bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nucleocapsid-specific humoral responses improve the control of SARS-CoV-2
Authors: Dangi Tanushree , Sanchez Sarah , Park Mincheol , Class Jacob , Richner Michelle , Richner Justin M. , Penaloza-MacMaster Pablo 
Published: March 2022

SummaryThe spike protein of SARS-CoV-2 is a critical antigen present in all approved SARS-CoV-2 vaccines. This surface viral protein is also the target for all monoclonal antibody therapies, but it is unclear whether antibodies targeting other viral proteins can also improve protection against COVID-19. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice. On the next day, the recipient mice were challenged intranasally with SARS-CoV-2 to evaluate whether nucleocapsid-specific humoral responses affect viral control. Interestingly, mice that received nucleocapsid-specific sera exhibited enhanced control of a SARS-CoV-2 infection. These findings provide the first demonstration that humoral responses specific to an internal coronavirus protein can help clear infection, warranting the inclusion of other viral antigens in next-generation SARS-CoV-2 vaccines and providing a rationale for the clinical evaluation of nucleocapsid-specific monoclonals to treat COVID-19.HighlightsA SARS-CoV-2 nucleocapsid vaccine elicits robust nucleocapsid-specific antibody responses.This nucleocapsid vaccine generates memory B cells (MBC).Nucleocapsid-specific humoral responses do not prevent SARS-CoV-2 infection.Nucleocapsid-specific humoral responses help control a SARS-CoV-2 infection.
Profibrotic priming of airway cell types and drug responses in early-stage idiopathic pulmonary fibrosis
Authors: Chua Robert Lorenz , Veith Carmen , Schneider Marc A. , Jechow Katharina , Xu Elizabeth Chang , Kreuter Michael , Boots Agnes W. , Eils Roland , Kahn Nicolas C. , Conrad Christian 
Published: March 2022

AbstractEarly genetic studies hinted the role of airway epithelial cells in the development of idiopathic pulmonary fibrosis (IPF), while recent single-cell RNA sequencing (scRNA-seq) atlases utilized explant IPF lungs and therefore represent late-stage disease. Here, we used air liquid interface (ALI) cultures of primary cells taken from the subsegmental bronchi of newly diagnosed IPF patients, reflecting early-stage fibrosis, to interrogate the transcriptional landscape of the airway mucosa. Profiling of 129,986 cells identified a shared proinflammatory state in epithelial cells and an early activation state of fibroblasts. Moreover, IPF basal cells initiated awry repair mechanisms and primed the airway mucosa for TGF-β activation. Treatment with nintedanib, pirfenidone, both established antifibrotic drugs, and saracatinib, an Src kinase inhibitor that can limit IPF progression, only significantly affected certain IPF signatures. This study provides insight into the early disease mechanisms of IPF and may serve as a resource to further investigate pharmacological inhibition effects.
Neuron-derived Thioredoxin-80: a novel regulator of type-I interferon response in microglia
Authors: Goikolea Julen , Roussarie Jean-Pierre , Gerenu Gorka , Loera-Valencia Raul , Latorre-Leal Maria , Cedazo-Minguez Angel , Rodriguez-Rodriguez Patricia , Maioli Silvia 
Published: March 2022

AbstractOxidative stress and neuroinflammation play a central role in Alzheimer’s Disease (AD) pathogenesis. However, the mechanism by which these processes lead to neurodegeneration is still not fully understood. Thioredoxin-1 (Trx1) is an antioxidant protein that can be cleaved into a peptide known as Thioredoxin-80 (Trx80), which modulates monocyte function in the periphery and shows anti-amyloidogenic properties in the brain. In this study we aimed to further clarify the biological function of this peptide and its regulation in the brain. We show that neurons are the main producers of Trx80 in the brain. Trx80 levels increase in vivo both in normal aging and in young APPNL-G-F mouse model of amyloid pathology. Trx80 levels were increased in neurons in primary culture treated with either rotenone or 27-hydroxycholesterol, what suggests that Trx80 production is stimulated upon oxidative stress. RNA-sequencing followed by differential gene expression analysis revealed that Trx80 induces microglia activation into a phenotype compatible with interferon response microglia. Finally, we determine that the induction of this microglia phenotype by Trx80 is Trem2-dependent. This study identifies Trx80 as a novel neuron-derived signaling mechanism that modulates microglia function under stress conditions. Strategies to regulate Trx80 levels could be beneficial against AD pathology.
PCA outperforms popular hidden variable inference methods for molecular QTL mapping
Authors: Zhou Heather J. , Li Lei , Li Yumei , Li Wei , Li Jingyi Jessica 
Published: March 2022

AbstractEstimating and accounting for hidden variables is widely practiced as an important step in molecular quantitative trait locus (molecular QTL, henceforth “QTL”) analysis for improving the power of QTL identification. However, few benchmark studies have been performed to evaluate the efficacy of the various methods developed for this purpose. Here we benchmark popular hidden variable inference methods including surrogate variable analysis (SVA), probabilistic estimation of expression residuals (PEER), and hidden covariates with prior (HCP) against principal component analysis (PCA)—a well-established dimension reduction and factor discovery method—via 362 synthetic and 110 real data sets. We show that PCA not only underlies the statistical methodology behind the popular methods but is also orders of magnitude faster, better-performing, and much easier to interpret and use. To help researchers use PCA in their QTL analysis, we provide an R packagePCAForQTLalong with a detailed guide, both of which are freely available athttps://github.com/heatherjzhou/PCAForQTL.
Improved eukaryotic detection compatible with large-scale automated analysis of metagenomes
Authors: Bazant Wojtek , Blevins Ann S. , Crouch Kathryn , Beiting Daniel P. 
Published: March 2022

AbstractBackgroundEukaryotes such as fungi and protists frequently accompany bacteria and archaea in microbial communities. Unfortunately, their presence is difficult to study with ‘shotgun’ metagenomic sequencing since prokaryotic signals dominate in most environments. Recent methods for eukaryotic detection use eukaryote-specific marker genes, but they do not incorporate strategies to handle the presence of eukaryotes that are not represented in the reference marker gene set, and they are not compatible with web-based tools for downstream analysis.ResultsHere we present CORRAL (for Clustering□Of□Related Reference ALignments), a tool for identification of eukaryotes in shotgun metagenomic data based on alignments to eukaryote-specific marker genes and Markov clustering. Using a combination of simulated datasets, mock community standards, and large publicly available human microbiome studies, we demonstrate that our method is not only sensitive and accurate but is also capable of inferring the presence of eukaryotes notincluded in the marker gene reference, such as novel strains. Finally, we deploy CORRAL on ourMicrobiomeDB.orgresource, producing an atlas of eukaryotes present in various environments of the human body and linking their presence to study covariates.ConclusionsCORRAL allows eukaryotic detection to be automated and carried out at scale. Implementation of CORRAL inMicrobiomeDB.orgcreates a running atlas of microbial eukaryotes in metagenomic studies. Since our approach is independent of the reference used, it may be applicable to other contexts where shotgun metagenomic reads are matched against redundant but non-exhaustive databases, such as identification of bacterial virulence genes or taxonomic classification of viral reads.
Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain
Authors: Zhou Yu-Peng , Sun Yang , Takahashi Kazue , Belov Vasily , Andrews Nick , Woolf Clifford J. , Brugarolas Pedro 
Published: March 2022

ABSTRACTNeuropathic pain affects 7-10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of α2δ-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in α2δ-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two 18F-labeled derivatives of gabapentin (trans-4-[18F]fluorogabapentin and cis-4-[18F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the α2δ-1 receptor with trans-4-[18F]fluorogabapentin having a higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to α2δ-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that α2δ-1 is a promising target for imaging specific features of neuropathic pain.
The vigor paradox: saccade velocity during deliberation encodes utility of effortful actions
Authors: Korbisch Colin C. , Apuan Daniel R. , Shadmehr Reza , Ahmed Alaa A. 
Published: March 2022

AbstractDuring deliberation, as the brain considers its options, the neural activity representing the goodness of each option rises toward a threshold, and the choice is often dictated by the option for which the rise is fastest. Here we report a surprising correlate of these activities: saccade vigor. We engaged human subjects in a decision-making task in which they considered effortful options, each requiring walking various durations and inclines. As they deliberated, they made saccades between the symbolic representations of those options. These saccades had no bearing on the effort that they would later expend, yet as they deliberated, saccade velocities increased. The rate of rise in vigor was faster for saccades toward the option that they later indicated as their choice, and encoded the difference in the subjective value of the two effortful options. Once deliberation ended, following a brief delay the subjects indicated their choice by making another saccade. Remarkably, vigor for this saccade dropped to baseline and no longer encoded subjective value. These results are consistent with an urgency model of decision-making in which a global signal in the brain drives both the neural circuits that make decisions, and the neural circuits that make movements. Paradoxically, this common drive is shared between the oculomotor circuits and the decision-making circuits, even when the decision involves effortful expenditure during a future event.SignificanceThere is a link between the decisions we make and the movements that follow. Not only do we prefer options of greater value, but we also move faster to acquire them. When deliberating between options, neural activity rises to a threshold and the option that wins this race is the one chosen. We report a potential correlate of this in the motor control circuits; during deliberation, saccade vigor to both options rise, but faster for the option ultimately chosen. Thus, our movements appear to mirror the neural activity conducting the decision-making process. Paradoxically, this is true even when the movements have no direct bearing on the decision at hand.
NLGC: Network Localized Granger Causality with Application to MEG Directional Functional Connectivity Analysis
Authors: Soleimani Behrad , Das Proloy , Karunathilake I.M. Dushyanthi , Kuchinsky Stefanie E. , Simon Jonathan Z. , Babadi Behtash 
Published: March 2022

AbstractIdentifying the directed connectivity that underlie networked activity between different cortical areas is critical for understanding the neural mechanisms behind sensory processing. Granger causality (GC) is widely used for this purpose in functional magnetic resonance imaging analysis, but there the temporal resolution is low, making it difficult to capture the millisecond-scale interactions underlying sensory processing. Magnetoencephalography (MEG) has millisecond resolution, but only provides low-dimensional sensor-level linear mixtures of neural sources, which makes GC inference challenging. Conventional methods proceed in two stages: First, cortical sources are estimated from MEG using a source localization technique, followed by GC inference among the estimated sources. However, the spatiotemporal biases in estimating sources propagate into the subsequent GC analysis stage, may result in both false alarms and missing true GC links. Here, we introduce the Network Localized Granger Causality (NLGC) inference paradigm, which models the source dynamics as latent sparse multivariate autoregressive processes and estimates their parameters directly from the MEG measurements, integrated with source localization, and employs the resulting parameter estimates to produce a precise statistical characterization of the detected GC links. We offer several theoretical and algorithmic innovations within NLGC and further examine its utility via comprehensive simulations and application to MEG data from an auditory task involving tone processing from both younger and older participants. Our simulation studies reveal that NLGC is markedly robust with respect to model mismatch, network size, and low signal-to-noise ratio, whereas the conventional two-stage methods result in high false alarms and mis-detections. We also demonstrate the advantages of NLGC in revealing the cortical network-level characterization of neural activity during tone processing and resting state by delineating task- and age-related connectivity changes.
Electroencephalographic dynamics of rhythmic breath-based meditation
Authors: Tripathi Vaibhav , Bhasker Lakshmi , Kharya Chhaya , Bhatia Manvir , Kochupillai Vinod 
Published: March 2022

ABSTRACTMeditation has been practised for millennia but the neuroscientific understanding of the dynamics is still lacking. Sudarshan Kriya Yoga (SKY) is an evidence based breathing based meditation technique that utilizes rhythmic breathing to induce a deep state of relaxation and calm. Multiple studies have found benefits of the SKY technique from genetic, physiological, psychological to behaviour levels. We collected Electroencephalographic (EEG) data in 43 subjects who underwent the SKY technique and analysed the brain rhythms at different stages of the technique namely preparatory breathing (Pranayama), rhythmic breathing (Kriya) and meditation (Yoga Nidra) using newly developed methods to analyse periodic and aperiodic components. Alpha waves amplitude in the parieto-occipital region decreased as the rhythmic breathing progressed and dropped sharply during the meditation period. Theta amplitudes and peak frequency increased in the centro-frontal region during the rhythmic breathing period but were marked by sustained low theta waves during the meditation period. The delta wave amplitude was not affected by breathing but both delta band power and peak frequency increased during the meditation period in the centro-frontal region. We also saw a decrease in the 1/f aperiodic signal across the brain during the meditation period suggesting a modification of excitation-inhibition balance. We see an overall slowing down of brain oscillations from alpha to theta to delta as the meditation progressed. The paper studies in depth the transitional dynamics of the SKY technique analysing the alpha, theta, delta waves and aperiodic signals and demonstrates that each phase in a breathing based meditation has a unique electrophysiological signature.
Blockade of redox second messengers inhibits JAK/STAT and MEK/ERK signaling sensitizing FLT3-mutant acute myeloid leukemia to targeted therapies
Authors: Germon Zacary P. , Sillar Jonathan R. , Mannan Abdul , Duchatel Ryan J. , Staudt Dilana , Murray Heather C. , Findlay Izac J. , Jackson Evangeline R. , McEwen Holly P. , Douglas Alicia M. , McLachlan Tabitha , Schjenken John E. , Skerrett-Bryne David A. , Huang Honggang , Melo-Braga Marcella N. , Plank Maximilian W. , Alvaro Frank , Chamberlain Janis , Iuliis Geoff De , Aitken R. John , Nixon Brett , Wei Andrew H. , Enjeti Anoop K. , Lock Richard B. , Larsen Martin R. , Lee Heather , de Bock Charles E. , Verrills Nicole M. , Dun Matthew D. 
Published: March 2022

AbstractFLT3-mutations are diagnosed in 25-30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is associated with the overproduction of reactive oxygen species (ROS), which drives genomic instability through the oxidation of DNA bases, promoting clonal evolution, treatment resistance and poor outcomes. ROS are also important second messengers, triggering cysteine oxidation in redox sensitive signaling proteins, however, the specific pathways influenced by ROS in AML remain enigmatic. Here we have surveyed the posttranslational architecture of primary AML patient samples and assessed oncogenic second messenger signaling. Signaling proteins responsible for growth and proliferation were differentially oxidized and phosphorylated between patient subtypes either harboring recuring mutation in FLT3 compared to patients expressing the wildtype-FLT3 receptor, particularly those mapping to the Src family kinases (SFKs). Patients harboring FLT3-mutations also showed increased oxidative posttranslational modifications in the GTPase Rac activated-NADPH oxidase-2 (NOX2) complex to drive autocratic ROS production. Pharmacological and molecular inhibition of NOX2 was cytotoxic specifically to FLT3-mutant AMLs, and reduced phosphorylation of the critical hematopoietic transcription factor STAT5 and MAPK/ERK to synergistically increase sensitivity to FLT3-inhibitors. NOX2 inhibition also reduced phosphorylation and cysteine oxidation of FLT3 in patient derived xenograft mouse models in vivo, highlighting an important link between oxidative stress and oncogenic signaling. Together, these data raise the promising possibility of targeting NOX2 in combination with FLT3-inhibitors to improve treatment of FLT3-mutant AML.One Sentence SummaryFLT3-precision therapies have entered the clinic for AML however, their durability is limited. Here we identify the Rac-NOX2 complex as the major driver of redox second messenger signaling in FLT3-mutant AML. Molecular and pharmacological inhibition of NOX2 decreased FLT3, STAT5 and MEK/ERK signaling to delay leukemia progression, and synergistically combined with FLT3 inhibitors.
Cost-effectively dissecting the genetic architecture of complex wool traits in rabbits by low-coverage sequencing
Authors: Wang Dan , Xie Kerui , Wang Yanyan , Hu Jiaqing , Li Wenqiang , Zhang Qin , Ning Chao , Fan Xinzhong 
Published: March 2022

AbstractWool traits of rabbits are important in fiber production and model organism research on hair growth, while the genetic architecture remains obscure. In this study, we focused on wool characteristics in Angora rabbits, a well-known fiber breed. Balancing genotyping cost and variant detection, we proposed low-coverage whole genome sequencing (LCS) followed by genotype imputation for genotyping. Different genotype imputation strategies, sequencing coverages and sample sizes were compared, and we found by BaseVar + STITCH, genotyping reached high accuracy (>0.97) at a depth of 1.0X and a sample size > 300. Multivariate GWAS followed by conditional GWAS and confidence interval estimation of QTLs were used to reveal the genetic architecture of wool traits. Six QTLs were detected with phenotypic variation contribution ranging from 0.42% to 7.50%. Gene-level mapping implicated FGF10 associated with fiber growth and diameter, which supported previous function research on fibroblast growth factor family in other species and provided genetic information for wool rabbit breeding. We suggest LCS as a cost-effective alternative for assessing common variants. GWAS combined with LCS can excavate QTLs and fine-map genes associated with quantitative traits. This study provides a powerful analysis mentality for investigating complex traits, which lays the foundation for genomic breeding.
The maternal X chromosome impairs cognition and accelerates brain aging through epigenetic modulation in female mice
Authors: Abdulai-Saiku Samira , Gupta Shweta , Wang Dan , Moreno Arturo J. , Huang Yu , Srivastava Deepak , Panning Barbara , Dubal Dena B. 
Published: March 2022

SummaryFemale mammalian cells harbor two X chromosomes, one of maternal and one of paternal origin. During development, one X randomly inactivates1–4. This renders either the maternal or paternal X active, causing X mosaicism that varies among individual females, with some showing considerable or complete skew in the general female population5–7. Parent-of-X-origin can modify epigenetics via DNA methylation8, 9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in aging and disease. However, whether X skewing – or its mosaicism – alters functions in females is largely unknown. Here we tested whether skew toward the maternal X (Xm) influences key functions of the body. Among cardiac, bone, metabolic, and brain functions, Xm selectively impaired cognition in female mice throughout the lifespan. Cognitive deficits were accompanied by Xm-mediated acceleration of biologic or epigenetic aging of the female hippocampus, a key center for learning and memory. Xm showed epigenetic imprinting of several genes within hippocampal neurons, suggesting silenced cognitive loci. Thus, the maternal X chromosome impaired cognition, accelerated brain aging, and silenced genes. Understanding how the maternal X impairs brain function could lead to new understanding of female heterogeneity in cognitive heath and to X chromosome-derived pathways against cognitive deficits and brain aging.