Bifurcation of closed orbits from equilibria of Newtonian systems with Coriolis forces

We consider autonomous Newtonian systems with Coriolis forces in two and three dimensions and study the existence of branches of periodic orbits emanating from equilibria. We investigate both degenerate and nondegenerate situations. While Lyapunov’s center theorem applies locally in the nondegen- erate, nonresonant context, equivariant degree theory provides a global answer which is significant also in some degenerate cases. We apply our abstract results to a problem from Celestial Mechanics. More precisely, in the three-dimensional version of the Restricted Triangular Four- Body Problem with possibly different primaries our results show the existence of at least seven branches of periodic orbits emanating from the stationary points

Implementation of the principles of sustainable development by agricultural producers in Poland

Purpose: The aim of the research is to identify and assess the opportunities and processes of implementing sustainable development in agricultural activities. It is also to assess farmers’ awareness and knowledge of the principles of sustainable development in agriculture. Design/Methodology/Approach: Research on the application of the principles of sustainable development in agricultural production was carried out in 2019. Data was collected in four voivodships using the interview questionnaire. The research area was chosen deliberately. They were voivodships with the largest share of sown crops. The collected material was analyzed in terms of farmers’ knowledge of the principles of sustainable development in agricultural production and the level of their application on the farm. Findings: Based on the collected information, it was found that the respondents had a high level of knowledge about the sustainable development of agriculture. The results show significant differences in the application of sustainable development principles. It was also found that there is a relationship between the level of education and age of farmers and the application of sustainable development principles among them. Knowing the principles of sustainable development has not always coincided with the application. Practical Implications: The results obtained may be used for development of the agricultural policy, aimed at agricultural farms, as well as in programming agricultural development and shaping farmers’ income. Originality/Value: The results are original because they can be used to develop future agricultural policy scenarios in terms of compensation for conducting agricultural production in a sustainable way.peer-reviewe

Cancer cell heterogeneity and plasticity: A paradigm shift in glioblastoma

Phenotypic plasticity has emerged as a major contributor to intra-tumoral heterogeneity and treatment resistance in cancer. Increasing evidence shows that glioblastoma (GBM) cells display prominent intrinsic plasticity and reversibly adapt to dynamic microenvironmental conditions. Limited genetic evolution at recurrence further suggests that resistance mechanisms also largely operate at the phenotypic level. Here we review recent literature underpinning the role of GBM plasticity in creating gradients of heterogeneous cells including those that carry cancer stem cell (CSC) properties. A historical perspective from the hierarchical to the nonhierarchical concept of CSCs towards the recent appreciation of GBM plasticity is provided. Cellular states interact dynamically with each other and with the surrounding brain to shape a flexible tumor ecosystem, which enables swift adaptation to external pressure including treatment. We present the key components regulating intra-tumoral phenotypic heterogeneity and the equilibrium of phenotypic states, including genetic, epigenetic, and microenvironmental factors. We further discuss plasticity in the context of intrinsic tumor resistance, where a variable balance between preexisting resistant cells and adaptive persisters leads to reversible adaptation upon treatment. Innovative efforts targeting regulators of plasticity and mechanisms of state transitions towards treatment-resistant states are needed to restrict the adaptive capacities of GBM.publishedVersio

Turning strength into weakness: protein degradation and autophagy as therapeutic targets in glioblastoma?

peer reviewe

How to move a “fried egg”: membrane blebbing in oligodendrogliomas

peer reviewe

Stabilization of stochastic dynamical systems of a random structure with Markov switches and Poisson perturbations

An optimal control for a dynamical system optimizes a certain objective function. Here we consider the construction of an optimal control for a stochastic dynamical system with a random structure, Poisson perturbations and random jumps, which makes the system stable in probability. Sufficient conditions of the stability in probability are obtained, using the second Lyapunov method, in which the construction of the corresponding functions plays an important role. Here we provide a solution to the problem of optimal stabilization in a general case. For a linear system with a quadratic quality function, we give a method of synthesis of optimal control based on the solution of Riccati equations. Finally, in an autonomous case, a system of differential equations was constructed to obtain unknown matrices that are used for the building of an optimal control. The method of a small parameter is justified for the algorithmic search of an optimal control. This approach brings a novel solution to the problem of optimal stabilization for a stochastic dynamical system with a random structure, Markov switches and Poisson perturbations.Comment: 15 pages, 0 figures, 25 reference

Glioblastoma organoids: pre-clinical applications and challenges in the context of immunotherapy

Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due to inappropriate preclinical model systems, which do not reflect the complexity of patient tumors. Furthermore, clinically relevant patient-derived models recapitulating the immune compartment are lacking, which represents a bottleneck for adequate immunotherapy testing. Emerging 3D organoid cultures offer innovative possibilities for cancer modeling. Here, we review available GBM organoid models amenable to a large variety of pre-clinical applications including functional bioassays such as proliferation and invasion, drug screening, and the generation of patient-derived orthotopic xenografts (PDOX) for validation of biological responses in vivo. We emphasize advantages and technical challenges in establishing immunocompetent ex vivo models based on co-cultures of GBM organoids and human immune cells. The latter can be isolated either from the tumor or from patient or donor blood as peripheral blood mononuclear cells (PBMCs). We also discuss the challenges to generate GBM PDOXs based on humanized mouse models to validate efficacy of immunotherapies in vivo. A detailed characterization of such models at the cellular and molecular level is needed to understand the potential and limitations for various immune activating strategies. Increasing the availability of immunocompetent GBM models will improve research on emerging immune therapeutic approaches against aggressive brain cancer.publishedVersio

Critical appraisal of the side population assay in stem cell and cancer stem cell research.

peer reviewedThe "Side Population" (SP) discrimination assay is a flow cytometry method used to detect stem cells based on the dye efflux properties of ABC transporters. We discuss the SP assay and its applications in stem cell biology, with an emphasis on the technical challenges related to sample preparation, data acquisition, analysis, and interpretation. We highlight the value of multicolor phenotyping, the impact of DNA ploidy, and the importance of distinguishing graft versus host cells for an appropriate SP discrimination. To improve the consistency and reliability of data between laboratories, we propose a set of recommendations for SP assay data reporting

Elucidating tumour-associated microglia/macrophage diversity along glioblastoma progression and under ACOD1 deficiency

In glioblastoma (GBM), tumour-associated microglia/macrophages (TAMs) represent the major cell type of the stromal compartment and contribute to tumour immune escape mechanisms. Thus, targeting TAMs is emerging as a promising strategy for immunotherapy. However, TAM heterogeneity and metabolic adaptation along GBM progression represent critical features for the design of effective TAM-targeted therapies. Here, we comprehensively study the cellular and molecular changes of TAMs in the GL261 GBM mouse model, combining single-cell RNA-sequencing with flow cytometry and immunohistological analyses along GBM progression and in the absence of Acod1 (also known as Irg1), a key gene involved in the metabolic reprogramming of macrophages towards an anti-inflammatory phenotype. Similarly to patients, we identify distinct TAM profiles, mainly based on their ontogeny, that reiterate the idea that microglia- and macrophage-like cells show key transcriptional differences and dynamically adapt along GBM stages. Notably, we uncover decreased antigen-presenting cell features and immune reactivity in TAMs along tumour progression that are instead enhanced in Acod1-deficient mice. Overall, our results provide insight into TAM heterogeneity and highlight a novel role for Acod1 in TAM adaptation during GBM progression.publishedVersio

Protocol for derivation of organoids and patient-derived orthotopic xenografts from glioma patient tumors

Tumor organoids and patient-derived orthotopic xenografts (PDOXs) are some of the most valuable pre-clinical tools in cancer research. In this protocol, we describe efficient derivation of organoids and PDOX models from glioma patient tumors. We provide detailed steps for organoid culture, intracranial implantation, and detection of tumors in the brain. We further present technical adjustments for standardized functional assays and drug testing.publishedVersio