bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease
Authors: Hin Nhi , Newman Morgan , Pederson Stephen , Lardelli Michael 
Published: May 2020

AbstractBackgroundIron trafficking and accumulation is associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets.ObjectiveTo identify sets of genes predicted to contain Iron Responsive Elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD.MethodsComprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3’ or 5’ untranslated regions (UTRs) were identified in human, mouse, and zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets.ResultsIRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are amongst the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3’ untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm.ConclusionOur results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE- containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions.
Arabidopsis SMN2/HEN2, Encoding DEAD-box RNA Helicase, Governs Proper Expression of the Resistance GeneSMN1/RPS6and Is Involved in Dwarf, Autoimmune Phenotypes ofmekk1andmpk4Mutants
Authors: Takagi Momoko , Iwamoto Naoki , Kubo Yuta , Morimoto Takayuki , Takagi Hiroki , Takahashi Fuminori , Nishiuchi Takumi , Tanaka Keisuke , Taji Teruaki , Kaminaka Hironori , Shinozaki Kazuo , Akimitsu Kazuya , Terauchi Ryohei , Shirasu Ken , Ichimura Kazuya 
Published: May 2020

AbstractInArabidopsis thaliana, a mitogen-activated protein kinase pathway, MEKK1–MKK1/MKK2–MPK4, is important for basal resistance, and disruption of this pathway results in dwarf, autoimmune phenotypes. To elucidate the complex mechanisms activated by the disruption of this pathway, we have previously developed a mutant screening system based on a dwarf autoimmune line that overexpressed the N-terminal regulatory domain of MEKK1. Here, we report that the second group of mutants,smn2, had defects in theSMN2gene, encoding a DEAD-box RNA helicase.SMN2is identical toHEN2, whose function is vital for the nuclear RNA exosome because it provides non-ribosomal RNA specificity for RNA turnover, RNA quality control, and RNA processing. AberrantSMN1/RPS6transcripts were detected insmn2andhen2mutants. Disease resistance againstPseudomonas syringaepv.tomatoDC3000 (hopA1), which is conferred bySMN1/RPS6, was decreased insmn2mutants, suggesting a functional connection betweenSMN1/RPS6andSMN2/HEN2. We produced double mutantsmekk1smn2andmpk4smn2to determine whether thesmn2mutations suppress the dwarf, autoimmune phenotypes of themekk1andmpk4mutants, as thesmn1mutations do. As expected, themekk1andmpk4phenotypes were suppressed by thesmn2mutations. These results suggested thatSMN2is involved in proper function ofSMN1/RPS6. The GO enrichment analysis using RNA-seq data showed that defense genes were downregulated insmn2, suggesting positive contribution ofSMN2to genome-wide expression of defense-related genes. In conclusion, this study provides novel insight into plant immunity viaSMN2/HEN2, an essential component of the nuclear RNA exosome.
Comprehensive characterization of N- and O- glycosylation of SARS-CoV-2 human receptor angiotensin converting enzyme 2
Authors: Shajahan Asif , Archer-Hartmann Stephanie , Supekar Nitin T. , Gleinich Anne S. , Heiss Christian , Azadi Parastoo 
Published: May 2020

AbstractThe emergence of the COVID-19 pandemic caused by SARS-CoV-2 has created the need for development of new therapeutic strategies. Understanding the mode of viral attachment, entry and replication has become a key aspect of such interventions. The coronavirus surface features a trimeric spike (S) protein that is essential for viral attachment, entry and membrane fusion. The S protein of SARS-CoV-2 binds to human angiotensin converting enzyme 2 (hACE2) for entry. Herein, we describe glycomic and glycoproteomic analysis of hACE2 expressed in HEK293 human cells. We observed high glycan occupancy (73.2 to 100%) at all seven possible N-glycosylation sites and surprisingly detected one novel O-glycosylation site. To deduce the detailed structure of glycan epitopes on hACE2 that may be involved in viral binding, we have characterized the terminal sialic acid linkages, the presence of bisecting GlcNAc, and the pattern of N-glycan fucosylation. We have conducted extensive manual interpretation of each glycopeptide and glycan spectrum, in addition to using bioinformatics tools to validate the hACE2 glycosylation. Our elucidation of the site-specific glycosylation and its terminal orientations on the hACE2 receptor, along with the modeling of hACE2 glycosylation sites can aid in understanding the intriguing virus-receptor interactions and assist in the development of novel therapeutics to prevent viral entry. The relevance of studying the role of ACE2 is further increased due to some recent reports about the varying ACE2 dependent complications with regard to age, sex, race, and pre-existing conditions of COVID-19 patients.
Engineering the Compression of Sequencing Reads
Authors: Kowalski Tomasz , Grabowski Szymon 
Published: May 2020

AbstractMotivationFASTQ remains among the widely used formats for high-throughput sequencing data. Despite advances in specialized FASTQ compressors, they are still imperfect in terms of practical performance tradeoffs.ResultsWe present a multi-threaded version of Pseudogenome-based Read Compressor (PgRC), an in-memory algorithm for compressing the DNA stream, based on the idea of building an approximation of the shortest common superstring over high-quality reads. The current version, v1.2, practically preserves the compression ratio and decompression speed of the previous one, reducing the compression time by a factor of about 4–5 on a 6-core/12-thread machine.AvailabilityPgRC 1.2 can be downloaded fromhttps://github.com/kowallus/PgRC.Contactsgrabow@kis.p.lodz.pl
Estimating RNA dynamics using one time point for one sample in a single-pulse metabolic labeling experiment
Authors: Hersch Micha , Biasini Adriano , Marques Ana C. , Bergmann Sven 
Published: May 2020

AbstractOver the past decade, experimental procedures such as metabolic labeling for determining RNA turnover rates at the transcriptome-wide scale have been widely adopted and are now turning to single cell measurements. Several computational methods to estimate RNA processing and degradation rates from such experiments have been suggested, but they all require several RNA sequencing samples. Here we present a method that can estimate RNA synthesis, processing and degradation rates from a single sample. Our method is computationally efficient and outputs rates that correlate well with previously published data sets. Using it on a single sample, we were able to reproduce the observation that dynamic biological processes tend to involve genes with higher metabolic rates, while stable processes involve genes with lower rates. This supports the hypothesis that cells control not only the mRNA steady-state abundance, but also its responsiveness, i.e., how fast steady-state is reached. In addition to saving experimental work and computational time, having a sample-based rate estimation has several advantages. It does not require an error-prone normalization across samples and enables the use of replicates to estimate uncertainty and perform quality control. Finally the method and theoretical results described here are general enough to be useful in other contexts such as nucleotide conversion methods and single cell metabolic labeling experiments.
Concomitant processing of choice and outcome in frontal corticostriatal ensembles correlates with performance of rats
Authors: Handa Takashi , Harukuni Rie , Fukai Tomoki 
Published: May 2020

SummaryThe frontal cortex-basal ganglia network plays a pivotal role in adaptive goal-directed behaviors. Medial frontal cortex (MFC) encodes information about choices and outcomes into sequential activation of neural population, or neural trajectory. While MFC projects to the dorsal striatum (DS), whether DS also displays temporally coordinated activity remains unknown. We studied this question by simultaneously recording neural ensembles in the MFC and DS of rodents performing an outcome-based alternative choice task. We found that the two regions exhibited highly parallel evolution of neural trajectories, transforming choice information into outcome-related information. When the two trajectories were highly correlated, spike synchrony was task-dependently modulated in some MFC-DS neuron pairs. Our results suggest that neural trajectories concomitantly process decision-relevant information in MFC and DS with increased spike synchrony between these regions.
Bottom-Illuminated Orbital Shaker for Microalgae Cultivation
Authors: Nedbal Jakub , Gao Lu , Suhling Klaus 
Published: May 2020

AbstractA bottom-illuminated orbital shaker designed for the cultivation of microalgae suspensions is described in this open-source hardware report. The instrument agitates and illuminates microalgae suspensions grown inside flasks. It was optimized for low production cost, simplicity, low power consumption, design flexibility, consistent, and controllable growth light intensity.The illuminated orbital shaker is especially well suited for low-resource research laboratories and education. It is an alternative to commercial instruments for microalgae cultivation. It improves on typical do-it-yourself microalgae growth systems by offering consistent and well characterized illumination light intensity. The illuminated growth area is 20 cm × 15 cm, which is suitable for three T75 tissue culture flasks or six 100 ml Erlenmeyer flasks. The photosynthetic photon flux density, is variable in eight steps (26 – 800 μmol · m−2· s−1) and programmable in a 24-hour light/dark cycle. The agitation speed is variable (0 – 210 RPM). The overall material cost is around £300, including an entry-level orbital shaker. The build takes two days, requiring electronics and mechanical assembly capabilities. The instrument build is documented in a set of open-source protocols, design files, and source code. The design can be readily modified, scaled, and adapted for other orbital shakers and specific experimental requirements.The instrument function was validated by growing fresh-water microalgaeDesmodesmus quadricaudaandChlorella vulgaris. The cultivation protocols, microalgae growth curves, and doubling times are included in this report.Specifications table
Structural and molecular determinants of CCS-mediated copper activation of MEK1/2
Authors: Grasso Michael , Bond Gavin J. , Kim Ye-Jin , Alwan Katherine B. , Boyd Stefanie , Dzebo Maria Matson , Valenzuela Sebastian , Tsang Tiffany , Schibrowsky Natalie A. , Matthews Megan L. , Burslem George M. , Wittung-Stafshede Pernilla , Winkler Duane D. , Blackburn Ninian J. , Marmorstein Ronen , Brady Donita C. 
Published: May 2020

SummaryNormal physiology relies on the precise coordination of intracellular signal transduction pathways that respond to nutrient availability to balance cell growth and cell death. We recently established a critical mechanistic function for the redox-active micronutrient copper (Cu) in the canonical mitogen activated protein kinase (MAPK) pathway at the level of MEK1 and MEK2. Here we report the X-ray crystal structure of Cu-MEK1 and reveal active site chemical ligands and oxidation state specificity for MEK1 Cu coordination. Mechanistically, the Cu chaperone CCS selectively bound to and facilitated Cu transfer to MEK1. Mutations in MEK1 that disrupt Cu(I) affinity or a CCS small molecule inhibitor reduced Cu-stimulated MEK1 kinase activity. These atomic and molecular level data provide the first mechanistic insights of Cu kinase signaling and could be exploited for the development of novel MEK1/2 inhibitors that either target the Cu structural interface or blunt dedicated Cu delivery mechanisms via CCS.
Schizophrenia-associated variation atZNF804Acorrelates with altered experience-dependent dynamics of sleep slow-waves and spindles in healthy young adults
Authors: Bartsch Ullrich , Corbin Laura J , Hellmich Charlotte , Taylor Michelle , Easey Kayleigh E , Durant Claire , Marston Hugh M , Timpson Nicholas J , Jones Matthew W 
Published: May 2020

ABSTRACTBackgroundThe rs1344706 polymorphism inZNF804Ais robustly associated with schizophrenia (SZ), yet brain and behavioral phenotypes related to this variant have not been extensively characterized. In turn, SZ is associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants.MethodsWe recruited healthy adult males, with no history of psychiatric disorder, from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the SZ-associated ‘A’ allele (N=25) or the alternative ‘C’ allele (N=22) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequencing task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation.ResultsAverage MST learning and sleep-dependent performance improvements were similar across genotype groups, but with increased variability in the AA group. CC participants showed increased slow-wave and spindle amplitudes, plus augmented coupling of slow-wave activity across recording electrodes after learning. Slow-waves and spindles in those with the AA genotype were insensitive to learning, whilst slow-wave coherence decreased following MST training.ConclusionWe describe evidence that rs1344706 polymorphism inZNF804Ais associated with changes in experience- and sleep-dependent, local and distributed neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of SZ-associated variants on neural circuit oscillations and function.
Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats
Authors: Goutaudier Raphaël , Coizet Véronique , Carcenac Carole , Carnicella Sebastien 
Published: May 2020

AbstractAlthough Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience, the first ligands used were not as selective as expected. Compound 21 (C21) was recently proposed as an alternative, butin vivocharacterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di using TH-Cre rats. In males, 1 mg.kg−1of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg−1circumvented this aspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg−1of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect. This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.
An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate
Authors: Ruess Holly , Lee Jeon , Guzman Carlos , Malladi Venkat , D’Orso Iván 
Published: May 2020

ABSTRACTA large body of work has revealed fundamental principles of HIV-1 integration into the human genome. However, the effect of the integration site to proviral transcription activity has so far remained elusive. Here we combine open-source, large-scale datasets including epigenetics, transcriptome, and 3D genome architecture to interrogate the chromatin states, transcription activity landscape, and nuclear sub-compartments around HIV-1 integration sites in CD4+T cells to decipher human genome codes shaping the transcription of proviral classes defined based on their position and orientation in the genome. Using a Hidden Markov Model, we describe the importance of specific chromatin states and genome architecture in the control of HIV-1 transcription activity. Additionally, implementation of a machine-learning logistic regression model reveals upstream chromatin accessibility, transcription activity, and categorical nuclear sub-compartments as optimal features predicting HIV-1 transcriptional outcomes. We finally demonstrate clinical relevance by interrogating the positions of intact proviruses persisting in patients under suppressive therapy and provide a compass compatible with clinical decision-making.
Decreased investigatory head scanning during exploration in learning-impaired, aged rats
Authors: Rao Geeta , Lee Heekyung , Gallagher Michela , Knierim James J. 
Published: May 2020

Abstract“Head scanning” is an investigatory behavior that has been linked to spatial exploration and the one-trial formation or strengthening of place cells in the hippocampus. Previous studies have demonstrated that a subset of aged rats with normal spatial learning performance show head scanning rates during a novel, local-global cue-mismatch manipulation that are similar to those of young rats. However, these aged rats demonstrated different patterns of expression of neural activity markers in brain regions associated with spatial learning, perhaps suggesting neural mechanisms that compensate for age-related brain changes. These prior studies did not investigate the head scanning properties of aged rats that had spatial learning impairments. The present study analyzed head scanning behavior in young, aged-unimpaired, and aged-impaired Long Evans rats. Aged-impaired rats performed the head scan behavior at a lower rate than the young rats. These results suggest that decreased attention to spatial landmarks may be a contributing factor to the spatial learning deficits shown by the aged-impaired rats.
Model for Deformation of Cells from External Electric Fields at or Near Resonant Frequencies
Authors: Martinez L. , Dhruv A. , Lin L. , Balaras E. , Keidar M. 
Published: May 2020

AbstractThis paper presents a numerical model to investigate the deformation of biological cells by applying external electric fields operating at or near cell resonant frequencies. Cells are represented as pseudo solids with high viscosity suspended in liquid media. The electric field source is an atmospheric plasma jet developed inhouse, for which the emitted energy distribution has been measured.Viscoelastic response is resolved in the entire cell structure by solving a deformation matrix assuming an isotropic material with a prescribed modulus of elasticity. To investigate cell deformation at resonant frequencies, one mode of natural cell oscillation is considered in which the cell membrane is made to radially move about its eigenfrequency. An electromagnetic wave source interacts with the cell and induces oscillation and viscoelastic response. The source carries energy in the form of a distribution function which couples a range of oscillating frequencies with electric field amplitude.Results show that cell response may be increased by the external electric field operating at or near resonance. In the elastic regime, response increases until a steady threshold value, and the structure moves as a damped oscillator. Generally, this response is a function of both frequency and magnitude of the source, with a maximum effect found at resonance. To understand the full effect of the source energy spectrum, the system is solved by considering five frequency-amplitude couplings. Results show that the total solution is a nonlinear combination of the individual solutions. Additionally, sources with different signal phases are simulated to determine the effect of initial conditions on the evolution of the system, and the result suggests that there may be multiple solutions within the same order of magnitude for elastic response and velocity. Cell rupture from electric stress may occur during application given a high energy source.SignificanceCold atmospheric plasma jets (CAPJs) have been widely researched for their potential applications in cancer therapy. Existing research has focused mainly on the ability of CAPJs to deliver a mixture of reactive species which can be absorbed by cancer cells and induce cell death. The objective of our study is to investigate the mechanical effect of CAPJ electromagnetic (EM) waves on interacting cells. By coupling the EM waves associated with plasma frequency and cell viscoelastic response, we have developed a numerical tool to investigate cell damage either by mechanical or thermal loads. This work is motivated by the promise of EM waves to function as a sensitizing agent for cancer cells in preparation for chemotherapy.
Advancing the genetic utility of pre-clinical species through a high-quality assembly of the cynomolgus monkey (Macaca fascicularis) genome
Authors: Oziolor Elias , Sullivan Shawn , Mangelson Hayley , Eacker Stephen M. , Agostino Michael , Whiteley Laurence , Cook Jon , Koza-Taylor Petra 
Published: May 2020

AbstractThe cynomolgus macaque is a non-human primate model, heavily used in biomedical research, but with outdated genomic resources. Here we have used the latest long-read sequencing technologies in order to assemble a fully phased, chromosome-level assembly for the cynomolgus macaque. We have built a hybrid assembly with PacBio, 10x Genomics, and HiC technologies, resulting in a diploid assembly that spans a length of 5.1 Gb with a total of 16,741 contigs (N50 of 0.86Mb) contained in 370 scaffolds (N50 of 138 Mb) positioned on 42 chromosomes (21 homologous pairs). This assembly is highly homologous to former assemblies and identifies novel inversions and provides higher confidence in the genetic architecture of the cynomolgus macaque genome. A demographic estimation is also able to capture the recent genetic bottleneck in the Mauritius population, from which the sequenced individual originates. We offer this resource as an enablement for genetic tools to be built around this important model for biomedical research.