bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virtual deep brain stimulation: Multiscale co-simulation of a spiking basal ganglia model and a whole-brain mean-field model with The Virtual Brain
Authors: Meier Jil M. , Perdikis Dionysios , Blickensdörfer André , Stefanovski Leon , Liu Qin , Maith Oliver , Ü. Dinkelbach Helge , Baladron Javier , Hamker Fred H. , Ritter Petra 
Published: May 2021

AbstractDeep brain stimulation (DBS) has been successfully applied in various neurodegenerative diseases as an effective symptomatic treatment. However, its mechanisms of action within the brain network are still poorly understood. Many virtual DBS models analyze a subnetwork around the basal ganglia and its dynamics as a spiking network with their details validated by experimental data. However, connectomic evidence shows widespread effects of DBS affecting many different cortical and subcortical areas. From a clinical perspective, various effects of DBS besides the motoric impact have been demonstrated. The neuroinformatics platform The Virtual Brain (TVB) offers a modeling framework allowing us to virtually perform stimulation, including DBS, and forecast the outcome from a dynamic systems perspective prior to invasive surgery with DBS lead placement. For an accurate prediction of the effects of DBS, we implement a detailed spiking model of the basal ganglia, which we combine with TVB via our previously developed co-simulation environment. This multiscale co-simulation approach builds on the extensive previous literature of spiking models of the basal ganglia while simultaneously offering a whole-brain perspective on widespread effects of the stimulation going beyond the motor circuit. In the first demonstration of our model, we show that virtual DBS can move the firing rates of a Parkinson’s disease patient’s thalamus - basal ganglia network towards the healthy regime while, at the same time, altering the activity in distributed cortical regions with a pronounced effect in frontal regions. Thus, we provide proof of concept for virtual DBS in a co-simulation environment with TVB. The developed modeling approach has the potential to optimize DBS lead placement and configuration and forecast the success of DBS treatment for individual patients.Highlights-We implement and validate a co-simulation approach of a spiking network model for subcortical regions in and around the basal ganglia and interface it with mean-field network models for each cortical region.-Our simulations are based on a normative connectome including detailed tracts between the cortex and the basal ganglia regions combined with subject-specific optimized weights for a healthy control and a patient with Parkinson’s disease.-We provide proof of concept by demonstrating that the implemented model shows biologically plausible dynamics during resting state including decreased thalamic activity in the virtual patient and during virtual deep brain stimulation including normalized thalamic activity and distributed altered cortical activity predominantly in frontal regions.-The presented co-simulation model can be used to tailor deep brain stimulation for individual patients.
Presynaptic Stochasticity Improves Energy Efficiency and Alleviates the Stability-Plasticity Dilemma
Authors: Schug Simon , Benzing Frederik , Steger Angelika 
Published: May 2021

AbstractWhen an action potential arrives at a synapse there is a large probability that no neurotransmitter is released. Surprisingly, simple computational models suggest that these synaptic failures enable information processing at lower metabolic costs. However, these models only consider information transmission at single synapses ignoring the remainder of the neural network as well as its overall computational goal. Here, we investigate how synaptic failures affect the energy efficiency of models of entire neural networks that solve a goal-driven task. We find that presynaptic stochasticity and plasticity improve energy efficiency and show that the network allocates most energy to a sparse subset of important synapses. We demonstrate that stabilising these synapses helps to alleviate the stability-plasticity dilemma, thus connecting a presynaptic notion of importance to a computational role in lifelong learning. Overall, our findings present a set of hypotheses for how presynaptic plasticity and stochasticity contribute to sparsity, energy efficiency and improved trade-offs in the stability-plasticity dilemma.
Whole-genome duplication shapes the aneuploidy landscape of human cancers
Authors: Prasad Kavya , Bloomfield Mathew , Levi Hagai , Keuper Kristina , Bernhard Sara V. , Baudoin Nicolaas C. , Leor Gil , Giam Maybelline , Wong Cheng Kit , Rancati Giulia , Storchova Zuzana , Cimini Daniela , Ben-David Uri 
Published: May 2021

AbstractAneuploidy – a hallmark of cancer – has tissue-specific recurrence patterns suggesting it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on the cellular and genomic context in which it arises. Whole-genome duplication (WGD) is a common macro-evolutionary event that occurs in >25% of human tumors during the early stages of tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy than tumors that have not, it remains unknown whether WGD affects aneuploidy recurrence patterns in human cancers. Here we analyzed clinical tumor samples from 449 WGD- tumors and 157 WGD+ tumors across 22 tumor types. We found distinct recurrence patterns of aneuploidy in WGD- and WGD+ tumors. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct co-occurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy vs. arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation in WGD- and WGD+ tumors. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Lastly, we induced WGD in human colon cancer cell lines, and followed aneuploidy formation in the isogenic WGD+/WGD-cells under standard or selective conditions. These experiments validated key findings from the clinical tumor analysis, and revealed a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors, and propose that the interaction between WGD and aneuploidy is a major contributor to tumor evolution.
Rpl24Bstmutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K
Authors: Knight John R. P. , Vlahov Nikola , Gay David M. , Ridgway Rachel A. , Faller William J. , Proud Christopher G. , Mallucci Giovanna R. , von der Haar Tobias , Smales C. Mark , Willis Anne E. , Sansom Owen J. 
Published: May 2021

AbstractIncreased protein synthesis supports the rapid proliferation associated with cancer. TheRpl24Bstmutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here we show thatRpl24Bstalso suppresses tumorigenesis and proliferation in a model of colorectal cancer with two common patient mutations,ApcandKras. In contrast to previous reports,Rpl24Bstmutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation inRpl24Bstmutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for theRpl24Bstmutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in colorectal cancer, as well as other cancers where theRpl24Bstmutation has a tumour suppressive effect in mouse models.
Bromelain and Acetylcysteine (BromAc) alone and in combination with Gemcitabine inhibits subcutaneous deposits of pancreatic cancer after intraperitoneal injection
Authors: Mekkawy Ahmad H. , Pillai Krishna , Badar Samina , Akhter Javed , Képénékian Vahan , Ke Kevin , Valle Sarah J. , Morris David L. 
Published: May 2021

AbstractObjectiveGemcitabine (GEM) is commonly chosen for treating pancreatic cancer. However, its use is limited by toxicity. Earlier in vitro studies with GEM in combination with Bromelain (Brom) and Acetylcysteine (Ac) indicated a substantial reduction in IC50. Here, we investigated the efficacy and safety of Brom and Ac (BromAc) in the pancreatic cancer model in vivo.DesignBoth low dose and high dose studies for safety and efficacy of BromAc and GEM were conducted in nude mice. Body weight, wellbeing and tumor volume were monitored. At autopsy, tumor weight, tumor density, percentage of tumor necrosis, expression of Ki67 antigen, and immunohistological evaluation of vital organs were compared between the treatment groups.ResultsThe low and high doses of BromAc alone and with chemotherapy agents were safe. A very significant reduction in pancreatic tumor volume, weight, and ki67 were seen with BromAc therapy and was equal to treatment with GEM alone and better than treatment with 5-FU. In addition, tumor density was significantly reduced by BromAc.ConclusionThese encouraging results are the firstin vivoevidence of the efficacy of BromAc in pancreatic cancer and provide some mechanistic leads.
Protective mitochondrial fission induced by stress responsive protein GJA1-20k
Authors: Shimura Daisuke , Nuebel Esther , Baum Rachel , Xiao Shaohua , Warren Junco S. , Hong TingTing , Rutter Jared , Shaw Robin M. 
Published: May 2021

AbstractThe Connexin43 gap junction geneGJA1has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound, and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 seconds of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin Related Protein 1 (DRP1). We find that GJA1-20k induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.
Magnitude-sensitive reaction times reveal non-linear time costs in multi-alternative decision-making
Authors: Marshall James A. R. , Reina Andreagiovanni , Hay Célia , Dussutour Audrey , Pirrone Angelo 
Published: May 2021

AbstractOptimality analysis of value-based decisions in binary and multi-alternative choice settings predicts that reaction times should be sensitive only to differences in stimulus magnitudes, but not to overall absolute stimulus magnitude. Yet experimental work in the binary case has shown magnitude sensitive reaction times, and theory shows that this can be explained by switching from linear to geometric time costs, but also by nonlinear subjective utility. Thus disentangling explanations for observed magnitude sensitive reaction times is difficult. Here for the first time we extend the theoretical analysis of geometric time-discounting to ternary choices, and present novel experimental evidence for magnitude-sensitivity in such decisions, in both humans and slime moulds. We consider the optimal policies for all possible combinations of linear and geometric time costs, and linear and nonlinear utility; interestingly, geometric discounting emerges as the predominant explanation for magnitude sensitivity.
The role of a mega-sporting event in attracting domestic tourists: the case of Seoul
Authors: Jeong Yunduk , Kim Sukkyu 
Published: May 2021

PurposeMega-sporting events reportedly can offer many tangible and intangible benefits to the host country and regions, such as job creation, image improvement, local pride enhancement, social overhead capital investment and tourism business development. However, a paucity of studies in the literature have developed integrative models or have explored domestic tourist behavior in a general, or the sports tourism, context. To address this gap, the present study investigates the relationships between event quality, personal involvement, destination image and destination loyalty in the context of event sports tourism in order to provide sporting destination managers with valuable information for sustainable sports tourism development.Design/methodology/approachThe authors collected information from 365 domestic tourists who attended the 100th National Sports Festival held in Seoul, South Korea, in 2019. Construct validity of the measurement scale was verified by confirmatory factor analysis (CFA), factor loadings, average variance (AVE) extracted and construct reliability (CR). Reliability of the measurement scale was verified by Cronbach's alpha analysis. The authors utilized structural equation modeling (SEM) with maximum likelihood estimation to analyze the predicted relationships.FindingsThe findings display the positive impacts of (1) event quality on destination image, (2) personal involvement on destination image, (3) personal involvement on destination loyalty and (4) destination image on destination loyalty. The findings indicate the key roles for event quality and personal involvement in improving destination image and the important roles of personal involvement and destination image in building destination loyalty.Originality/valueThe present study (1) contributes to the recent debate in the sports tourism literature over the relationship between the destination image and destination loyalty and (2) shows that there is no mediating role of the destination image on the relationship between the event quality and destination loyalty, and personal involvement and destination loyalty.
Holistic and integrative review into the barriers to women’s advancement to the corporate top in Europe
Authors: van ’t Foort-Diepeveen Rosalien Alexandra , Argyrou Aikaterini , Lambooy Tineke 
Published: May 2021

Purpose
This paper aims to analyze the barriers discussed in the extant literature as to why women are underrepresented in the corporate top and explains how these barriers interrelate. An understanding of the interrelatedness of the barriers can help develop suitable and effective measures to improve women’s representation.

Design/methodology/approach
The systematic review method was applied. The search resulted in 51 relevant academic articles from multiple disciplines which were used for the analysis.

Findings
Barriers identified include gender stereotypes, bias in recruitment and promotion, devaluation of women, masculine and long-hours organizational culture, work-family issues and the lack of professional support. The interrelatedness of these barriers is analyzed by means of a conceptual framework.

Research limitations/implications
The adopted method requires the use of search engines and search terms and consequently relevant articles may have been overlooked. The study is geographically demarcated to Europe and, hence is only applicable to developing suitable and effective measures in a European context. More research is needed into which measures are appropriate and effective to overcome the barriers identified.

Practical implications
The insights can be used by companies to foster gender equality and by companies and governments to develop appropriate and effective measures to overcome these barriers.

Originality/value
This review contributes to the literature by uncovering the interrelatedness of the barriers. Understanding the interrelatedness is crucial for developing appropriate measures to overcome the barriers and ultimately to achieve gender equality at the corporate top.
Change readiness in individuals experiencing homelessness and multiple complex needs
Authors: Lord Alex , Tickle Anna , Buckell Anna 
Published: May 2021

Purpose
This study aims to understand how staff in homelessness services conceptualise readiness for change in the individuals they support and how this informs their decision-making in practice.

Design/methodology/approach
A qualitative design was used. Ten staff members participated in semi-structured interviews. Data were examined through inductive–deductive thematic analysis, using a social constructivist epistemological lens.

Findings
Five main themes were constructed: “multiple complex needs mean multiple complex changes”, “talk versus behaviour”, “change is not a linear trajectory”, “the role of consistent boundaried relationships” and “change is not solely within the individual’s control”.

Practical implications
This research challenges existing notions of “readiness for change” as located within individuals and a prerequisite for using support from services. It has implications for staff and services, particularly those which are time-limited and address only single problems; service users may not be ready for some changes, but it should not be assumed they are not ready for change in other areas of their life. The offer of supportive relationships may precede and contribute to readiness for positive changes. Support should be offered based not only an individual’s intra-psychic readiness for change but also how the system might actively work to promote hope that change can be achieved and maintained.

Originality/value
To the best of the authors’ knowledge, this is the first study to explore staff members’ conceptualisations of readiness to change in relation to individuals with multiple complex needs and how this might influence practice.
An agent-based model for simulating COVID-19 transmissions on university campus and its implications on mitigation interventions: a case study
Authors: Zhou Yuan , Li Lin , Ghasemi Yasaman , Kallagudde Rakshitha , Goyal Karan , Thakur Deependra 
Published: May 2021

Purpose
Universities across the USA are facing challenging decision-making problems amid the COVID-19 pandemic. The purpose of this study is to facilitate universities in planning disease mitigation interventions as they respond to the pandemic.

Design/methodology/approach
An agent-based model is developed to mimic the virus transmission dynamics on campus. Scenario-based experiments are conducted to evaluate the effectiveness of various interventions including course modality shift (from face-to-face to online), social distancing, mask use and vaccination. A case study is performed for a typical US university.

Findings
With 10%, 30%, 50%, 70% and 90% course modality shift, the number of total cases can be reduced to 3.9%, 20.9%, 35.6%, 60.9% and 96.8%, respectively, comparing against the baseline scenario (no interventions). More than 99.9% of the total infections can be prevented when combined social distancing and mask use are implemented even without course modality shift. If vaccination is implemented without other interventions, the reductions are 57.1%, 90.6% and 99.6% with 80%, 85% and 90% vaccine efficacies, respectively. In contrast, more than 99% reductions are found with all three vaccine efficacies if mask use is combined.

Practical implications
This study provides useful implications for supporting universities in mitigating transmissions on campus and planning operations for the upcoming semesters.

Originality/value
An agent-based model is developed to investigate COVID-19 transmissions on campus and evaluate the effectiveness of various mitigation interventions.
Supervisor support and turnover intentions of yacht captains: the role of work–family conflict and psychological resilience during the COVID-19 pandemic
Authors: Yorulmaz Murat , Sevinc Figen 
Published: May 2021

PurposeThe purpose of this study was to investigate work–family conflict’s (WFC) mediating role and psychological resilience’s (PR) moderating role on the perceived supervisor support (SS) of yacht captains and their turnover intentions (TI) during the COVID-19 pandemic.Design/methodology/approachThe authors followed a quantitative approach and conducted a questionnaire survey of 320 Turkish yacht captains. The data were analyzed using SPSS 22 (Process macro v3.4) and AMOS 22 statistics package programs.FindingsPerceived SS has direct and indirect effects on TI with WFC being the intermediate variable. WFC’s effect on TI varies according to the yacht captains’ levels of PR.Practical implicationsThis study empirically uncovered the impact of supervisor support and PR levels, the most important factors for ensuring hospitality employees exhibit positive organizational attitudes and behaviors. This study shows that the success of yacht captains in this stressful work environment depends on positively perceived SS and PR levels. PR regulates the relationship between WFC and TIs. Thus, supervisors should prioritize meeting their employees’ expectations to effectively and efficiently manage their human resources, and supervisor support is essential for meeting these expectations.Originality/valueAccording to the authors’ knowledge, this study is the first to assess the effect of supervisor support on TI, the mediating role of WFC and the moderating role of PR. In addition, the authors aimed to fill the research gaps on yacht captains, as a profession requiring expertise and field experience, and on PR in the tourism industry.