Dynamics of flexible shells and Sharkovskiy's periodicity

Complex vibration of flexible elastic shells subjected to transversal and sign-changeable local load in the frame of nonlinear classical theory is studied. A transition from partial to ordinary differential equations is carried out using the higher-order Bubnov-Galerkin approach. Numerical analysis is performed applying theoretical background of nonlinear dynamics and qualitative theory of differential equations. Mainly the so-called Sharkovskiy periodicity is studied

Mathematical modeling of functionally graded porous geometrically nonlinear micro/nano cylindrical panels

Relevance. The study investigates the problem of stress-strain state and stability of porous functional-gradient size-dependent cylindrical panels. The composition and properties of alloys can differ and significantly affect the performance characteristics of products. Therefore, the research of material properties is relevant and contributes to the creation of new types of products demanded by the oil and gas industry. Aim. Development of a new model and creation of accurate methods for analyzing the stress-strain state of porous functional-gradient size-dependent micro/nano cylindrical panels taking into account geometrical nonlinearity. Methods. The method of variational iterations – the extended Kantorovich method is used to analyze the stress-strain state of cylindrical panels. The validity of the results is ensured by comparing the solutions obtained by the method of variational iterations in the first and second approximations with the solutions obtained by the authors, by the Bubnov–Galerkin method in higher approximations, by the finite difference method of the second order of accuracy, for which their convergence is investigated depending on a number of partitions of the integration area in the finite difference method and the number of series terms in the expansion of the basic functions in the Bubnov–Galerkin method. The results obtained by these methods are compared with the solutions obtained by other authors. It should be noted that the solutions obtained by the method of variational iterations for bending of functionally graded cylindrical panels under the action of transverse uniformly distributed load can be considered accurate. Results and conclusions. The authors have constructed the model of porous functional-gradient size-dependent cylindrical panels. Its use will allow studying the properties of alloys for producing drill pipes. The influence of material porosity type, porosity index, functional-gradient index, boundary conditions, size-dependent parameter, curvature parameters on the stress-strain state of cylindrical panels was analyzed using the developed method of variational iterations

Immunogenic cell death induced by a new photodynamic therapy based on photosens and photodithazine

Background: Anti-cancer therapy is more successful when it can also induce an immunogenic form of cancer cell death (ICD). Therefore, when developing new treatment strategies, it is extremely important to choose methods that induce ICD and thereby activate anti-tumor immune response leading to the most effective destruction of tumor cells. The aim of this work was to analyze whether the clinically widely used photosensitizers, photosens (PS) and photodithazine (PD), can induce ICD when used in photodynamic therapy (PDT). Methods: Cell death in murine glioma GL261 or fibrosarcoma MCA205 cells was induced by PS- or PD-PDT and cell death was analyzed by MTT or flow cytometry. Intracellular distribution of PS and PD was studied by using the laser scanning microscope. Calreticulin exposure and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of dying cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and maturation (CD11c(+)CD86(+), CD11c(+)CD40(+)) of BMDCs and production of IL-6 in the supernatant were measured. In vivo immunogenicity was analyzed in mouse tumor prophylactic vaccination model. Results: We determined the optimal concentrations of the photosensitizers and found that at a light dose of 20 J/cm(2) (lambda ex 615-635 nm) both PS and PD efficiently induced cell death in glioma GL261 and fibrosarcoma MCA205 cells. We demonstrate that PS localized predominantly in the lysosomes and that the cell death induced by PS-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) and by ferrostatin-1 and DFO (ferroptosis inhibitors), but not by the necroptosis inhibitor necrostatin-1 s. By contrast, PD accumulated in the endoplasmic reticulum and Golgi apparatus, and the cell death induced by PD-PDT was inhibited only by z-VAD-fmk. Dying cancer cells induced by PS-PDT or PD-PDT emit calreticulin, HMGB1 and ATP and they were efficiently engulfed by BMDCs, which then matured, became activated and produced IL-6. Using dying cancer cells induced by PS-PDT or PD-PDT, we demonstrate the efficient vaccination potential of ICD in vivo. Conclusions: Altogether, these results identify PS and PD as novel ICD inducers that could be effectively combined with PDT in cancer therapy

Use of interpolation methods for modeling the stress-strain state of operated oil storage tanks

The aim of the research is the comparison of two approaches for computer modeling of the stress-strain state of thin-walled shells of engineering structures, considering the imperfections of the geometric shapes arising due to their operation. The object of the study is the operated steel vertical cylindrical reservoir with imperfections of the geometric shape intended for storage of petroleum products. The first, so-called classical, approach provides geometric modeling of the surface of the tank's shell with the subsequent import of the geometric model into one of the systems of finite element analysis to calculate the stress-strain state of the structure and determine its technical condition, and the possibility of further operation. The geometric modeling of the shell surface with imperfections was performed using a two-dimensional interpolation method based on the 1st order smoothness outlines implemented in the point calculus. The calculation of the stress-strain state of the shell was carried out in the SCAD Office computer complex, taking into account geometric and structural non-linearity on the basis of the octahedral tangential stress theory. The second approach assumes modeling of an array of functions of vertical deflection of the tank wall by means of interpolation, solution of an array of differential equations of the elastic cylindrical shell under axisymmetric loading, improved by introduction of vertical deflection functions of the wall, followed by two-dimensional interpolation and analysis of the deformed state of the shell based on displacements arising in the tank wall from the hydrostatic load. As a result of the effective use of two-dimensional interpolation in the process of implementing the second approach, it was possible to achieve a significant increase in the speed of the numerical solution while maintaining sufficient accuracy for engineering calculations

Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ3

AbstractA series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born’s method was shown to be due to inhibition of fibrinogen binding to αIIbβ3. Molecular docking of RGD mimetics to αIIbβ3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics

Effect of novel porphyrazine photosensitizers on normal and tumor brain cells

Photodynamic therapy (PDT) is a clinically approved procedure for targeting tumor cells. Though several different photosensitizers have been developed, there is still much demand for novel photosensitizers with improved properties. In this study we aim to characterize the accumulation, localization and dark cytotoxicity of the novel photosensitizers developed in-house derivatives of porphyrazines (pz I-IV) in primary murine neuronal cells, as well as to identify the concentrations at which pz still effectively induces death in glioma cells yet is nontoxic to nontransformed cells. The study shows that incubation of primary neuronal and glioma cells with pz I-IV leads to their accumulation in both types of cells, but their rates of internalization, subcellular localization and dark toxicity differ significantly. Pz II was the most promising photosensitizer. It efficiently killed glioma cells while remaining nontoxic to primary neuronal cells. This opens up the possibility of evaluating pz II for experimental PDT for glioma

CX3CL1 release during immunogenic apoptosis is associated with enhanced anti-tumour immunity

IntroductionImmunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damage-associated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a “find me” signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD.MethodsIn this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGA-SKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients.ResultsOur findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1.ConclusionThese data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis

ATP Release from Dying Autophagic Cells and Their Phagocytosis Are Crucial for Inflammasome Activation in Macrophages

Pathogen-activated and damage-associated molecular patterns activate the inflammasome in macrophages. We report that mouse macrophages release IL-1β while co-incubated with pro-B (Ba/F3) cells dying, as a result of IL-3 withdrawal, by apoptosis with autophagy, but not when they are co-incubated with living, apoptotic, necrotic or necrostatin-1 treated cells. NALP3-deficient macrophages display reduced IL-1β secretion, which is also inhibited in macrophages deficient in caspase-1 or pre-treated with its inhibitor. This finding demonstrates that the inflammasome is activated during phagocytosis of dying autophagic cells. We show that activation of NALP3 depends on phagocytosis of dying cells, ATP release through pannexin-1 channels of dying autophagic cells, P2X7 purinergic receptor activation, and on consequent potassium efflux. Dying autophagic Ba/F3 cells injected intraperitoneally in mice recruit neutrophils and thereby induce acute inflammation. These findings demonstrate that NALP3 performs key upstream functions in inflammasome activation in mouse macrophages engulfing dying autophagic cells, and that these functions lead to pro-inflammatory responses