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DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.

Compartmental models play an important role to describe the dynamics of systems that involve mass movements between different types of pools. We develop a theory to analyse the average ages of mass in different pools in a linear compartmental system with time-dependent (i.e. non-autonomous) transfer rates, which involves transit times that characterize the average time a particle has spent in a particular pool. We apply our theoretical results to investigate a nine-dimensional compartmental system with time-dependent fluxes between pools modelling the carbon cycle which is a modification of the Carnegie–Ames–Stanford approach model. Knowledge of transit time and mean age allows calculation of carbon storage in a pool as a function of time. The general result that has important implications for understanding and managing carbon storage is that the change in storage in different pools does not change monotonically through time: as rates change monotonically a pool which initially shows a decrease may then show an increase in storage or vice versa. Thus caution is needed in extrapolating even the direction of future changes in storage in carbon storage in different pools with global change.

Various inequivalent notions of attraction for autonomous dynamical systems have been proposed, each of them useful to understand specific aspects of attraction. Milnor’s notion of a measure attractor considers invariant sets with positive measure basin of attraction, while Ilyashenko’s weaker notion of a statistical attractor considers positive measure points that approach the invariant set in terms of averages. In this paper we propose generalisations of these notions to nonautonomous evolution processes in continuous time. We demonstrate that pullback/forward measure/statistical attractors can be defined in an analogous manner and relate these to the respective autonomous notions when an autonomous system is considered as nonautonomous. There are some subtleties even in this special case–we illustrate an example of a two-dimensional flow with a one-dimensional measure attractor containing a single point statistical attractor. We show that the single point can be a pullback measure attractor for this system. Finally, for the particular case of an asymptotically autonomous system (where there are autonomous future and past limit systems) we relate pullback (respectively, forward) attractors to the past (respectively, future) limit systems.

The tumor microenvironment influences prostate cancer aggressiveness, and by focusing on how different changes to the microenvironment can affect the cancer, we aimed to identify novel stromal subtypes in localized prostate cancer (LPC), characterize these subtypes, and utilize subtypes to increase accuracy in prostate cancer risk stratification. Subtype identification was conducted using non-negative matrix factorization with consensus clustering on a stroma-specific expression signature in RNA sequencing data. A discovery cohort (127 LPC patients) and two independent validation cohorts (406 LPC & 126 LPC patients) were used for subtype identification. All three cohorts were subsequently used for subtype characterization and prognostic evaluation. Identified subtypes were characterized by evaluation of clinical characteristics, by gene set enrichment analysis, and by cell-type deconvolution analysis. Survival differences between subtypes were assessed using Kaplan-Meier and univariate Cox regression analyses with biochemical recurrence (BCR) as endpoint. Lastly, a high-risk stromal subtype was investigated for its ability to improve risk stratification for intermediate risk prostate cancer using hazard ratio changes from univariate Cox regression analysis. We identified three stromal subtypes (S1-S3) in prostate cancer. Of these, subtype S3 showed characteristics of a highly reactive stromal environment with significantly (adj. p < 0.05) decreased cell polarity and stroma related functions, significantly (adj. p < 0.05) reduced fibroblast infiltration, and a significantly (adj. p < 0.05) increased immune cells infiltration compared to the other subtypes. Survival analysis also revealed significant (p < 0.05) association of S3 with BCR in all three cohorts (HR = 3.2, 2.1, and 3.4 in cohorts 1, 2 and 3 respectively). Lastly, S3 significantly (p < 0.05) improved the risk prediction for patients with intermediate recurrence risk according to the clinical nomogram CAPRA-S (cohort 1, delta HR = 1.4; cohort 2, delta HR = 2.3; cohort 3, delta HR = 4.2). In conclusion, by focusing on the stromal alteration in prostate cancer, this study sheds new light on the influence of tumor microenvironment on LPC aggressiveness. A stromal subtype characterized by dysregulated stromal functions and changes in stroma and immune cells infiltration predicted adverse outcome in patients with a high prognostic ambiguity. This utilization of stromal information to improve risk assessment for clinically intermediate risk PC indicates a potential use in future evaluation of PC aggressiveness. Citation Format: Martin Rasmussen, Jacob Fredsøe, Paul V. Salachan, Marcus P. Blanke, Benedicte P. Ulhøi, Michael Borre, Karina D. Sørensen. Novel stroma-derived prostate cancer subtypes are associated with risk of clinical progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5839.

The authors have recently developed a microworld, a simplified process control simulator, to simulate a nuclear power plant. The microworld provides an environment that can be readily manipulated to gather data using a range of participants, from students to fully qualified operators. Because the microworld represents a simplified domain, it is possible to have more precise experimental control compared with the complex and confounding environment afforded by a full-scope simulator. In this paper, we discuss collecting human reliability data from a microworld. We review the generalizability of human error data from the microworld compared to other data sources like full-scope simulator studies and compare advantages and disadvantages of microworld simulator studies to support human reliability data collection needs.

We introduce the notion of Lyapunov exponents for random dynamical systems, conditioned to tra-jectories that stay within a bounded domain for asymptotically long times. This is motivated by thedesire to characterize local dynamical properties in the presence of unbounded noise (when almost alltrajectories are unbounded). We illustrate its use in the analysis of local bifurcations in this context.The theory of conditioned Lyapunov exponents of stochastic differential equations builds on thestochastic analysis of quasi-stationary distributions for killed processes and associated quasi-ergodic dis-tributions. We show that conditioned Lyapunov exponents describe the asymptotic stability behaviourof trajectories that remain within a bounded domain and – in particular – that negative conditionedLyapunov exponents imply local synchronisation. Furthermore, a conditioned dichotomy spectrum isintroduced and its main characteristics are established.

Dynamic Probabilistic Risk Analysis (PRA) methods couple stochastic methods (e.g., RAVEN) with safety analysis codes (e.g., RELAP5-3D) to determine risk associated to complex systems such as nuclear plants. Compared to classical PRA methods, which are based on static logic structures (e.g., Event-Trees, Fault-Trees), they can evaluate with higher resolution the safety impact of timing and sequencing of events on the accident progression. Recently, special attention has been given to nuclear plant sites which consist of multiple units and, in particular, on the safety impact of system dependencies, shared systems and common resources on core damage frequencies. In the literature, classical PRA methods have been employed to model multi-unit sites in a limited number of cases while Dynamic PRA methods have never been applied to analyze a full multi-unit model. This paper presents a PRA analysis of a multi-unit plant using Dynamic PRA methods. We employ RAVEN as stochastic tool coupled with RELAP5-3D. The site under consideration consists of three units (each unit is composed by a reactor and its associated spent fuel pool) while the considered initiating event is a seismic induced station blackout event. This paper describes in detail how the multi-unit site has been constructed and, in particular, how unit dependencies and shared resources are modeled from both a deterministic and stochastic point of view.

Background: Different learning styles require different teaching methods, and the use of simulator as a learning tool can thus be an important contribution to driver instruction. Road traffic is a highly complex and high-risk environment. For this reason, driver training is an important factor of providing road safety. Educating professional driving instructors is an important contribution to increased road safety, and fewer dead and injured in road traffic. This study explored how simulator training in driver education could be beneficial by investigating authorized driver instructors as well as driving instructor students’ perceptions after testing the simulator. Our research question was: Which factors influence perception and use of driving simulators in teaching and learning driving skills? For this study, 28 individual semi-structured interviews were conducted of driving instructors and students of driving instructors in three rounds over a period of one year. Thematic analysis was used for analysing the data. Results: We found that perceived transferability (main category) is of importance when teaching and learning driving skills through the use of a simulator. The transferability is dependent upon two underlying factors (categories), that seems to influence the perception and use of the simulator: 1) a technological focus or 2) a pedagogical focus. While holding a mainly technological focus, the simulator is viewed as a tool or pedagogical multimedium that provide learning by itself. On the other hand, a pedagogical focus sees the simulator as a tool that should be used in a larger pedagogical context. We found that increased experience of using the simulator technology seemed to influence the instructors and instructor students to shift from a technological focus, to a more pedagogical focus. Conclusion: A driving simulator has the possibility to be beneficial for learning and teaching the complexity of driving, from technical manoeuvring to strategic decision making, but for the instructor to effectively use a simulator for teaching, there need to exist a sense of perceived transferability for the instructor. As increased use of the simulator seems to shift the instructor focus from a more technological to a pedagogical focus – experience with and use of the simulator as a pedagogical tool should be implemented in the educational program for driving instructors. Keywords: learning, simulator, driver training, driver instructor education, higher education, simulation-based teaching, experiential learning, technology acceptance

Lagrangian coherent sets are known to crucially determine transport and mixing processes in non-autonomous flows. Prominent examples include vortices and jets in geophysical fluid flows. Coherent sets can be identified computationally by a probabilistic transfer-operator-based approach within a set-oriented numerical framework. Here, we study sudden changes in flow patterns that correspond to bifurcations of coherent sets. Significant changes in the spectral properties of a numerical transfer operator are heuristically related to critical events in the phase space of a time-dependent system. The transfer operator approach is applied to different example systems of increasing complexity. In particular, we study the 2002 splitting event of the Antarctic polar vortex.

This paper provides a stagewise overview of the important issues that play a role in technology adoption and use in organizations. In the current literature, there is a lack of consistency and clarity about the different stages of the technology adoption process, the important issues at each stage, and the differentiation between antecedents, after-effects, enablers, and barriers to technology adoption. This paper collected the relevant issues in technology adoption and use, mentioned dispersedly and under various terminologies, in the recent literature. The qualitative literature review was followed by thematic analysis of the data. The resulting themes were organized into a thematic map depicting three stages of the technology adoption process: pre-change, change, and post-change. The relevant themes and subthemes at each stage were identified and their significance discussed. The themes at each stage are antecedents to the next stage. All the themes of the pre-change and change stages are neutral, but the way they are managed and executed makes them enablers or barriers in effect. The thematic map is a continuous cycle where every round of technology adoption provides input for the subsequent rounds. Based on how themes have been addressed and executed in practice, they can either enhance or impair the subsequent technology adoption. This thematic map can be used as a qualitative framework by academics and practitioners in the field to evaluate technological changes. Copyright © 2021 Saghafian, Laumann and Skogstad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Our study investigated what factors contribute to the perceived usability of Virtual Reality technology by small firms operating in a conservative industry. For this purpose, we interviewed the developers and users of a newly developed Virtual Reality-equipped heavy machinery. We conducted eleven semi-structured interviews and used thematic analysis to identify the main themes that influenced the perceived usability of the technology by the consumers. This was significant as it contributed to their decisions about purchasing and continuing to use the technology. Consequently, it impacted the developers of the technology in their competitive capability in a conservative and homogenous industrial arena. The dimension and depth of perceived usability by this specific groups are discussed, and the practical implications are provided.

This is the peer reviewed version of the following article: Aykanat, T., Rasmussen, M., Ozerov, M., Niemelä, E., Paulin, L., Vähä, J.-P., ...Primmer, C. R. (2020). Life‐history genomic regions explain differences in Atlantic salmon marine diet specialization. Journal of Animal Ecology, ?(?), 1-15., which has been published in final form at https://doi.org/10.1111/1365-2656.13324. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. 1. Animals employ various foraging strategies along their ontogeny to acquire energy, and with varying degree of efficiencies, to support growth, maturation and subsequent reproduction events. Individuals that can efficiently acquire energy early are more likely to mature at an earlier age, as a result of faster energy gain which can fuel maturation and reproduction. 2. We aimed to test the hypothesis that heritable resource acquisition variation that covaries with efficiency along the ontogeny would influence maturation timing of individuals. 3. To test this hypothesis, we utilized Atlantic salmon as a model which exhibits a simple, hence trackable, genetic control of maturation age. We then monitored the variation in diet acquisition (quantified as stomach fullness and composition) of individuals with different ages, and linked it with genomic regions (haploblocks) that were previously identified to be associated with age‐at‐maturity. 4. Consistent with the hypothesis, we demonstrated that one of the life‐history genomic regions tested (six6) was indeed associated with age‐dependent differences in stomach fullness. Prey composition was marginally linked to six6, and suggestively (but non‐significantly) to vgll3 genomic regions. We further showed Atlantic salmon switched to the so‐called ‘feast and famine’ strategy along the ontogeny, where older age groups exhibited heavier stomach content, but that came at the expense of running on empty more often. 5. These results suggest genetic variation underlying resource utilization may explain the genetic basis of age structure in Atlantic salmon. Given that ontogenetic diet has a genetic component and the strong spatial diversity associated with these genomic regions, we predict populations with diverse maturation age will have diverse evolutionary responses to future changes in marine food web structures.

Methods have previously been developed for the approximation of Lyapunov functions using radial basis functions. However these methods assume that the evolution equations are known. We consider the problem of approximating a given Lyapunov function using radial basis functions where the evolution equations are not known, but we instead have sampled data which is contaminated with noise. We propose an algorithm in which we first approximate the underlying vector field, and use this approximation to then approximate the Lyapunov function. Our approach combines elements of machine learning/ statistical learning theory with the existing theory of Lyapunov function approximation. Error estimates are provided for our algorithm.

In this paper, we investigate how managers enhance sense-making during technological changes in safety-critical industries. Implementation of new technologies is not a linear and predictable process. Technologies evolve faster than we can fully prepare for. This means that new challenges are introduced into the sociotechnical system in which the technology is embedded, leading to shifts in paradigms, interpretation, and business practices. These new technology-induced changes have been less the focus of previous work on sense-making compared to the more traditional paradigms and core practices. In this paper, we focus on the managerial role in these changes. We examine the relevant literature on technological change implementation and organizational sense-making in the past three years and use thematic analysis to capture the main themes plausible within the scope of the paper. Several themes and sub-themes are derived and presented. The resulting themes shed light on what the managers need to be aware of and do to support and enhance the sense-making process during technological changes, which leads to empowerment of the employees to do their own sense-making and maintain reliable operations.

We present formulas for quasi-ergodic limits of finite absorbing Markov chains. Since the irreducible case has been solved in 1965 by Darroch and Seneta, we focus on the reducible case, and our results are based on a very precise asymptotic analysis of the (exponential and polynomial) growth behaviour along admissible paths, Comment: 30 pages

The aim of this research was to explore trainees’ perceptions and evaluation of Virtual Reality fire extinguisher training. Virtual Reality technology is being adopted by many industries for various purposes including safety training for safety critical industries. The future direction of Virtual Reality training requires an understanding of trainees’ evaluation of it; this fact motivated this research. Data were collected from 85 participants using a questionnaire after the training. Observation notes were taken to provide a better understanding of the context. Qualitative research with a thematic analysis was used to analyze the data. The results of this analysis revealed that the most salient themes reflect on issues surrounding the realism of the Virtual Reality simulation, namely different emotional and bodily experiences during the training, while the benefits of the training (health, safety, environmental advantages, efficiency and convenience, repeatability and variety of scenarios) make it a good supplement. Nevertheless, improved realism is needed to make it more effective and enhance transfer and acceptance. This study encourages the consideration of important matters (such as realism and emotions) when using Virtual Reality for fire training. It also describes the positive perceptions of this type of training (repeatability of training, safety and environmental concerns). Copyright © 2020 Saghafian, Laumann, Akhtar and Skogstad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Human reliability analysis (HRA) may be performed prospectively for a newly designed system or retrospectively for an as-built system, typically in response to a safety incident. The SPAR-H HRA method was originally developed for retrospective analysis in the U.S. nuclear industry. As HRA has found homes in new safety critical areas, HRA methods developed predominantly for nuclear power applications are being used in novel ways. The Petro-HRA method represents a significant adaptation of the SPAR-H method for petroleum applications. Current guidance on Petro-HRA considers only prospective applications of the method, such as for review of new systems to be installed at offshore installations. In this paper, we review retrospective applications of Petro-HRA and analyze the Macando Oil Well-Deepwater Horizon accident as a case study.

We study stochastic resonance in an over-damped approximation of the stochastic Duffing oscillator from a random dynamical systems point of view. We analyse this problem in the general framework of random dynamical systems with a nonautonomous forcing. We prove the existence of a unique global attracting random periodic orbit and a stationary periodic measure. We use the stationary periodic measure to define an indicator for the stochastic resonance.