of lipocalin 2 in brain injury and recovery after ischemic and hemorrhagic stroke.

Ischemic and hemorrhagic stroke (including intracerebral hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage) is the dominating cause of disability and death worldwide. Neuroinflammation, blood-brain barrier (BBB) disruption, neuronal death are the main pathological progress, which eventually causes brain injury. Increasing evidence indicated that lipocalin 2 (LCN2), a 25k-Da acute phase protein from the lipocalin superfamily, significantly increased immediately after the stroke and played a vital role in these events. Meanwhile, there exists a close relationship between LCN2 levels and the worse clinical outcome of patients with stroke. Further research revealed that LCN2 elimination is associated with reduced immune infiltrates, infarct volume, brain edema, BBB leakage, neuronal death, and neurological deficits. However, some studies revealed that LCN2 might also act as a beneficial factor in ischemic stroke. Nevertheless, the specific mechanism of LCN2 and its primary receptors (24p3R and megalin) involving in brain injury remains unclear. Therefore, it is necessary to investigate the mechanism of LCN2 induced brain damage after stroke. This review focuses on the role of LCN2 and its receptors in brain injury and aiming to find out possible therapeutic targets to reduce brain damage following stroke.

CMTM Family Genes Affect Prognosis and Modulate Immunocytes Infiltration in Grade II/III Glioma Patients by Influencing the Tumor Immune Landscape and Activating Associated Immunosuppressing Pathways.

Lower-grade glioma (LGG) is one of the most common primary tumor types in adults. The chemokine-like factor (CKLF)-like Marvel transmembrane domain-containing (CMTM) family is widely expressed in the immune system and can modulate tumor progression. However, the role of the CMTM family in LGG remains unknown. A total of 508 LGG patients from The Cancer Genome Atlas (TCGA) database were used as a training cohort, and 155 LGG patients from the Chinese Glioma Genome Atlas (CGGA) array database, 142 LGG patients from the CGGA RNA-sequencing database, and 168 LGG patients from the GSE108474 database were used as the validation cohorts. Patients were subdivided into two groups using consensus clustering. The ENET algorithm was applied to build a scoring model based on the cluster model. Finally, ESTIMATE, CIBERSORT, and xCell algorithms were performed to define the tumor immune landscape. The expression levels of the CMTM family genes were associated with glioma grades and isocitrate dehydrogenase (IDH) status. Patients in cluster 2 and the high-risk score group exhibited a poor prognosis and were enriched with higher grade, wild-type IDH (IDH-WT), 1p19q non-codeletion, MGMT promoter unmethylation, and IDH-WT subtype. Patients in cluster 1 and low-risk score group were associated with high tumor purity and reduced immune cell infiltration. Enrichment pathways analysis indicated that several essential pathways involved in tumor progression were associated with the expression of CMTM family genes. Importantly, PD-1, PD-L1, and PD-L2 expression levels were increased in cluster 2 and high-risk groups. Therefore, the CMTM family contributes to LGG progression through modulating tumor immune landscape.

Controlling fingering instabilities in Hele-Shaw flows in the presence of wetting film effects.

In this paper, the interfacial motion between two immiscible viscous fluids in the confined geometry of a Hele-Shaw cell is studied. We consider the influence of a thin wetting film trailing behind the displaced fluid, which dynamically affects the pressure drop at the fluid-fluid interface by introducing a nonlinear dependence on the interfacial velocity. In this framework, two cases of interest are analyzed: The injection-driven flow (expanding evolution), and the lifting plate flow (shrinking evolution). In particular, we investigate the possibility of controlling the development of fingering instabilities in these two different Hele-Shaw setups when wetting effects are taken into account. By employing linear stability theory, we find the proper time-dependent injection rate Q(t) and the time-dependent lifting speed b[over ̇](t) required to control the number of emerging fingers during the expanding and shrinking evolution, respectively. Our results indicate that the consideration of wetting leads to an increase in the magnitude of Q(t) [and b[over ̇](t)] in comparison to the nonwetting strategy. Moreover, a spectrally accurate boundary integral approach is utilized to examine the validity and effectiveness of the controlling protocols at the fully nonlinear regime of the dynamics and confirms that the proposed injection and lifting schemes are feasible strategies to prescribe the morphologies of the resulting patterns in the presence of the wetting film.

Functions of RNF Family in the Tumor Microenvironment and Drugs Prediction in Grade II/III Gliomas.

Increasing evidence has demonstrated that RING finger (RNF) proteins played a vital role in cellular and physiological processes and various diseases. However, the function of RNF proteins in low-grade glioma (LGG) remains unknown. In this study, 138 RNF family members revealed their role in LGG. The TCGA database was used as the training cohort; two CGGA databases and GSE108474 were selected as external validation cohorts. Patients were grouped into cluster 1 and cluster 2, both in the training and validation cohorts, using consensus clustering analysis. The prognosis of patients in cluster 1 is significantly better than that in cluster 2. Meanwhile, biofunction prediction was further introduced to explore the potential mechanisms that led to differences in survival outcomes. Patients in Cluster 2 showed more complicated immunocytes infiltration and highly immunosuppressive features than cluster 1. Enrichment pathways such as negative regulation of mast cell activation, DNA replication, mismatch repair, Th17 cell differentiation, antigen processing and presentation, dendritic cell antigen processing and presentation, dendritic cell differentiation were also enriched in cluster 2 patients. For the last, the main contributors were distinguished by employing a machine learning algorithm. A lot of targeted and small molecule drugs that are sensitive to patients in cluster 2 were predicted. Importantly, we discovered TRIM8, DTX2, and TRAF5 as the most vital contributors from the RNF family, which were related to immune infiltration in LGG tumor immune landscape. In this study, we demonstrated the predicted role of RNF proteins in LGG. In addition, we found out three markers among RNF proteins that are closely related to the immune aspects of LGG, which might serve as novel therapeutic targets for immunotherapy in the future.

Large-scale analysis reveals the specific clinical and immune features of CD155 in glioma.

Recent studies demonstrated that CD155 plays an important role in anti-tumor immune responses. However, its role in glioma remains unclear. Here, we identify CD155 as a promising immune target in glioma. CD155 expression was significantly highly expressed in glioblastoma but not in normal brain tissue. Subsequent analysis based on genetic and clinical data from 1173 glioma patients in Rembrandt and TCGA dataset suggested that CD155 related genes of immune response were mainly positively correlated with CD155 expression. CD155 expression was positively correlated with immune-related metagenes STAT1, HCK, LCK, and MHC I but negatively associated with IgG. CD155 expression was positively correlated with biomarker gene expression of infiltrating immune cells, suggested that high CD155 expression in gliomas tend to have more infiltrating immune cells compared with gliomas with low CD155 expression. Pearson correlation analysis showed that CD155 is associated with CD96, CD226, Nectin4, PD-L1, B7-H2, NR2F6 and GITR, implying the potential synergistic effects of these checkpoint proteins. These findings implied that CD155 is a promising immunotherapy target, combined with existing immune checkpoint blockade therapies for glioma.

Morphologies and Properties of PET Nano Porous Luminescence Fiber: Oil Absorption and Fluorescence-Indicating Functions.

A polyethylene terephthalate nano porous luminescence fiber (PNPLF) was prepared through electrospun technology. The SEM and TEM images show that the surfaces of the fibers are covered with pores. The diameter of the fiber is 250-500 nm, and the diameter of the pores is 20-180 nm. The water and oil contact angles of PNPLF are 135° and 27°, respectively. The oil absorption value of the as-prepared PNPLF achieves 135 g/g and has a good oil absorption function. The as-prepared PNPLF has good luminescence properties and fluorescent-indicating function. Even trace amounts of oil can also cause obvious change of fluorescence intensity of PNPLF which has a good stability from 20 °C to 70 °C. The breaking stress of yarn of PNPLF reaches 117cN. Furthermore, the good mechanical properties and thermal properties of PNPLF provide important basic conditions for their wide applications.

Axisymmetric multicomponent vesicles: A comparison of hydrodynamic and geometric models.

Using a mathematical model, we investigate the role of hydrodynamic forces on three-dimensional axisymmetric multicomponent vesicles. The equations are derived using an energy variation approach that accounts for different surface phases, the excess energy associated with surface domain boundaries, bending energy and inextensibility. The equations are high-order (fourth order) nonlinear and nonlocal. To solve the equations numerically, we use a nonstiff, pseudo-spectral boundary integral method that relies on an analysis of the equations at small scales. We also derive equations governing the dynamics of inextensible vesicles evolving in the absence of hydrodynamic forces and simulate numerically the evolution of this geometric model. We find that compared with the geometric model, hydrodynamic forces provide additional paths for relaxing inextensible vesicles. The presence of hydrodynamic forces may enable the dynamics to overcome local energy barriers and reach lower energy states than those accessible by geometric motion or energy minimization algorithms. Because of the intimate connection between morphology, surface phase distribution and biological function, these results have important consequences in understanding the role vesicles play in biological processes.

Dynamics of multicomponent vesicles in a viscous fluid.

We develop and investigate numerically a thermodynamically consistent model of two-dimensional multicomponent vesicles in an incompressible viscous fluid. The model is derived using an energy variation approach that accounts for different lipid surface phases, the excess energy (line energy) associated with surface phase domain boundaries, bending energy, spontaneous curvature, local inextensibility and fluid flow via the Stokes equations. The equations are high-order (fourth order) nonlinear and nonlocal due to incompressibil-ity of the fluid and the local inextensibility of the vesicle membrane. To solve the equations numerically, we develop a nonstiff, pseudo-spectral boundary integral method that relies on an analysis of the equations at small scales. The algorithm is closely related to that developed very recently by Veerapaneni et al. [81] for homogeneous vesicles although we use a different and more efficient time stepping algorithm and a reformulation of the inextensibility equation. We present simulations of multicomponent vesicles in an initially quiescent fluid and investigate the effect of varying the average surface concentration of an initially unstable mixture of lipid phases. The phases then redistribute and alter the morphology of the vesicle and its dynamics. When an applied shear is introduced, an initially elliptical vesicle tank-treads and attains a steady shape and surface phase distribution. A sufficiently elongated vesicle tumbles and the presence of different surface phases with different bending stiffnesses and spontaneous curvatures yields a complex evolution of the vesicle morphology as the vesicle bends in regions where the bending stiffness and spontaneous curvature are small.

Control of viscous fingering patterns in a radial Hele-Shaw cell.

We study numerically and experimentally the dynamics and control of viscous fingering patterns in a circular Hele-Shaw cell. The nonlocality and nonlinearity of the system, especially interactions among developing fingers, make the emergent pattern difficult to predict and control. By controlling the injection rate of the less viscous fluid, we can precisely suppress the evolving interfacial instabilities. There exist denumerable attractive, self-similarly evolving symmetric, universal shapes. Experiments confirm the feasibility of the control strategy, which is summarized in a morphology diagram.