bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome
Authors: Shamanskiy Victor , Mikhailova Alina A. , Ushakova Kristina , Mikhailova Alina G. , Oreshkov Sergei , Knorre Dmitry , Tretiakov Evgenii O. , Ri Natalia , Overdevest Jonathan B. , Lukowski Samuel W. , Gostimskaya Irina , Yurov Valerian , Liou Chia-Wei , Lin Tsu-Kung , Kunz Wolfram S. , Reymond Alexandre , Mazunin Ilya , Bazykin Georgii A. , Gunbin Konstantin , Fellay Jacques , Tanaka Masashi , Khrapko Konstantin , Popadin Konstantin 
Published: April 2019

AbstractAging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Deletions in mitochondrial DNA (mtDNA) are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded DNA might play a role in the formation of deletions. By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a "hot spot" where one deletion breakpoint occurred within the region of 6-9kb and another within 13-16kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp and a second arm at 13447-13459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. An analysis of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.
High accuracy DNA sequencing on a small, scalable platform via electrical detection of single base incorporations
Authors: Esfandyarpour Hesaam , Parizi Kosar B. , Barmi Meysam R. , Rategh Hamid , Wang Lisen , Paliwal Saurabh , Golnabi HamidReza , Kenney Paul , Reel Richard , Lee Frank , Gomes Xavier , Stern Seth , Ramachandran Ashok , Sankar Subra , Doomson Solomon , Ung Rick , Jouzi Maryam , Babu Ramya Akula Suresh , Nabi Ali , Castillo Nestor , Lei Raymond , Fallahi Mohammad , LoPrete Eric , Kemper Austin , Bagchi Srijeeta , Tarbox Robert , Choudhary Pallavi , Nezamfar Hooman , Hsie Linda , Monier Nicolas , Clark Tyson A. , Spence Eric , Yang Fei , Bronson Benjamin , Sutton Gina , Schweidenback Caterina , Lundy John , Ho An , Tangprasertchai Narin , Thomas Anthony , Baxter Brian , Shastry Shankar , Barua Anooshka , Chen Yongzhi , Hashemzadeh Hamid , Shtern David , Kim Eugene , Thomas Christopher , Tanti Patrice , Mazouchi Ali , Tumurbaatar Erden , Nieboer Jordan , Knopf Christopher , Tram Hien , Sood Vipal , Stingley Sam , Cahill Megan , Roy Sid , Sha Ky , Dong Bin , Witney Frank R. , Davis Ronald W. 
Published: April 2019

AbstractHigh throughput DNA sequencing technologies have undergone tremendous development over the past decade. Although optical detection-based sequencing has constituted the majority of data output, it requires a large capital investment and aggregation of samples to achieve optimal cost per sample. We have developed a novel electronic detection-based platform capable of accurately detecting single base incorporations. The GenapSys technology with its electronic detection modality allows the system to be compact, accessible, and affordable. We demonstrate the performance of the system by sequencing several different microbial genomes with varying GC content. The platform is capable of generating up to 2 Gb of high-quality nucleic acid sequence in a single run. We routinely generate sequence data that exceeds 99% raw accuracy with read lengths of up to 175 bp. Average quality scores remain above Q30 (99.9% raw sequencing accuracy) beyond 150 bp, with more than 85% of total bases at or above Q30. The utility of the platform is highlighted by targeted sequencing of the human genome. We show high concordance of SNP detection on the human NA12878 HapMap cell line with data generated on the Illumina sequencing platform. In addition, we sequenced a targeted panel of cancer-associated genes in a well characterized reference standard. With multiple library preparation approaches on this sample, we were able to identify low frequency mutations at expected allele frequencies.
Magia: Robust automated image processing and kinetic modeling toolbox for PET neuroinformatics
Authors: Karjalainen Tomi , Tuisku Jouni , Santavirta Severi , Kantonen Tatu , Tuominen Lauri , Hirvonen Jussi , Hietala Jarmo , Rinne Juha O. , Nummenmaa Lauri 
Published: April 2019

AbstractIntroductionModelling of the radioactivity images produced by PET scanners into biologically meaningful quantities, such as binding potential, is a complex multi-stage process involving data retrieval, preprocessing, drawing reference regions, kinetic modelling, and post-processing of parametric images. The process is challenging to automatize mainly because of manual work related to input generation, thus prohibiting large-scale standardized analysis of brain PET data. To resolve this problem, we introduce the Magia pipeline that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia in the automatic brain-PET data processing with four tracers binding to different binding sites: [11C]raclopride, [11C]carfentanil, [11C]MADAM, and [11C]PiB.Materials and methodsFor each tracer, we processed 30 historical control subjects’ data with manual and automated methods. Five persons manually delineated the reference regions (cerebellar or occipital cortex depending on tracer) for each subject according to written and visual instructions. The automatic reference-region extraction was based on FreeSurfer parcellations. We first assessed inter-operator variance resulting from manual delineation of reference regions. Then we compared the differences between the manually and automatically produced reference regions and the subsequently obtained metrics.ResultsThe manually delineated reference regions were remarkably different from each other. The differences translated into differences in outcome measures (binding potential or SUV-ratio), and the intra-class correlation coefficients were between 47 % and 96 % for the tracers. While the Magia-derived reference regions were topographically very different from the manually defined reference regions, Magia produced outcome measures highly consistent with average of the manually obtained estimates. For [11C]carfentanil and [11C]PiB there was no bias, while for [11C]raclopride and [11C]MADAM Magia produced 3-5 % higher binding potentials as a result of slightly lower time-integrals of reference region time-activity curves.ConclusionEven if Magia produces reference regions that are anatomically different from manually drawn reference regions, the resulting outcome measures are highly similar. Based on these results and considering the high inter-operator variance of the manual method, the high level of standardization and strong scalability of Magia, we conclude that Magia can be reliably used to process brain PET data.
ColiCoords: A Python package for the analysis of bacterial fluorescence microscopy data
Authors: Smit Jochem H. , Li Yichen , Warszawik Eliza M. , Herrmann Andreas , Cordes Thorben 
Published: April 2019

AbstractSingle-molecule fluorescence microscopy studies of bacteria provide unique insights into the mechanisms of cellular processes and protein machineries in ways that are unrivalled by any other technique. With the cost of microscopes dropping and the availability of fully automated microscopes, the volume of microscopy data produced has increased tremendously. These developments have moved the bottleneck of throughput from image acquisition and sample preparation to data analysis. Furthermore, requirements for analysis procedures have become more stringent given the requirement of various journals to make data and analysis procedures available. To address this we have developed a new data analysis package for analysis of fluorescence microscopy data of rod-like cells. Our software ColiCoords structures microscopy data at the single-cell level and implements a coordinate system describing each cell. This allows for the transformation of Cartesian coordinates of both cellular images (e.g. from transmission light or fluorescence microscopy) and single-molecule localization microscopy (SMLM) data to cellular coordinates. Using this transformation, many cells can be combined to increase the statistical significance of fluorescence microscopy datasets of any kind. Coli-Coords is open source, implemented in the programming language Python, and is extensively documented. This allows for modifications for specific needs or to inspect and publish data analysis procedures. By providing a format that allows for easy sharing of code and associated data, we intend to promote open and reproducible research.The source code and documentation can be found via the project’s GitHub page.
Selective Prespacer Processing Ensures Precise CRISPR-Cas Adaptation
Authors: Kim Sungchul , Loeff Luuk , Colombo Sabina , Brouns Stan J.J. , Joo Chirlmin 
Published: April 2019

AbstractCRISPR-Cas immunity protects prokaryotes against foreign genetic elements. CRISPR-Cas uses the highly conserved Cas1-Cas2 complex to establish inheritable memory (spacers). It remains elusive how Cas1-Cas2 acquires spacers from cellular DNA fragments (prespacers) and how it integrates them into the CRISPR array in the correct orientation. By using the high spatiotemporal resolution of single-molecule fluorescence, we reveal that Cas1-Cas2 obtains prespacers in various forms including single-stranded DNA and partial duplexes by selecting them in the DNA-length and PAM-dependent manner. Furthermore, we identify DnaQ exonucleases as enzymes that can mature the Cas1-Cas2-loaded precursor prespacers into an integration-competent size. Cas1-Cas2 protects the PAM sequence from maturation, which results in the production of asymmetrically trimmed prespacers and subsequent spacer integration in the correct orientation. This kinetic coordination in prespacer selection and PAM trimming provides comprehensive understanding of the mechanisms that underlie the integration of functional spacers in the CRISPR array.
Cell-type specific epigenetic links to schizophrenia risk in brain
Authors: Mendizabal Isabel , Berto Stefano , Usui Noriyoshi , Toriumi Kazuya , Chatterjee Paramita , Douglas Connor , Huh Iksoo , Jeong Hyeonsoo , Layman Thomas , Tamminga Carol , Preuss Todd M. , Konopka Genevieve , Yi Soojin V. 
Published: April 2019

AbstractThe importance of cell-type specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generated cell-type specific whole-genome methylomes (N=95) and transcriptomes (N=89) from neurons and oligodendrocytes from brains of schizophrenia and matched controls. The methylomes of these two cell-types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation difference between control and schizophrenia brains is subtle compared to cell-type difference, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell-type differentially methylated sites, highlighting the significance of cell-type specific epigenetic dysregulation in a complex neuropsychiatric disorder. Our resource provides novel and comprehensive methylome and transcriptome data from distinct cell populations from schizophrenia brains, further revealing reduced cell-type epigenetic distinction in schizophrenia.
Spatiotemporally distinct neural mechanisms underlie our reactions to and comparison between value-based options
Authors: Frömer R. , Shenhav A. 
Published: April 2019

AbstractPrevious research suggests that people evaluate options in at least two ways: (1) appraising their overall value and (2) choosing between them. Here we test whether these processes are temporally dissociable, with appraisal-related processes tied to the time one’s options appear and choice-related processes tied to the time a decision is made. We recorded EEG while participants individually rated and subsequently made choices between consumer goods. As predicted, we found appraisal-related neural activity locked to the onset of the stimuli and choice-related activity locked to (and preceding) the response. Patterns of appraisal- and choice-related activity were further associated with distinct topographical profiles. Using a novel neural index of one’s certainty about a given item’s value, we also provide evidence that choices and choice-related activity were further modulated by this option-specific value certainty. Taken together, our results support the hypothesis that spatiotemporally distinct mechanisms underlie appraisal and choice, suggesting that commonly observed neural correlates of choice value may reflect either or both of these processes.
Biodistribution and inflammatory response to intracranial delivery of scintillating nanoparticles
Authors: Fischer Máté , Zimmerman Amber , Zhang Eric , Kolis Joseph , Dickey Ashley , Burdette Mary K. , Afaghpour-Becklund Mitra , Chander Praveen , Foulger Stephen H. , Brigman Jonathan L. , Weick Jason. P. 
Published: April 2019

AbstractNanoparticle-based delivery systems have become a popular method for targeting tumors and impermeable tissue with drugs for treatment and imaging markers for biodetection. Nanomaterials are beneficial for medical treatment because they can be modified to have increased stability and carrying capacity, and their size and surface modifications allow them to reach otherwise impenetrable tissue. Localized or systemic injection can be used for delivery of nanoparticles; however, systemic injection without appropriate surface modifications is subjected to uptake by the mononuclear phagocytic system which clears particles from the circulation rapidly limiting their accumulation at target tissue and reducing efficacy. Here we demonstrate the biodistribution of Yttrium oxyorthosilicate nanoparticles doped with Cerium after localized injection to the cerebral cortex as well as the immune response at the site of injection over time.
Identifying microbial species by single-molecule DNA optical mapping and resampling statistics
Authors: Bouwens Arno , Deen Jochem , Vitale Raffaele , D’Huys Laurens , Goyvaerts Vince , Descloux Adrien , Borrenberghs Doortje , Grussmayer Kristin , Lukes Tomas , Camacho Rafael , Su Jia , Ruckebusch Cyril , Lasser Theo , Van De Ville Dimitri , Hofkens Johan , Radenovic Aleksandra , Janssen Kris Pieter Frans 
Published: April 2019

ABSTRACTSingle molecule DNA mapping has the potential to serve as a powerful complement to high-throughput sequencing in metagenomic analysis. Offering longer read lengths and forgoing the need for complex library preparation and amplification, mapping stands to provide an unbiased view into the composition of complex viromes and/or microbiomes. To fully enable mapping-based metagenomics, sensitivity and specificity of DNA map analysis and identification need to be improved. Using detailed simulations and experimental data, we first demonstrate how fluorescence imaging of surface stretched, sequence specifically labeled DNA fragments can yield highly sensitive identification of targets. Secondly, a new analysis technique is introduced to increase specificity of the analysis, allowing even closely related species to be resolved. Thirdly, we show how an increase in resolution improves sensitivity. Finally, we demonstrate that these methods are capable of identifying species with long genomes such as bacteria with high sensitivity.
The outer membrane lipoprotein NlpI nucleates hydrolases within peptidoglycan multi-enzyme complexes inEscherichia coli
Authors: Banzhaf Manuel , Yau Hamish C. L. , Verheul Jolanda , Lodge Adam , Kritikos George , Mateus André , Hov Ann Kristin , Stein Frank , Wartel Morgane , Pazos Manuel , Solovyova Alexandra S. , Savitski Mikhail M , den Blaauwen Tanneke , Typas Athanasios , Vollmer Waldemar 
Published: April 2019

AbstractThe peptidoglycan (PG) sacculus provides bacteria with the mechanical strength to maintain cell shape and resist osmotic stress. Enlargement of the mesh-like sacculus requires the combined activity of PG synthases and hydrolases. InEscherichia coli, the activity of the two bifunctional PG synthases is driven by lipoproteins anchored in the outer membrane. However, the regulation of PG hydrolases is less well understood, with only regulators for PG amidases having been described. Here, we identify the lipoprotein NlpI as a general adaptor protein for PG hydrolases. NlpI binds to different classes of hydrolases and can specifically form multimeric complexes with various PG endopeptidases. In addition, NlpI seems to contribute both to PG elongation and cell division biosynthetic complexes based on its localization and genetic interactions. In line with such a role, we reconstitute PG multi-enzyme complexes containing NlpI, the PG synthesis regulator LpoA, its cognate bifunctional synthase, PBP1A, and different endopeptidases. Our results indicate that PG regulators and adaptors are part of PG biosynthetic multi-enzyme complexes, regulating and potentially coordinating the spatiotemporal action of PG synthases and hydrolases.SignificanceThe activity of PG hydrolases may cause lysis of the bacterial cell if left unregulated. Hence, the cell must have ways of regulating and coordinating their activities. Our current understanding of how this occurs is incomplete. In this work, we present the outer membrane (OM) anchored lipoprotein, NlpI, as a scaffold of peptidoglycan hydrolases. We propose that NlpI facilitates the formation of multi-enzyme complexes and that, along with other regulators, it coordinates a safe enlargement and separation of the PG layer inE. coli.
Predicting cognitive and mental health traits and their polygenic architecture using large-scale brain connectomics
Authors: Maglanoc Luigi A. , Kaufmann Tobias , van der Meer Dennis , Marquand Andre F. , Wolfers Thomas , Jonassen Rune , Hilland Eva , Andreassen Ole A. , Landrø Nils Inge , Westlye Lars T. 
Published: April 2019

AbstractCognitive abilities and mental disorders are complex traits sharing a largely unknown neuronal basis and aetiology. Their genetic architectures are highly polygenic and overlapping, which is supported by heterogeneous phenotypic expression and substantial clinical overlap. Brain network analysis provides a non-invasive means of dissecting biological heterogeneity yet its sensitivity, specificity and validity in clinical applications remains a major challenge. We used machine learning on static and dynamic temporal synchronization between all brain network nodes in 10,343 healthy individuals from the UK Biobank to predict (i) cognitive and mental health traits and (ii) their genetic underpinnings. We predicted age and sex to serve as our reference point. The traits of interest included individual level educational attainment and fluid intelligence (cognitive) and dimensional measures of depression, anxiety, and neuroticism (mental health). We predicted polygenic scores for educational attainment, fluid intelligence, depression, anxiety, and different neuroticism traits, in addition to schizophrenia. Beyond high accuracy for age and sex, permutation tests revealed above chance-level prediction accuracy for educational attainment and fluid intelligence. Educational attainment and fluid intelligence were mainly negatively associated with static brain connectivity in frontal and default mode networks, whereas age showed positive correlations with a more widespread pattern. In comparison, prediction accuracy for polygenic scores was at chance level across traits, which may serve as a benchmark for future studies aiming to link genetic factors and fMRI-based brain connectomics.SignificanceAlthough cognitive abilities and susceptibility to mental disorders reflect individual differences in brain function, neuroimaging is yet to provide a coherent account of the neuronal underpinnings. Here, we aimed to map the brain functional connectome of (i) cognitive and mental health traits and (ii) their polygenic architecture in a large population-based sample. We discovered high prediction accuracy for age and sex, and above-chance accuracy for educational attainment and intelligence (cognitive). In contrast, accuracies for dimensional measures of depression, anxiety and neuroticism (mental health), and polygenic scores across traits, were at chance level. These findings support the link between cognitive abilities and brain connectomics and provide a reference for studies mapping the brain connectomics of mental disorders and their genetic architectures.