bluuebunny/crossref_metadata_2025_split huggingface dataset:
An overview of the quality assurance and quality control of magnetic resonance imaging data for the Ontario Neurodegenerative Disease Research Initiative (ONDRI): pipeline development and neuroinformatics
Authors: Scott Christopher J.M. , Arnott Stephen R. , Chemparathy Aditi , Dong Fan , Solovey Igor , Gee Tom , Schmah Tanya , Chavez Sofia , Lobaugh Nancy , Nanayakkara Nuwan , Liang Shuai , Zamyadi Mojdeh , Ozzoude Miracle , Holmes Melissa F. , Szilagyi Gregory M. , Ramirez Joel , Symons Sean , Black Sandra E. , Bartha Robert , Strother Stephen ,   the ONDRI investigators
Published: January 2020

ABSTRACTLarge scale research studies combining magnetic resonance imaging data generated at multiple sites on multiple vendor platforms are becoming more commonplace. The Ontario Neurodegenerative Disease Research Initiative (ONDRI -http://ondri.ca/), a project funded by the Ontario Brain Institute (OBI), is a recently established province-wide natural history study, which has recruited more than 500 participants from neurodegenerative disease groups including amyotrophic lateral sclerosis, fronto-temporal dementia, Parkinson’s disease, Alzheimer’s disease, mild cognitive impairment, and cerebrovascular disease (previously referred to as the vascular cognitive impairment cohort). Because of its multi-site nature, all captured data must be standardized and meet minimum quality standards to reduce variability. The goal of the ONDRI imaging platform is to maximize data quality by implementing vendor-specific harmonized MR imaging protocols (consistent with the Canadi-an Dementia Imaging Protocol -http://www.cdip-pcid.ca/), monitoring protocol adherence, qualitatively assessing image quality, measuring signal-to-noise and contrast-to-noise, monitoring system stability, and applying corrections based on the analysis of images from two different phantoms regularly acquired at each site. To maximize image quality, this work describes the use of various automatic pipelines and manual assessment steps, integrated within an established informatics and databasing platform, the Stroke Patient Recovery Research Database (SPReD) built on the Extensible Neuroimaging Archive Toolkit (XNAT), and contained within the Brain-CODE (Centre for Ontario Data Exploration) framework. The purpose of the current paper is to describe the steps undertaken by ONDRI to achieve this high standard of data integrity. Data have been successfully collected for the past 4 years with the pipelines and assessments identifying deviations, allowing for timely interventions and assessment of image quality.
The potential cost-effectiveness of controlling dengue in Indonesia using wMel Wolbachia released at scale: a modelling study
Authors: Brady Oliver J. , Kharisma Dinar D. , Wilastonegoro Nandyan N. , O’Reilly Kathleen M. , Hendricx Emilie , Bastos Leonardo S. , Yakob Laith , Shepard Donald S. 
Published: January 2020

AbstractBackgroundRelease of virus-blocking Wolbachia infected mosquitoes is an emerging disease control strategy that aims to control dengue and other arboviral infections. Early entomological data and modelling analyses have suggested promising outcomes and wMel Wolbachia releases are now ongoing or planned in 12 countries. To help inform potential scale-up beyond single city releases, we assessed this technology’s cost-effectiveness under different programmatic options.MethodsUsing costing data from existing Wolbachia releases, previous estimates of Wolbachia effectiveness, and a spatially-explicit model of release and surveillance requirements, we predicted the costs and effectiveness of the on-going programme in Yogyakarta City and three new hypothetical programmes in Yogyakarta Special Autonomous Region, Jakarta and Bali.ResultsWe predicted Wolbachia to be a highly cost-effective intervention when deployed in high density urban areas with gross cost-effectiveness ratios below $1,500 per DALY averted. When offsets from the health system and societal perspective were included, such programmes even became cost saving over 10-year time horizons with favourable benefit-cost ratios of 1.35 to 3.40. Sequencing Wolbachia releases over ten years could reduce programme costs by approximately 38% compared to simultaneous releases everywhere, but also delays the benefits. Even if unexpected challenges occurred during deployment, such as emergence of resistance in the medium-term or low effective coverage, Wolbachia would remain a cost saving intervention.ConclusionsWolbachia releases in high density urban areas is expected to be highly cost-effective and could potentially be the first cost saving intervention for dengue. Sites with strong public health infrastructure, fiscal capacity, and community support should be prioritized.
tDCS to the left DLPFC improves cognitive control but not action cancellation in patients with ADHD: a behavioral and electrophysiological study
Authors: Dubreuil-Vall Laura , Gomez-Bernal Federico , Villegas Ana C. , Cirillo Patricia , Surman Craig , Ruffini Giulio , Widge Alik S. , Camprodon Joan A. 
Published: January 2020

AbstractADHD is a neurodevelopmental disorder associated with significant morbidity and mortality that affects 5% of children, adolescents and adults worldwide. Pharmacological and behavioral therapies exist, but critical symptoms such as dysexecutive deficits remain unaffected. In this randomized, placebo-controlled, double-blind, cross-over study we assess the cognitive and physiological effects of tDCS in adult ADHD patients in order to understand (1) the role of DLPFC laterality in ADHD dysexecutive deficits, (2) the physiological dynamics sustaining the modulation of executive function by tDCS, and (3) the impact of state-dependent dynamics of tDCS effect. The participants consisted of a random sample of 40 adult patients with a primary diagnosis of ADHD. Each patient performed three experimental sessions in which they received 30 minutes of 2mA tDCS stimulation targeting the left DLPFC (anodal F3, cathodal Fp2), the right DLPFC (anodal F4, cathodal Fp1) and Sham. Before and after each session, half of the patients completed the Flanker task (EFT) and the other half performed the Stop Signal Task (SST), while we assessed cognitive (reaction time, accuracy) and neurophysiological measures (EEG Event-Related-Potentials). Results show that anodal tDCS to the left DLPFC modulated cognitive (reaction time) and physiological measures (P300 amplitude) in the Flanker task in a state-dependent manner, but there were no significant effects in the Stop Signal Reaction Time of the SST. We interpret these results as an improvement in interference cognitive control (captured by the EFT) but not in action cancellation (assessed by the SST), supporting the hypothesis of the existence of different impulsivity constructs with overlapping but distinct anatomical substrates and therapeutic strategies. We conclude that anodal tDCS over the left DLPFC using a simple bipolar montage has pro-cognitive effects in dysexecutive patients with ADHD associated with the modulation of physiological signatures of cognitive control (i.e. treatment target), supporting specific hypotheses and strategies for neuromodulation treatment development under an experimental therapeutics framework aiming to link target engagement (cognitive and physiological) with clinical benefit. In addition, we also provide empirical evidence supporting the value of the P200, N200 and P300 as cross-sectional biomarkers of cognitive performance across tasks. Last, we provide mechanistic support for the state-dependent nature of the effects of tDCS, highlighting the importance of controlling the neural states before and during stimulation as a relevant therapeutic strategy.
Pleiotropic effects of statins on ischemic heart disease: a Mendelian Randomization study in the UK Biobank
Authors: Schooling CM , Zhao JV , Yeung SL Au , Leung GM 
Published: January 2020

AbstractObjectivesStatins appear to have pleiotropic effects. We examined whether specifically statins, of the major lipid modifiers, operate on ischemic heart disease (IHD) via testosterone. As a validation, we assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone.DesignA sex-specific univariable and multivariable Mendelian randomization studySettingA large, population-based cohort study recruited in the UK from 2006-10, the UK BiobankParticipants179918 men with 25410 IHD cases and 212080 women with 12511 IHD casesMain Outcome measuresTestosterone and IHDResultsOf the three lipid modulations considered, statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe, only genetically predicted statin use in men affected testosterone (−0.15 effect size testosterone per effect size lower (of low-density lipoprotein cholesterol), 95% confidence interval (CI) −0.23 to −0.06). The genetically predicted effect of statin use on IHD in specifically men was partially mediated by testosterone (odds ratio (OR) 0.55 per effect size lower (low-density lipoprotein cholesterol), 95% CI 0.38 to 0.79, compared to OR 0.73, 95% CI 0.46 to 1.11 after allowing for testosterone). The estimate for the effect of genetically predicted statin use, independent of testosterone, was very similar in women, giving overall meta-analyzed OR 0.72, 95% CI 0.57 to 0.90 per effect size lower of low-density lipoprotein cholesterol. The genetically predicted effect of anakinra use also affected testosterone (0.022 per effect size (of IL-1Ra), 95% CI 0.01 to 0.04), and increased IHD in men.ConclusionsStatins may partially operate via testosterone in men, which may contribute to sex-specific pleiotropic effects. Anakinra operating by testosterone may also explain its unexpected effects. Our findings could facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific investigations and possibly treatments.Section 1: What is already known on this topicStatins appear to have pleiotropic effects on cardiovascular disease. Whether such effects exist and why they should occur is unclear, but could be highly relevant to the prevention and treatment of the leading cause of death.Section 2: What this study addsOur study shows that statins have similar protective effects on ischemic heart disease via low-density lipoprotein cholesterol in men and women, but unlike other major lipid modifiers statins have an additional effect specific to men via testosterone, while any harms of anakinra in men may operate by a similar mechanism. Our findings highlighting the possibility of sex-specific causes of cardiovascular disease and the need for sex-specific investigations, prevention and treatment.
Corollary Discharge versus Efference Copy: Distinct Neural Signals in Speech Preparation Differentially Modulate Auditory Responses
Authors: Li Siqi , Zhu Hao , Tian Xing 
Published: January 2020

AbstractActions influence sensory processing in a complex way to shape behavior. For example, during actions, a copy of motor signals—termedcorollary discharge(CD) orefference copy(EC)—can be transmitted to sensory regions and modulate perception. However, the sole inhibitory function of the motor copies is challenged by mixed empirical observations as well as multifaceted computational demands for behaviors. We hypothesized that the content in the motor signals available at distinct stages of actions determined the nature of signals (CDvs.EC) and constrained their modulatory functions on perceptual processing. We tested this hypothesis using speech in which we could precisely control and quantify the course of action. In three electroencephalography (EEG) experiments using a novel delayed articulation paradigm, we found that preparation without linguistic contents suppressed auditory responses to all speech sounds, whereas preparing to speak a syllable selectively enhanced the auditory responses to the prepared syllable. A computational model demonstrated that a bifurcation of motor signals could be a potential algorithm and neural implementation to achieve the distinct functions in the motor-to-sensory transformation. These results suggest that distinct motor signals are generated in the motor-to-sensory transformation and integrated with sensory input to modulate perception.
Parallel evolution in the integration of a co-obligate aphid symbiosis
Authors: Monnin David , Jackson Raphaella , Kiers E. Toby , Bunker Marie , Ellers Jacintha , Henry Lee M. 
Published: January 2020

SUMMARYInsects evolve dependencies - often extreme - on microbes for nutrition. These include cases where insects harbour multiple endosymbionts that function collectively as a metabolic unit. How do these metabolic co-dependencies originate, and is there a predictable sequence of events leading to the integration of new symbionts? While dependency on multiple nutrient-provisioning symbionts has evolved numerous times across sap-feeding insects, there is only one known case of metabolic co-dependency in aphids, betweenBuchnera aphidicolaandSerratia symbioticain the Lachninae subfamily. Here we identify three additional independent transitions to the same co-obligate symbiosis in different aphids. A comparison of recent and ancient associations allows us to investigate intermediate stages of metabolic and physical integration between the typically facultative symbiont,Serratia, and the ancient obligate symbiontBuchnera. We find that these uniquely replicated evolutionary events support the idea that co-obligate associations initiate in a predictable manner, through parallel evolutionary processes. Specifically, we show (i) how the repeated losses of the riboflavin pathway inBuchneraleads to dependency onSerratia, (ii) evidence of a stepwise process of symbiont integration, whereby dependency evolves first, then essential amino acid pathways are lost (at ~30-60MYA), which coincides with increased physical integration of the companion symbiont; and (iii) dependency can evolve prior to specialised structures (e.g. bacteriocytes), and in one case with no direct nutritional basis. More generally, our results suggest the energetic costs of synthesising nutrients may provide a unified explanation for the sequence of gene loses that occur during the evolution of co-obligate symbiosis.
Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly
Authors: Aubrey Liam D. , Blakeman Ben J. F. , Lutter Liisa , Serpell Christopher J. , Tuite Mick F. , Serpell Louise C. , Xue Wei-Feng 
Published: January 2020

ABSTRACTAmyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-curve based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.
Ignoring fossil age uncertainty leads to inaccurate topology and divergence times in time calibrated tree inference
Authors: Barido-Sottani Joëlle , van Tiel Nina , Hopkins Melanie J. , Wright David F. , Stadler Tanja , Warnock Rachel C. M. 
Published: January 2020

AbstractTime calibrated trees are challenging to estimate for many extinct groups of species due to the incompleteness of the rock and fossil records. Additionally, the precise age of a sample is typically not known as it may have occurred at any time during the time interval spanned by the rock layer.Bayesian phylogenetic approaches provide a coherent framework for incorporating multiple sources of evidence and uncertainty. In this study, we simulate datasets with characteristics typical of Palaeozoic marine invertebrates, in terms of character and taxon sampling. We use these datasets to examine the impact of different age handling methods on estimated topologies and divergence times obtained using the fossilized birth-death process. Our results reiterate the importance of modeling fossil age uncertainty, although we find that the overall impact of fossil age uncertainty depends on both fossil taxon sampling and character sampling. When character sampling is low, different approaches to handling fossil age uncertainty make little to no difference in the accuracy and precision of the results. However, when character sampling is high, sampling the fossil ages as part of the inference gives topology and divergence times estimates that are as good as those obtained by fixing ages to the truth, whereas fixing fossil ages to incorrect values results in higher error and lower coverage. Modeling fossil age uncertainty is thus critical, as fixing incorrect fossil ages will negate the benefits of improved fossil and character sampling.
d-PBWT: dynamic positional Burrows-Wheeler transform
Authors: Sanaullah Ahsan , Zhi Degui , Zhang Shaojie 
Published: January 2020

AbstractDurbin’s PBWT, a scalable data structure for haplotype matching, has been successfully applied to identical by descent (IBD) segment identification and genotype imputation. Once the PBWT of a haplotype panel is constructed, it supports efficient retrieval of all shared long segments among all individuals (long matches) and efficient query between an external haplotype and the panel. However, the standard PBWT is an array-based static data structure and does not support dynamic updates of the panel. Here, we generalize the static PBWT to a dynamic data structure, d-PBWT, where the reverse prefix sorting at each position is represented by linked lists. We developed efficient algorithms for insertion and deletion of individual haplotypes. In addition, we verified that d-PBWT can support all algorithms of PBWT. In doing so, we systematically investigated variations of set maximal match and long match query algorithms: while they all have average case time complexity independent of database size, they have different worst case complexities, linear time complexity with the size of the genome, and dependency on additional data structures.
Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like Calcium Dependent Protein Kinase 1, a multistage growth regulator ofP. falciparum
Authors: Jain Ravi , Gupta Sakshi , Munde Manoj , Pati Soumya , Singh Shailja 
Published: January 2020

AbstractUponPlasmodium falciparummerozoites exposure to low [K+] environment in blood plasma, there is escalation of cytosolic [Ca2+] which activates Ca2+-Dependent Protein Kinase 1 (CDPK1), a signaling hub of intra-erythrocytic proliferative stages of parasite. Given its high abundance and multidimensional attributes in parasite life-cycle, this is a lucrative target for desiging antimalarials. Towards this, we have virtually screened MyriaScreenII diversity collection of 10,000 drug-like molecules, which resulted in 18 compounds complementing ATP-binding pocket of CDPK1.In vitroscreening for toxicity in mammalian cells revealed that these compounds are non-toxic in nature. Further, SPR analysis demonstrated differential binding affinity of these compounds towards recombinantly purified CDPK1 protein. Selection of lead compound 1 was performed by evaluating their inhibitory effects on phosphorylation and ATP binding activities of CDPK1. Further,in vitrobiophysical evaluations by ITC and FS revealed that binding of compound 1 is driven by formation of energetically favorable non-covalent interactions, with different binding constants in presence and absence of Ca2+, and TSA authenticated stability of compound 1 bound CDPK1 complex. Finally, compound 1 strongly inhibited intra-erythrocytic growth ofP. falciparum in vitro. Concievably, we propose a novel CDPK1-selective inhibitor, step towards developing pan-CDPK kinase inhibitors, prerequisite for cross-stage anti-malarial protection.
Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease
Authors: Janelidze Shorena , Stomrud Erik , Smith Ruben , Palmqvist Sebastian , Mattsson Niklas , Airey David C. , Proctor Nicholas K. , Chai Xiyun , Shcherbinin Sergey , Sims John R. , Dage Jeffrey L. , Hansson Oskar 
Published: January 2020

ABSTRACTCerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the brain. Tau can be phosphorylated at multiple other sites including threonine 217, and here we investigated the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n=194), p-tau217 had stronger correlations with the tau PET tracer [18F]flortaucipir, and more accurately identified individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 were higher compared to p-tau181 and better correlated with [18F]flortaucipir retention. P-tau217 correlated better than p-tau181 with PET measures of neocortical amyloid-β burden and more accurately distinguished AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir were corroborated in an independent EXPEDITION3 trial cohort (n=32). These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.
Mining downy mildew susceptibility genes: a diversity study in grapevine
Authors: Pirrello Carlotta , Zeilmaker Tieme , Bianco Luca , Giacomelli Lisa , Moser Claudio , Vezzulli Silvia 
Published: January 2020

AbstractSeveral pathogens continuously threaten viticulture worldwide. Until now, the investigation on resistance loci has been the main trend to understand the interaction between grapevine and mildew causal agents. Dominantly inherited gene-based resistance has shown to be race-specific in some cases, to confer partial immunity and to be potentially overcome within a few years since its introgression. Recently, on the footprint of research conducted on Arabidopsis, the putative hortologues of genes associated with downy mildew susceptibility in this species, have been discovered also in the grapevine genome. In this work, we deep-resequenced four putative susceptibility genes in 190 highly genetically diverse grapevine genotypes to discover new sources of broad-spectrum recessively inherited resistance. The scouted genes areVvDMR6-1, VvDMR6-2, VvDLO1, VvDLO2and predicted to be involved in susceptibility to downy mildew. From all identified mutations, 56% were Single Nucleotide Polymorphisms (SNPs) in heterozygosity, while the remaining 44% were homozygous. Regarding the identified mutations with putative impact on gene function, we observed ~4% genotypes mutated inVvDMR6-1and ~8% mutated inVvDMR6-2, only a handful of genotypes that were mutated in both genes. ~2% and ~7% genotypes showed mutations inVvDLO1andVvDLO2respectively, and again a few genotypes resulted mutated in both genes. In particular, 80% of impacting mutations were heterozygous while 20% were homozygous. The current results will inform grapevine genetics and corroborate genomic-assisted breeding programs for resistance to biotic stresses.Significance statementA survey on the genetic diversity of downy mildew susceptibility genes in grapevine varieties and wild species reveals a potential valuable for genomic-assisted breeding as well as tailored gene editing to induce disease resistance.