Technical review on derivation methods for behavior dependent functional responses

Abstract Functional responses measure the trophic interactions between species, taking into account the density and behavior of the interacting species. In predator-prey interactions, the prey preference of the predator and the antipredator behavior of the prey together determine the feeding rate of the predator and the survival rate of the prey. Consequently, the behavior dependent functional responses make it possible to establish dynamic ecological models providing insight, among others, into the coexistence of predator and prey species and the efficiency of agents in biological pest control. In this paper the derivation methods of functional responses are reviewed. Basically, there are three classes of such methods: heuristic, stochastic and deterministic ones. All of them can take account of the behavior of the predator and prey. There are three main stochastic methods for the derivation of functional responses: renewal theory, Markov chain and the Wald equality-based method. All these methods assume that during the foraging process the prey densities do not change, which provides a mathematical basis for heuristic derivation. There are two deterministic methods using differential equations. The first one also assumes that during the foraging process the prey densities do not change, while the second one does not use that assumption. These derivation methods are appropriate to handle the behavior dependent functional responses, which is essential in the derivation of ecological games, when the payoff of prey and predator depends on the strategies of the prey and predator at the same time

To save or not to save your family member’s life? Evolutionary stability of self-sacrificing life history strategy in monogamous sexual populations

Abstract Background For the understanding of human nature, the evolutionary roots of human moral behaviour are a key precondition. Our question is as follows: Can the altruistic moral rule “Risk your life to save your family members, if you want them to save your life” be evolutionary stable? There are three research approaches to investigate this problem: kin selection, group selection and population genetics modelling. The present study is strictly based on the last approach. Results We consider monogamous and exogamous families, where at an autosomal locus, dominant-recessive alleles determine the phenotypes in a sexual population. Since all individuals’ survival rate is determined by their altruistic family members, we introduce a new population genetics model based on the mating table approach and adapt the verbal definition of evolutionary stability to genotypes. In general, when the resident is recessive, a homozygote is an evolutionarily stable genotype (ESG), if the number of survivors of the resident genotype of the resident homozygote family is greater than that of non-resident heterozygote survivors of the family of the resident homozygote and mutant heterozygote genotypes. Using the introduced genotype dynamics we proved that in the recessive case ESG implies local stability of the altruistic genotype. We apply our general ESG conditions for self-sacrificing life history strategy when the number of new-born offspring does not depend on interactions within the family and the interactions are additive. We find that in this case our ESG conditions give back Hamilton’s rule for evolutionary stability of the self-sacrificing life history strategy. Conclusions In spite of the fact that the kidney transplantations was not a selection factor during the earlier human evolution, nowadays “self-sacrificing” can be observed in the live donor kidney transplantations, when the donor is one of the family members. It seems that selection for self-sacrificing in family produced an innate moral tendency in modulating social cognition in human brain

Opportunistic random searcher versus intentional search image user

We consider two types of optimal foragers: a random searcher and a search image user. A search image user can find its desired prey with higher and undesired prey with lower probability than a random searcher. Our model considers the density-dependent travelling time and the time duration of reproduction (oviposition). In the framework of optimal foraging theory for one predator-two prey systems, we find that there are ranges of prey densities in which the search image user has a higher net energy intake, and there are other ranges of prey densities in which the random searcher has higher net energy intake. The damsel bug Nabis pseudoferus Remane (Hemiptera: Nabidae) is a generalist predator rather than an omnivore. This species has a wide range of arthropod prey (predominantly insects and mites). Several aspects of the biology of this species have been studied, especially its cannibalistic behaviour, which is a quite important feature because N. pseudoferus is often used as a biological control agent against lepidopteran pests in greenhouse crops. Experimentally, we found that Nabis is a search image user in the above sense

Prenylation Inhibition-Induced Cell Death in Melanoma: Reduced Sensitivity in BRAF Mutant/PTEN Wild-Type Melanoma Cells.

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells

Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations

BRAF and NRAS are the two most frequent onco- genic driver mutations in melanoma and are pivotal compo- nents of both the EGF and FGF signaling network. Accord- ingly, we investigated the effect of BRAF and NRAS onco- genic mutation on the response to the stimulation and inhibi- tion of epidermal and fibroblast growth factor receptors in melanoma cells. In the three BRAF mutant, two NRAS mutant and two double wild-type cell lines growth factor re- ceptor expression had been verified by qRT-PCR. Cell prolif- eration and migration were determined by the analysis of 3- days-long time-lapse videomicroscopic recordings. Of note, a more profound response was found in motility as compared to proliferation and double wild-type cells displayed a higher sensitivity to EGF and FGF2 treatment when compared to mutant cells. Both baseline and induced activation of the growth factor signaling was assessed by immunoblot analysis of the phosphorylation of the downstream effectors Erk1/2. Low baseline and higher inducibility of the signaling pathway was characteristic in double wild-type cells. In contrast, onco- genic BRAF or NRAS mutation did not influence the re- sponse to EGF or FGF receptor inhibitors in vitro. Our find- ings demonstrate that the oncogenic mutations in melanoma have a profound impact on the motogenic effect of the activa- tion of growth factor receptor signaling. Since emerging mo- lecularly targeted therapies aim at the growth factor receptor signaling, the appropriate mutational analysis of individual melanoma cases is essential in both preclinical studies and in the clinical trials and practice

Cell migration or cytokinesis and proliferation? – Revisiting the “go or grow” hypothesis in cancer cells in vitro

The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The “go or grow” hypothesis postulates that migration and proliferation spatiotemporally excludes each other. We evaluated this hypothesis on 35 cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility. We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive

Cell migration after zoledronic acid treatment in melanoma cells.

<p>(<b>A-C</b>) Migrated distance as a function of time and (<b>D</b>) average migrated distance after zoledronic acid (ZA) treatment in melanoma cells measured by videomicroscopy. A profound and significant increase in migrated distance was found in all of the BRAF mutant cells. A modest but significant increase in migration was found in VM-47 triple wild-type and VM-15 NRAS mutant cells. Colors blue, red and green indicate BRAF, NRAS mutation and wild-type for these genes, respectively. Data shown as average ± SEM are from at least three independent measurements. Asterisks indicate significant difference of p < 0.05 from the respective control with unpaired two-tailed T test.</p

<i>In vivo</i> effects of zoledronic acid treatment.

<p>Effect of zoledronic acid (ZA) treatment using <i>in vivo</i> subcutaneous xenograft model of human melanoma cells in SCID mice (<b>A, C, E</b>). ZA treatment failed to show effects in the subcutaneous growth of melanoma cells with either mutation. (<b>B, D, F</b>) Effect of ZA treatment using <i>in vivo</i> spleen liver colonization model of human melanoma cells in SCID mice. ZA did not inhibit the primary tumor or metastatic growth of melanoma cells. Data shown as average ± SEM.</p

Cell viability, clonogenic growth and apoptosis in melanoma cells after zoledronic acid treatment.

<p>(<b>A</b>) Dose-response analysis of cell viability of human melanoma cell lines with different mutations after 72hs treatment with ZA measured by SRB assay; Most pronounced reduction in cell viability was observed in two NRAS mutant lines (<b>B</b>) Long-term effect of 10 days of 5 μM ZA treatment on clonogenic growth. Resistance was found in BRAF mutant and PTEN wild-type cells. Of note, NRAS and BRAF double mutant cells demonstrated intermediate sensitivity (<b>C</b>) Apoptosis induction after 25μM ZA treatment demonstrated by the proportion of TUNEL positive cells and (<b>D</b>) apoptosis induction of 72hs ZA treatment evaluated by the immunoblot of cleaved PARP. Limited apoptosis induction was found in BRAF mutant and PTEN wild-type cells and in the MDM2 over expressing WM239 cells. Colors green, red, blue, and dark-blue indicate triple wild-type, NRAS, BRAF, and BRAF mutant/PTEN-null mutational status of the cells, respectively. Data shown as average ± SEM are from at least 5 repeats. Asterisks indicate the lowest concentration of ZA treatment resulting in a significant difference with p < 0.05 from control by ANOVA and Dunnett’s post hoc test in the cell viability assay. Data shown as average ± SEM are from at least 3 measurements. Asterisks indicate significant difference of p < 0.05 between given mutational group and the BRAF mutant PTEN wild-type group by Kruskal-Wallis and Dunn’s post hoc test in the clonogenic assay, and p < 0.05 difference from the respective control by unpaired two tailed T test in the apoptosis assay. (C = control; Z = zoledronic acid).</p