death process
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Mathematics ◽  
2022 ◽  
Vol 10 (2) ◽  
pp. 251
Virginia Giorno ◽  
Amelia G. Nobile

We consider a time-inhomogeneous Markov chain with a finite state-space which models a system in which failures and repairs can occur at random time instants. The system starts from any state j (operating, F, R). Due to a failure, a transition from an operating state to F occurs after which a repair is required, so that a transition leads to the state R. Subsequently, there is a restore phase, after which the system restarts from one of the operating states. In particular, we assume that the intensity functions of failures, repairs and restores are proportional and that the birth-death process that models the system is a time-inhomogeneous Prendiville process.

2022 ◽  
pp. 129-140
Olga Korosteleva

2022 ◽  
Ignacio Rodriguez-Brenes ◽  
Dominik Wodarz ◽  
Natalia Komarova

Spatial stochastic simulations of evolutionary processes are computationally expensive. Here, based on spatially explicit decoupling approximations (SEDA) introduced by us earlier, we derive a deterministic approximation to a spatial stochastic birth-death process in the presence of two types: the less advantageous resident type and a more advantageous mutant. At the core of this technique are two essential steps: (1) a system of ODEs that approximate spatial interactions among neighboring individuals must be solved; (2) the time-variable has to be rescaled with a factor (called "alpha") that depends on the kinetic parameters of the wild type and mutant individuals. An explicit formula for alpha is derived, which is a power law of division and death rates of the two types. The method is relatively fast and provides excellent time-series agreement with the stochastic simulation results for the spatial agent-based model. The methodology can be used to describe hard selective sweep events, including the expansion of driver mutations in carcinogenesis, bacterial evolution, and aspects of resistance dynamics.

2022 ◽  
Congyue Zhang ◽  
Chaoqun Zhang ◽  
Huifang Zhou ◽  
Zhankai Hu ◽  
Dianxing Sun

Abstract Background: Hepatocellular carcinoma (HCC) is the most common malignancy globally, and ferroptosis is an iron-dependent cell death process. Furthermore, aberrant expression of long non-coding RNAs (lncRNAs) driving HCC development and progression has increased attention. Materials and Methods: We collected lncRNA expression profiles associated with ferroptosis from The Cancer Genome Atlas (TCGA) and FerrDb databases and clinicopathological and overall survival (OS) information to determine the association between ferroptosis-related lncRNAs(FRlncRNAs) and survival of HCC patients by co-expression analysis. A prognostic lncRNA model of 22 differentially expressed lncRNAs was constructed using Cox regression analysis and the LASSO algorithm. Kaplan-Meier analysis revealed that a high-risk lncRNAs profile was associated with poor prognosis in HCC. Our risk assessment model outperformed conventional clinical data in predicting the prognosis of HCC. Result: GSEA revealed immune and tumor-related pathways in individuals in the high- and low-risk groups. In addition, TCGA showed that T cell functions, including B cells, Cytolytic, macrophages, MHC-class-I, mast cells, neutrophils, NK cells, helper T cells, Type-I-IFN, and Type-II-IFN, were significantly different between high and low-risk groups. Immune checkpoints such as TNFSF18, IDO2, CD276, NRP1, and TNFSF4 were also differentially expressed between the two risk groups. Conclusions: Our findings provide a robust prognostic and immune response prediction model for HCC patients based on lncRNAs associated with ferroptosis.

Yifei Qin ◽  
Zhuo Pei ◽  
Zhuan Feng ◽  
Peng Lin ◽  
Shijie Wang ◽  

Ferroptosis, a form of programmed cell death process driven by iron-dependent lipid peroxidation, plays an important role in tumor suppression. Although previous study showed that intracellular Merlin-Hippo signaling suppresses ferroptosis of epithelial tumor cells through the inactivation of YAP signaling, it remains elusive if the proto-oncogenic transcriptional co-activator YAP could serve as a potential biomarker to predict cancer cell response to ferroptosis-inducing therapies. In this study, we show that both total YAP staining and nuclear YAP staining were more prevalent in HCC tissues than in nontumorous regions. Compared to low-density HCC cells, high-density cells showed decreased nuclear localization of YAP and conferred significant resistance to ferroptosis. Oncogenic activation of YAP signaling by overexpression of YAP(S127A) mutant sensitized ferroptosis of HCC cells cultured in confluent density or in the 3D tumor spheroid model. Furthermore, we validated the lipoxygenase ALOXE3 as a YAP-TEAD target gene that contributed to YAP-promoted ferroptosis. Overexpression of ALOXE3 effectively increased the vulnerability of HCC cells to ferroptotic cell death. In an orthotopic mouse model of HCC, genetic activation of YAP rendered HCC cells more susceptible to ferroptosis. Finally, an overall survival assay further revealed that both a high expression of YAP and a low expression of GPX4 were correlated with increased survival of HCC patients with sorafenib treatment, which had been proven to be an inducer for ferroptosis by inhibition of the xc-amino acid antiporter. Together, this study unveils the critical role of intracellular YAP signaling in dictating ferroptotic cell death; it also suggests that pathogenic alterations of YAP signaling can serve as biomarkers to predict cancer cell responsiveness to future ferroptosis-inducing therapies.

2021 ◽  
Aviva M. Tolkovsky ◽  
Maria Grazia Spillantini

Abstract How neurons die in neurodegenerative diseases is still unknown. The distinction between apoptosis as a genetically controlled mechanism, and necrosis, which was viewed as an unregulated process, has blurred with the ever-increasing number of necrotic-like death subroutines underpinned by genetically defined pathways. It is therefore pertinent to ask whether any of them apply to neuronal cell death in tauopathies. Although Alzheimer’s disease (AD) is the most prevalent tauopathy, tauopathies comprise an array of over 30 diseases in which the cytoplasmic protein tau aggregates in neurons, and also, in some diseases, in glia. Animal models have sought to distil the contribution of tau aggregation to the cell death process but despite intensive research, no one mechanism of cell death has been unequivocally defined. The process of tau aggregation, and the fibrillar structures that form, touch on so many cellular functions that there is unlikely to be a simple linear pathway of death; as one is blocked another is likely to take the lead. It is timely to ask how far we have advanced into defining whether any of the molecular players in the new death subroutines participate in the death process. Here we briefly review the currently known cell death routines and explore what is known about their participation in tau aggregation-related cell death. We highlight the involvement of cell autonomous and the more recent non-cell autonomous pathways that may enhance tau-aggregate toxicity, and discuss recent findings that implicate microglial phagocytosis of live neurons with tau aggregates as a mechanism of death.

2021 ◽  
Vol 11 ◽  
Xing Liu ◽  
Pengshuo Yang ◽  
Lu Han ◽  
Qing Zhou ◽  
Qingsong Qu ◽  

Ferroptosis is an iron-dependent programmed cell death process. Although ferroptosis inducers hold promising potential in the treatment of breast cancer, the specific role and mechanism of the ferroptosis-related gene EMC2 in breast cancer have not been entirely determined. The potential roles of EMC2 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Tumor Immune Estimation Resource (TIMER), Shiny Methylation Analysis Resource Tool (SMART), starBase, and cBioPortal for cancer genomics (cBioPortal) datasets. The expression difference, mutation, survival, pathological stage, DNA methylation, non-coding RNAs (ncRNAs), and immune cell infiltration related to EMC2 were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify the differences in biological processes and functions among different related genes. The expression levels of core prognostic genes were then verified in breast invasive carcinoma samples using immunohistochemistry and breast invasive carcinoma cell lines using real-time polymerase chain reaction. High expression levels of EMC2 were observed in most cancer types. EMC2 expression in breast cancer tissue samples correlated with poor overall survival. EMC2 was mutated and methylated in a variety of tumors and affected survival. The LINC00665-miR-410-3p axis was identified as the most potential upstream ncRNA-related pathway of EMC2 in breast cancer. EMC2 levels were significantly positively correlated with tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint expression. Our study offers a comprehensive understanding of the oncogenic roles of EMC2 across different tumors. The upregulation of EMC2 expression mediated by ncRNAs is related to poor prognosis and tumor immune infiltration in breast cancer.

2021 ◽  
Soumaya Belhadj ◽  
Nina Hermann ◽  
Gustav Christensen ◽  
Torsten Strasser ◽  
François Paquet-Durand

AbstractCalpains are a family of calcium-activated proteases involved in numerous disorders. Notably, previous studies have shown that calpain activity was substantially increased in various models for inherited retinal degeneration (RD). In the present study, we tested the capacity of the t-BOC-Leu-Met-CMAC calpain-specific substrate to detect calpain activity in living retina, in organotypic retinal explant cultures derived from wild-type mice, as well as from rd1 and RhoP23H/+ RD-mutant mice. Test conditions were refined until the calpain substrate readily detected large numbers of cells in the photoreceptor layer of RD retina but not in wild-type retina. At the same time, the calpain substrate was not obviously toxic to photoreceptor cells. Comparison of calpain activity with an immunostaining for activated calpain-2 furthermore suggested that individual calpain isoforms may be active in distinct temporal stages of photoreceptor cell death. Notably, calpain-2 activity may be a relatively short-lived event, occurring only towards the end of the cell death process. Finally, our results support the development of calpain activity detection as a novel in vivo biomarker for RD, suitable for combination with non-invasive imaging techniques.

Louis Asiedu ◽  
Felix Mettle ◽  
Emmanuel Aidoo ◽  
Stella Lawerh

The main aim of this study is to fit a model for predicting pension liability. The study proposed a stochastic population model to determine the status of a pension scheme. By categorizing the members of the Social Security and National Insurance Trust (SSNIT) pension scheme of Ghana into five groups, the birth and death process with emigration and the pure death process coupled with assumption of the Yule’s process, were combined to successfully formulate a model for forecasting the surplus of SSNIT to be used as a proxy for assessing the solvency status of the scheme. The reliability of the proposed model was corroborated by very high coverage probabilities of the estimates of expected surpluses produced.  The study demonstrated how easy it is to use the proposed model to carry out sensitivity analysis which allows the exploration of various scenarios leading to formulation and implementation of policies to enhance the solvency of the scheme. One major advantage of the proposed model is that, it uses more information (variables) compared to others proposed elsewhere for the same purpose. This contributes to the precision of estimates from the model. A key finding of the study is that SSNIT would have still been solvent had she increased pension by 50%.  

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