bluuebunny/crossref_metadata_2025_split huggingface dataset:
3D imaging of colorectal cancer organoids identifies responses to Tankyrase inhibitors
Authors: Badder Luned M. , Hollins Andrew J. , Herpers Bram , Yan Kuan , Ewan Kenneth B. , Shone Jennifer R. , Badder Delyth A. , Naven Marc , Ashelford Kevin , Hargest Rachel , Clarke Alan R. , Esdar Christina , Buchstaller Hans-Peter , Wienke Dirk , Price Leo S. , Shaw Paul , Dale Trevor C. 
Published: July 2019

AbstractAberrant activation of the Wnt signalling pathway is required for tumour initiation and survival in the majority of colorectal cancers. The development of inhibitors of Wnt signalling has been the focus of multiple drug discovery programs targeting colorectal cancer and other malignancies associated with aberrant pathway activation. However, progression of new clinical entities targeting the Wnt pathway has been slow. One challenge lies with the limited predictive power of 2D cancer cell lines because they fail to fully recapitulate intratumoural phenotypic heterogeneity. In particular, the relationship between 2D cancer cell biology and cancer stem cell function is poorly understood. By contrast, 3D tumour organoids provide a platform in which complex cell-cell interactions can be studied. However, complex 3D models provide a challenging platform for the quantitative analysis of drug responses of therapies that have differential effects on tumour cell subpopulations. Here, we generated tumour organoids from colorectal cancer patients and tested their responses to inhibitors of Tankyrase (TNKSi) which are known to modulate Wnt signalling. Using compounds with 3 orders of magnitude difference in cellular mechanistic potency together with image-based assays, we demonstrate that morphometric analyses can capture subtle alterations in organoid responses to Wnt inhibitors that are consistent with activity against a cancer stem cell subpopulation. Overall our study highlights the value of phenotypic readouts as a quantitative method to asses drug-induced effects in a relevant preclinical model.
The microbiome wants what it wants: microbial evolution overtakes experimental host-mediated indirect selection
Authors: Arora Jigyasa , Brisbin Margaret Mars , Mikheyev Alexander S. 
Published: July 2019

AbstractMicrobes ubiquitously inhabit animals and plants, often affecting their host’s phenotype. As a result, even in a constant genetic background, the host’s phenotype may evolve through indirect selection on the microbiome. ‘Microbiome engineering’ offers a promising novel approach for attaining desired host traits but has been attempted only a few times. Building on the known role of the microbiome on development in fruit flies, we attempted to evolve earlier eclosing flies by selecting on microbes in the growth media. We carried out parallel evolution experiments in no- and high-sugar diets by transferring media associated with fast-developing fly lines over the course of four rounds of selection. In each round, we used sterile eggs from the same inbred population, and assayed fly mean eclosion times. Ultimately, flies eclosed seven to twelve hours earlier, depending on the diet, but selection had no effect. 16S sequencing showed that the microbiome did evolve, particularly in the no sugar diet, with an increase in alpha diversity over time. Thus, while microbiome evolution did affect host eclosion times, these effects were incidental. Instead, any experimentally enforced selection effects were swamped by independent microbial evolution. These results imply that selection on host phenotypes must be strong enough to overcome other selection pressures simultaneously operating on the microbiome. The independent evolutionary trajectories of the host and the microbiome may limit the extent to which indirect selection on the microbiome can ultimately affect host phenotype. Random-selection lines accounting for independent microbial evolution are essential for experimental microbiome engineering studies.
Ecological association between seagrass and mangrove ecosystems increases seagrass population longevity in island ecosystem
Authors: Mishra Amrit Kumar , Apte Deepak 
Published: July 2019

AbstractWe report for first time about tropical seagrass meadows association with mangrove ecosystems and its effect on seagrass population dynamics off India in Andaman Sea. Two sites of Neil island, i.e. site 1, associated with mangroves and site 2 without mangroves were selected. Quadrat sampling (n=5) were used to collect sediment and seagrass samples. Reconstruction techniques were used to derive population age structure. T. hemprichii population was found mostly with sandy substrate at both sites, with silt consisting very low fraction at site 1. Density, biomass, productivity and morphometric features of T. hemprichii were significantly higher at site1. Reproductive density was higher at site 1, whereas reproductive effort to produce fruits were higher at site 2. The rhizome (vertical+ horizontal) production rates were higher at site 1 and the vertical elongation rate was higher at site 2. Plastochrome interval for site1 and 2 were 25.49 and 26.80 days respectively leading to formation of 14.31 and 13.62 leaves per year. T. hemprichii population at site 1 had four years of longevity and higher younger plants compared to site 2. The long-term average recruitment and present recruitment rate were higher at site 1 compared to site 2, resulting in steady state growth of the overall population at site 1. Higher number of younger plants suggests fitness of the T. hemprichii population at site 1, which increases the ecological significance of mangrove ecosystems have on seagrass population dynamics. This association should be considered for better management and conservation practices of coastal seascapes under global change scenarios.
What can we learn from over 100,000 Escherichia coli genomes?
Authors: Abram Kaleb , Udaondo Zulema , Bleker Carissa , Wanchai Visanu , Wassenaar Trudy M. , Robeson Michael S. , Ussery Dave W. 
Published: July 2019

ABSTRACTThe explosion of microbial genome sequences in public databases allows for large-scale population genomic studies of bacterial species, such as Escherichia coli. In this study, we examine and classify more than one hundred thousand E. coli and Shigella genomes. After removing outliers, a semi-automated Mash-based analysis of 10,667 assembled genomes reveals 14 distinct phylogroups. A representative genome or medoid identified for each phylogroup serves as a proxy to classify more than 95,000 unassembled genomes. This analysis shows that most sequenced E. coli genomes belong to 4 phylogroups (A, C, B1 and E2(O157)). Authenticity of the 14 phylogroups described is supported by pangenomic and phylogenetic analyses, which show differences in gene preservation between phylogroups. A phylogenetic tree constructed with 2,613 single copy core genes along with a matrix of phylogenetic profiles is used to confirm that the 14 phylogroups change at different rates of gene gain/loss/duplication. The methodology used in this work is able to identify previously uncharacterized phylogroups in E. coli species. Some of these new phylogroups harbor clonal strains that have undergone a process of genomic adaptation to the acquisition of new genomic elements related to virulence or antibiotic resistance. This is, to our knowledge, the largest E. coli genome dataset analyzed to date and provides valuable insights into the population structure of the species.
Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators
Authors: Chi Ximin , Gong Deshun , Ren Kang , Zhou Gewei , Huang Gaoxingyu , Lei Jianlin , Zhou Qiang , Yan Nieng 
Published: July 2019

AbstractThe type-2 ryanodine receptor (RyR2) is responsible for releasing Ca2+from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report four cryo-EM structures of porcine RyR2 bound to distinct modulators that collectively provide mechanistic insight into RyR2 regulation. Ca2+alone induces a contraction of the Central domain that facilitates the dilation of S6 bundle, but is insufficient to open the pore. The small molecule agonist PCB95 helps Ca2+to overcome the barrier for opening. FKBP12.6 induces a relaxation of the Central domain that decouples it from the S6 bundle, stabilizing RyR2 in a closed state. Caffeine locks the Central domain in a constitutively contracted state, while further addition of ATP opens the channel by strengthening the coupling between the U-motif and S6. Our study marks an important step towards mechanistic understanding of the complicated regulation of this key channel whose aberrant activity engenders life-threatening cardiac disorders.
Common neural and transcriptional correlates of inhibitory control underlie emotion regulation and memory control
Authors: Liu Wei , Peeters Nancy , Fernández Guillén , Kohn Nils 
Published: July 2019

AbstractInhibitory control is crucial for regulating emotions, and it may also enable memory control. However, evidence for their shared neurobiological correlates is limited. Here, we report meta-analyses of neuroimaging studies on emotion regulation, or memory control, and link neural commonalities to transcriptional commonalities using the Allen Human Brain Atlas (AHBA). Based on 95 fMRI studies, we reveal a role of the right inferior parietal lobule embedded in a frontal-parietal-insular network during emotion and memory control, which is similarly recruited during response inhibition. These co-activation patterns also overlap with the networks associated with “inhibition”, “cognitive control”, and “working memory” when consulting the Neurosynth. Using the AHBA, we demonstrate that emotion and memory control-related brain activity patterns are associated with transcriptional profiles of a specific set of “inhibition-related” genes. Gene ontology enrichment analysis of these “inhibition-related” genes reveal associations with the neuronal transmission and risk for major psychiatric disorders as well as seizures and alcoholic dependence. In summary, this study identified a neural network and a set of genes associated with inhibitory control across emotion regulation, memory control. These findings facilitate our understanding of the neurobiological correlates of inhibitory control and may contribute to the development of novel brain stimulation and pharmacological interventions.
Functional reconstitution of TatB into thylakoidal Tat translocase
Authors: Zinecker Sarah , Jakob Mario , Klösgen Ralf Bernd 
Published: July 2019

AbstractWe have established an experimental system for the functional analysis of thylakoidal TatB, a component of the membrane-integral TatBC receptor complex of the thylakoidal Twin-arginine protein transport (Tat1) machinery. For this purpose, the intrinsic TatB activity of isolated pea thylakoids was inhibited by affinity-purified antibodies and substituted by supplementing the assays with TatB protein either obtained byin vitrotranslation or purified after heterologous expression inE. coli. Tat transport activity of such reconstituted thylakoids, which was analyzed with the authentic Tat substrate pOEC16, reached routinely 20 - 25% of the activity of mock-treated thylakoid vesicles analysed in parallel. In contrast, supplementation of the assays with the purified antigen comprising all but the N-terminal transmembrane helix of thylakoidal TatB did not result in Tat transport reconstitution which confirms that transport relies strictly on the activity of the TatB protein added and is not due to restoration of the intrinsic TatB activity by antibody release. Unexpectedly, even a mutant TatB protein (TatB,E10C) assumed to be incapable of assembling into the TatBC receptor complex showed low but considerable transport reconstitution underlining the sensitivity of the approach and its suitability for further functional mutant analyses. Finally, quantification of TatB demand suggests that TatA and TatB are required in approximately equimolar amounts to achieve Tat-dependent thylakoid transport.
Reduced responsiveness of the reward system underlies tolerance to cannabis impairment in chronic users
Authors: Mason N.L , Theunissen E.L. , Hutten N.R.P.W. , Tse D.H.Y. , Toennes S.W. , Jansen J.F.A. , Stiers P. , Ramaekers J.G. 
Published: July 2019

AbstractCannabis is the most commonly used illicit drug in the world. However due to a changing legal landscape, and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly, cannabis impairment. Importantly, a growing body of evidence suggests regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo controlled, cross-over study assessed the acute influence of cannabis on brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional (OUs) and 12 chronic (CUs) cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, and underwent ultra-high field functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS). In OUs, cannabis induced significant neurometabolic alterations in reward circuitry, namely decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in CUs. The finding that cannabis altered circuitry and distorted behavior in OUs, but not CUs, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment.
Numerical investigation of the POD reduced-order model for fast predictions of two-phase flows in porous media
Authors: Li Jingfa , Zhang Tao , Sun Shuyu , Yu Bo 
Published: July 2019

PurposeThis paper aims to present an efficient IMPES algorithm based on a global model order reduction method, proper orthogonal decomposition (POD), to achieve the fast solution and prediction of two-phase flows in porous media.Design/methodology/approachThe key point of the proposed algorithm is to establish an accurate POD reduced-order model (ROM) for two-phase porous flows. To this end, two projection methods including projecting the original governing equations (Method I) and projecting the discrete form of original governing equations (Method II) are respectively applied to construct the POD-ROM, and their distinctions are compared and analyzed in detail. It is found the POD-ROM established by Method I is inapplicable to multiphase porous flows due to its failed introduction of fluid saturation and permeability that locate on the edge of grid cell, which would lead to unphysical results.FindingsBy using Method II, an efficient IMPES algorithm that can substantially speed up the simulation of two-phase porous flows is developed based on the POD-ROM. The computational efficiency and numerical accuracy of the proposed algorithm are validated through three numerical examples, and simulation results illustrate that the proposed algorithm displays satisfactory computational speed-up (one to two orders of magnitude) without sacrificing numerical accuracy obviously when comparing to the standard IMPES algorithm that without any acceleration technique. In addition, the determination of POD modes number, the relative errors of wetting phase pressure and saturation, and the influence of POD modes number on the overall performances of the proposed algorithm, are investigated.Originality/value1. Two projection methods are applied to establish the POD-ROM for two-phase porous flows and their distinctions are analyzed. The reason why POD-ROM is difficult to be applied to multiphase porous flows is clarified firstly in this study. 2. A highly efficient IMPES algorithm based on the POD-ROM is proposed to accelerate the simulation of two-phase porous flows. 3. Satisfactory computational speed-up (one to two orders of magnitude) and prediction accuracy of the proposed algorithm are observed under different conditions.
Multi-site planning and scheduling: state-of-the-art review and future research directions
Authors: Badhotiya Gaurav Kumar , Soni Gunjan , Mittal M.L. 
Published: July 2019

Purpose
This paper aims to deal with integrated planning and scheduling problem in multi-site manufacturing environment and provides a comprehensive review of literature. Classification schemes and various aspects of planning and scheduling problem in multi-site manufacturing are highlighted.

Design/methodology/approach
A structured review methodology is adopted to classify the relevant literature. Taxonomy for classification of the problem is presented, followed by review of modelling approaches, solution strategies and challenges faced in multi-site integrated planning and scheduling problem.

Findings
The paper is concluded with interesting research findings and a short view on directions related to modelling approach, solution strategy and technique for further developments in the area of multi-site integrated planning and scheduling.

Research limitations/implications
The findings of this study would be helpful for future researchers and practitioners to provide a knowledge base and to further work in this area.

Originality/value
This study attempts to consolidate the diverse literature available and highlight the various aspects of planning and scheduling in multi-site manufacturing.
ICOs, the next generation of IPOs
Authors: Hashemi Joo Mohammad , Nishikawa Yuka , Dandapani Krishnan 
Published: July 2019

PurposeThe purpose of this paper is to recognize the benefits of the initial coin offering (ICO) as a way of raising funds and to present a detailed comparison between the ICO and the initial public offering to realize the future possibilities that this new funding method holds.Design/methodology/approachIt is an exhaustive review of the ICO, the mechanism of crowdfunding, the blockchain technology behind it, benefits and current shortcomings of the ICO, and the potential future development of the ICO as a convenient and efficient way of raising capital.FindingsICOs have brought billions of dollars of funding to startups and projects worldwide in less than two years. Concurrently, many successful ICOs yielded extremely high returns to investors and believers of this new way of funding businesses.Research limitations/implicationsWhile the ICO is a revolutionary vehicle for business funding, it has raised concerns among users as well as potential investors about its risk and lack of regulation. The future of this innovative funding method highly depends on further development and placement of appropriate regulatory supervision, better understanding of risk and benefits and attaining the confidence of users.Originality/valueThis is a review of the advantages and drawbacks of the ICO. If the current fraud, market and cybersecurity risks can be mitigated and standardized regulations are developed, the ICO has a future to become an established way of capital funding or even replace the existing options, regardless of the size and age of companies.
A comparative analysis of taxation and revenue trends in the Middle East and North Africa (MENA) region
Authors: Alsharari Nizar Mohammad 
Published: July 2019

Purpose
The purpose of this paper is to gain insight into how well past reforms have performed against revenue, equity and efficiency benchmarks of tax policymaking, so that the direction of future reform of tax system might be determined. It also presents a comparative analysis of taxation and revenue trends in the Middle East and North Africa (MENA) region over the data set period 1990-2012.

Design/methodology/approach
By overviewing the development and relative significance of resource revenues, allocating non-resource taxes and examining the tax policies of constituent countries, this paper presents a comparative review of taxation and revenue trends in the MENA region.

Findings
Findings showed, on average, a slight decline in non-resource revenues against the significant rise in income from resources. The analysis of government revenues and current taxation structures provide insight into how prior reforms have performed against the standard measures of tax policy-making (i.e. revenue, equity and efficiency) and directions for change leading to the establishment of simple tax systems. The study observes regional differences, such as the higher tax and revenues of the Maghreb sub-region over the Mashreq, except for value-added tax, where low rates were associated with equal or greater revenue. Similarities were also found, including the partial compensation by income taxes (not indirect taxes) for revenue lost through trade liberalization. The challenges of tax reform are found to vary across countries and opportunities for improving equity and reducing the complexity of tax systems across the region are identified.

Research limitations/implications
Reforms in all tax systems could have major implications for the country, employment, earnings and tax revenues; but recommendations would require political value judgments and government decisions. The study suggests eliminating the current tax system, thereby replacing one of the more distortionary taxes in the current system with a neutral and efficient tax.

Originality/value
The paper signals the need, even of the oil-rich states of the Gulf Cooperation Council, for governments to build tax systems capable of capturing and spending revenues effectively into the future.
From operational excellence to organizational significance: setting the tempo for change
Authors: Yeo Roland K. 
Published: July 2019

Purpose
The paper aims to discuss the transformation of a multinational organization, Global Co, through the deployment of an operational excellence system at a time of turbulence and complexity. It illuminates the opportunities and challenges of implementing the system from the perspective of learning and change.

Design/methodology/approach
A case study method was utilized in the research based on a four-year longitudinal study. Formal and informal interviews, unobtrusive observations and archival records formed the core of the data collection that led to key insights reported in this paper.

Findings
A structured approach to managing work processes is essential for ensuring efficiency and reliability in work output. Performance improvement is sustained by operational discipline that strives for consistency in daily work practices. Organizations develop self-healing mechanisms to help address work-related gaps and issues, turning constraints into enablers for improvement.

Originality/value
The paper provides a wider dimension of organizational performance from the learning and change perspective. It considers organizations as organisms with self-healing properties supported by operational discipline. It redefines the impact of operational excellence through organizational significance.