bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selection bias in instrumental variable analyses
Authors: Hughes Rachael A. , Davies Neil M. , Davey Smith George , Tilling Kate 
Published: September 2017

AbstractParticipants in epidemiological and genetic studies are rarely true random samples of the populations they are intended to represent, and both known and unknown factors can influence participation in a study (known as selection into a study). The circumstances in which selection causes bias in an instrumental variable (IV) analysis are not widely understood by practitioners of IV analyses. We use directed acyclic graphs (DAGs) to depict assumptions about the selection mechanism (factors affecting selection) and show how DAGs can be used to determine when a two-stage least squares (2SLS) IV analysis is biased by different selection mechanisms. Via simulations, we show that selection can result in a biased IV estimate with substantial confidence interval undercoverage, and the level of bias can differ between instrument strengths, a linear and nonlinear exposure-instrument association, and a causal and noncausal exposure effect. We present an application from the UK Biobank study, which is known to be a selected sample of the general population. Of interest was the causal effect of education on the decision to smoke. The 2SLS exposure estimates were very different between the IV analysis ignoring selection and the IV analysis which adjusted for selection (e.g., 1.8 [95% confidence interval −1.5, 5.0] and −4.5 [−6.6, −2.4], respectively). We conclude that selection bias can have a major effect on an IV analysis and that statistical methods for estimating causal effects using data from nonrandom samples are needed.
The neurobiology of agrammatic sentence comprehension: a lesion study
Authors: Rogalsky Corianne , LaCroix Arianna N. , Chen Kuan-Hua , Anderson Steven W. , Damasio Hanna , Love Tracy , Hickok Gregory 
Published: September 2017

AbstractBroca’s area has long been implicated in sentence comprehension. Damage to this region is thought to be the central source of “agrammatic comprehension” in which performance is substantially worse (and near chance) on sentences with noncanonical word orders compared to canonical word order sentences (in English). This claim is supported by functional neuroimaging studies demonstrating greater activation in Broca’s area for noncanonical versus canonical sentences. However, functional neuroimaging studies also have frequently implicated the anterior temporal lobe (ATL) in sentence processing more broadly, and recent lesion-symptom mapping studies have implicated the ATL and mid temporal regions in agrammatic comprehension. The present study investigates these seemingly conflicting findings in 66 left hemisphere patients with chronic focal cerebral damage. Patients completed two sentence comprehension measures, sentence-picture matching and plausibility judgments. Patients with damage including Broca’s area (but excluding the temporal lobe; n=11) on average did not exhibit the expected agrammatic comprehension pattern, e.g. their performance was > 80% on noncanonical sentences in the sentence-picture matching task. Patients with ATL damage (n=18) also did not exhibit an agrammatic comprehension pattern. Across our entire patient sample, the lesions of patients with agrammatic comprehension patterns in either task had maximal overlap in posterior superior temporal and inferior parietal regions. Using voxel-based lesion symptom mapping (VLSM), we find that lower performances on canonical and noncanonical sentences in each task are both associated with damage to a large left superior temporal-inferior parietal network including portions of the ATL, but not Broca’s area. Notably however, response bias in plausibility judgments was significantly associated with damage to inferior frontal cortex, including gray and white matter in Broca’s area, suggesting that the contribution of Broca’s area to sentence comprehension may be related to task-related cognitive demands.
A near complete haplotype-phased genome of the dikaryotic wheat stripe rust fungusPuccinia striiformisf. sp.triticireveals high inter-haplotype diversity
Authors: Schwessinger Benjamin , Sperschneider Jana , Cuddy William S. , Garnica Diana P. , Miller Marisa E. , Taylor Jennifer M. , Dodds Peter N. , Figueroa Melania , Robert Park F. , Rathjen John 
Published: September 2017

AbstractA long-standing biological question is how evolution has shaped the genomic architecture of dikaryotic fungi. To answer this, high quality genomic resources that enable haplotype comparisons are essential. Short-read genome assemblies for dikaryotic fungi are highly fragmented and lack haplotype-specific information due to the high heterozygosity and repeat content of these genomes. Here we present a diploidaware assembly of the wheat stripe rust fungusPuccinia striiformisf. sp.triticibased on long-reads using the FALCON-Unzip assembler. RNA-seq datasets were used to infer high quality gene models and identify virulence genes involved in plant infection referred to as effectors. This represents the most completePuccinia striiformisf. sp.triticigenome assembly to date (83 Mb, 156 contigs, N50 1.5 Mb) and provides phased haplotype information for over 92% of the genome. Comparisons of the phase blocks revealed high inter-haplotype diversity of over 6%. More than 25% of all genes lack a clear allelic counterpart. When investigating genome features that potentially promote the rapid evolution of virulence, we found that candidate effector genes are spatially associated with conserved genes commonly found in basidiomycetes. Yet candidate effectors that lack an allelic counterpart are more distant from conserved genes than allelic candidate effectors, and are less likely to be evolutionarily conserved within theP. striiformisspecies complex andPucciniales. In summary, this haplotype-phased assembly enabled us to discover novel genome features of a dikaryotic plant pathogenic fungus previously hidden in collapsed and fragmented genome assemblies.ImportanceCurrent representations of eukaryotic microbial genomes are haploid, hiding the genomic diversity intrinsic to diploid and polyploid life forms. This hidden diversity contributes to the organism’s evolutionary potential and ability to adapt to stress conditions. Yet it is challenging to provide haplotype-specific information at a whole-genome level. Here, we take advantage of long-read DNA sequencing technology and a tailored-assembly algorithm to disentangle the two haploid genomes of a dikaryotic pathogenic wheat rust fungus. The two genomes display high levels of nucleotide and structural variations, which leads to allelic variation and the presence of genes lacking allelic counterparts. Non-allelic candidate effector genes, which likely encode important pathogenicity factors, display distinct genome localization patterns and are less likely to be evolutionary conserved than those which are present as allelic pairs. This genomic diversity may promote rapid host adaptation and/or be related to the age of the sequenced isolate since last meiosis.
Dysconnection of right parietal and frontal cortex in neglect syndrome
Authors: Dietz Martin J. , Nielsen Jørgen F. , Roepstorff Andreas , Garrido Marta I. 
Published: September 2017

ABSTRACTA lesion to the right hemisphere of the brain often leads to perceptual neglect of the left side of the sensorium. The fact that lesions to different cortical regions lead to the same symptoms points to neglect as a dysconnection syndrome that may result from the dysconnection of a distributed network, rather than a disruption of computation in any particular brain region. To test this hypothesis, we used Bayesian analysis of effective connectivity based on electroencephalographic recordings in patients with left-sided neglect after a right-hemisphere lesion. While age-matched healthy controls showed a contralateral increase in connection strength between parietal and frontal cortex with respect to the laterality of the stimuli, neglect patients showed a dysconnection between parietal and frontal cortex in the right hemisphere when stimuli appeared on their neglected side, but preserved connectivity in the left hemisphere when stimuli appeared on their right. Crucially, this parieto-frontal feedback connectivity was aggravated in patients with more severe symptoms. In contrast, patients and controls did not show differences in the local connectivity within regions. These findings suggest that the aetiology of neglect may lie in the dysconnection of a distributed network, rather than the disruption of any particular brain region.
Social behavior in bees influences the abundance ofSodalis(Enterobacteriaceae) symbionts
Authors: Rubin Benjamin E. , Sanders Jon G. , Turner Kyle M. , Pierce Naomi E. , Kocher Sarah D. 
Published: September 2017

AbstractSocial interactions can facilitate transmission of microbes between individuals, reducing variation in gut communities within social groups. Thus, the evolution of social behaviors and symbiont community composition have the potential to be tightly linked. We explored this connection by characterizing the diversity of bacteria associated with both social and solitary bee species within the behaviorally variable family Halictidae using 16S amplicon sequencing. Contrary to expectations, we found few differences in bacterial abundance or variation between social forms, and most halictid species appear to share similar gut bacterial communities. However, several strains ofSodalis,a genus described as a symbiont in a variety of insects but yet to be characterized in bees, differ in abundance between social and solitary bees. Phylogenetic reconstructions based on whole-genome alignments indicate thatSodalishas independently colonized halictids at least three times. These strains appear to be mutually exclusive within individual bees, although they are not host-species-specific and no signatures of vertical transmission were observed, suggesting thatSodalisstrains compete for access to hosts.De novogenome assemblies indicate that these three lineages are subject to widespread relaxed selection and thatSodalisis undergoing genome degeneration during the colonization of these hosts.
Actin enhances ER-mitochondrial calcium transfer and IMM constriction during mitochondrial division
Authors: Chakrabarti Rajarshi , Ji Wei-Ke , Stan Radu V. , de Juan Sanz Jaime , Ryan Timothy A. , Higgs Henry N. 
Published: September 2017

SummaryMitochondrial division requires division of both the inner and outer mitochondrial membranes (IMM and OMM, respectively). Interaction with endoplasmic reticulum (ER) promotes OMM division by recruitment of the dynamin Drp1, but effects on IMM division are not well characterized. We previously showed that actin polymerization through the ER-bound formin INF2 stimulates Drp1 recruitment in mammalian cells. Here, we show that INF2-mediated actin polymerization stimulates a second mitochondrial response independent of Drp1: a rise in mitochondrial matrix calcium through the mitochondrial calcium uniporter. ER stores supply the increased mitochondrial calcium, and the role of actin is to increase ER-mitochondria contact. Myosin IIA is also required for this mitochondrial calcium increase. Elevated mitochondrial calcium in turn activates IMM constriction in a Drp1-independent manner. IMM constriction requires electron transport chain activity. IMM division precedes OMM division. These results demonstrate that actin polymerization independently stimulates the dynamics of both membranes during mitochondrial division: IMM through increased matrix calcium, and OMM through Drp1 recruitment.
Population-level distribution and putative immunogenicity of cancer neoepitopes
Authors: Wood Mary A. , Paralkar Mayur , Paralkar Mihir P. , Nguyen Austin , Struck Adam J. , Ellrott Kyle , Margolin Adam , Nellore Abhinav , Thompson Reid F. 
Published: September 2017

AbstractBackgroundTumor neoantigens are a driver of cancer immunotherapy response; however, current neoantigen prediction tools produce many candidates that require further prioritization for research/clinical applications. Additional filtration criteria and population-level understanding may help to produce refined lists of putative neoantigens. Herein, we show neoepitope immunogenicity is likely related to measures of peptide novelty and report population-level behavior of these and other metrics.MethodsWe propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to tumor neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, as well as to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq [1].ResultsWe show neoepitope burden varies across TCGA disease sites and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria. Similarity of amino acid sequence was typically high between paired tumor-normal epitopes, but in 24.6% of cases, neoepitopes were more similar to other human peptides, or even to bacterial (56.8% of cases) or viral peptides (15.5% of cases), than their paired normal counterparts. Applied to peptides with neoepitope-specific immune response, a linear model incorporating neoepitope binding affinity, protein sequence similarity between neoepitopes and their closest viral peptides, and paired binding affinity difference was able to predict immunogenicity with an AUROC of 0.66.ConclusionsOur proposed neoepitope prioritization criteria emphasize neoepitope novelty and refine patient neoepitope predictions for focus on biologically meaningful candidate neoantigens. We have demonstrated that neoepitopes should be considered not only with respect to their paired normal epitope, but with respect to the entire human proteome, as well as bacterial and viral peptides, with potential implications for neoepitope immunogenicity and personalized vaccines for cancer treatment. We conclude that putative neoantigens are highly variable across individuals as a function of both cancer genetics and personalized HLA repertoire, while the overall behavior of filtration criteria reflects predictable patterns.
Mechanisms of improved specificity of engineered Cas9s revealed by single molecule analysis
Authors: Singh Digvijay , Wang Yanbo , Mallon John , Yang Olivia , Fei Jingyi , Poddar Anustup , Ceylan Damon , Bailey Scott , Ha Taekjip 
Published: September 2017

ABSTRACTIn microbes, CRISPR-Cas systems provide adaptive immunity against invading genetic elements. Cas9 in complex with a guide-RNA targets complementary DNA for cleavage and has been repurposed for wide-ranging biological applications. New Cas9s have been engineered (eCas9 and Cas9-HF1) to improve specificity, but how they help reduce off-target cleavage is not known. Here, we developed single molecule DNA unwinding assay to show that sequence mismatches affect cleavage reactions through rebalancing the internal unwinding/rewinding equilibrium. Increasing PAM-distal mismatches facilitate rewinding, and the associated cleavage impairment shows that cleavage proceeds from the unwound state. Engineered Cas9s depopulate the unwound state more readily upon mismatch detection. Intrinsic cleavage rate is much lower for engineered Cas9s, preventing cleavage from transiently unwound off-targets. DNA interrogation experiments showed that engineered Cas9s require about one additional base pair match for stable binding, freeing them from sites that would otherwise sequester them. Therefore, engineered Cas9s achieve their improved specificity (1) by inhibiting stable DNA binding to partially matching sequences, (2) by making DNA unwinding more sensitive to mismatches, and (3) by slowing down intrinsic cleavage reaction.
Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome
Authors: Li Cai , Lenhard Boris , Luscombe Nicholas M. 
Published: September 2017

AbstractPrevious studies revealed widespread transcription initiation and fast turnover of transcription start sites (TSSs) in mammalian genomes. Yet how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary and functional genomic data, particularly focusing on TSSs that emerged in the primate lineages. We found that intrinsic factors of repetitive sequences and their proximity to established regulatory modules (extrinsic factors) contribute significantly to origin of new TSSs. In early periods, young TSSs experience rapid sequence evolution driven by endogenous mutational mechanisms that reduce the instability of associated repetitive sequences. In later periods, the regulatory functions of young TSSs are gradually modified, and with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the roles of repetitive sequences in these processes.
Quantifying Seasonal and Diel Variation in Anopheline and Culex Human Biting Rates in Southern Ecuador
Authors: Ryan Sadie J. , Lippi Catherine A. , Boersch-Supan Philipp H. , Heydari Naveed , Silva Mercy , Adrian Jefferson , Noblecilla Leonardo F. , Ayala Efraín B. , Encalada Mayling D. , Larsen David A. , Krisher Jesse T. , Krisher Lyndsay , Fregosi Lauren , Stewart-Ibarra Anna M. 
Published: September 2017

AbstractBackgroundQuantifying mosquito biting rates for specific locations enables estimation of mosquito-borne disease risk, and can inform intervention efforts. Measuring biting itself is fraught with ethical concerns, so the landing rate of mosquitoes on humans is often used as a proxy measure. Southern coastal Ecuador was historically endemic for malaria (P. falciparumandP. vivax), although successful control efforts in the 2000s eliminated autochthonous transmission (since 2011). This study presents an analysis of data collected during the elimination period.MethodsWe examined human landing catch (HLC) data for three mosquito taxa: 2 malaria vectors,Anopheles albimanusandAnopheles punctimacula, and groupedCulex spp. These data were collected by the National Vector Control Service of the Ministry of Health over a 5-year time span (2007 – 2012) in five cities in southern coastal Ecuador, at multiple households, in all months of the year, during dusk-dawn (18:00-6:00) hours, often at both indoor and outdoor locations. Hurdle models were used to determine if biting activity was fundamentally different for the three taxa, and to identify spatial and temporal factors influencing bite rate. Due to the many different approaches to studying and quantifying bite rates in the literature, we also created a glossary of terms, to facilitate comparative studies in the future.ResultsBiting trends varied significantly with species and time. All taxa exhibited exophagic feeding behavior, and outdoor locations increased both the odds and incidence of bites across taxa.An. albimanuswas most frequently observed biting, with an average of 4.7 bites per hour. The highest and lowest respective months for significant biting activity were March and July forAn. albimanus,July and August forAn. punctimacula, and February and July forCulex spp.ConclusionsFine-scale spatial and temporal differences exist in biting patterns among mosquito taxa in southern coastal Ecuador. This analysis provides detailed information for targeting vector control and household level behavioral interventions. These data were collected as part of routine vector surveillance conducted by the Ministry of Health, but such data have not been collected since. Reinstating such surveillance measures would provide important information to aid in preventing malaria re-emergence.
Sodium valproate rescues expression ofTRANK1in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness
Authors: Jiang Xueying , Detera-Wadleigh Sevilla D , Akula Nirmala , Mallon Barbara S. , Hou Liping , Xiao Tiaojiang , Felsenfeld Gary , Gu Xinglong , McMahon Francis J. 
Published: September 2017

SUMMARYBiological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human induced pluripotent stem cells (hiPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. HiPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baselineTRANK1expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA). Although rs9834970 has no known function, we demonstrated that a nearby SNP, rs90832, strongly affects binding by the transcription factor, CTCF, and that the high-affinity allele usually occurs on haplotypes carrying the rs9834970 risk allele. Decreased expression ofTRANK1perturbed expression of many genes involved in neural development and differentiation. These findings have important implications for the pathophysiology of major mental illnesses and the development of novel therapeutics.HighlightshiPSC-derived neural cells carrying a mental illness risk allele showed lower expression ofTRANK1Valproic acid rescuedTRANK1expression in cells carrying the risk alleleRisk haplotypes usually carry an allele that increased CTCF bindingReduced expression ofTRANK1perturbed genes involved in neural development and differentiationIn BriefUsing neural derivatives of human induced pluripotent stem cells, Jiang et al. demonstrate that genetic variants associated with mental illness alter transcription factor binding and decrease expression of a nearby gene, an effect which is rescued by valproic acid.
A high-throughput fluorescent indicator displacement assay and principal component/cluster data analysis for determination of ligand-nucleic acid structural selectivity
Authors: del Villar-Guerra Rafael , Gray Robert D. , Trent John O. , Chaires Jonathan B. 
Published: September 2017

ABSTRACTWe describe a high-throughput fluorescence indicator displacement assay (HT-FID) to evaluate the affinity and the selectivity of compounds binding to different DNA structures. We validated the assay using a library of 30 well-known nucleic acid binders containing a variety chemical scaffolds. We used a combination of principal component analysis and hierarchical clustering analysis to interpret the results obtained. This analysis classified compounds based on selectivity for AT-rich, GC-rich and G4 structures. We used the FID assay as a secondary screen to test the binding selectivity of an additional 20 compounds selected from the NCI diversity set III library that were identified as G4 binders using a thermal shift assay. The results showed G4 binding selectivity for only a few of the 20 compounds. Overall, we show that this HT-FID assay, coupled with PCA and HCA, provides a useful tool for the discovery of ligands selective for particular nucleic acid structures.