bluuebunny/crossref_metadata_2025_split huggingface dataset:
Full-length optic nerve regeneration in the absence of genetic manipulations
Authors: Feng Qian , Wong Kimberly , Benowitz Larry I. 
Published: August 2022

SummaryThe inability of mature retinal ganglion cells (RGCs) to regenerate axons after optic nerve injury can be partially reversed by manipulating cell-autonomous and/or -non-autonomous factors, among which are neuroimmune interactions. We report here that preconditioning resulting from a mild lens injury (conditioning LI, cLI) prior to optic nerve damage induces far greater axon regeneration than LI or the pro-inflammatory agent zymosan after nerve injury or preconditioning with Zymosan. Unlike other instances of immune-supported regeneration, cLI is unaltered by depleting mature neutrophils, T cells or blocking receptors for identified inflammation-associated growth factors (Oncomodulin, SDF1, CCL5), and is only partially diminished by suppressing peripheral monocyte recruitment. Repeated LI leads to full-length optic nerve regeneration, and pharmacological removal of local resident macrophages with the colony stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 enables some axons to re-innervate the brain in just 6 weeks. Thus, cell non-autonomous interventions not involving genetic manipulations can induce high levels of optic nerve regeneration, paving the way to uncover potent, translatable therapeutic targets for CNS repair.
Imputed genomes and haplotype-based analyses of the Picts of early medieval Scotland reveal fine-scale relatedness between Iron Age, early medieval and the modern people of the UK
Authors: Morez Adeline , Britton Kate , Noble Gordon , Günther Torsten , Götherström Anders , Rodríguez-Varela Ricardo , Kashuba Natalija , Martiniano Rui , Talamo Sahra , Evans Nicholas J. , Irish Joel D. , Donald Christina , Girdland-Flink Linus 
Published: August 2022

AbstractThe origins and ancestry of the Picts of early medieval Scotland (ca. AD 300-900) has been traditionally seen as a problem, prompted in part by exotic medieval origin myths, their enigmatic symbols and inscriptions, and the meagre textual evidence. The Picts, first mentioned in the late 3rd century AD resisted the Romans and went on to form a powerful kingdom that ruled over a large territory in northern Britain. In the 9th and 10th centuries Gaelic language, culture and identity became dominant, transforming the Pictish realm into Alba, the precursor to the medieval kingdom of Scotland. To date, no comprehensive analysis of Pictish genomes has been published, and questions about their biological relationships to other cultural groups living in Britain remain unanswered. Here we present two high-quality Pictish genomes (2.4 and 16.5X coverage) from central and northern Scotland dated from the 5th-7th century which we impute and co-analyse with >8,300 previously published ancient and modern genomes. Using allele frequency and haplotype-based approaches, we can firmly place the Pictish genomes within the Iron Age gene pool in Britain and demonstrate local biological affinity. We also demonstrate the presence of population structure within Pictish groups, with Orcadian Picts being genetically distinct from their mainland contemporaries. When investigating Identity-By-Descent (IBD) with present-day genomes, we observe broad affinities between the mainland Pictish genomes and the present-day people living in western Scotland, Wales, Northern Ireland and Northumbria, but less with the rest of England, the Orkney islands and eastern Scotland - where the political centres of Pictland were located. The pre-Viking Age Orcadian Picts evidence a high degree of IBD sharing across modern Scotland, Wales, Northern Ireland, and the Orkney islands, demonstrating substantial genetic continuity in the Orkney for the last ~2,000 years. Analysis of mitochondrial DNA diversity at the Pictish cemetery of Lundin Links (n = 7) reveals absence of female endogamy, with implications for broader social organisation. Overall, our study provides novel insights into the genetic affinities and population structure of the Picts and direct relationships between ancient and present-day groups of the UK.
ADrosophilaglial cell atlas reveals a mismatch between detectable transcriptional diversity and morphological diversity
Authors: Lago-Baldaia Inês , Cooper Maia , Seroka Austin , Trivedi Chintan , Powell Gareth T. , Wilson Stephen , Ackerman Sarah D. , Fernandes Vilaiwan M. 
Published: August 2022

AbstractMorphology is a defining feature of neuronal identity. Like neurons, glia display diverse morphologies, both across and within glial classes, but are also known to be morphologically plastic. Here, we explored the relationship between glial morphology and transcriptional signature using theDrosophilacentral nervous system, where glia are categorized into five main classes (outer and inner surface glia, cortex glia, ensheathing glia, and astrocytes), which show within-class morphological diversity. We analysed and validated single cell RNA sequencing data ofDrosophilaglia in two well-characterized tissues from distinct developmental stages, containing distinct circuit types: the embryonic ventral nerve cord (motor) and the adult optic lobes (sensory). Our analysis identified a new morphologically and transcriptionally distinct surface glial population in the ventral nerve cord. However, many glial morphological categories could not be distinguished transcriptionally, and indeed, embryonic and adult astrocytes were transcriptionally analogous despite differences in developmental stage and circuit type. While we did detect extensive within-class transcriptomic diversity for optic lobe glia, this could be explained entirely by glial residence in the most superficial neuropil (lamina) and an associated enrichment for immune-related gene expression. In summary, we generated a single-cell transcriptomic atlas of glia inDrosophila, and our extensivein vivovalidation revealed that glia exhibit more diversity at the morphological level than was detectable at the transcriptional level. This atlas will serve as a resource for the community to probe glial diversity and function.
YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth
Authors: Zhuo Shu , Li Xu , Cho Yong Suk , Liu Yuchen , Yang Yingzi , Zhu Jian , Jiang Jin 
Published: August 2022

AbstractHippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ-TEAD transcriptional complex. Here we uncover a context-dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR+ PCa growth by antagonizing TEAD-mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR-TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of Hippo/MST1/2 kinase or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR+ PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants.YAP acts as a context-dependent tumor suppressor in AR+ PCaTEAD interacts with AR to enhance its promoter/enhancer occupancyYAP inhibits AR activity by competing for TEAD bindingSmall molecule Hippo pathway inhibitor impedes AR+ PCa growth
Analysis of Lower-Grade Gliomas in MRI Through Segmentation and Genomic Cluster-Shape Feature Correlation
Authors: Paradkar Rohit , Paradkar Ria 
Published: August 2022

AbstractGliomas, which originate from glial cells, are considered the most aggressive type of brain tumors. Currently, glioma research efforts are focused mainly on high-grade gliomas. This project aims to analyze lower-grade gliomas (LGG) in MRI and extend the understanding of LGGs. LGG segmentation, which outlines tumors in MRIs, is crucial to developing effective treatment plans. However, segmentation performed manually by radiologists is tedious, time-consuming, and often leads to inter-observer variability. Another unexplored area of LGG research is genomic subtypes. These subtypes can play a large factor in how LGGs can be treated, however there is currently no noninvasive method of identifying these subtypes. Recent studies suggest that LGG shape features have a correlation with genomic subtypes and should be investigated as a viable factor in LGG treatment options. This presents a need for additional research as most LGGs eventually develop into high-grade gliomas. The specific aims of this project include analyzing LGGs through deep learning-based segmentation, shape feature extraction, and statistical analysis to identify correlation between selected shape features and genomic subtypes. To realize these goals, programs were written and run using a publicly available LGG dataset. In terms of automatic segmentation, two models were created using different convolutional neural networks (CNN). The highest performing model used U-Net with a ResNeXt-50 backbone and yielded a 91.4% accuracy in terms of mean intersection over union (IoU) after testing. Shape feature extraction included three geometric features and 4 radiomic features which quantified tumor shape in 2D and 3D. Angular Standard Deviation (ASD), Margin Fluctuation (MF), Bounding Ellipsoid Volume Ratio (BEVR), Elongation, Major and Minor Axis Length, and Volume were tested for correlation with genomic subtype data using 49 Pearson’s chi-squared tests. P-values less than or equal to 0.05 suggested correlation. Statistical analysis found 16 statistically significant associations. The strongest associations were between MF and the RNASeq cluster (p < 0.00003), ASD and the RNASeq Cluster (p < 0.0005), and volume and the RPPA cluster (p < 0.0035).
Detection of alternative isoforms of gene fusions from long-read RNA-seq with FLAIR-fusion
Authors: Felton Colette , Tang Alison D , Knisbacher Binyamin A , Wu Catherine J , Brooks Angela N 
Published: August 2022

AbstractGene fusions are important cancer drivers and drug targets, but are difficult to reliably identify with short-read RNA-sequencing. Long-read RNA sequencing data are more likely to span a fusion breakpoint and provide more sequence context around the breakpoint. This allows for more reliable identification of gene fusions and for detecting alternative splicing in gene fusions. Notably, alternative splicing of fusions has been shown to be a mechanism for drug resistance and altered levels of oncogenicity. Here, we present FLAIR-fusion, a computational tool to identify gene fusions and their isoforms from long-read RNA-sequencing data. FLAIR-fusion can detect fusions and their isoforms with high precision and recall, even with error-prone reads. We also investigated different library preparation methods and found that direct-cDNA has a higher incidence of artifactual chimeras than direct-RNA and PCR-cDNA methods. FLAIR-fusion is able to filter these technical artifacts from all of these library prep methods and consistently identify known fusions and their isoforms across cell lines. We ran FLAIR-fusion on amplicon sequencing from multiple tumor samples and cell lines and detected alternative splicing in the previously validated fusionGUCYA2-PIWIL4,which shows that long-read sequencing can detect novel splicing events from cancer gene panels. We also detect fusion isoforms from long-read sequencing in chronic lymphocytic leukemias with the splicing factor mutationSF3B1 K700E, and find that up to 10% of gene fusions had more than one unique isoform. We also compared long-read fusion detection tools with short-read fusion detection tools on the same samples and found greater consensus in the long-read tools. Our results demonstrate that gene fusion isoforms can be effectively detected from long-read RNA-sequencing and are important in the characterization of the full complexity of cancer transcriptomes.
Polymorphic short tandem repeats make widespread contributions to blood and serum traits
Authors: Margoliash Jonathan , Fuchs Shai , Li Yang , Zhang Xuan , Massarat Arya , Goren Alon , Gymrek Melissa 
Published: August 2022

AbstractShort tandem repeats (STRs), genomic regions each consisting of a sequence of 1-6 base pairs repeated in succession, represent one of the largest sources of human genetic variation. However, many STR effects are not captured well by standard genome-wide association studies (GWAS) or downstream analyses that are mostly based on single nucleotide polymorphisms (SNPs). To study the involvement of STRs in complex traits, we imputed genotypes for 445,720 autosomal STRs into genotype array data from 408,153 White British UK Biobank participants and tested for association with 44 blood and serum biomarker phenotypes. We used two fine-mapping methods, SuSiE and FINEMAP, to identify 119 high-confidence STR-trait associations across 93 unique STRs predicted as causal variants under all fine-mapping settings tested. Using these results, we estimate that STRs account for 5.2-7.6% of causal variants identifiable from GWAS signals for these traits. Our high confidence STR-trait associations implicate STRs in some of the strongest hits for multiple phenotypes, including a CTG repeat inAPOBassociated with circulating apolipoprotein B levels, a CGG repeat in the promoter ofCBLassociated with multiple platelet traits and a poly-A repeat inTAOK1associated with mean platelet volume. Replication analyses in additional population groups and orthogonal expression data further support the role of a subset of the candidate STRs we identify. Together, our study suggests that polymorphic tandem repeats make widespread contributions to complex traits, provides a set of stringently selected candidate causal STRs, and demonstrates the need to routinely consider a more complete view of human genetic variation in GWAS.
Alveolar macrophage lipid burden correlates with clinical improvement in patients with Pulmonary Alveolar Proteinosis
Authors: Lee Elinor , Williams Kevin J. , McCarthy Cormac , Bridges James P. , Redente Elizabeth F. , de Aguiar Vallim Thomas Q. , Wang Tisha , Tarling Elizabeth J. 
Published: August 2022

AbstractPulmonary alveolar proteinosis (PAP) is a life-threatening rare lung syndrome characterized by the accumulation of surfactant and lipid-loaded macrophages within the alveoli for which there is no cure and no approved therapies. The clinical diagnosis of PAP, often made by invasive lung biopsies and/or cytology of bronchoalveolar lavage fluid does not identify the underlying cause of disease. In addition, no biomarkers exist to inform prognosis or therapeutic options in PAP. We now report on the use of comprehensive mass spectrometry to profile and define the lipid signature of alveolar macrophages obtained from PAP patients. In addition, we quantify how these macrophage-associated lipids change during clinical treatment. Our studies demonstrate that clinical improvement in treated PAP patients is associated with a decrease in total lipid content, indicating that levels of these macrophage-associated lipids correlate with the severity of the disease.
RELIEF: a structured multivariate approach for removal of latent inter-scanner effects
Authors: Zhang Rongqian , Oliver Lindsay D. , Voineskos Aristotle N. , Park Jun Young 
Published: August 2022

AbstractCombining data collected from multiple study sites is becoming common and is advantageous to researchers to increase the generalizability and replicability of scientific discoveries. However, at the same time, unwantedinter-scanner biasesare commonly observed across neuroimaging data collected from multiple study sites or scanners, rendering difficulties in integrating such data to obtain reliable findings. While several methods for handling such unwanted variations have been proposed, most of them use univariate approaches that could be too simple to capture all sources of scanner-specific variations. To address these challenges, we propose a novel multivariate harmonization method, called RELIEF (REmoval ofLatentInter-scannerEffects throughFactorization) for estimating and removing both explicit and latent scanner effects. Our method is the first approach to introduce the simultaneous dimension reduction and factorization of interlinked matrices to a data harmonization context, which provides a new direction in methodological research for correcting inter-scanner biases. Analyzing diffusion tensor imaging (DTI) data from the Social Processes Initiative in Neurobiology of the Schizophrenia (SPINS) study and conducting extensive simulation studies, we show that RELIEF outperforms existing harmonization methods in mitigating inter-scanner biases and retaining biological associations of interest to increase statistical power. RELIEF is publicly available as an R package.
Recovery of forearm and fine digit function after chronic spinal cord injury by simultaneous blockade of inhibitory matrix CSPG production and the receptor PTPσ
Authors: Milton Adrianna J. , Silver Daniel J. , Kwok Jessica , McClellan Jacob , Warren Philippa M. , Silver Jerry 
Published: August 2022

AbstractSpinal cord injuries, for which there are limited effective clinical treatments, result in enduring paralysis and hypoesthesia due, in part, to the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic modulation of the potently inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) can rapidly restore robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited rapid, albeit modest, improvements in upper arm function. In the present study, we sought to further optimize and elucidate the capacity for nerve sprouting and/or regeneration to restore gross as well as fine motor control of the forearm and digits at lengthy chronic stages post injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic, non-invasive combinatorial treatment strategy designed to both reduce and overcome inhibitory CSPGs simultaneously and spatially extensively. Following a three-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment has a profound effect on functional recovery of the chronically paralyzed forelimb and paw, specifically during walking as well as precision movements of the digits. Our exciting pre-clinical findings will begin to enhance our understanding of the basic mechanisms underlying functionally beneficial regenerative events occurring at chronic injury stages for clinically relevant translational benefits.Significance statementOvercoming the persistent axon inhibitory environment following a functionally debilitating incomplete spinal cord lesion has long proven to be an elusive dilemma, especially months to years after the initial spinal injury. Current therapeutic and rehabilitative techniques for patients suffering from chronic cervical spinal insults minimally, if at all, address this structural hindrance and support limited return of crucial behaviors such as voluntary use of the arms and hands. Our investigation into the behavioral and anatomical consequences of systemically perturbing the high-affinity binding interaction between the receptor PTPσ and the extracellular chondroitin sulfate proteoglycans highlight an underlying barrier to the restoration of forelimb/paw walking and eating behavior 12-weeks after a cervical spinal hemi-transection.
Characterization of enhancer fragments in Drosophila robo2
Authors: Hauptman Gina , Reichert Marie C. , Abdal Rhida Muna A. , Evans Timothy A. 
Published: August 2022

AbstractReceptor proteins of the Roundabout (Robo) family regulate axon guidance decisions during nervous system development. Among the three Drosophila robo family genes (robo1, robo2, and robo3), robo2 displays a dynamic expression pattern and regulates multiple axon guidance outcomes, including preventing midline crossing in some axons, promoting midline crossing in others, forming lateral longitudinal axon pathways, and regulating motor axon guidance. The identity and location of enhancer elements regulating robo2’s complex and dynamic expression pattern in different neural cell types are unknown. Here, we characterize a set of 17 transgenic lines expressing GAL4 under the control of DNA sequences derived from noncoding regions in and around robo2, to identify enhancers controlling specific aspects of robo2 expression in the embryonic ventral nerve cord. We identify individual fragments that confer expression in specific cell types where robo2 is known to function, including early pioneer neurons, midline glia, and lateral longitudinal neurons. Our results indicate that robo2’s dynamic expression pattern is specified by a combination of enhancer elements that are active in different subsets of cells. We show that robo2’s expression in lateral longitudinal axons represents two genetically separable subsets of neurons, and compare their axon projections with each other and with Fasciclin II (FasII), a commonly used marker of longitudinal axon pathways. In addition, we provide a general description of each fragment’s expression in embryonic tissues outside of the nervous system, to serve as a resource for other researchers who may be interested in robo2 expression and its functional roles outside the CNS.