bluuebunny/crossref_metadata_2025_split huggingface dataset:
NeuronUnit: A package for data-driven validation of neuron models using SciUnit
Authors: Gerkin Richard C. , Birgiolas Justas , Jarvis Russell J. , Omar Cyrus , Crook Sharon M. 
Published: June 2019

ABSTRACTValidating a quantitative scientific model requires comparing its predictions against many experimental observations, ideally from many labs, using transparent, robust, statistical comparisons. Unfortunately, in rapidly-growing fields like neuroscience, this is becoming increasingly untenable, even for the most conscientious scientists. Thus the merits and limitations of existing models, or whether a new model is an improvement on the state-of-the-art, is often unclear.Software engineers seeking to verify, validate and contribute to a complex software project rely on suites of simple executable tests, called “unit tests”. Drawing inspiration from this practice, we previously developed SciUnit, an easy-to-use framework for developing data-driven “model validation tests” – executable functions, here written in Python. Each such test generates and statistically validates predictions from a model against one relevant feature of empirical data to produce a score indicating agreement between the model and the data. Suites of such validation tests can be used to clearly identify the merits and limitations of existing models and developmental progress on new models.Here we describe NeuronUnit, a library that builds upon SciUnit and integrates with several existing neuroinformatics resources to support the validation of single-neuron models using data gathered by neurophysiologists and neuroanatomists. NeuronUnit integrates with existing technologies like Jupyter, Pandas, NeuroML and resources such as NeuroElectro, The Allen Institute, and The Human Brain Project in order to make neuron model validation as easy as possible for computational neuroscientists.
Zebrafish mbnl mutants model physical and molecular phenotypes of myotonic dystrophy
Authors: Hinman Melissa N. , Richardson Jared I. , Sockol Rose A. , Aronson Eliza D , Stednitz Sarah J. , Murray Katrina N. , Berglund J. Andrew , Guillemin Karen 
Published: June 2019

AbstractThe muscleblind RNA binding proteins (MBNL1, MBNL2, and MBNL3) are highly conserved across vertebrates and are important regulators of RNA alternative splicing. Loss of MBNL protein function through sequestration by CUG or CCUG RNA repeats is largely responsible for the phenotypes of the human genetic disorder myotonic dystrophy (DM). We generated the first stable zebrafish (Danio rerio) models of DM-associated MBNL loss of function through mutation of the three zebrafish mbnl genes. In contrast to mouse models, zebrafish double and triple homozygous mbnl mutants were viable to adulthood. Zebrafish mbnl mutants displayed disease-relevant physical phenotypes including decreased body size and impaired movement. They also exhibited widespread alternative splicing changes, including the misregulation of many DM-relevant exons. Physical and molecular phenotypes were more severe in compound mbnl mutants than in single mbnl mutants, suggesting partially redundant functions of Mbnl proteins. The high fecundity and larval optical transparency of this complete series of zebrafish mbnl mutants will make them useful for studying DM-related phenotypes and how individual Mbnl proteins contribute to them, and for testing potential therapeutics.
Multimodal memory components and their long-term dynamics identified in cortical layers II/III but not layer Vb
Authors: Li Dong , Wang Guangyu , Xie Hong , Hu Yi , Guan Ji-Song , Hilgetag Claus C. 
Published: June 2019

AbstractActivity patterns of cerebral cortical regions represent the present environment in which animals receive multi-modal inputs. They are also shaped by the history of previous activity that reflects learned information on past multimodal exposures. We studied the long-term dynamics of cortical activity patterns during the formation of multimodal memories by analysing in vivo high-resolution 2-photon mouse brain imaging of Immediate Early Gene expression, resolved by cortical layers. Strikingly, in layers II/III, the patterns showed similar dynamics across functional distinct cortical areas and the consistency of dynamic patterns lasts for one to several days. In contrast, in layer Vb, the activity dynamics varied across functional distinct areas, and the present activities are sensitive to the previous activities at different time depending on the cortical locations, indicating that the information stored in the cortex at different time points is distributed across different cortical areas. These results suggest different roles of layer II/III and layer Vb neurons in the long-term multimodal perception of the environment.
Discovering novel long non-coding RNA predictors of anticancer drug sensitivity beyond protein-coding genes
Authors: Nath Aritro , Lau Eunice Y.T. , Lee Adam M. , Geeleher Paul , Cho William C.S. , Huang R. Stephanie 
Published: June 2019

AbstractLarge-scale cancer cell line screens have identified thousands of protein-coding genes (PCGs) as biomarkers of anticancer drug response. However, systematic evaluation of long non-coding RNAs (lncRNAs) as pharmacogenomic biomarkers has so far proven challenging. Here, we study the contribution of lncRNAs as drug response predictors beyond spurious associations driven by correlations with proximal PCGs, tissue-lineage or established biomarkers. We show that, as a whole, the lncRNA transcriptome is equally potent as the PCG transcriptome at predicting response to hundreds of anticancer drugs. Analysis of individual lncRNAs transcripts associated with drug response reveals nearly half of the significant associations are in fact attributable to proximal cis-PCGs. However, adjusting for effects of cis-PCGs revealed significant lncRNAs that augment drug response predictions for most drugs, including those with well-established clinical biomarkers. In addition, we identify lncRNA-specific somatic alterations associated with drug response by adopting a statistical approach to determine lncRNAs carrying somatic mutations that undergo positive selection in cancer cells. Lastly, we experimentally demonstrate that two novel lncRNA, EGFR-AS1 and MIR205HG, are functionally relevant predictors of anti-EGFR drug response.
Nuclear genetic regulation of human mitochondrial RNA modification
Authors: Ali Aminah T. , Idaghdour Youssef , Hodgkinson Alan 
Published: June 2019

AbstractRNA modifications affect the stability and function of RNA species, regulating important downstream processes. Modification levels are often dynamic, varying between tissues and individuals, although it is not always clear what modulates this variation or what impact it has on biological systems. Here, we quantify variation in RNA modification levels at functionally important positions in the mitochondrial genome across 11,552 samples from 39 tissue/cell types and find evidence that modification levels impact mitochondrial transcript processing. We identify novel links between mitochondrial RNA modification levels in whole blood and genetic variants in the nuclear genome, including missense mutations inLONP1andPNPT1, as well as missense mutations inMRPP3,SLC25A26andMTPAPthat associate with RNA modification levels across multiple tissue types. Genetic variants linked to modification levels are associated with multiple disease phenotypes, including blood pressure, breast cancer and Moyamoya disease, suggesting a role for these processes in complex disease.
Dissecting the binding mechanisms of transcription factors to DNA using a statistical thermodynamics framework
Authors: Martin Patrick C.N. , Zabet Nicolae Radu 
Published: June 2019

AbstractTranscription Factors (TFs) bind to DNA and control activity of target genes. Here, we present ChIPanalyser, a user-friendly, versatile and powerful R/Bioconductor package predicting and modelling the binding of TFs to DNA. ChIPanalyser performs similarly to state-of-the-art tools, but is an explainable model and provides biological insights into binding mechanisms of TFs. We focused on investigating the binding mechanisms of three TFs that are known architectural proteins CTCF, BEAF-32 and su(Hw) in three Drosophila cell lines (BG3, Kc167 and S2). While CTCF preferentially binds only to a subset of high affinity sites located mainly in open chromatin, BEAF-32 binds to most of its high affinity binding sites available in open chromatin. In contrast, su(Hw) binds to both open chromatin and also partially closed chromatin. Most importantly, differences in TF binding profiles between cell lines for these TFs are mainly driven by differences in DNA accessibility and not by differences in TF concentrations between cell lines. Finally, we investigated binding of Hox TFs in Drosophila and found that Ubx binds only in open chromatin, while Abd-B and Dfd are capable to bind in both open and partially closed chromatin. Overall, our results show that TFs display different binding mechanisms and that our model is able to recapitulate this diverse repertoire of mechanisms.
Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation
Authors: Hildebrandt Matthew R , Reuter Miriam S , Wei Wei , Tayebi Naeimeh , Liu Jiajie , Sharmin Sazia , Mulder Jaap , Lesperance L Stephen , Brauer Patrick M , Kinnear Caroline , Piekna Alina , Romm Asli , Howe Jennifer , Pasceri Peter , Mok Rebecca S , Meng Guoliang , Rozycki Matthew , de Carvalho Rodrigues Deivid , Martinez Elisa C , Szego Michael J , Zúñiga-Pflücker Juan Carlos , Anderson Michele K , Prescott Steven A , Rosenblum Norman D , Kamath Binita M , Mital Seema , Scherer Stephen W , Ellis James 
Published: June 2019

SummaryInduced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSCs, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users further demonstrated line versatility by generating kidney organoids, T-lymphocytes and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole genome sequencing (WGS) based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harboured at least one pre-existing or acquired variant with cardiac, neurological or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cell types found in six tissues for disease modeling, and clinical annotation highlighted variant-preferred lines for use as unaffected controls in specific disease settings.
Inferring disease-associated microRNAs using semi-supervised multi-label graph convolutional networks
Authors: Pan Xiaoyong , Shen Hong-Bin 
Published: June 2019

AbstractMicroRNAs (miRNAs) play crucial roles in many biological processes involved in diseases. The associations between diseases and protein coding genes (PCGs) have been well investigated, and further the miRNAs interact with PCGs to trigger them to be functional. Thus, it is imperative to computationally infer disease-miRNA associations under the context of interaction networks.In this study, we present a computational method, DimiG, to infer miRNA-associated diseases using semi-supervised Graph Convolutional Network model (GCN). DimiG is a multi-label framework to integrate PCG-PCG interactions, PCG-miRNA interactions, PCG-disease associations and tissue expression profiles. DimiG is trained on disease-PCG associations and a graph constructed from interaction networks of PCG-PCG and miRNA-PCG using semi-supervised GCN, which is further used to score associations between diseases and miRNAs. We evaluate DimiG on a benchmark set collected from verified disease-miRNA associations. Our results demonstrate that the new DimiG yields promising performance and outperforms the best published baseline method not trained on disease-miRNA associations by 11% and is also superior to two state-of-the-art supervised methods trained on disease-miRNA associations. Three case studies of prostate cancer, lung cancer and Inflammatory bowel disease further demonstrate the efficacy of DimiG, where the top miRNAs predicted by DimiG for them are supported by literature or databases.
Cas3 Mediated Target DNA Recognition and Cleavage is Independent of the Composition and Architecture of Cascade Surveillance Complex
Authors: Nimkar Siddharth , Anand B. 
Published: June 2019

ABSTRACTIn type I CRISPR-Cas system, Cas3 –a nuclease cum helicase– in cooperation with Cascade surveillance complex cleaves the target DNA. Unlike the Cascade/I-E, which is composed of five subunits, the Cascade/I-C is made of only three subunits lacking the CRISPR RNA processing enzyme Cas6, whose role is assumed by Cas5. How these differences in the composition and organisation of Cascade subunits in type I-C influences the Cas3/I-C binding and its target cleavage mechanism is poorly understood. Here, we show that Cas3/I-C is intrinsically a single-strand specific promiscuous nuclease. Apart from the helicase domain, a constellation of highly conserved residues –that are unique to type I-C– located in the uncharacterised C-terminal domain appears to influence the nuclease activity. Recruited by Cascade/I-C, the HD nuclease of Cas3/I-C nicks the single-stranded region of the nontarget strand and positions the helicase motor. Powered by ATP, the helicase motor reels in the target DNA, until it encounters the roadblock en route, which stimulates the HD nuclease. Remarkably, we show that Cas3/I-C supplants Cas3/I-E for CRISPR interference in type I-E in vivo, suggesting that the target cleavage mechanism is evolutionarily conserved between type I-C and type I-E despite the architectural difference exhibited by Cascade/I-C and Cascade/I-E.
Hyperacetylated Chromatin Domains Mark Cell Type-Specific Genes and Suggest Distinct Modes of Enhancer Function
Authors: Fox Sierra , Myers Jacquelyn A. , Davidson Christina , Getman Michael , Kingsley Paul D. , Frankiewicz Nicholas , Bulger Michael 
Published: June 2019

AbstractStratification of enhancers by relative signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell type-specific, highly expressed genes and associated pathways. We have examined a distinct method of stratification that focuses on peak breadth, termed “hyperacetylated chromatin domains” (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does when applied to multiple datasets. Moreover, genetic manipulations of selected gene loci suggest that at least some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of covalent histone modifications across domains, and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements.
Antibiotic uptake across gram-negative outer membranes: better predictions towards better antibiotics
Authors: Ferreira Ricardo J. , Kasson Peter M. 
Published: June 2019

ABSTRACTCrossing the gram-negative bacterial membrane poses a major barrier to antibiotic development, as many small molecules that can biochemically inhibit key bacterial processes are rendered microbiologically ineffective by their poor cellular uptake. The outer membrane is the major permeability barrier for many drug-like molecules, and the chemical properties that enable efficient uptake into mammalian cells fail to predict bacterial uptake. We have developed a computational method for accurate prospective prediction of outer-membrane uptake of drug-like molecules, which we combine with a new medium-throughput experimental assay. Parallel molecular dynamics simulations are used to successfully and quantitatively predict experimental permeabilities. For most polar molecules we test, outer membrane permeability also correlates well with whole-cell uptake. The ability to accurately predict and measure outer-membrane uptake of a wide variety of small molecules will enable simpler determination of which molecular scaffolds and which derivatives are most promising prior to extensive chemical synthesis. It will also assist in formulating a more systematic understanding of the chemical determinants of outer-membrane permeability.
Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency by Genome Sequencing Analysis
Authors: Choy Kwong Wai , Wang Huilin , Shi Mengmeng , Chen Jingsi , Yang Zhenjun , Zhang Rui , Yan Huanchen , Wang Yanfang , Chen Shaoyun , Chau Matthew Hoi Kin , Cao Ye , Chan Olivia YM , Kwok Yvonne K , Zhu Yuanfang , Chen Min , Leung Tak Yeung , Dong Zirui 
Published: June 2019

AbstractBackgroundIncreased Nuchal Translucency (NT) is an important biomarker associated with increased risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic etiologies from single nucleotide variants to those affecting millions of base-pairs. Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal microarray analysis (CMA), however, both of them have limited resolution. The diversity of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) for comprehensive detection of genomic variants. Herein, we aim to evaluate the feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT.MethodsWe retrospectively applied GS (>30-fold) for fetuses with increased NT (≥3.5-mm), who underwent routine prenatal diagnosis. Detection of single-nucleotide variants, copy-number variants and structural rearrangements was performed simultaneously and the results were integrated for interpretation in accordance with the guidelines of the American College of Medical Genetics and Genomics. Pathogenic or likely pathogenic (P/LP) variants were selected for validation and parental confirmation, when available.ResultsOverall, 50 fetuses were enrolled, including 34 cases with isolated increased NT and 16 cases with other fetal structural malformations. Routine CMA and karyotyping reported eight P/LP CNVs, yielding a diagnostic rate of 16.0% (8/50). In comparison, GS provided a 2-fold increase in diagnostic yield (32.0%, 16/50), including one mosaic turner syndrome, eight cases with microdeletions/microduplications and seven cases with P/LP point mutations. Moreover, GS identified two cryptic insertions and two inversions. Follow-up study further demonstrated the potential pathogenicity of an apparently balanced insertion which disrupted an OMIM autosomal dominant disease-causing gene at the inserted site.ConclusionsOur study demonstrates that applying GS in fetuses with increased NT can comprehensively detect and delineate the various genomic variants that are causative to the diseases. Importantly, prenatal diagnosis by GS doubled the diagnostic yield compared with routine protocols. Given a comparable turn-around-time and less DNA required, our study provides strong evidence to facilitate GS in prenatal diagnosis, particularly in fetuses with increased NT.
Constant Infusion Radiotracer Administration for High Temporal Resolution Positron Emission Tomography (PET) of the Human Brain: Application to [18F]-Fluorodexoyglucose PET (FDG-PET)
Authors: Jamadar Sharna D , Ward Phillip GD , Carey Alexandra , McIntyre Richard , Parkes Linden , Sasan Disha , Fallon John , Li Shenpeng , Chen Zhaolin , Egan Gary F 
Published: June 2019

AbstractFunctional Positron Emission Tomography (fPET) provides a method to track molecular dynamics in the human brain. With a radioactively labelled glucose-analogue, [18F]-flurodeoxyglucose (FDG-fPET), it is now possible to index the dynamics of glucose metabolism with temporal resolutions approaching those of functional magnetic resonance imaging (fMRI). This direct measure of glucose uptake has enormous potential for understanding normal and abnormal brain function, and probing the effects of metabolic and neurodegenerative diseases. Further, new advances in hybrid MR-PET hardware makes it possible to capture fluctuations in glucose and blood oxygenation simultaneously using fMRI and FDG-fPET.The temporal resolution and signal-to-noise of the FDG-fPET images is critically dependent upon the administration of the radioactive tracer. In this work we present two alternative continuous infusion protocols and compare them to a traditional bolus approach. We detail a method for acquiring blood samples, time-locking PET, MRI and experimental stimulus, and administrating the non-traditional tracer delivery. By applying a visual stimulus, we demonstrate cortical maps of the glucose-response to external stimuli on an individual level with a temporal resolution of 16-seconds.SummaryRadiotracer infusion protocols for positron emission tomography (PET) provide improved temporal resolution over bolus administration. Here, we describe radiotracer administration for two protocols, constant infusion and bolus plus infusion protocol. We compare this to the standard bolus administration protocol. Using [18-F] fluorodeoxyglucose PET (FDG-PET) as an example, we show that temporal resolutions of approximately 16sec are achievable using these protocols.
Assessment of two immunoassays for detection of IgM antibodies to scrub typhus using a serum panel
Authors: Elangovan Divyaa , Perumalla Susmitha , Rose Winsley , Verghese Valsan Philip , Gowri M.S. , Jude Prakash John Antony 
Published: June 2019

AbstractIntroductionScrub typhus is a vector borne zoonotic disease caused byOrientia tsutsugamushi, endemic to tsutsugamushi triangle. As the characteristic eschar is not always present, laboratory testing especially serological assay are the main stay of diagnosis.Materials and methodsA total of 346 well-characterized sera from normals and patients with scrub typhus, malaria, dengue, enteric fever and gram negative septicaemia were tested for IgM antibodies by ST IgM ELISA and ST Ig M ICTResultsThe sensitivity and specificity of Scrub typhus IgM ICT and ELISA were 98.7, 96.3 and 97.4, 99.3 respectively. The IgM ICT and ELISA had a excellent concordance (99%) and a very high negative predictive value.ConclusionThe findings from this study suggest that IgM ICT and IgM ELISA can be used interchangeably for serodiagnosis of scrub typhus in resource poor settings.