bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using Topic Modeling via Non-negative Matrix Factorization to Identify Relationships between Genetic Variants and Disease Phenotypes: A Case Study of Lipoprotein(a) (LPA)
Authors: Zhao Juan , Feng QiPing , Wu Patrick , Warner Jeremy L. , Denny Joshua C. , Wei Wei-Qi 
Published: May 2018

AbstractGenome-wide and phenome-wide association studies are commonly used to identify important relationships between genetic variants and phenotypes. Most of these studies have treated diseases as independent variables and suffered from heavy multiple adjustment burdens due to the large number of genetic variants and disease phenotypes. In this study, we propose using topic modeling via non-negative matrix factorization (NMF) for identifying associations between disease phenotypes and genetic variants. Topic modeling is an unsupervised machine learning approach that can be used to learn the semantic patterns from electronic health record data. We chose rs10455872 in LPA as the predictor since it has been shown to be associated with increased risk of hyperlipidemia and cardiovascular diseases (CVD). Using data of 12,759 individuals from the biobank at Vanderbilt University Medical Center, we trained a topic model using NMF from 1,853 distinct phecodes extracted from the cohort’s electronic health records and generated six topics. We quantified their associations with rs10455872 in LPA. Topics indicating CVD had positive correlations with rs10455872 (P < 0.001), replicating a previous finding. We also identified a negative correlation between LPA and a topic representing lung cancer (P < 0.001). Our results demonstrate the applicability of topic modeling in exploring the relationship between the genome and clinical diseases.Author summaryIdentifying the clinical associations of genetic variants remains crucial in understanding how the human genome modulates disease risk. Traditional phenome-wide association studies consider each disease phenotype as an independent variable, however, diseases often present as complex clusters of comorbid conditions. In this study, we propose using topic modeling to model electronic health record data as a mixture of topics (e.g., disease clusters or relevant comorbidities) and testing associations between topics and genetic variants. Our results demonstrated the feasibility of using topic modeling to replicate and discover novel associations between the human genome and clinical diseases.
The ecology of the Chloroflexi in full-scale activated sludge wastewater treatment plants
Authors: Nierychlo Marta , Miłobędzka Aleksandra , Petriglieri Francesca , McIlroy Bianca , Nielsen Per Halkjær , McIlroy Simon Jon 
Published: May 2018

AbstractFilamentous bacteria belonging to the phylum Chloroflexi have received considerable attention in wastewater treatment systems for their suggested role in operational problem of impaired sludge settleability known as bulking. Their consistently high abundance in full-scale systems, even in the absence of bulking, indicates that they make a substantial contribution to the nutrient transformations during wastewater treatment. In this study, extensive 16S rRNA amplicon surveys of full-scale Danish WWTPs were screened to identify the most numerically important Chloroflexi genera. Fluorescencein situhybridization probes were designed for theirin situcharacterization. All abundant phylotypes of the phylum were identified as facultative anaerobic chemoorganotrophs involved in fermentation of sugars. These groups were all filamentous but differed in their morphology and spatial arrangement.‘CandidatusVilligracilis’ was predominantly located within the activated sludge flocs, where they possibly have structural importance, and their abundance was relatively stable. Conversely, the abundance of‘CandidatusAmarolinea’ was highly dynamic, relative to other genera, sometimes reaching abundances in excess of 30% of the biovolume, suggesting their likely role in bulking episodes. This study gives an important insight into the role of Chloroflexi in WWTPs, thus contributing to the broader goal of understanding the ecology of these biotechnologically important systems.
In-Search Assignment of Monoisotopic Peaks Improves the Identification of Cross-Linked Peptides
Authors: Lenz Swantje , Giese Sven H. , Fischer Lutz , Rappsilber Juri 
Published: May 2018

ABSTRACTCross-linking/mass spectrometry (CLMS) has undergone a maturation process akin to standard proteomics by adapting key methods such as false discovery rate control and quantification. A seldom-used search setting in proteomics is the consideration of multiple (lighter) alternative values for the monoisotopic precursor mass to compensate for possible misassignments of the monoisotopic peak. Here, we show that monoisotopic peak assignment is a major weakness of current data handling approaches in cross-linking. Cross-linked peptides often have high precursor masses, which reduces the presence of the monoisotopic peak in the isotope envelope. Paired with generally low peak intensity, this generates a challenge that may not be completely solvable by precursor mass assignment routines. We therefore took an alternative route by ‘in-search assignment of the monoisotopic peak’ in Xi (Xi-MPA), which considers multiple precursor masses during database search. We compare and evaluate the performance of established preprocessing workflows that partly correct the monoisotopic peak and Xi-MPA on three publicly available datasets. Xi-MPA always delivered the highest number of identifications with ~2 to 4-fold increase of PSMs without compromising identification accuracy as determined by FDR estimation and comparison to crystallographic models.
Genome-Wide Identification of HES1 Target Genes Uncover Novel Roles for HES1 in Pancreatic Development
Authors: de Lichtenberg Kristian Honnens , Funa Nina , Nakic Nikolina , Ferrer Jorge , Zhu Zengrong , Huangfu Danwei , Serup Palle 
Published: May 2018

AbstractNotch signalling and the downstream effector HES1 is required for multiple pancreatic cell fate choices during development, but the direct target genes remain poorly characterised. Here we identify direct HES1 target genes on a genome-wide scale using ChIP-seq and RNA-seq analyses combined with human embryonic stem cell (hESC) directed differentiation of CRISPR/Cas9-generatedHES1-/-mutant hESC lines. We found that HES1 binds to a distinct set of endocrine-specific genes, a set of genes encoding basic Helix-Loop-Helix (bHLH) proteins not normally expressed in the pancreas, genes in the Notch pathway, and the known HES1 target NEUROG3. RNA-seq analysis of wild type,HES1-/-,NEUROG3-/-, andHES1-/-NEUROG3-/-mutant hESC lines allowed us to uncover NEUROG3-independent, direct HES1 target genes. Among the HES1 bound genes that were derepressed inHES1-/-NEUROG3-/-cells compared toNEUROG3-/-cells, we found members of the endocrine-specific gene set, the Notch pathway genesDLL1,DLL4, andHEY1, as well as the non-pancreatic bHLH genesASCL1andATOH1. We also found a large number of transcripts specific to the intestinal secretory lineage to be increased inHES1-/-NEUROG3-/-cells. Together, our data reveal that HES1 employs a multi-layered control of endocrine differentiation, controls Notch ligand expression independent of NEUROG3, and prevents initiation of ectopic intestinal transcriptional programmes in pancreas progenitors.
A Rigorous Interlaboratory Examination of the Need to Confirm NGS-Detected Variants with an Orthogonal Method in Clinical Genetic Testing
Authors: Lincoln Stephen E. , Truty Rebecca , Lin Chiao-Feng , Zook Justin M. , Paul Joshua , Ramey Vincent H. , Salit Marc , Rehm Heidi L. , Nussbaum Robert L. , Lebo Matthew S. 
Published: May 2018

AbstractOrthogonal confirmation of NGS-detected germline variants has been standard practice, although published studies have suggested that confirmation of the highest quality calls may not always be necessary. The key question is how laboratories can establish criteria that consistently identify those NGS calls that require confirmation. Most prior studies addressing this question have limitations: These studies are generally small, omit statistical justification, and explore limited aspects of the underlying data. The rigorous definition of criteria that separate high-accuracy NGS calls from those that may or may not be true remains a critical issue.We analyzed five reference samples and over 80,000 patient specimens from two laboratories. We examined quality metrics for approximately 200,000 NGS calls with orthogonal data, including 1662 false positives. A classification algorithm used these data to identify a battery of criteria that flag 100% of false positives as requiring confirmation (CI lower bound: 98.5–99.8% depending on variant type) while minimizing the number of flagged true positives. These criteria identify false positives that the previously published criteria miss. Sampling analysis showed that smaller datasets resulted in less effective criteria.Our methodology for determining test and laboratory-specific criteria can be generalized into a practical approach that can be used by many laboratories to help reduce the cost and time burden of confirmation without impacting clinical accuracy.
Encoding of 3D head direction information in the human brain
Authors: Kim Misun , Maguire Eleanor A. 
Published: May 2018

AbstractHead direction cells are critical for navigation because they convey information about which direction an animal is facing within an environment. To date, most studies on head direction encoding have been conducted on a horizontal two-dimensional (2D) plane, and little is known about how three-dimensional (3D) direction information is encoded in the brain despite humans and other animals living in a 3D world. Here, we investigated head direction encoding in the human brain while participants moved within a virtual 3D “spaceship” environment. Movement was not constrained to planes and instead participants could move along all three axes in volumetric space as if in zero gravity. Using functional MRI multivoxel pattern similarity analysis, we found evidence that the thalamus, particularly the anterior portion, and the subiculum encoded the horizontal component of 3D head direction (azimuth). In contrast, the retrosplenial cortex was significantly more sensitive to the vertical direction (pitch) than to the azimuth. Our results also indicated that vertical direction information in the retrosplenial cortex was significantly correlated with behavioural performance during a direction judgment task. Our findings represent the first evidence showing that the ‘classic’ head direction system that has been identified on a horizontal 2D plane also seems to encode vertical and horizontal heading in 3D space in the human brain.
Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors
Authors: Ahmad Shiekh Tanveer , Rogers Alexandra D. , Chen Myra J. , Dixit Rajiv , Adnani Lata , Frankiw Luke S. , Lawn Samuel O. , Blough Michael D. , Alshehri Mana , Wu Wei , Robbins Stephen M. , Cairncross J. Gregory , Schuurmans Carol , Chan Jennifer A. 
Published: May 2018

ABSTRACTCapicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic’s function in the brain. Here, we investigated the relationship between Cic expression and cell type specification in the brain. Cic is strongly expressed in astrocytic and neuronal lineage cells but is more weakly expressed in stem cells and oligodendroglial lineage cells. Using a new conditionalCicknockout mouse, we show that forebrain-specificCicdeletion increases proliferation and self-renewal of neural stem cells. Furthermore,Cicloss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage selection effects in the developing brain are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal and tumorigenicity. Our results identify Cic is an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.
TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells
Authors: Rasmussen Kasper D. , Berest Ivan , Kessler Sandra , Nishimura Koutarou , Simón-Carrasco Lucía , Vassilou George S. , Pedersen Marianne T. , Christensen Jesper , Zaugg Judith B. , Helin Kristian 
Published: May 2018

ABSTRACTThe epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development, lead to altered DNA methylation landscapes and to an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed Acute Myeloid Leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we demonstrate that loss of TET2 leads to enzymatic activity-dependent attenuation of chromatin binding of the hematopoietic TF CDX4. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provide a compelling example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.
Cryopreservation of InfectiousCryptosporidium parvumOocysts
Authors: Jaskiewicz Justyna J. , Sandlin Rebecca D. , Swei Anisa A. , Widmer Giovanni , Toner Mehmet , Tzipori Saul 
Published: May 2018

AbstractCryptosporidiosis in an enteric infection caused byCryptosporidiumparasites and is a major cause of acute infant diarrhea in the developing world. A major bottleneck to research progress is the lack of methods to cryopreserveCryptosporidiumoocysts, thus requiring routine propagation in laboratory animals. Here, we report a method to cryopreserveC. parvumoocysts by ultra-fast cooling. Cryopreserved oocysts exhibits high viability and robustin vitroexcystation, and are infectious to interferon-γ knockout mice. The course of the infection is comparable to what we observe with unfrozen oocysts. Oocyst viability and infectivity is not visibly changed after several weeks of cryogenic storage. Cryopreservation will facilitate the sharing of oocysts from well characterized isolates and transgenic strains among different laboratories.
Leveraging pathogen community distributions to understand outbreak and emergence potential
Authors: Dallas Tad A. , Carlson Colin J. , Poisot Timothée 
Published: May 2018

ABSTRACTUnderstanding pathogen outbreak and emergence events has important implications to the management of infectious disease. Apart from preempting infectious disease events, there is considerable interest in determining why certain pathogens are consistently found in some regions, and why others spontaneously emerge or reemerge over time. Here, we use a trait-free approach which leverages information on the global community of human infectious diseases to estimate the potential for pathogen outbreak, emergence, and re-emergence events over time. Our approach uses pairwise dissimilarities among pathogen distributions between countries and country-level pathogen composition to quantify pathogen outbreak, emergence, and re-emergence potential as a function of time (e.g., number of years between training and prediction), pathogen type (e.g., virus), and transmission mode (e.g., vector-borne). We find that while outbreak and re-emergence potential are well captured by our simple model, prediction of emergence events remains elusive, and sudden global emergences like an influenza pandemic seem beyond the predictive capacity of the model. While our approach allows for dynamic predictability of outbreak and re-emergence events, data deficiencies and the stochastic nature of emergence events may preclude accurate prediction. Together, our results make a compelling case for incorporating a community ecological perspective into existing disease forecasting efforts.
Consumer empowerment in insurance
Authors: Buehler Pascal , Maas Peter 
Published: May 2018

PurposeThe purpose of this paper is to enhance the understanding of consumer empowerment in the relationship between consumers and service providers. It draws on self-efficacy theory to conceptualize consumer empowerment and explain the impact on perceived performance risk in insurance decision making.Design/methodology/approachThis study employs data collected from an online survey involving 487 consumers in Switzerland, who recently decided on an insurance service. A structural equation model quantifies both the psychological effects on consumers’ perception of insurance services and behavioral effects on their decision-making process.FindingsPerceived consumer empowerment is conceptualized by perceived self-efficacy and perceived controllability. Both have a significant impact on perceived performance risk, while the former is partially mediated by the preference to delegate the decision to a surrogate. Moreover, customers’ involvement in the purchase process moderates both the direct and indirect effect of perceived self-efficacy on perceived performance risk.Research limitations/implicationsThe results are based on consumers’ perceptions from a single country. Furthermore, consumers’ perceptions were surveyed with a time lag after the decision-making process. To increase rigor, perceptions should be collected during decision making.Practical implicationsResults show that consumer empowerment can be employed as a risk reduction strategy. Consumers with self-efficacy and controllability beliefs perceive significantly less performance risk; however, practitioners should consider that consumers are also motivated to make decisions independently rather than delegating their decisions. Furthermore, consumer empowerment depends on consumer will. For largely indifferent consumers, empowerment does not affect risk or decision delegation preference.Originality/valueThe study is among the few empirical works to examine the effects of consumer empowerment on the consumer-service provider relationship on an individual level. Furthermore, applying consumer empowerment in relationship marketing implies a shift in research focus to the question of how consumers construe decision-making situations rather than objectively measuring the state of consumer relationship.
How sociable is your university brand? An empirical investigation of university social augmenters’ brand equity
Authors: Eldegwy Ahmed , Elsharnouby Tamer H. , Kortam Wael 
Published: May 2018

PurposeThe purpose of this paper is to integrate branding and higher education literature to conceptualize, develop, and empirically examine a model of university social augmenters’ brand equity.Design/methodology/approachDrawing on an empirical survey of 401 undergraduate students enrolled in private universities in Egypt, this study model was tested using structural equation modeling.FindingsThe findings reveal that university social augmenters’ reputation, coach-to-student interactions, and student-to-student interactions influence students’ satisfaction with social augmenters. The results also suggest that students satisfied with university social augmenters are more likely to exhibit outcomes of brand equity – namely, brand identification, willingness to recommend, and willingness to incur an additional premium cost.Practical implicationsThe results offer managerial implications for university administrators in their quest to enrich students’ university experiences and build strong sub-brands within the university setting. University social augmenters are found to have strong brand equity manifestations and may hold the potential to differentiate university brands in an industry dominated by experience and credence.Originality/valueThis research contributes to the extant literature by filling two gaps in university branding literature. First, previous research has never unified separate streams of literature related to augmented services and brand equity. Second, limited conceptual and empirical research on university branding in general and university social augmentation in particular has been conducted in emerging markets, which has resulted in conceptual ambiguity for the key factors constructing students’ university social experiences.
OFDI from China: a deliberately macro re-evaluation
Authors: Giorgioni Gianluigi 
Published: May 2018

PurposeThe purpose of this paper is to provide a critical overview of the recent phenomenon of outward foreign direct investment (OFDI) from China, from a more macro and historical perspective.Design/methodology/approachThe paper critically reviews the extant literature and re-assesses available data on OFDI from China.FindingsIt is argued that despite the explosion of academic interest the phenomenon was neither unpredicted nor sudden.Originality/valueThe paper also argues that OFDI from China is not yet so important and neither presents insurmountable challenges to the established literature on FDI.
Determinants of Greenfield emerging market outward FDI into the UK
Authors: Godwin Eun Sun , Cook Mark 
Published: May 2018

Purpose
The purpose of this paper is to examine the determinants of Greenfield emerging market (EM) outward foreign direct investment (OFDI) into the UK, a developed market (DM) host. Despite the increasing significance of EM OFDI, this particular theme of EM OFDI to a DM host has received relatively little attention from researchers. This paper seeks to address this shortfall.

Design/methodology/approach
Considering the distinctiveness of EM OFDI in its firm-specific characteristics, given circumstances and motivations, this paper applies adapted “Resource-based view (RBV)” framework and institutional theory to build a theoretical framework. A range of hypotheses regarding “strategic-asset seeking”, “market seeking” and “institution seeking” motivations of EM OFDI, which reflect both “pull factors” (advantages in hosts) and “push factors” (disadvantages at home), were then developed. Using panel data for the years 2003–2012, the research questions were analysed using a sample of the then most important EM source countries which had undertaken Greenfield FDI into the UK.

Findings
The analysis results supported the hypotheses that strategic-asset seeking and institution seeking motivations were important in determining EM OFDI to the UK, with the coefficients of relevant variables showing statistical significance and expected sign (i.e. positive). However, the hypothesis on market seeking motivation of EM OFDI cannot be supported as the coefficient of the relevant variable, whilst showing the expected sign, had a statistically insignificant coefficient. Amongst the three control variables, the source countries’ exports and imports as a percentage of GDP was statistically significant and had the correct sign whilst, the UK’s share of intra-EU trade, whilst statistically significant, had the opposite sign to that expected. The third control variable, the exchange rate was not statistically significant, though it had the correct sign.

Originality/value
This paper provides an adjusted theoretical framework for the analysis of EM OFDI to DM with a novel application of institutional theory and RBV. It also qualifies and extends existing works on EM OFDI by including a wider range of EM source countries and DM hosts with empirical analysis results as well as theoretical suggestions. In addition, the paper offers up a range of policy implications for DM hosts.