Heterogeneity, turn-over rate and karyotype space shape susceptibility to missegregation-induced extinction

The incidence of somatic copy number alterations (SCNAs) per base pair of the genome is orders of magnitudes larger than that of point mutations. This makes SCNAs phenotypically effective. One mitotic event stands out in its potential to significantly change a cell's SCNA burden -- a chromosome missegregation. We have presented a general deterministic framework for modeling whole chromosome missegregations and use it to evaluate the possibility of missegregation-induced population extinction (MIE). The model predicts critical curves that separate viable from non-viable populations as a function of their turnover- and mis-segregation rates. Missegregation- and turnover rates estimated for nine cancer types are then compared to these predictions for various biological assumptions. The assumption of heterogeneous missegregation rates within a tumor was sufficient to explain the observed data. By contrast, when assuming constant mis-segregation rates, several cancers were located in regions predicted as unviable. Intra-tumor heterogeneity, including heterogeneity in mis-segregation rates, increases as tumors progress. Our predictions suggest that this intra-tumor heterogeneity hinders the chance of success of therapies aimed at MIE.

The natural history of TB disease - a synthesis of data to quantify progression and regression across the spectrum

Background: Prevalence surveys have found a substantial burden of subclinical (asymptomatic but infectious) TB, from which individuals can progress, regress or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of TB disease. Methods: We created deterministic framework of TB disease with progression and regression between three states of pulmonary TB disease: minimal (non-infectious), subclinical, and clinical (symptomatic and infectious) disease. We estimated ranges for each parameter by considering all data from a systematic review in a Bayesian framework, enabling quantitative estimation of TB disease pathways. Findings: Twenty-four studies contributed data from 6030 individuals. Results suggested that, after five years, 24.7%(95% uncertainty interval, UI, 21.3%-28.6%) of individuals with prevalent subclinical disease at baseline had either progressed to clinical disease or died from TB, whereas 16.1%(95%UI, 13.8%-18.5%) had recovered after regressing to minimal disease. Over the course of five years 30% (95%UI, 27.2%-32.6%) of the subclinial cohort never developed symptoms. For those with clinical disease at baseline, 39%(95%UI, 35.8%-41.9%) and 10.3%(95%UI, 8.5%-12.4%) had died or recovered from TB, with the remainder in, or undulating between, the three disease states. The ten-year mortality of people with untreated prevalent infectious disease was 38%. Interpretation: Our results show that for people with subclinical disease, classic clinical disease is neither inevitable nor an irreversible outcome. As such, reliance on symptom- based screening means a large proportion of people with infectious disease may never be detected. Funding: TB Modelling and Analysis Consortium and European Research Council

Coastal Adaptation and Uncertainties: The Need of Ethics for a Shared Coastal Future

Coastal hydro-morphodynamics present significant uncertainties, one order of magnitude larger for sediment transport than for the driving hydrodynamics. Met-ocean factors (waves, currents, and levels essentially) are normally selected from a probability distribution, where only the central trend is considered, and then the analysis of hydro-morphodynamic processes is carried out within a deterministic framework. This analysis is often based on a non-updated topo-bathymetry, with implicit error intervals for many variables, which results in uncertainties that, unless presented from an ethical perspective, tend to hinder proactive decision making and thus result in growing coastal degradation. To address this challenge, the article starts with the uncertainty in water/sediment fluxes and resulting morphodynamic impacts under average and storm conditions, proving the need to include explicit error levels in the analysis and subsequent assessments. The article develops this approach for field and lab data, considering how they are extrapolated to estimate key variables in coastal sustainability and engineering decisions, illustrated in terms of the longshore sand transport. Such a key variable estimation presents large uncertainties and thus requires a stricter ethical approach for extreme events, which serves to illustrate the transmission of uncertainties. The article concludes with a short overview of the implications that these uncertainties may have for coastal risk assessments and proactive decision making, discussing how large error levels without a suitable ethical assessment may result in socio-economic mistrust, which will limit the necessary optimism to address future coastal sustainability.

Firm-level attributes of inflationary expectations of entrepreneurs: evidence from the Pakistan economy

PurposeThe purpose of this research is to bring upfront some unconventional attributes of inflationary expectations of entrepreneurs. Firm-level attributes are instrumental in shaping the behavior of entrepreneurs, which affect the way in which they form their expectations regarding some key economic variables, like inflation. Inflationary expectations are considered important based on their significant role in affecting decisions taken by individuals, firms and policy makers. Among all economic segments, it is vital to account the inflationary expectations of entrepreneurs representing firms because their decisions critically define the future path of actual inflation and inflation inertia. This basic purpose of this paper is to offer a deterministic framework for these expectations contingent upon the firm-level attributes.Design/methodology/approachThis paper provides survey-based evidence on inflationary expectations of entrepreneurs of the selected manufacturing, trading and service sector firms from Pakistan. Additionally, the study has focused on identifying some firm-level attributes, including market experience of the firm, scale of production, myopia in price setting behavior, forward and backward-looking behavior, rationality of the entrepreneur and the entrepreneur's relative firm-level experience as determinants of these expectations. The specified variables are constructed based on responses captured through a structured questionnaire.FindingsWithin an ordinal logistic framework, the study finds that the said attributes including market experience of the firm, scale of production, myopic tendency of entrepreneur in price setting, forward and backward-looking behavior, rationality of the entrepreneur and the entrepreneur's relative firm-level experience play a pivotal role in explaining differentials and heterogeneity in reported level of inflationary expectations.Originality/valueThe study brings upfront some unconventional attributes of inflationary expectations at entrepreneurial level. The work is unique in a sense that it provokes researchers to account behavioral and individualistic attributes within a deterministic framework for inflationary expectations.

Non-Deterministic Methods and Surrogates in the Design of Rockfill Dams

The parameters of the constitutive models used in the design of rockfill dams are associated with a high degree of uncertainty. This occurs because rockfill dams are comprised of numerous zones, each with different soil materials, and it is not feasible to extract materials from such structures to accurately ascertain their behavior or their respective parameters. The general approach involves laboratory tests using small material samples or empirical data from the literature. However, such measures lack an accurate representation of the actual scenario, resulting in uncertainties. This limits the suitability of the model in the design process. Inverse analysis provides an option to better understand dam behavior. This procedure involves the use of real monitored data, such as deformations and stresses, from the dam structure via installed instruments. Fundamentally, it is a non-destructive approach that considers optimization methods and actual performance data to determine the values of the parameters by minimizing the differences between simulated and observed results. This paper considers data from an actual rockfill dam and proposes a surrogate assisted non-deterministic framework for its inverse analysis. A suitable error/objective function that measures the differences between the actual and simulated displacement values is defined first. Non-deterministic algorithms are used as the optimization technique, as they can avoid local optima and are more robust when compared to the conventional deterministic methods. Three such approaches, the genetic algorithm, differential evolution, and particle swarm optimization are evaluated to identify the best strategy in solving problems of this nature. A surrogate model in the form of a polynomial regression is studied and recommended in place of the actual numerical model of the dam to reduce computation cost. Finally, this paper presents the relevant dam parameters estimated by the analysis and provides insights into the performance of the three procedures to solve the inverse problem.

Asymptotic Behavior and Stationary Distribution of a Nonlinear Stochastic Epidemic Model with Relapse and Cure

In this paper, by introducing environmental perturbation, we extend an epidemic model with graded cure, relapse, and nonlinear incidence rate from a deterministic framework to a stochastic differential one. The existence and uniqueness of positive solution for the stochastic system is verified. Using the Lyapunov function method, we estimate the distance between stochastic solutions and the corresponding deterministic system in the time mean sense. Under some acceptable conditions, the solution of the stochastic system oscillates in the vicinity of the disease-free equilibrium if the basic reproductive number R0≤1, while the random solution oscillates near the endemic equilibrium, and the system has a unique stationary distribution if R0>1. Moreover, numerical simulation is conducted to support our theoretical results.

ASYMPTOTIC BEHAVIOUR OF THE STOCHASTIC MAKI–THOMPSON MODEL WITH A FORGETTING MECHANISM ON OPEN POPULATIONS

Rumours have become part of our daily lives, and their spread has a negative impact on a variety of human affairs. Therefore, how to control the spread of rumours is an important topic. In this paper, we extend the classic Maki–Thompson model from a deterministic framework to a stochastic framework with a forgetting mechanism, because real-world person-to-person communications are inevitably affected by random factors. By constructing suitable stochastic Lyapunov functions, we show that the asymptotic behaviour of the stochastic rumour model is governed by the basic reproductive number. If this number is less than one, then the solution of the stochastic rumour model oscillates around the rumour-free equilibrium under extra mild conditions, indicating the extinction of the rumour with a probability of one. Otherwise, the solution always fluctuates around the endemic equilibrium under certain parametric restrictions, implying that the rumour will continually persist. In addition, we discuss a possible intervention strategy that stops the spread of rumours by strengthening the intensity of white noise, which is very different from the deterministic rumour model without white noise. Also, numerical simulations are conducted to support our analytical results.

Asset Pricing and Volatility of Indian Stock Market

This paper shows a basic market portion model of two sorts of dealers, for example, fundamentalists and chartists under a market situation. It is discovered that the Asset costs, riches elements and market conduct are portrayed by the elements of the basic deterministic framework. We give the hypothetical and exact contentions for a recessed shape for the security advertise line, or a reducing minimal premium for showcase hazard. In capital market balance with basic portfolio limitations, various financial specialists by and large hold various arrangements of theoretical or tricky protections. We show that the volatility depends on covariance of aggregate risk aversion and the stock returns. We found that the heterogeneity increases volatility and thereby it leads in rise of beta. Here the statistical approach is provided to estimate the volatility of the assets included in the portfolio. This paper draws out the connection between the alpha (returns) and beta (hazard). A sober minded examination of securities exchange information affirms the presence of a critical and solid, inward crosssectional connection between normal return and gauge past market beta. This paper additionally reports a descending slanting of security advertises line, which is more bewildering than the normal and customary "smoothed" SML. We additionally found that the incline of SML turns out to be increasingly "modified" when speculators become overweening with expanded exchanging volume. Here high-beta stocks are the most exchanged stocks and are connected with the least hazard balanced returns and bringing about a way more noteworthy gainfulness of the wagering against-beta. Hence the asset pricing can be made with the help of security market line or characteristic line which best describes the prominent attributes of the securities that are leaping on the market line. The Capital asset pricing model can be perfectly justified with the help of SML.

Diversifying Method

By investigating Kant’s anthropology, this chapter presents him as a thinker who was firmly committed to a conception of the human being as shaped by its situatedness in the empirical world of history and culture. However, due to Kant’s own methodological constraints, he could recognize this situatedness only if approached through a deterministic framework that traces the causes and effects of the laws of nature. Human freedom here becomes almost unrecognizable, which makes it necessary for us to acknowledge the systematic nature of Kant’s general “scientific” enterprise. This enterprise employs different methodological strategies and disciplines that all in their own way clarify what it means to be human: a creature that is able to know and understand, but also able to act freely. Kant’s anthropology appeals to us in our capacity to act, thereby performing a function his theoretical sciences fail to cover.