bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imputation aware tag SNP selection to improve power for multi-ethnic association studies
Authors: Wojcik Genevieve L. , Fuchsberger Christian , Taliun Daniel , Welch Ryan , Martin Alicia R , Shringarpure Suyash , Carlson Christopher S. , Abecasis Goncalo , Kang Hyun Min , Boehnke Michael , Bustamante Carlos D. , Gignoux Christopher R. , Kenny Eimear E. 
Published: February 2017

AbstractThe emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. Consequently, a new generation of genotyping arrays are being developed designed with tag single nucleotide polymorphisms (SNPs) to improve rare variant imputation. Selection of these tag SNPs poses several challenges as rare variants tend to be continentally-or even population-specific and reflect fine-scale linkage disequilibrium (LD) structure impacted by recent demographic events. To explore the landscape of tag-able variation and guide design considerations for large-cohort and biobank arrays, we developed a novel pipeline to select tag SNPs using the 26 population reference panel from Phase of the 1000 Genomes Project. We evaluate our approach using leave-one-out internal validation via standard imputation methods that allows the direct comparison of tag SNP performance by estimating the correlation of the imputed and real genotypes for each iteration of potential array sites. We show how this approach allows for an assessment of array design and performance that can take advantage of the development of deeper and more diverse sequenced reference panels. We quantify the impact of demography on tag SNP performance across populations and provide population-specific guidelines for tag SNP selection. We also examine array design strategies that target single populations versus multi-ethnic cohorts, and demonstrate a boost in performance for the latter can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Finally, we demonstrate the utility of improved array design to provide meaningful improvements in power, particularly in trans-ethnic studies. The unified framework presented will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.
QuASAR-MPRA: Accurate allele-specific analysis for massively parallel reporter assays
Authors: Kalita Cynthia A. , Moyerbrailean Gregory A. , Brown Christopher , Wen Xiaoquan , Luca Francesca , Pique-Regi Roger 
Published: February 2017

ABSTRACTMotivationThe majority of the human genome is composed of non-coding regions containing regulatory elements such as enhancers, which are crucial for controlling gene expression. Many variants associated with complex traits are in these regions, and may disrupt gene regulatory sequences. Consequently, it is important to not only identify true enhancers but also to test if a variant within an enhancer affects gene regulation. Recently, allele-specific analysis in high-throughput reporter assays, such as massively parallel reporter assays (MPRA), have been used to functionally validate non-coding variants. However, we are still missing high-quality and robust data analysis tools for these datasets.ResultsWe have further developed our method for allele-specific analysis QuASAR (quantitative allele-specific analysis of reads) to analyze allele-specific signals in barcoded read counts data from MPRA. Using this approach, we can take into account the uncertainty on the original plasmid proportions, over-dispersion, and sequencing errors. The provided allelic skew estimate and its standard error also simplifies meta-analysis of replicate experiments. Additionally, we show that a beta-binomial distribution better models the variability present in the allelic imbalance of these synthetic reporters and results in a test that is statistically well calibrated under the null. Applying this approach to the MPRA data by Tewheyet al.(2016), we found 602 SNPs with significant (FDR 10%) allele-specific regulatory function in LCLs. We also show that we can combine MPRA with QuASAR estimates to validate existing experimental and computational annotations of regulatory variants. Our study shows that with appropriate data analysis tools, we can improve the power to detect allelic effects in high throughput reporter assays.Availabilityhttp://github.com/piquelab/QuASAR/tree/master/mpraContactfluca@wayne.edu;rpique@wayne.edu
Reliable CRISPR/Cas9 genome engineering inCaenorhabiditis elegansusing a single efficient sgRNA and an easily selectable phenotype
Authors: El Mouridi Sonia , Lecroisey Claire , Tardy Philippe , Mercier Marine , Leclercq-Blondel Alice , Zariohi Nora , Boulin Thomas 
Published: February 2017

ABSTRACTCRISPR/Cas9 genome engineering strategies allow the directed modification of theC. elegansgenome to introduce point mutations, generate knock-out mutants and insert coding sequences for epitope or fluorescent tags. Three practical aspects however complicate such experiments. First, the efficiency and specificity of single-guide RNAs (sgRNA) cannot be reliably predicted. Second, the detection of animals carrying genome edits can be challenging in the absence of clearly visible or selectable phenotypes. Third, the sgRNA target site must be inactivated after editing to avoid further double-strand break events. We describe here a strategy that addresses these complications by transplanting the protospacer of a highly efficient sgRNA into a gene of interest to render it amenable to genome engineering. This sgRNA targeting thedpy-10gene generates genome edits at comparatively high frequency. We demonstrate that the transplanted protospacer is cleaved at the same time as thedpy-10gene. Our strategy generates scarless genome edits because it no longer requires the introduction of mutations in endogenous sgRNA target sites. Modified progeny can be easily identified in the F1 generation, which drastically reduces the number of animals to be tested by PCR or phenotypic analysis. Using this strategy, we reliably generated precise deletion mutants, transcriptional reporters, and translational fusions with epitope tags and fluorescent reporter genes. In particular, we report here the first use of the new red fluorescent protein mScarlet in a multicellular organism. wrmScarlet, aC. elegans-optimized version, dramatically surpassed TagRFP-T by showing an 8-fold increase in fluorescence in a direct comparison.
Immune Loss as a Driver of Coexistence During Host-Phage Coevolution
Authors: Weissman Jake L , Holmes Rayshawn , Barrangou Rodolphe , Moineau Sylvain , Fagan William F , Levin Bruce , Johnson Philip L F 
Published: February 2017

AbstractBacteria and their viral pathogens face constant pressure for augmented immune and infective capabilities, respectively. Under this reciprocally imposed selective regime, we expect to see a runaway evolutionary arms race, ultimately leading to the extinction of one species. Despite this prediction, in many systems host and pathogen coexist with minimal coevolution even when well-mixed. Previous work explained this puzzling phenomenon by invoking fitness tradeoffs, which can diminish an arms race dynamic. Here we propose that the regular loss of immunity by the bacterial host can also produce host-phage coexistence. We pair a general model of immunity with an experimental and theoretical case study of the CRISPR-Cas immune system to contrast the behavior of tradeoff and loss mechanisms in well-mixed systems. We find that, while both mechanisms can produce stable coexistence, only immune loss does so robustly within realistic parameter ranges.
The Potential Role of Genetic Assimilation during Maize Domestication
Authors: Lorant Anne , Pedersen Sarah , Holst Irene , Hufford Matthew B. , Winter Klaus , Piperno Dolores , Ross-Ibarra Jeffrey 
Published: February 2017

ABSTRACTDomestication research has largely focused on identification of morphological and genetic differences between extant populations of crops and their wild relatives. Little attention has been paid to the potential effects of environment despite substantial known changes in climate from the time of domestication to modern day. Recent research, in which maize and teosinte (i.e., wild maize) were exposed to environments similar to the time of domestication, resulted in a plastic induction of domesticated phenotypes in teosinte and little response to environment in maize. These results suggest that early agriculturalists may have selected for genetic mechanisms that cemented domestication phenotypes initially induced by a plastic response of teosinte to environment, a process known as genetic assimilation. To better understand this phenomenon and the potential role of environment in maize domestication, we examined differential gene expression in maize (Zea mays ssp. mays) and teosinte (Zea mays ssp. parviglumis) between past and present conditions. We identified a gene set of over 2000 loci showing a change in expression across environmental conditions in teosinte and invariance in maize. In fact, overall we observed both greater plasticity in gene expression and more substantial re-wiring of expression networks in teosinte across environments when compared to maize. While these results suggest genetic assimilation played at least some role in domestication, genes showing expression patterns consistent with assimilation are not significantly enriched for previously identified domestication candidates, indicating assimilation did not have a genome-wide effect.
Beyond a Liberal Critique of ‘Trickle Down': Urban Planning in the City of Malmö
Authors: Holgersen Ståle , Baeten Guy 
Published: February 2017

AbstractThis article scrutinizes the much used, but less examined, concept of ‘trickle down' in an urban setting. We make a distinction between the production of and distribution in the city, and argue that trickle down in contemporary urban policy could be regarded as the liberal link between production and distribution. Based on interviews with key figures and document analyses, we look at the transformation of the Swedish city of Malmö from an industrial to a post‐industrial city, where, during the last two decades, we have found three concurrent components: the ideology of trickle down; several urban policy programs and governmental policies to ‘make' money and resources trickle down; as well as increased economic polarization and segregation. A liberal critique of trickle down would argue that market mechanisms cannot by themselves solve distribution, and that government policies therefore are needed. We argue for the need to go beyond a liberal critique of trickle down and stress how unequal distribution is built into the unequal production of the city.
SWATMOD‐Prep: Graphical User Interface for Preparing Coupled SWAT‐MODFLOW Simulations
Authors: Bailey Ryan , Rathjens Hendrik , Bieger Katrin , Chaubey Indrajeet , Arnold Jeffrey 
Published: February 2017

AbstractThis article presents SWATMOD‐Prep, a graphical user interface that couples a SWAT watershed model with a MODFLOW groundwater flow model. The interface is based on a recently published SWAT‐MODFLOW code that couples the models via mapping schemes. The spatial layout of SWATMOD‐Prep guides the user through the process of importing shape files (sub‐basins, hydrologic response units [HRUs], river network) from an existing SWAT model, creating a grid, performing necessary geo‐processing operations to link the models, writing out SWAT‐MODFLOW files, and running the simulation. The option of creating a new single‐layer MODFLOW model for near‐surface alluvial aquifers is available, with the user prompted to provide groundwater surface elevation (through a digital elevation model), aquifer thickness, and necessary aquifer parameter values. The option of simulating nitrate transport in the aquifer also is available, using the reactive transport model RT3D. The interface is in the public domain. It is programmed in Python, with various software packages used for geo‐processing operations (e.g., selection, intersection of rasters) and inputting/outputting data, and is written for Windows. The use of SWATMOD‐Prep is demonstrated for the Little River Experimental Watershed, Georgia. SWATMOD‐Prep and SWAT‐MODFLOW executables are available with an accompanying user's manual at: http://swat.tamu.edu/software/swat-modflow/. The user's manual also accompanies this article as Supporting Information.
Harm avoidance and childhood adversities in patients with obsessive–compulsive disorder and their unaffected first‐degree relatives
Authors: Bey K. , Lennertz L. , Riesel A. , Klawohn J. , Kaufmann C. , Heinzel S. , Grützmann R. , Kathmann N. , Wagner M. 
Published: February 2017

ObjectiveThe etiology of obsessive–compulsive disorder (OCD) is assumed to involve interactions between genetically determined vulnerability factors and significant environmental features. Here, we aim to investigate how the personality trait harm avoidance and the experience of childhood adversities contribute to OCD.MethodA total of 169 patients with OCD, 157 healthy comparison subjects, and 57 unaffected first‐degree relatives of patients with OCD participated in the study. Harm avoidance was assessed using the Temperament and Character Inventory, and the severity of childhood adversities was measured with the Childhood Trauma Questionnaire.ResultsBoth patients with OCD and relatives showed elevated levels of harm avoidance compared to controls. Furthermore, patients exhibited significantly higher scores than relatives. This linear pattern was observed throughout all subscales of harm avoidance, and remained stable after controlling for the severity of depressive and obsessive–compulsive symptoms. With regard to childhood adversities, patients with OCD reported higher levels than relatives and controls.ConclusionOur results provide further evidence for a diathesis‐stress model of OCD. While patients and unaffected relatives share elevated levels of harm avoidance, supporting the role of harm avoidance as an endophenotype of OCD, a heightened severity of childhood adversity was only observed in patients. The assumed biological underpinnings of these findings are discussed.
Cytochrome P450‐mediated interaction between perazine and risperidone: implications for antipsychotic polypharmacy
Authors: Paulzen Michael , Haen Ekkehard , Hiemke Christoph , Stegmann Benedikt , Lammertz Sarah E. , Gründer Gerhard , Schoretsanitis Georgios 
Published: February 2017

BackgroundAlthough clinically widespread, scientific evidence for antipsychotic polypharmacy is still limited. Combining different drugs increases the potential for drug–drug interactions, enhancing the risk of adverse drug reactions. We aimed to unravel the potential pharmacokinetic interactions between risperidone (RIS) and perazine.MethodsUsing a therapeutic drug monitoring database containing plasma concentrations of RIS and its active metabolite [9‐hydroxyrisperidone (9‐OH‐RIS)], we considered two groups: a group of patients under antipsychotic monotherapy with RIS (n = 40) and a group of patients that was comedicated with perazine (n = 16). Groups were matched for demographic characteristics and daily dosage of RIS. Plasma concentrations, concentrations corrected for the dose (C/D) of RIS, 9‐OH‐RIS and the active moiety (RIS + 9‐OH‐RIS), as well as the metabolic ratios of concentrations of 9‐OH‐RIS/RIS, were compared using nonparametric tests.ResultsAll parameters other than plasma concentrations and the C/D ratio of 9‐OH‐RIS differed between groups. Median values for plasma concentrations of the active moiety and C/D of the active moiety were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Differences were driven by variations in the plasma concentrations and C/D of RIS, which were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Metabolic ratios were lower in the perazine group (P = 0.003).DiscussionThe coadministration of perazine in RIS‐medicated patients leads to significantly higher plasma concentrations and C/D values of RIS and its active moiety, and a lower metabolic ratio, reflecting the cytochrome P450 (CYP) 2D6 phenotype. We suggest that the mechanism underlying the effect of perazine on RIS metabolism is based on an inhibition of CYP2D6 and CYP3A4 activity.
Putting knowledge into practice: Does information on adverse drug interactions influence people's dosing behaviour?
Authors: Dohle Simone , Dawson Ian G. J. 
Published: February 2017

ObjectiveAdverse drug events relating to drug–drug interactions are a common cause of patient harm. Central to avoiding this harm is the patients’ understanding that certain drug combinations present a synergistic risk. Two studies tested whether providing individuals with information about a drug combination that presents a synergistic (cf. additive) risk would elicit higher perceived risk and, therefore, would result in greater precaution in terms of dosing behaviour.DesignBoth studies employed an experimental design.MethodsParticipants were presented with a scenario describing how two symptoms of an infection could each be treated by a different drug. In Experiment 1, information about the effects of combining the two drugs was varied: (1) no information, (2) combination elicits an additive risk, or (3) combination elicits a synergistic risk. In Experiment 2, the size of the risk (small or large) and the participant's role (patient or doctor) was also varied.ResultsIn both experiments, perceived risk and negative affect increased in response to information about the increased probability of side effects from the drug–drug interaction. Despite these increases, participants did not adjust their drug dosing behaviour in either experiment: Dosing was similar when these interactions were large or small, or when they were due to synergistic or additive effects.ConclusionsPeople may struggle to transfer their knowledge of drug–drug interaction risks into decision‐making behaviours. Care should be taken not to assume that holding accurate risk perceptions of a drug's side effect will result in decisions that help avoid adverse drug events.
Statement of contribution

What is already known on this subject?

Adverse effects of drug–drug interactions are a cause of hospital admissions and increase morbidity and mortality.

Patients’ understanding that certain drug combinations present a synergistic risk is crucial to avoid harm.

It is not clear whether synergistic drug interactions increase risk perception and influence dosing decisions.

What does this study add?

Perceived risk and negative affect increased in response to synergistic risk information.

Despite these increases, participants did not adjust their drug dosing behaviour.

People struggle to transfer their knowledge of drug‐related risks into behavioural decisions.
Vitamin D regulates immunoglobulin mucin domain molecule‐4 expression in dendritic cells
Authors: Liu Z.‐Q. , Li M.‐G. , Geng X.‐R. , Liu J. , Yang G. , Qiu S.‐Q. , Liu Z.‐G. , Yang P.‐C. 
Published: February 2017

SummaryBackgroundDendritic cell (DC)‐derived immunoglobulin domain molecule (TIM)4 plays a critical role in the initiation of T helper (Th)2 polarization. Vitamin D (VitD) involves the regulation of a number of immune responses.ObjectivesThis study tests a hypothesis that VitD regulates TIM4 expression in DCs.MethodsPeripheral blood samples were collected from patients with allergic rhinitis (AR) and healthy subjects. DCs were isolated from the samples and analyzed for the expression of TIM4.ResultsWe observed that the levels of calcitriol, the active form of VitD3, in the sera of AR patients were lower than that in healthy subjects. The peripheral DC expressed higher levels of TIM4 and lower levels of VDR. A negative correlation was identified between the data of serum calcitriol and TIM4 in DCs. Exposure DCs to calcitriol in the culture increased the expression of VDR. We also found that VDR bound to the TIM4 promoter locus in DCs to repress the TIM4 gene transcription and expression.Conclusions and clinical relevanceVitD deficiency may contribute to the pathogenesis of AR by increasing the TIM4 expression. The results suggest that to regulate the serum calcitriol levels and the expression of VDR in DCs may be necessary to be taken into account in the treatment of AR.
Conjunctival provocation test in diagnosis of peanut allergy in children
Authors: Lindvik H. , Lødrup Carlsen K. C. , Mowinckel P. , Navaratnam J. , Borres M. P. , Carlsen K.‐H. 
Published: February 2017

SummaryBackgroundPeanut allergy frequently causes severe allergic reactions. Diagnosis includes detection of IgE to peanuts in serum or by skin prick tests. While children may have allergic sensitization without having clinical peanut allergy, oral peanut challenge is often required for accurate diagnosis. The conjunctival provocation test is used for diagnosis and evaluation of treatment effect in inhalant allergies, but it has not been evaluated as a tool for diagnosing peanut allergy.ObjectiveTo investigate whether the conjunctival provocation tests may be feasible, accurate and safe in diagnosing clinically relevant peanut allergy in patients with suspected peanut allergy.MethodsThis cross‐sectional case–control study in children with clinical or laboratory suspected peanut allergy included 102 children recruited from the regional paediatric departments and specialist practices during one year from April 2011. A peanut‐tolerant control group of 28 children of similar age was recruited locally. A double‐blind placebo‐controlled conjunctival provocation test with peanut extract was performed in all children, while oral peanut provocation was performed as double‐blind placebo‐controlled challenge in children with suspected peanut allergy and as an open challenge in the control children.ResultsAll 81 children with a positive double‐blind placebo‐controlled oral food challenge (OFC) also had a positive conjunctival provocation test. None of the children with negative conjunctival provocation test had a positive OFC. The sensitivity and the specificity of the conjunctival provocation test were 0.96 and 0.83, respectively. No children had severe adverse reaction caused by the conjunctival provocation test, whereas 23 children suffered an anaphylactic reaction to the OFC.Conclusion and Clinical RelevanceConjunctival allergen challenge appears to be feasible, accurate and safe in diagnosing children referred for suspected peanut allergy.