bluuebunny/crossref_metadata_2025_split huggingface dataset:
To cure or not to cure: consequences of immunological interactions in CML treatment
Authors: César Fassoni Artur , Roeder Ingo , Glauche Ingmar 
Published: December 2018

AbstractRecent clinical findings in Chronic Myeloid Leukemia (CML) patients suggest that the number and function of immune effector cells are modulated by Tyrosine Kinase Inhibitors (TKI) treatment. There is further evidence that the success or failure of treatment cessation at least partly depends on the patient’s immunological constitution. Here, we propose a general ODE model to functionally describe the interactions between immune effector cells with leukemic cells during the TKI treatment of CML. In total, we consider 20 different sub-models, which assume different functional interactions between immune effector and leukemic cells. We show that quantitative criteria, which are purely based on the quality of model fitting, are not able to identify optimal models. On the other hand, the application of qualitative criteria based on a dynamical system framework allowed us to identify nine of those models as more suitable than the others to describe clinically observed patterns and, thereby, to derive conclusion about the underlying mechanisms. Additionally, including aspects of early CML onset, we can demonstrate that certain critical parameters, such as the strength of immune response or leukemia proliferation rate, need to change during CML growth prior to diagnosis, leading to bifurcations that alter the attractor landscape. Finally, we show that the crucial parameters determining the outcome of treatment cessation are not identifiable with tumor load data only, thereby highlighting the need to measure immune cell number and function to properly derive mathematical models with predictive power.MSC Classification: 92B05, 37N25, 34C60, 37G35
Intraspecific variation promotes species coexistence and trait clustering through higher order interactions
Authors: Baruah Gaurav , John Robert 
Published: December 2018

AbstractEcological and evolutionary effects of individual variation on species coexistence remains unclear. Competition models for coexistence have emphasized species-level differences in pairwise interactions, and invoked no role for intraspecific variation. These models show that stronger competitive interactions result in smaller numbers of coexisting species. However, the presence of higher-order interactions (HOIs) among species appears to have a stabilizing influence on communities. How species coexistence is affected in a community where both pairwise and higher-order interactions are pervasive is not known. Furthermore, the effect of individual variation on species coexistence in complex communities with pairwise and HOIs remains untested. Using a Lotka-Volterra model, we explore the effects of intraspecific variation on the patterns of species coexistence in a competitive community dictated by pairwise and HOIs. We found that HOIs greatly stabilize species coexistence across different levels of strength in competition. Notably, high intraspecific variation promoted species coexistence, particularly when competitive interactions were strong. However, species coexistence promoted by higher levels of variation was less robust to environmental perturbation. Additionally, species’ traits tend to cluster together when individual variation in the community increased. We argue that individual variation can promote species coexistence by reducing trait divergence and attenuating the inhibitory effects of dominant species through HOIs
Schizophrenia risk conferred by protein-coding de novo mutations
Authors: Howrigan Daniel P. , Rose Samuel A. , Samocha Kaitlin E. , Fromer Menachem , Cerrato Felecia , Chen Wei J. , Churchhouse Claire , Chambert Kimberly , Chandler Sharon D. , Daly Mark J. , Dumont Ashley , Genovese Giulio , Hwu Hai-Gwo , Laird Nan , Kosmicki Jack A. , Moran Jennifer L. , Roe Cheryl , Singh Tarjinder , Wang Shi-Heng , Faraone Stephen V. , Glatt Stephen J. , McCarroll Steven A. , Tsuang Ming , Neale Benjamin M. 
Published: December 2018

AbstractProtein-coding de novo mutations (DNMs) in the form of single nucleotide changes and short insertions/deletions are significant genetic risk factors for autism, intellectual disability, developmental delay, and epileptic encephalopathy. In contrast, the burden of DNMs has thus far only had a modest documented impact on schizophrenia (SCZ) risk. Here, we analyze whole-exome sequence from 1,695 SCZ affected parent-offspring trios from Taiwan along with DNMs from 1,077 published SCZ trios to better understand the contribution of coding DNMs to SCZ risk. Among 2,772 SCZ affected probands, the increased burden of DNMs is modest. Gene set analyses show that the modest increase in risk from DNMs in SCZ probands is concentrated in genes that are either highly brain expressed, under strong evolutionary constraint, and/or overlap with genes identified as DNM risk factors in other neurodevelopmental disorders. No single gene meets the criteria for genome-wide significance, but we identify 16 genes that are recurrently hit by a protein-truncating DNM, which is a 3.15-fold higher rate than mutation model expectation of 5.1 genes (permuted 95% CI=1-10 genes, permuted p=3e-5). Overall, DNMs explain only a small fraction of SCZ risk, and this risk is polygenic in nature suggesting that coding variation across many different genes will be a risk factor for SCZ in the population.
Multi-tissue analysis reveals short tandem repeats as ubiquitous regulators of gene expression and complex traits
Authors: Fotsing Stephanie Feupe , Margoliash Jonathan , Wang Catherine , Saini Shubham , Yanicky Richard , Shleizer-Burko Sharona , Goren Alon , Gymrek Melissa 
Published: December 2018

AbstractShort tandem repeats (STRs) have been implicated in a variety of complex traits in humans. However, genome-wide studies of the effects of STRs on gene expression thus far have had limited power to detect associations and provide insights into putative mechanisms. Here, we leverage whole genome sequencing and expression data for 17 tissues from the Genotype-Tissue Expression Project (GTEx) to identify STRs for which repeat number is associated with expression of nearby genes (eSTRs). Our analysis reveals more than 28,000 eSTRs. We employ fine-mapping to quantify the probability that each eSTR is causal and characterize a group of the top 1,400 fine-mapped eSTRs. We identify hundreds of eSTRs linked with published GWAS signals and implicate specific eSTRs in complex traits including height and schizophrenia, inflammatory bowel disease, and intelligence. Overall, our results support the hypothesis that eSTRs contribute to a range of human phenotypes and will serve as a valuable resource for future studies of complex traits.
RACER: A data visualization strategy for exploring multiple genetic associations
Authors: Sabik Olivia L. , Farber Charles R. 
Published: December 2018

SummaryGenome-wide association studies (GWASs) have identified thousands of loci associated with risk of various diseases; however, the genes responsible for the majority of loci have not been identified. One means of uncovering potential causal genes is the identification of expression quantitative trait loci (eQTL) that colocalize with disease loci. Statistical methods have been developed to assess the likelihood that two associations (e.g. disease locus and eQTL) share a common causal variant, however, visualization of the two loci is often a crucial step in determining if a locus is pleiotropic. While the current convention is to plot two associations side-by-side, it is difficult to compare across two x-axes, even if they are identical. Thus, we have developed the Regional Association ComparER (RACER) package, which creates “mirror plots”, in which the two associations are plotted on a shared x-axis. Mirror plots provide an effective tool for the visual exploration and presentation of the relationship between two genetic associations.Availability and ImplementationRACER is provided under the GNU General Public License version 3 (GPL-3.0). Source code is available at https://github.com/oliviasabik/RACER.Contactols5fg@virginia.eduSupplementary informationSupplementary data are available online with the paper, see the Supplemental Data Manifest.
An integrated genome-wide multi-omics analysis of gene expression dynamics in the preimplantation mouse embryo
Authors: Israel Steffen , Ernst Mathias , Psathaki Olympia E. , Drexler Hannes C. A. , Casser Ellen , Suzuki Yutaka , Makalowski Wojciech , Boiani Michele , Fuellen Georg , Taher Leila 
Published: December 2018

AbstractEarly mouse embryos have an atypical translational machinery comprised of cytoplasmic lattices, poorly competent for translation. Thus, the impact of transcriptomic changes on the operational levels of proteins has likely been overestimated in the past. To find out, we used liquid chromatography–tandem mass spectrometry to detect and quantify 6,550 proteins in the oocyte and in six developmental stages (from zygote to blastocyst) collected in triplicates, and we also performed mRNA sequencing.In contrast to the known split between the 2-cell and 4-cell stages at the transcript level, on the protein level the oocyte-to-embryo transition appeared to last until the morula stage. In general, protein abundance profiles were weakly correlated with those of their cognate mRNAs and we found little or no concordance between changes in protein and transcript expression relative to the oocyte at early stages. However, concordance increased towards morula and blastocyst, hinting at a more direct coupling of proteins with transcripts at these stages, in agreement with the increase in free ribosome abundance. Independent validation by immunofluorescence and qPCR confirmed the existence of genes featuring strongly positively and negatively correlated protein and transcript. Moreover, consistent coverage of most known protein complexes indicates that our dataset represents a large fraction of the expressed proteome. Finally, we identified 20 markers, including members of the endoplasmic reticulum pathway, for discriminating between early and late stages.This resource contributes towards closing the gap between the ‘predicted’ phenotype, based on mRNA, and the ‘actual’ phenotype, based on protein, of the mouse embryo.
Selection for synchronized replication of genes encoding the same protein complex during tumorigenesis
Authors: Chen Ying , Li Ke , Chu Xiao , Carey Lucas B. , Qian Wenfeng 
Published: December 2018

ABSTRACTDNA replication alters the dosage balance among genes; at the mid-S phase, early-replicating genes have doubled their copies while late-replicating genes have not. Dosage imbalance among proteins, especially within members of a protein complex, is toxic to cells. Here, we propose the synchronized replication hypothesis: genes sensitive to stoichiometric relationships will be replicated simultaneously to maintain stoichiometry. In support of this hypothesis, we observe that genes encoding the same protein complex have similar replication timing, but surprisingly, only in fast-proliferating cells such as embryonic stem cells and cancer cells. The synchronized replication observed in cancer cells, but not in slow-proliferating differentiated cells, is due to convergent evolution during tumorigenesis that restores synchronized replication timing within protein complexes. Collectively, our study reveals that the selection for dosage balance during S phase plays an important role in the optimization of the replication-timing program; that this selection is relaxed during differentiation as the cell cycle is elongated, and restored as the cell cycle shortens during tumorigenesis.
A novel computational complete deconvolution method using RNA-seq data
Authors: Kang Kai , Meng Qian , Shats Igor , Umbach David M. , Li Melissa , Li Yuanyuan , Li Xiaoling , Li Leping 
Published: December 2018

AbstractThe cell type composition of many biological tissues varies widely across samples. Such sample heterogeneity hampers efforts to probe the role of each cell type in the tissue microenvironment. Current approaches that address this issue have drawbacks. Cell sorting or single-cell based experimental techniques disrupt in situ interactions and alter physiological status of cells in tissues. Computational methods are flexible and promising; but they often estimate either sample-specific proportions of each cell type or cell-type-specific gene expression profiles, not both, by requiring the other as input. We introduce a computational Complete Deconvolution method that can estimate both sample-specific proportions of each cell type and cell-type-specific gene expression profiles simultaneously using bulk RNA-Seq data only (CDSeq). We assessed our method’s performance using several synthetic and experimental mixtures of varied but known cell type composition and compared its performance to the performance of two state-of-the art deconvolution methods on the same mixtures. The results showed CDSeq can estimate both sample-specific proportions of each component cell type and cell-typespecificgene expression profiles with high accuracy. CDSeq holds promise for computationally deciphering complex mixtures of cell types, each with differing expression profiles, using RNA-seq data measured in bulk tissue (MATLAB code is available at https://github.com/kkang7/CDSeq_011).
International travelers and genomics uncover a ‘hidden’ Zika outbreak
Authors: Grubaugh Nathan D. , Saraf Sharada , Gangavarapu Karthik , Watts Alexander , Tan Amanda L. , Oidtman Rachel J. , Ladner Jason T. , Oliveira Glenn , Matteson Nathaniel L. , Kraemer Moritz U.G. , Vogels Chantal B.F. , Hentoff Aaron , Bhatia Deepit , Stanek Danielle , Scott Blake , Landis Vanessa , Stryker Ian , Cone Marshall R. , Kopp Edgar W. , Cannons Andrew C. , Heberlein-Larson Lea , White Stephen , Gillis Leah D. , Ricciardi Michael J. , Kwal Jaclyn , Lichtenberger Paola K. , Magnani Diogo M. , Watkins David I. , Palacios Gustavo , Hamer Davidson H. ,   for the GeoSentinel Surveillance Network, Gardner Lauren M. , Alex Perkins T. , Baele Guy , Khan Kamran , Morrison Andrea , Isern Sharon , Michael Scott F. , Andersen Kristian G. 
Published: December 2018

AbstractThe ongoing Zika epidemic in the Americas has challenged public health surveillance, response, and control systems. Even as the epidemic appears to be near its end in the Americas, it is unclear whether substantial Zika virus transmission may still be ongoing. This issue is exacerbated by large discrepancies in local case reporting and significant delays in detecting outbreaks due to surveillance gaps. To uncover locations with lingering outbreaks in the Americas, we investigated travel-associated Zika cases diagnosed in the United States and Europe to identify signatures of transmission dynamics that were not captured by local reporting. We found that a large and unreported Zika outbreak occurred in Cuba during 2017, a year after peak transmission in neighboring countries, with cases still appearing in 2018. By sequencing Zika virus from infected travelers, we show that the 2017 outbreak in Cuba was sparked by long-lived lineages of Zika virus introduced from multiple places in the Americas a year prior. Our data suggest that while aggressive mosquito control in Cuba may initially have been effective at mitigating Zika virus transmission, in the absence of vaccines, herd immunity, or strong international coordination, such control measures may need to be maintained to be effective. Our study highlights how Zika virus may still be ‘silently’ spreading in the Americas and provides a framework for more accurately understanding outbreak dynamics.
Externalizing Europe: the global effects of European data protection
Authors: Bendiek Annegret , Römer Magnus 
Published: December 2018

PurposeThis paper aims to explain how the EU projects its own data protection regime to third states and the US in particular. Digital services have become a central element in the transatlantic economy. A substantial part of that trade is associated with the transfer of data, most of it personal, requiring many of the new products and services emerging to adhere to data protection standards. Yet different conceptions of data protection exist across the Atlantic, with the EU putting a particular focus on protecting the fundamental right to privacy.Design/methodology/approachUsing the distinction between positive and negative forms of market integration as a starting point (Scharpf, 1997), this paper examines the question of how the EU is projecting its own data protection regime to third states. The so-called California effect (Vogel, 1997) and the utilization of trade agreements in the EU’s foreign policy and external relations are well researched. With decreasing effectiveness and limited territorial reach of its enlargement policy, the EU found trade agreements to be particularly effective to set standards on a global level (Lavenex and Schimmelfennig, 2009). The existence of the single market makes the Union not only an important locus of regulation but also a strong economic actor with the global ambition of digital assertiveness. In the past, establishing standards for the EU’s vast consumer market has proven effective in compelling non-European market participants to join.FindingsAs the globe’s largest consumer market, Europe aims to project its own data protection laws through the market place principle (lex loci solutionis), requiring any data processor to follow its laws whenever European customers’ data are processed. This paper argues that European data protection law creates a “California Effect”, whereby the EU exerts pressure on extra-territorial markets by unilateral standard setting.Originality/valueWith its GDPR, the EU may have defused the problem of European citizens’ data being stored and evaluated according to the US law. However, it has also set a precedent of extra-territorial applicability of its legislation – despite having previously criticized the USA for such practices. By now, international companies increasingly store data of European customers in Europe to prevent conflicts with EU law. With this decision, the EU will apply its own law on others’ sovereign territory. Conflicts created through the extra-territorial effects of national law may contradict the principle of due diligence obligations but are nevertheless not illegitimate. They may, however, have further unintended effects: Other major economies are likely to be less reluctant in the future about passing legal provisions with extra-territorial effect.
Continuing professional development of academic librarians in Trinidad and Tobago
Authors: Bowen-Chang Portia , Hosein Yacoob 
Published: December 2018

PurposeThis study aims to present a detailed investigation into the approaches of academic librarians in Trinidad and Tobago in pursuing continuing professional development (CPD) activities. The paper also examines the extent of their participation in CPD at both the institutional and external levels in contributing to the development of their careers.Design/methodology/approachThe instrument used was a questionnaire which assesses the effectiveness of the librarians in their involvement in and attitude toward CPD activities.FindingsThe paper demonstrates the active role and willingness of academic librarians in Trinidad and Tobago in providing and participating in CPD training and support to library and information personnel at both the national and international levels.Originality/valueThe paper underscores the effectiveness of a group of academic librarians in Trinidad and Tobago who pursue and provide a high level of CPD activities to professionals.
Social cohesion and immigrant health: does language-efficacy matter?
Authors: Maleku Arati , Kim Youn Kyoung , Lee Guijin 
Published: December 2018

PurposeWhile social cohesion is important for the promotion of immigrant health, language is a core component through which immigrant groups establish social connections. Since language is a vehicle through which immigrant groups establish social linkages and that English language proficiency has been established as a virtual requirement for full participation in US society, the purpose of this paper is to examine the role of language in establishing social cohesion affecting immigrant health.Design/methodology/approachUsing the 2012 California Health Interview Survey, the authors investigated the role of language efficacy in the relationship between social cohesion and utilization of healthcare among immigrant groups with good and poor health statuses (n=11,134). Mediation analyses were conducted using PROCESS Macro.FindingsThe direct effect of social cohesion on healthcare utilization and the effect of English language efficacy on healthcare utilization were significant for both groups. English language efficacy was a significant mediator between social cohesion and healthcare utilization among immigrants with good health statuses.Research limitations/implicationsLimitations include generalizability issues across immigrant sub-populations, limited measures in terms of English language efficacy and limitations with measures variables such as length of stay.Social implicationsThis study highlights that language is the channel that plays a crucial role not only to establish and maintain social cohesion for positive health outcomes, but also the ripple effects of promoting trust, belonging, opportunity of upward mobility and inclusion.Originality/valueThe findings of the study add value to other pertinent issues of linguistic diversity, positive social relationships and well-being of diverse communities.
The moderating effect of religiosity on resource-capability-competitive advantage interaction
Authors: Sachitra Vilani , Siong-Choy Chong 
Published: December 2018

Purpose
The purpose of this paper is to investigate the moderating effect of religiosity of farm owners on the resource-capability-competitive advantage interaction.

Design/methodology/approach
A self-administered structured questionnaire was developed to collect data from farm owners who possess the experience in commercial cultivation of three main minor export crops in Sri Lanka.

Findings
The results of linear regression analysis on 456 responses received suggest that the religiosity of farm owners significantly moderates the relationships between resources, capabilities and competitive advantage of the minor export crop farms, confirming the study hypotheses.

Research limitations/implications
Future studies should consider the specific impact of different religious affiliations, traits and/or precepts of the farm owners. In addition, educational level, income level and mental capacity of the farm owners should be considered too since they may form part of the observed relationships.

Originality/value
The study has addressed the gap in literature by highlighting the potential of religiosity in the interaction between resources, capabilities and competitive advantage. From the practical standpoint, besides providing some directions to the farm owners, the results also benefit different stakeholders such as policy makers, government and local communities in suggesting and implementing appropriate measures with regard to selecting suitable resources and integrating them with proper capabilities for greater competitive advantage of the agribusiness sector.