bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple sclerosis iPSC-derived oligodendroglia conserve their intrinsic properties to functionally interact with axons and glia in vivo
Authors: Mozafari Sabah , Starost Laura , Manot-Saillet Blandine , Garcia-Diaz Beatriz , Xu Yu Kang T. , Roussel Delphine , Levy Marion J. F. , Ottoboni Linda , Kim Kee-Pyo , Schöler Hans R. , Kennedy Timothy E. , Antel Jack P. , Martino Gianvito , Angulo Maria Cecilia , Kuhlmann Tanja , Baron-Van Evercooren Anne 
Published: May 2020

AbstractThe remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic regulators of the oligodendroglial biology or reflect MS oligodendrocyte intrinsic properties. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient, dysmyelinating mouse model, to compare side-by-side induced pluripotent stem-cell-derived O4+ oligodendroglia from MS and healthy donors following their engraftment in the developing CNS. We show that the MS-progeny survives, proliferates and differentiates into oligodendrocytes to the same extent as controls. Quantitative multi-parametric imaging indicates that MS and control oligodendrocytes generate equal amounts of myelin, withbona-fidenodes of Ranvier and promote equal restoration of their host slow conduction. Moreover, the MS-derived progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glial cells. Thus, MS pluripotent stem cell-derived progeny fully integrates into functional axo-glial and glial-glial components, reinforcing the view that the MS oligodendrocyte differentiation block is not due to intrinsic oligodendroglial deficits. These biological findings as well as the fully integrated human-murine chimeric model should facilitate the development of pharmacological or cell-based therapies to promote CNS remyelination.One Sentence SummaryMultiple Sclerosis oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia and glia-glia connections after engraftment in the murine CNS, reinforcing the view that the MS oligodendrocyte differentiation block is not due to major intrinsic oligodendroglial deficits but most likely to environmental conditions.
Phase-amplitude coupling profiles differ in frontal and auditory cortices
Authors: García-Rosales Francisco , López-Jury Luciana , González-Palomares Eugenia , Cabral-Calderin Yuranny , Kössl Manfred , Hechavarria Julio C. 
Published: May 2020

AbstractNeural oscillations are at the core of important computations in the mammalian brain. Interactions between oscillatory activities in different frequency bands, such as delta (1-4 Hz), theta (4-8 Hz), or gamma (>30 Hz), are a powerful mechanism for binding fundamentally distinct spatiotemporal scales of neural processing. Phase-amplitude coupling (PAC) is one such plausible and well-described interaction, but much is yet to be uncovered regarding how PAC dynamics contribute to sensory representations. In particular, although PAC appears to have a major role in audition, the characteristics of coupling profiles in sensory and integration (i.e. frontal) cortical areas remain obscure. Here, we address this question by studying PAC dynamics in the frontal-auditory field (FAF; an auditory area in the bat frontal cortex) and the auditory cortex (AC) of the batCarollia perspicillata. By means of simultaneous electrophysiological recordings in frontal and auditory cortices examining local-field potentials (LFPs), we show that the amplitude of gamma-band activity couples with the phase of low-frequency LFPs in both structures. Our results demonstrate that the coupling in FAF occurs most prominently in delta/high-gamma frequencies (1-4/75-100 Hz), whereas in the AC the coupling is strongest in the theta/low-gamma (2-8/25-55 Hz) range. We argue that distinct PAC profiles may represent different mechanisms for neuronal processing in frontal and auditory cortices, and might complement oscillatory interactions for sensory processing in the frontal-auditory cortex network.
Transcriptional memory-like imprints and enhanced functional activity in γδ T cells following resolution of malaria infection
Authors: Kumarasingha Rasika , Ioannidis Lisa J. , Abeysekera Waruni , Studniberg Stephanie , Wijesurendra Dinidu , Mazhari Ramin , Poole Daniel P. , Mueller Ivo , Schofield Louis , Hansen Diana S. , Eriksson Emily M. 
Published: May 2020

Abstractγδ T cells play an essential role in the immune response to malaria infection. However, long-lasting effects of malaria infection on the γδ T cell population still remain inadequately understood. This study investigated transcriptional changes and memory-like functional capacity of malaria pre-exposed γδ T cells using aPlasmodium chabaudiinfection model. We show that multiple genes associated with effector function (chemokines, cytokines and cytotoxicity) and antigen-presentation were upregulated inP. chabaudi-exposed γδ T cells compared to γδ T cells from naïve mice. This transcriptional profile was positively correlated with profiles observed in conventional memory CD8+T cells and was accompanied by enhanced reactivation upon secondary encounter withPlasmodium-infected red blood cellsin vitro. Collectively our data demonstrate thatPlasmodiumexposure result in “memory-like imprints” in the γδ T cell population and also promotes γδ T cells that can support antigen-presentation during subsequent infections.
A CHCHD10 variant causing ALS elicits an unfolded protein response through the IRE1/XBP1 pathway
Authors: Straub Isabella R. , Weraarpachai Woranontee , Shoubridge Eric A. 
Published: May 2020

AbstractMutations inCHCHD10, coding for a mitochondrial intermembrane space protein, are a rare cause of autosomal dominant amyotrophic lateral sclerosis (ALS). Mutation-specific toxic gain of function or haploinsuffuciency models have been proposed to explain pathogenicity. To decipher the metabolic dysfunction associated with the haploinsufficient p.R15L variant we integrated transcriptomic, metabolomic and proteomic data sets in patient cells subjected to nutrient stress. Patient cells had a complex I deficiency resulting in an increased NADH/NAD+ratio, downregulation of the TCA cycle, and a reorganization of one carbon metabolism. This led to phosphorylation of AMPK, activation of an endoplasmic reticulum and mitochondrial unfolded protein response (UPR), and the production of GDF15 and FGF21, which are markers of mitochondrial disease. The endoplasmic reticulum UPR was mediated through the IRE1/XBP1 pathway, and was accompanied by reduced eIF2alpha phosphorylation, dephosphorylation of both JNK isoforms, and up regulation of several dual specific phosphatases. This study demonstrates that loss of CHCHD10 function elicits a striking energy deficit that activates cellular stress pathways, which may underlie the selective vulnerability of motor neurons.
Volitional Control of Individual Neurons in the Human Brain
Authors: Patel Kramay , Katz Chaim N. , Kalia Suneil K. , Popovic Milos R. , Valiante Taufik A. 
Published: May 2020

AbstractCan the human brain, a complex interconnected structure of over 80 billion neurons learn to control itself at the most elemental scale – a single neuron. We directly linked the firing rate of a single (direct) neuron to the position of a box on a screen, which participants tried to control. Remarkably, all subjects upregulated the firing rate of the direct neuron in memory structures of their brain. Learning was accompanied by improved performance over trials, simultaneous decorrelation of the direct neuron to local neurons, and direct neuron to beta frequency oscillation phase-locking. Such previously unexplored neuroprosthetic skill learning within memory related brain structures, and associated beta frequency phase-locking implicates the ventral striatum. Our demonstration that humans can volitionally control neuronal activity in mnemonic structures, may provide new ways of probing the function and plasticity of human memory without exogenous stimulation.
sPepFinder expedites genome-wide identification of small proteins in bacteria
Authors: Li Lei , Chao Yanjie 
Published: May 2020

ABSTRACTSmall proteins shorter than 50 amino acids have been long overlooked. A number of small proteins have been identified in several model bacteria using experimental approaches and assigned important functions in diverse cellular processes. The recent development of ribosome profiling technologies has allowed a genome-wide identification of small proteins and small ORFs (smORFs), but our incomplete understanding of small proteins hindersde novocomputational prediction of smORFs in non-model bacterial species. Here, we have identified several sequence features for smORFs by a systematic analysis of all the known small proteins inE. coli, among which the translation initiation rate is the strongest determinant. By integrating these features into a support vector machine learning model, we have developed a novel sPepFinder algorithm that can predict conserved smORFs in bacterial genomes with a high accuracy of 92.8%.De novoprediction inE. colihas revealed several novel smORFs with evidence of translation supported by ribosome profiling. Further application of sPepFinder in 549 bacterial species has led to the identification of > 100,000 novel smORFs, many of which are conserved at the amino acid and nucleotide levels under purifying selection. Overall, we have established sPepFinder as a valuable tool to identify novel smORFs in both model and non-model bacterial organisms, and provided a large resource of small proteins for functional characterizations.
Bulk and single-cell gene expression profiling of SARS-CoV-2 infected human cell lines identifies molecular targets for therapeutic intervention
Authors: Emanuel Wyler , Kirstin Mösbauer , Vedran Franke , Asija Diag , Theresa Gottula Lina , Roberto Arsie , Filippos Klironomos , David Koppstein , Salah Ayoub , Christopher Buccitelli , Anja Richter , Ivano Legnini , Andranik Ivanov , Tommaso Mari , Simone Del Giudice , Patrick Papies Jan , Alexander Müller Marcel , Daniela Niemeyer , Matthias Selbach , Altuna Akalin , Nikolaus Rajewsky , Christian Drosten , Markus Landthaler 
Published: May 2020

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing global health threat with more than two million infected people since its emergence in late 2019. Detailed knowledge of the molecular biology of the infection is indispensable for understanding of the viral replication, host responses, and disease progression. We provide gene expression profiles of SARS-CoV and SARS-CoV-2 infections in three human cell lines (H1299, Caco-2 and Calu-3 cells), using bulk and single-cell transcriptomics. Small RNA profiling showed strong expression of the immunity and inflammation-associated microRNA miRNA-155 upon infection with both viruses. SARS-CoV-2 elicited approximately two-fold higher stimulation of the interferon response compared to SARS-CoV in the permissive human epithelial cell line Calu-3, and induction of cytokines such as CXCL10 or IL6. Single cell RNA sequencing data showed that canonical interferon stimulated genes such as IFIT2 or OAS2 were broadly induced, whereas interferon beta (IFNB1) and lambda (IFNL1-4) were expressed only in a subset of infected cells. In addition, temporal resolution of transcriptional responses suggested interferon regulatory factors (IRFs) activities precede that of nuclear factor-κB (NF-κB). Lastly, we identified heat shock protein 90 (HSP90) as a protein relevant for the infection. Inhibition of the HSP90 charperone activity by Tanespimycin/17-N-allylamino-17-demethoxygeldanamycin (17-AAG) resulted in a reduction of viral replication, and of TNF and IL1B mRNA levels. In summary, our study established in vitro cell culture models to study SARS-CoV-2 infection and identified HSP90 protein as potential drug target for therapeutic intervention of SARS-CoV-2 infection.
Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease
Authors: Bandres-Ciga S , Saez-Atienzar S , Kim JJ , Makarious MB , Faghri F , Diez-Fairen M , Iwaki H , Leonard H , Botia J , Ryten M , Hernandez D , Gibbs JR , Ding J , Gan-Or Z , Noyce A , Pihlstrom L , Torkamani A , Scholz SW , Traynor B , Ehrlich D , Scherzer CR , Bookman M , Cookson M , Blauwendraat C , Nalls MA , Singleton AB ,   on behalf of the International Parkinson Disease Genomics Consortium
Published: May 2020

ABSTRACTPolygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological pathways underlying PD using the largest currently available cohorts of genetic data and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership - Parkinson’s disease initiative (AMP-PD), among other sources. We placed these insights into a cellular context. We applied large-scale pathway-specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk in a cohort of 457,110 individuals by focusing on a compilation of 2,199 publicly annotated gene sets representative of curated pathways, of which we nominate 46 pathways associated with PD risk. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data, including 4,331 individuals. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for adult dopaminergic neurons, serotonergic neurons, and radial glia. Subsequently, we created a novel way of buildingde novopathways by constructing a network expression community map using transcriptomic data derived from the blood of 1,612 PD patients, which revealed 54 connecting networks associated with PD. Our analyses highlight several promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.
Transcriptional kinetics and molecular functions of long non-coding RNAs
Authors: Johnsson Per , Ziegenhain Christoph , Hartmanis Leonard , Hendriks Gert-Jan , Hagemann-Jensen Michael , Reinius Björn , Sandberg Rickard 
Published: May 2020

AbstractAn increasing number of studies have demonstrated the regulatory importance of long non-coding RNAs (lncRNAs), yet little is known about their transcriptional dynamics and it remains challenging to determine their regulatory functions. Here, we used allele-sensitive single-cell RNA-seq (scRNA-seq) to demonstrate that lncRNAs have lower burst frequencies with twice as long duration between bursts, compared to mRNAs. Additionally, we observed an increased cell-to-cell variability in lncRNA expression that was due to more sporadic bursting (lower frequency) with larger numbers of RNA molecules being produced. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell-state specific functions involved in cell cycle progression and apoptosis. Finally, utilizing allele-resolved RNA expression, we identifiedcisfunctioning lncRNAs and observed that knockdown of these lncRNAs modulated either transcriptional burst frequency or size of the nearby protein-coding gene. Collectively, our results identify distinct transcriptional regulation of lncRNAs and we demonstrate a role for lncRNAs in the regulation of transcriptional bursting of mRNAs.
Verification of genetic engineering in yeasts with nanopore whole genome sequencing
Authors: Collins Joseph H. , Keating Kevin W. , Jones Trent R. , Balaji Shravani , Marsan Celeste B. , Çomo Marina , Newlon Zachary J. , Mitchell Tom , Bartley Bryan , Adler Aaron , Roehner Nicholas , Young Eric M. 
Published: May 2020

ABSTRACTYeast genomes can be assembled from sequencing data, but genome integrations and episomal plasmids often fail to be resolved with accuracy, completeness, and contiguity. Resolution of these features is critical for many synthetic biology applications, including strain quality control and identifying engineering in unknown samples. Here, we report an integrated workflow, named Prymetime, that uses sequencing reads from inexpensive NGS platforms, assembly and error correction software, and a list of synthetic biology parts to achieve accurate whole genome sequences of yeasts with engineering annotated. To build the workflow, we first determined which sequencing methods and software packages returned an accurate, complete, and contiguous genome of an engineered S. cerevisiae strain with two similar plasmids and an integrated pathway. We then developed a sequence feature annotation step that labels synthetic biology parts from a standard list of yeast engineering sequences or from a custom sequence list. We validated the workflow by sequencing a collection of 15 engineered yeasts built from different parent S. cerevisiae and nonconventional yeast strains. We show that each integrated pathway and episomal plasmid can be correctly assembled and annotated, even in strains that have part repeats and multiple similar plasmids. Interestingly, Prymetime was able to identify deletions and unintended integrations that were subsequently confirmed by other methods. Furthermore, the whole genomes are accurate, complete, and contiguous. To illustrate this clearly, we used a publicly available S. cerevisiae CEN.PK113 reference genome and the accompanying reads to show that a Prymetime genome assembly is equivalent to the reference using several standard metrics. Finally, we used Prymetime to resequence the nonconventional yeasts Y. lipolytica Po1f and K. phaffii CBS 7435, producing an improved genome assembly for each strain. Thus, our workflow can achieve accurate, complete, and contiguous whole genome sequences of yeast strains before and after engineering. Therefore, Prymetime enables NGS-based strain quality control through assembly and identification of engineering features.
Think Like an Expert: Neural Alignment Predicts Understanding in Students Taking an Introduction to Computer Science Course
Authors: Meshulam Meir , Hasenfratz Liat , Hillman Hanna , Liu Yun-Fei , Nguyen Mai , Norman Kenneth A. , Hasson Uri 
Published: May 2020

AbstractHow do students understand and remember new information? Despite major advances in measuring human brain activity during and after educational experiences, it is unclear how learners internalize new content, especially in real-life and online settings. In this work, we introduce a neural measure for predicting and assessing learning outcomes. Our approach hinges on the idea that successful learning involves forming the “right” set of neural representations, which are captured in “canonical” activity patterns shared across individuals. Specifically, we hypothesized that understanding is mirrored in “neural alignment”: the degree to which an individual learner’s neural representations match those of experts, as well as those of other learners. We tested this hypothesis in a longitudinal functional MRI study that regularly scanned college students enrolled in an introduction to computer science course. We additionally scanned graduate student “experts” in computer science. We found that alignment among students successfully predicted overall performance in a final exam. Furthermore, within individual students, concepts that evoked better alignment with the experts and with their fellow students were better understood, revealing neural patterns associated with understanding specific concepts. These results provide support for a novel neural measure of concept understanding that can be used to assess and predict learning outcomes in real-life contexts.
Spontaneous activity changes in large-scale cortical networks in older adults couple to distinct hemodynamic morphology
Authors: Sitnikova Tatiana , Hughes Jeremy W. , Howard Casey M. , Stephens Kimberly A. , Woolrich Mark W. , Salat David H. 
Published: May 2020

AbstractNeurovascular coupling is a dynamic core mechanism supporting brain energy demand. Therefore, even spontaneous changes in neural activity are expected to evoke a vascular hemodynamic response (HDR). Here, we developed a novel procedure for estimating transient states in intrinsic activity of neural networks based on source-localized electroencephalogram in combination with HDR estimation based on simultaneous rapid-acquisition functional magnetic resonance imaging. We demonstrate a readily apparent spatiotemporal correspondence between electrophysiological and HDR signals, describing for the first time how features of neurovascular coupling may differ among large-scale brain networks. In the default mode network, the HDR pattern in our older adult participants was associated with a surrogate marker of cerebrovascular deterioration and predicted alterations in temporal structure of fast intrinsic electrophysiological activity linked to memory decline. These results show the potential of our technique for making inferences about neural and vascular processes in higher-level cognitive networks in healthy and at-risk populations.
Social networks predict the life and death of honey bees
Authors: Wild Benjamin , Dormagen David M , Zachariae Adrian , Smith Michael L , Traynor Kirsten S , Brockmann Dirk , Couzin Iain D , Landgraf Tim 
Published: May 2020

AbstractIn complex societies, individuals’ roles are reflected by interactions with other conspecifics. Honey bees (Apis mellifera) generally change tasks as they age, but developmental trajectories of individuals can vary drastically due to physiological and environmental factors. We introduce a succinct descriptor of an individual’s social network that can be obtained without interfering with the colony. Thisnetwork ageaccurately predicts task allocation, survival, activity patterns, and future behavior. We analyze developmental trajectories of multiple cohorts of individuals in a natural setting and identify distinct developmental pathways and critical life changes. Our findings suggest a high stability in task allocation on an individual level. We show that our method is versatile and can extract different properties from social networks, opening up a broad range of future studies. Our approach highlights the relationship of social interactions and individual traits, and provides a scalable technique for understanding how complex social systems function.