bluuebunny/crossref_metadata_2025_split huggingface dataset:
Latent factor modelling of scRNA-seq data uncovers novel pathways dysregulated in cell subsets of autoimmune disease patients
Authors: Palla Giovanni , Ferrero Enrico 
Published: November 2019

SummaryLatent factor modelling applied to single-cell RNA-sequencing (scRNA-seq) data is a useful approach to discover gene signatures associated with cell states. However, it is often unclear what method is best suited for specific tasks and how latent factors should be interpreted from a biological perspective.Here, we compare four state-of-the-art methods and explore their stability, predictive power and coverage of known biology. We then propose an approach that leverages the derived latent factors to directly assign pathway activities to specific cell subsets. By applying this framework to scRNA-seq datasets from biopsies of rheumatoid arthritis and systemic lupus erythematosus patients, we discover both known and novel disease-relevant gene signatures in specific cellular subsets in a fully unsupervised way. Focusing on rheumatoid arthritis, we identify an inflammatory Oncostatin M receptor signalling signature active in a subset of synovial fibroblasts and dysregulation of the GAS6 - MERTK axis in a subset of synovial monocytes with efferocytic function.Overall, we provide insights into strengths and weaknesses of latent factors models for the analysis of scRNA-seq data, we develop a framework to identify cell subtypes in a function- or phenotype-driven way and use it to identify novel pathways dysregulated in rheumatoid arthritis.
Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain
Authors: Dubey Vikas , Bozorg Behruz , Wüstner Daniel , Khandelia Himanshu 
Published: November 2019

AbstractLysosomal accumulation of cholesterol is a hallmark of Niemann Pick type C (NPC) disease caused by mutations primarily in the lysosomal membrane protein NPC1. NPC1 contains a transmembrane sterol sensing domain (SSD), which is supposed to regulate protein activity upon cholesterol binding, but the mechanisms underlying this process are poorly understood. Using atomistic simulations, we show that the binding of cholesterol to the SSD of NPC1 suppresses conformational dynamics of the luminal domains which otherwise bring the luminal N-terminal domain (NTD) closer to the lipid bilayer. The presence of an additional 20% membrane cholesterol has negligible impact on this process. We propose that cholesterol acts as an allosteric effector, and the modulation of NTD dynamics by the SSD-bound cholesterol constitutes an allosteric feedback mechanism in NPC1 which controls cholesterol abundance in the lysosomal membrane.
BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation
Authors: Edwards Drake , Maganti Rohin , Tanksley Jarred P. , Luo Jie , Park James J.H. , Balkanska-Sinclair Elena , Ling Jinjie , Floyd Scott R. 
Published: November 2019

ABSTRACTEffective spatio-temporal control of transcription and replication during S-phase is paramount to maintaining genomic integrity and cell survival. Dysregulation of these systems can lead to conflicts between the transcription and replication machinery causing DNA damage and cell death. BRD4, a BET bromodomain protein and known transcriptional regulator, interacts with P-TEFb to ensure efficient transcriptional elongation by stimulating phosphorylation of RNA Polymerase II (RNAPII). Here we report that disruption of BET bromodomain protein function causes RNAPII pausing on the chromatin and DNA damage affecting cells in S-phase. We find that this persistent, RNAPII-dependent pausing leads to accumulation of RNA:DNA hybrids (R-loops), which are known to lead to transcription-replication conflicts (TRCs), DNA damage, and cell death. Furthermore, we show that resolution of R-loops abrogates BET bromodomain inhibitor-induced DNA damage, and that BET bromodomain inhibition induces both R-loops and DNA damage at sites of BRD4 occupancy. Finally, we see that the BRD4 C-terminal domain, which interacts with P-TEFb, is required to prevent R-loop formation and DNA damage caused by BET bromodomain inhibition and that oncogenes which promote transcription and replication exacerbate BET bromodomain inhibitor-induced DNA damage. Together, these findings demonstrate that BET bromodomain inhibitors can damage DNA via induction of R-loops and TRCs in highly replicative cells.
Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models
Authors: Ikezu Seiko , Ingraham Dixie Kaitlin L. , Koro Lacin , Watanabe Takashi , Kaibuchi Kozo , Ikezu Tsuneya 
Published: November 2019

AbstractThe accumulation of phosphorylated tau protein (pTau) in the entorhinal cortex (EC) is the earliest tau pathology in Alzheimer’s disease (AD). Tau tubulin kinase-1 (TTBK1) is a neuron-specific tau kinase and expressed in the EC and hippocampal regions in both human and mouse brains. Here we report that collapsin response mediator protein-2 (CRMP2), a critical mediator of growth cone collapse, is a new downstream target of TTBK1 and is accumulated in the EC region of early stage AD brains. TTBK1 transgenic mice show severe axonal degeneration in the perforant path, which is exacerbated by crossing with Tg2576 mice expressing Swedish familial AD mutant of amyloid precursor protein (APP). TTBK1 mice show accumulation of phosphorylated CRMP2 (pCRMP2), in the EC at 10 months of age, whereas age-matched APP/TTBK1 bigenic mice show pCRMP2 accumulation in both the EC and hippocampal regions. Amyloid-β peptide (Aβ) and TTBK1 suppresses the kinetics of microtubule polymerization and TTBK1 reduces the neurite length of primary cultured neurons in Rho kinase-dependent manner in vitro. Silencing of TTBK1 or expression of dominant-negative Rho kinase demonstrates that Aβ induces CRMP2 phosphorylation at threonine 514 in a TTBK1-dependent manner, and TTBK1 enhances Aβ-induced CRMP2 phosphorylation in Rho kinase-dependent manner in vitro. Furthermore, TTBK1 expression induces pCRMP2 complex formation with pTau in vitro, which is enhanced upon Aβ stimulation in vitro. Finally, pCRMP2 forms a complex with pTau in the EC tissue of TTBK1 mice in vivo, which is exacerbated in both the EC and hippocampal tissues in APP/TTBK1 mice. These results suggest that TTBK1 and Aβ synergistically induce phosphorylation of CRMP2, which may be causative for the neurite degeneration and somal accumulation of pTau in the EC neurons, indicating critical involvement of TTBK1 and pCRMP2 in the early AD pathology.
Genomic patterns of introgression in interspecific populations created by crossing wheat with its wild relative
Authors: Nyine Moses , Adhikari Elina , Clinesmith Marshall , Jordan Katherine W. , Fritz Allan K. , Akhunov Eduard 
Published: November 2019

AbstractIntrogression from wild relatives is a valuable source of novel allelic diversity for breeding. We investigated the genomic patterns of introgression fromAegilops tauschii, the diploid ancestor of the wheat D genome, into winter wheat (Triticum aestivum) cultivars. The population of 351 BC1F3:5lines was selected based on phenology from crosses between six hexaploid wheat lines and 21 wheat-Ae. tauschiioctoploids. SNP markers developed for this population and a diverse panel of 116Ae. tauschiiaccessions by complexity-reduced genome sequencing were used to detect introgression based on the identity-by-descent analysis. Overall, introgression frequency positively correlated with recombination rate, with a high incidence of introgression at the ends of chromosomes and low in the pericentromeric regions, and was negatively related to sequence divergence between the parental genomes. Reduced introgression in the pericentromeric low-recombining regions spans nearly 2/3 of each chromosome arm, suggestive of the polygenic nature of introgression barriers that could be associated with multilocus negative epistasis between the alleles of wild and cultivated wheat. On the contrary, negative selection against the wild allele ofTg, controlling free-threshing trait and located in the high-recombining chromosomal region, led to reduced introgression only within ∼10 Mbp region aroundTg. These results are consistent with the effect of selection on linked variation described by the Hill-Robertson effect, and offer insights into the introgression population development for crop imrpovement to ensure retention of introgressed diversity across entire genome.
Persistence of a novel regeneration-associated transitional cell state in pulmonary fibrosis
Authors: Kobayashi Yoshihiko , Tata Aleksandra , Konkimalla Arvind , Katsura Hiroaki , Lee Rebecca F. , Ou Jianhong , Banovich Nicholas E. , Kropski Jonathan A. , Tata Purushothama Rao 
Published: November 2019

AbstractStem cell senescence is often seen as an age associated pathological state in which cells acquire an abnormal and irreversible state. Here, we show that alveolar stem cell differentiation during lung regeneration involves a unique previously uncharacterized transitional state that exhibits cardinal features normally associated with cell senescence. Specifically, using organoid cultures, multiple in vivo injury models coupled with single cell transcriptomics and lineage tracing analysis, we find that alveolar stem cell differentiation involves a novel, pre-alveolar type-1 transitional state (PATS) en route to their terminal maturation. PATS can be distinguished based on their unique transcriptional signatures, including enrichment for TP53, TGFβ, and DNA damage repair signaling, and cellular senescence in both in vivo and ex vivo regenerating tissues. Significantly, PATS undergo extensive cell stretching, which makes them vulnerable to DNA damage, a feature commonly associated with most degenerative lung diseases. Importantly, we find enrichment of PATS-like state in human fibrotic lung tissues, suggesting that persistence of such transitional states underlies the pathogenesis of pulmonary fibrosis. Our study thus redefines senescence as a state that can occur as part of a normal tissue maintenance program, and can be derailed in human disease, notably fibrosis.
Systematic localization of Gram-negative bacterial membrane proteins
Authors: Sueki Anna , Stein Frank , Savitski Mikhail , Selkrig Joel , Typas Athanasios 
Published: November 2019

AbstractThe molecular architecture and function of the Gram-negative bacterial cell envelope is dictated by protein composition and localization. Proteins that localize to the inner (IM) and outer (OM) membranes of Gram-negative bacteria play critical and distinct roles in cellular physiology, however, approaches to systematically interrogate their distribution across both membranes and the soluble cell fraction are lacking. We employed multiplexed quantitative mass spectrometry to assess membrane protein localization in a proteome-wide fashion by separating IM and OM vesicles from exponentially growing E. coli K-12 cells on a sucrose density gradient. The migration patterns for >1600 proteins were classified in an unbiased manner, accurately recapitulating decades of knowledge in membrane protein localization in E. coli. For 559 proteins that are currently annotated as peripherally associated to the IM (Orfanoudaki and Economou, 2014) and display potential for dual localization to either the IM or cytoplasm, we could allocate 110 to the IM and 206 as soluble based on their fractionation patterns. In addition, we uncovered 63 cases, in which our data disagreed with current localization annotation in protein databases. For 42 of them, we were able to find supportive evidence for our localization findings in literature. We anticipate our systems-level analysis of the E. coli membrane proteome will serve as a useful reference dataset to query membrane protein localization, as well as provide a novel methodology to rapidly and systematically map membrane protein localization in more poorly characterized Gram-negative species.
Unsupervised Machine Learning for Data Encoding applied to Ovarian Cancer Transcriptomes
Authors: George Tom M , Lio Pietro 
Published: November 2019

AbstractMachine learning algorithms are revolutionising how information can be extracted from complex and high-dimensional data sets via intelligent compression. For example, unsupervised Autoen-coders train a deep neural network with a low-dimensional “bottlenecked” central layer to reconstruct input vectors. Variational Autoencoders (VAEs) have shown promise at learning meaningful latent spaces for text, image and more recently, gene-expression data. In the latter case they have been shown capable of capturing biologically relevant features such as a patients sex or tumour type. Here we train a VAE on ovarian cancer transcriptomes from The Cancer Genome Atlas and show that, in many cases, the latent spaces learns an encoding predictive of cisplatin chemotherapy resistance. We analyse the effectiveness of such an architecture to a wide range of hyperparameters as well as use a state-of-the-art clustering algorithm, t-SNE, to embed the data in a two-dimensional manifold and visualise the predictive power of the trained latent spaces. By correlating genes to resistance-predictive encodings we are able to extract biological processes likely responsible for platinum resistance. Finally we demonstrate that variational autoencoders can reliably encode gene expression data contaminated with significant amounts of Gaussian and dropout noise, a necessary feature if this technique is to be applicable to other data sets, including those in non-medical fields.
The effect of competition mind-set on persuasion: mediation role of processing style
Authors: Kim Yeung-Jo 
Published: November 2019

Purpose
The purpose of this paper is to examine the effect of a competition mind-set on persuasion. Specifically, this research examined the effect of a fit between a competition mind-set and messages on the persuasive effectiveness.

Design/methodology/approach
Participants were randomly assigned to a condition of 2 (competition: competition mind-set vs control) × 2 (message: concrete feasibility vs abstract desirability) between-subjects design.

Findings
This research demonstrated that participants in the competition mind-set (vs control) condition expressed the messages as more persuasive and evaluated the product more favorably when they were exposed to concrete feasibility messages. Furthermore, this effect was mediated by a local processing style.

Originality/value
The present research provides a useful marketing communication strategy. For the effectiveness of messages, concrete feasibility-related merits should be emphasized in competition contexts.
Curbing PPP construction projects’ failure using enhanced stakeholder management success in developing countries
Authors: Eyiah-Botwe Emmanuel , Aigbavboa Clinton O. , Thwala Wellington Didibhuku 
Published: November 2019

Purpose
Globally, inadequate resources, skills deficiency and poor infrastructure have necessitated public-private partnerships (PPPs) as investment initiative for public sector projects. The purpose of this paper is to evaluate the key constructs for improved stakeholder management (SM) success in curbing PPP projects’ failure in developing countries to fill the research gap. Pre-stakeholder identification (PSI); implementation, monitoring and feedback (IMF) factors impact on PPP projects’ success in Ghana were examined.

Design/methodology/approach
In total, 16 models were studied as part of literature review followed by a qualitative three-round Delphi survey for SM key factors and validated using a quantitative questionnaire survey. The findings were analysed using structural equation modelling and a model fit test.

Findings
PSI, IMF factors directly influence PPP SM success model hence are key constructs. Furthermore, stakeholder consideration, a clear statement of objectives, adopting design and build are variables established as influencing PPP projects failures. Stakeholder identification, engagement, communication and analysis are generic factors.

Practical implications
Project managers can achieve stakeholder satisfaction and improve PPP projects delivery by considering the innovative PPP SM model. Furthermore, considering the identified factors and variables in holistic models will enhance stakeholder involvement thereby curbing PPP projects failure.

Social implications
Reducing PPP projects’ failure will enhance socio-economic growth.

Originality/value
PSI; IMF factors have never been included in holistic PPP SM model. They are proposed to curb PPP projects’ failure.
Predicting adolescents’ behavioural intentions in adulterated food management
Authors: Kim Yunhwa 
Published: November 2019

Purpose
The purpose of this paper is to determine the function of adulterated food management (AFM) in the behavioural intentions of adolescents on food safety concerns.

Design/methodology/approach
The methodology is exploratory in nature and uses analysis of variance and regression in determining the predictive power of the independent variables (AFM’s mediator variables) on the dependent variables (food safety concern and AFM behaviour intention). For this, a survey was conducted on middle and high school students in South Korea using a five-point Likert scale.

Findings
Perceived beliefs on, and competency and behavioural intention in, AFM significantly differed depending on food safety concern level (p<0.01). When perceived beliefs and competencies of AFM were regressed against behavioural intention, the model was highly significant and showed huge variance (R2=0.65). The factors influencing AFM in behavioural intention differed among all three groups: high concern group (efficacy, attitude and situation management), medium concern group (benefits, efficacy, attitude, situation management and hygiene practices) and low concern group (benefits, barriers and situation management). Therefore, AFM education should be observed with emphasis on varying points depending on the level of food safety concern.

Research limitations/implications
As this study only focused on exploring probable predictors for the criterion (perceived food safety concern), the contributions of each mediator factor to the full model are not covered in this study. Future investigations can include the study of individual variables and residuals to remove biases that may be present in the model.

Originality/value
The study will contribute to the safety of society and the health of adolescents by solving the issue of food safety and the problem of adulterated food in the aspect of the beliefs and competence of adolescents according to their concern level.
BPM and change management
Authors: Binci Daniele , Belisari Sara , Appolloni Andrea 
Published: November 2019

PurposeThe purpose of this paper is to focus on the implementation of an ambidexterity strategy in a large Italian Company that works in the energy field. The aim of the study is to understand how contextual ambidexterity has been achieved during a business process management (BPM) approach by describing the main variables that interacted during the project implementation.Design/methodology/approachThe authors based their study both on primary (direct observation and interviews) and secondary (company manuals, books and procedures) qualitative investigations of BPM approach based on three business process re-engineering (BPR) projects and nine total quality management (TQM) projects, focused on change team behaviors, dynamics and dialogues.FindingsThe authors observed that the implementation of simultaneously radical and incremental change projects has been influenced by the exploration and exploitation activities related to every single TQM and BPR project considered. The findings suggest that the overall project has been influenced by four main underlying variables, which are task specialization and systems interoperability (knowledge transfer), identity and leadership (knowledge conversion) and two output variables (ambiguity and feedback to change), that, by interacting, enable ambidexterity.Research limitations/implicationsBPM is an important option to consider within the ambidexterity theory, being conceptually conceived as an approach in which TQM and BPR actually complement each other. Moreover, the results contextualize the importance of the change management team (CMT) to manage the connections between knowledge creation and refinement, and vice versa, depending particularly on the knowledge conversion process enabled by a flexible team culture. The focus of the study is mainly at the BPR and TQM project level. The authors consider structural ambidexterity and its enabling mechanisms as the framework in which BPM is implemented. Moreover, research limitations are related both to the specificity of the context, a large, highly specialized and mechanistic company and to the qualitative approach that may reduce the generalization of the empirical results.Practical implicationsManagers need to be cognizant and aware both of the BPM techniques, in order to sustain ambidexterity, and of ambiguity and change feedback as variables that enable the effective connection of the different steps of innovation or refinement strategy and, therefore, of ambidexterity. Moreover, the contextual factors such as leadership and people identity should be considered and managed as important variables related to change.Originality/valueThe originality of this paper is related to improving the understanding of how to implement the theoretical concept of ambidexterity in a real world organization, by providing new evidence that highlights the importance of contextual ambidexterity within a structural ambidexterity strategy during a BPM project.
Risk connectedness of selected CESEE stock markets: a spillover index approach
Authors: Škrinjarić Tihana , Šego Boško 
Published: November 2019

Purpose
The purpose of this paper is to empirically evaluate risk spillovers between selected CESEE (Central, Eastern and South-Eastern Europe) stock markets in order to evaluate the possibilities of an international diversification of a portfolio.

Design/methodology/approach
The VAR model and the Diebold and Yilmaz (2009, 2012) spillover index are used, with rolling indices estimation over time in order to observe dynamics, which is important for investment strategies. Data are monthly and include selected CESEE stock market indices which were available to the researcher.

Findings
The empirical analysis for the period of January 2012–June 2019 indicates that some country risks were the net emitter of shocks in the system (Slovenia and Czech Republic), whereas some were net receivers (Croatia and Ukraine). The results are robust with respect to changing the length of the rolling window analysis, which means that investors could utilize such an approach in a dynamic portfolio selection.

Research limitations/implications
Observing only selected markets due to data (un)availability.

Practical implications
The paper shows how international investors can utilize the aforementioned methodology in order to make a more detailed analysis of the dynamics of stock markets connectedness so that international portfolios can be rebalanced according to the results and investors’ preferences.

Originality/value
This is the first such research which focuses on CESEE countries, since existing research is focused on more developed stock markets. Moreover, the empirical analysis extends to commenting the pairwise net indices over time, which is important for the dynamic portfolio rebalancing over time.