bluuebunny/crossref_metadata_2025_split huggingface dataset:
Naught all zeros in sequence count data are the same
Authors: Silverman Justin D. , Roche Kimberly , Mukherjee Sayan , David Lawrence A. 
Published: November 2018

AbstractGenomic studies feature multivariate count data from high-throughput DNA sequencing experiments, which often contain many zero values. These zeros can cause artifacts for statistical analyses and multiple modeling approaches have been developed in response. Here, we apply common zero-handling models to gene-expression and microbiome datasets and show models disagree on average by 46% in terms of identifying the most differentially expressed sequences. Next, to rationally examine how different zero handling models behave, we developed a conceptual framework outlining four types of processes that may give rise to zero values in sequence count data. Last, we performed simulations to test how zero handling models behave in the presence of these different zero generating processes. Our simulations showed that simple count models are sufficient across multiple processes, even when the true underlying process is unknown. On the other hand, a common zero handling technique known as “zero-inflation” was only suitable under a zero generating process associated with an unlikely set of biological and experimental conditions. In concert, our work here suggests several specific guidelines for developing and choosing state-of-the-art models for analyzing sparse sequence count data.
miR-425 suppresses EMT and inhibits the development of TNBC (triple-negative breast cancer) by targeting TGF-β 1/SMAD 3 signaling pathway
Authors: Liu Yingping , Qiao Hongfei , Chen Jinglong 
Published: November 2018

AbstractBackgroundEMT has the crucial effect on the progression and metastasis of tumor. This work will elucidate the role of miR-425 in EMT and development of TNBC.MethodsThe differential miRNA expression among non-tumor, para-tumor (adjacent tissue of tumor) and tumor tissues was analyzed. The luciferase activities of TGF-β1 3’ UTR treated with miR-425 were determined. Then human breast cancer cell lines were dealt with mimics or inhibitors of miR-425, and then the cell proliferation and migration, invasion ability were assessed. The expression of TGF-β1 and markers of epithelial cell and mesenchymal cell were analyzed. The influences of miR-425 on development of TNBC through inducing EMT by targeting TGF-β 1 and TGF-β1/SMAD3 signaling pathway in TNBC cell lines were investigated. Furthermore, Xenograft mice were used to explore the potential roles of miR-425 on EMT and development of TNBC in vivo.ResultsCompared with non-tumor tissues, 9 miRNAs were upregulated and 3 miRNAs were down-regulated in tumor tissues. The relative expression of miR-425 in tumor tissues was obviously much lower than that in para-tumor and non-tumor tissues. MiR-425 suppressed TGF-β1 expression, additionally inhibited expression of mesenchymal cell markers, while exerted effects on cell proliferation and migration of TNBC cell lines. Moreover, the agomir of miR-425 could protect against development process in murine TNBC xenogarft model.ConclusionsOur results demonstrated that miR-425 targets to TGF-β1, and was a crucial suppressor on EMT and development of TNBC through inhibiting TGF-β1/SMAD3 signaling pathway. It suggested that aim at TGF-β1/SMAD3 signaling pathway by enhancing relative miR-425 expression, was a feasible therapy strategy for TNBC.
Quantitative Analysis Reveals Reciprocal Regulations Underlying Recovery Dynamics of Thymocytes and Thymic Environment
Authors: Kaneko Kazumasa B. , Tateishi Ryosuke , Miyao Takahisa , Akiyama Nobuko , Yokota Ryo , Akiyama Taishin , Kobayashi Tetsuya J. 
Published: November 2018

AbstractThymic crosstalk, a set of reciprocal regulations between thymocytes and thymic environment, is relevant for orchestrating the appropriate development of thymocytes as well as the recovery of the thymus from various exogenous insults. Nevertheless, the dynamic and regulatory aspects of the thymic crosstalk have not yet been clarified. In this work, we inferred the interactions shaping the thymic crosstalk and its resultant dynamics between the thymocytes and the thymic epithelial cells (TECs) by quantitative analysis and modelling of the recovery dynamics induced by irradiation. The analysis identified regulatory interactions consistent with the known molecular evidence and revealed their dynamic roles in the recovery process. Moreover, the analysis also predicted, and a subsequent experiment verified a new regulation of CD4+CD8+ double positive (DP) thymocytes, which temporarily increases their proliferation rate upon the decrease in their population size. Our model established the pivotal step towards a dynamic understanding of the thymic crosstalk as a regulatory network system.
Selection at behavioral, developmental and metabolic genes is associated with the northward expansion of a successful tropical colonizer
Authors: Bourgeois Yann , Boissinot Stéphane 
Published: November 2018

AbstractWhat makes a species able to colonize novel environments? This question is key to understand the dynamics of adaptive radiations and ecological niche shifts, but the mechanisms that underlie expansion into novel habitats remain poorly understood at a genomic scale. Lizards from the genusAnolisare typically tropical and the green anole(Anolis carolinensis)constitutes an exception since it expanded into temperate North America from subtropical Florida. Thus, we used the green anole as a model to investigate signatures of selection associated with colonization of a new environment, namely temperate North America. To this end, we analyzed 29 whole genome sequences, representing the entire genetic diversity of the species. We used a combination of recent methods to quantify both positive and balancing selection in northern populations, including FSToutlier methods, machine learning and ancestral recombination graphs. We naively scanned for genes of interest and assessed the overlap between multiple tests. Strikingly, we identified many genes involved in behavior, suggesting that the recent successful colonization of northern environments may have been linked to behavioral shifts as well as physiological adaptation. These results were robust to recombination, gene length and clustering. Using a candidate genes strategy, we determined that genes involved in response to cold or behavior displayed more frequently signals of selection, while controlling for local recombination rate and gene length. In addition, we found signatures of balancing selection at immune genes in all investigated genetic groups, but also at genes involved in neuronal and anatomical development in Florida.
Deciphering the Regulatory Landscape of γδ T Cell Development by Single-Cell RNA-Sequencing
Authors: Sagar  , Pokrovskil Maria , Herman Josip S. , Naik Shruti , Sock Elisabeth , Lausch Ute , Wegner Michael , Tanriver Yakup , Littman Dan R. , Grün Dominic 
Published: November 2018

SUMMARYRecent studies have established γδ T cells as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases and tissue homeostasis. However, differentiation of γδ T cells in the adult thymus remains poorly understood, due to the rare frequency of this lineage. Here, we infer high-resolution developmental trajectories of this rare population by single-cell RNA-sequencing. We reveal previously unknown subtypes and identify the transcription factor c-MAF as a novel key regulator of IL-17-producing γδ T cell (γδT17) differentiation. c-MAF knockout mice exhibit a complete block in γδT17 differentiation, absence of these cells from peripheral organs, and protection from an autoimmune phenotype in a psoriasis model. Single-cell RNA-sequencing of Sox13 and Rorc knockout mice pinpoints c-MAF as an essential missing link between these lineage-specifying factors. These findings significantly enhance our understanding of γδ T cell ontogeny. Our experimental strategy provides a blueprint for deciphering differentiation of rare cell types.
Learning probabilistic representations with randomly connected neural circuits
Authors: Maoz Ori , Tkacčik Gašper , Esteki Mohamad Saleh , Kiani Roozbeh , Schneidman Elad 
Published: November 2018

AbstractThe brain represents and reasons probabilistically about complex stimuli and motor actions using a noisy, spike-based neural code. A key building block for such neural computations, as well as the basis for supervised and unsupervised learning, is the ability to estimate the surprise or likelihood of incoming high-dimensional neural activity patterns. Despite progress in statistical modeling of neural responses and deep learning, current approaches either do not scale to large neural populations or cannot be implemented using biologically realistic mechanisms. Inspired by the sparse and random connectivity of real neuronal circuits, we present a new model for neural codes that accurately estimates the likelihood of individual spiking patterns and has a straightforward, scalable, efficiently learnable, and realistic neural implementation. This model’s performance on simultaneously recorded spiking activity of >100 neurons in the monkey visual and prefrontal cortices is comparable or better than that of current models. Importantly, the model can be learned using a small number of samples, and using a local learning rule that utilizes noise intrinsic to neural circuits. Slower, structural changes in random connectivity, consistent with rewiring and pruning processes, further improve the efficiency and sparseness of the resulting neural representations. Our results merge insights from neuroanatomy, machine learning, and theoretical neuroscience to suggest random sparse connectivity as a key design principle for neuronal computation.
Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei
Authors: Jiang Shan , Williams Katherine , Kong Xiangduo , Zeng Weihua , Ma Xinyi , Tawil Rabi , Yokomori Kyoko , Mortazavi Ali 
Published: November 2018

AbstractFSHD is characterized by the misexpression of DUX4 in skeletal muscle. However, DUX4 is lowly expressed in patient samples and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed pooled RNA-seq differentiation time-course in FSHD2 patient-derived primary myoblasts and identified early-and late-induced sets of FSHD-associated genes. Using single-cell and single-nucleus RNA-seq on FSHD2 myoblasts and myotubes respectively, we captured DUX4 expression in single-nuclei and found that only some DUX4 targets are coexpressed. We identified two populations of FSHD myotube nuclei with distinct transcriptional profiles. One population is highly enriched with DUX4 and FSHD related genes, including the DUX4 paralog DUXA (“FSHD-Hi”). The other population has no expression of DUX4 and expresses low amounts of FSHD related genes (“FSHD-Lo”), but is marked by the expression of CYTL1 and CHI3L1. “FSHD-Hi” myotube nuclei upregulated a set of transcription factors (TFs) that may form a self-sustaining network of gene dysregulation, which perpetuates this disease after DUX4 is no longer expressed.
Speech Synthesis from ECoG using Densely Connected 3D Convolutional Neural Networks
Authors: Angrick Miguel , Herff Christian , Mugler Emily , Tate Matthew C. , Slutzky Marc W. , Krusienski Dean J. , Schultz Tanja 
Published: November 2018

AbstractObjectiveDirect synthesis of speech from neural signals could provide a fast and natural way of communication to people with neurological diseases. Invasively-measured brain activity (electrocorticography; ECoG) supplies the necessary temporal and spatial resolution to decode fast and complex processes such as speech production. A number of impressive advances in speech decoding using neural signals have been achieved in recent years, but the complex dynamics are still not fully understood. However, it is unlikely that simple linear models can capture the relation between neural activity and continuous spoken speech.ApproachHere we show that deep neural networks can be used to map ECoG from speech production areas onto an intermediate representation of speech (logMel spectrogram). The proposed method uses a densely connected convolutional neural network topology which is well-suited to work with the small amount of data available from each participant.Main resultsIn a study with six participants, we achieved correlations up tor= 0.69 between the reconstructed and original logMel spectrograms. We transfered our prediction back into an audible waveform by applying a Wavenet vocoder. The vocoder was conditioned on logMel features that harnessed a much larger, pre-existing data corpus to provide the most natural acoustic output.SignificanceTo the best of our knowledge, this is the first time that high-quality speech has been reconstructed from neural recordings during speech production using deep neural networks.
Quantitative PCR provides a simple and accessible method for quantitative microbiome profiling
Authors: Jian Ching , Luukkonen Panu , Yki-Järvinen Hannele , Salonen Anne , Korpela Katri 
Published: November 2018

AbstractThe use of relative next generation sequencing (NGS) abundance data can lead to misinterpretations of microbial community structures as the increase of one taxon leads to concurrent decrease of the other(s). To overcome compositionality, we provide a quantitative NGS solution, which is achieved by adjusting the relative 16S rRNA gene amplicon NGS data with quantitative PCR (qPCR-based) total bacterial counts. By comparing the enumeration of dominant bacterial groups on different taxonomic levels in human fecal samples using taxon-specific 16S rRNA gene-targeted qPCR we show that quantitative NGS is able to estimate absolute bacterial abundances accurately. We also observed a higher degree of correspondence in the estimated microbe-metabolite relationship when quantitative NGS was applied. Being conceptually and methodologically analogous to amplicon-based NGS, our qPCR-based method can be readily incorporated into the standard, high-throughput NGS sample processing pipeline for more accurate description of interactions within and between the microbes and host.
BAPC-assistedCRISPR/Cas9 System: Targeted Delivery into Adult Ovaries for Heritable Germline Gene Editing (Arthropoda: Hemiptera)
Authors: Hunter Wayne B. , Gonzalez Maria T. , Tomich John 
Published: November 2018

ABSTRACTInnovative gene targeting strategies are often limited in application across arthropod species due to problems with successful delivery. In hemipterans, embryonic injections often used to deliver CRISPR components fail due to nearly complete embryo mortality. The Asian citrus psyllid,Diaphorina citri, Kuwayama, (Hemiptera: Liviidae), is the vector for a pathogenic bacterium,CandidatusLiberibacter asiaticus, CLas, which is devastating the U.S. citrus industries. The disease called, Huanglongbing, HLB, (aka. Citrus greening disease), is transmitted during psyllid feeding. Infection causes severe tree decline, loss of fruits, and eventually tree death. The citrus tree pathogen, CLas, is a fastidious alpha-proteobacterium, which has spread into all citrus growing regions worldwide. The economic losses are estimated in the billions of dollars, in U.S.A., Brazil, and China. Innovative technologies aimed at reducing psyllid populations using targeting RNA suppression, like RNAi, or gene-editing tools, like CRISPR/Cas9 have potential to reduce psyllid vectors and the pathogen in a highly specific manner. Breakthroughs that improve gene editing in psyllids, such as theBAPC-assisted-CRISPR/Cas9 System, enabled delivery by injection of CRISPR/Cas9 components directly into nymphs and adult females. Injection near ovaries produced heritable germline gene editing in subsequent generations. This method opens the world of gene editing across arthropods and bypasses the need for microinjection of eggs. Effective development of therapeutic treatments to reduce insect vectors, and stop pathogen transmission would provide sustainable citrus and grapevine industries.
Induction of Interferon-Stimulated Genes and Cellular Stress Pathways by Morpholinos
Authors: Lai Jason K.H. , Gagalova Kristina , Stainier Didier Y.R. 
Published: November 2018

AbstractThe phenotypes caused by morpholino-mediated interference of gene function in zebrafish are often not observed in the corresponding mutant(s). We took advantage of the availability of a relatively large collection of transcriptomic datasets to identify common signatures that characterize morpholino-injected animals (morphants). In addition to the previously reported activation of tp53 expression, we observed increased expression of the interferon-stimulated genes (ISGs), isg15 and isg20, an extrinsic cell death pathway gene, casp8, and other cellular stress response genes including phlda3, mdm2 and gadd45aa. Studies involving segmentation stage embryos were more likely to show upregulation of these genes. We also found that these genes could be upregulated by an increasing dose of egfl7 morpholino, or high doses of standard control morpholino. Thus, these data suggest that morpholinos can stimulate the innate immune response in zebrafish, as was recently reported in Xenopus.
661W photoreceptor cell line as a cell model for studying retinal ciliopathies
Authors: Wheway Gabrielle , Nazlamova Liliya , Turner Dann , Cross Stephen 
Published: November 2018

AbstractThe retina contains several ciliated cell types, including the retinal pigment epithelium (RPE) and photoreceptor cells. The photoreceptor cilium is one of the most highly modified sensory cilia in the human body. The outer segment of the photoreceptor is a highly elaborate primary cilium, containing stacks or folds of membrane where the photopigment molecules are located. Perhaps unsurprisingly, defects in cilia often lead to retinal phenotypes, either as part of syndromic conditions involving other organs, or in isolation in the so-called retinal ciliopathies.The study of retinal ciliopathies has been limited by a lack of retinal cell lines. RPE1 retinal pigment epithelial cell line is commonly used in such studies, but the existence of a photoreceptor cell line has largely been neglected in the retinal ciliopathy field. 661W cone photoreceptor cells, derived from mouse, have been widely used as a model for studying macular degeneration, but not described as a model for studying retinal ciliopathies such as retinitis pigmentosa.Here, we characterise the 661W cell line as a model for studying retinal ciliopathies. We fully characterise the expression profile of these cells over many passages, using whole transcriptome RNA sequencing, and provide this data on Gene Expression Omnibus (GEO) for the advantage of the scientific community. We show that these cells robustly express the majority of markers of cone cell origin, including short wave and medium wave opsin. Western blotting confirms expression of selected markers.Using immunostaining and confocal microscopy, alongside scanning electron microscopy, we show that these cells grow long primary cilia, reminiscent of photoreceptor outer segments, and localise many cilium proteins to the axoneme, membrane and transition zone. Immunostaining shows that opsins are localised to the base of this primary cilium. We show that siRNA knockdown of cilia genes Ift88 results in loss of cilia, and that this can be assayed by high-throughput screening. We present evidence that the 661W cell line is a useful cell model for studying retinal ciliopathies.
Expression variation analysis for tumor heterogeneity in single-cell RNA-sequencing data
Authors: Davis-Marcisak Emily F. , Orugunta Pranay , Stein-O’Brien Genevieve , Puram Sidharth V. , Torres Evanthia Roussos , Hopkins Alexander , Jaffee Elizabeth M. , Favorov Alexander V. , Afsari Bahman , Goff Loyal A. , Fertig Elana J. 
Published: November 2018

ABSTRACTTumor heterogeneity provides a complex challenge to cancer treatment and is a critical component of therapeutic response, disease recurrence, and patient survival. Single-cell RNA-sequencing (scRNA-seq) technologies reveal the prevalence of intra-and inter-tumor heterogeneity. Computational techniques are essential to quantify the differences in variation of these profiles between distinct cell types, tumor subtypes, and patients to fully characterize intra-and inter-tumor molecular heterogeneity. We devised a new algorithm, Expression Variation Analysis in Single Cells (EVAsc), to perform multivariate statistical analyses of differential variation of expression in gene sets for scRNA-seq. EVAsc has high sensitivity and specificity to detect pathways with true differential heterogeneity in simulated data. We then apply EVAsc to several public domain scRNA-seq tumor datasets to quantify the landscape of tumor heterogeneity in several key applications in cancer genomics, i.e. immunogenicity, cancer subtypes, and metastasis. Immune pathway heterogeneity in hematopoietic cell populations in breast tumors corresponded to the amount diversity present in the T-cell repertoire of each individual. In head and neck squamous cell carcinoma (HNSCC) patients, we found dramatic differences in pathway dysregulation across basal primary tumors. Within the basal primary tumors we also identified increased immune dysregulation in individuals with a high proportion of fibroblasts present in the tumor microenvironment. Moreover, cells in HNSCC primary tumors had significantly more heterogeneity across pathways than cells in metastases, consistent with a model of clonal outgrowth. These results demonstrate the broad utility of EVAsc to quantify inter-and intra-tumor heterogeneity from scRNA-seq data without reliance on low dimensional visualization.
Resilience of BST-2/Tetherin structure to single amino acid substitutions
Authors: Roy Ian R. , Sutton Camden K. , Berndsen Christopher E. 
Published: November 2018

ABSTRACTHuman Tetherin, also known as BST-2 or CD317, is a dimeric, extracellular membrane-bound protein that consists of N and C terminal membrane anchors connected by an extracellular domain. BST-2 is involved in binding enveloped viruses, such as HIV, and inhibiting viral release in addition to a role in NF-kB signaling. Viral tethering by Tetherin can be disrupted by the interaction with Vpu in HIV-1 in addition to other viral proteins. The structural mechanism of Tetherin function is not clear and the effects of human Tetherin mutations identified by sequencing consortiums are not known. To address this gap in the knowledge, we used data from the Ensembl database to construct and model known human missense mutations within the ectodomain to investigate how the structure of the ectodomain influences function. From the data, we identified an island of sequence stability within the ectodomain, which corresponds to functionally or structurally important region identified in previous biochemical and biophysical studies. Additionally, most mutations have little effect on structure, suggesting that they would not affect function. These findings are in agreement with biochemical and cellular studies which suggest that mutations that do not disrupt the alpha helices of Tetherin have little apparent effect on function. Thus, Tetherin sequence is likely less important than structure and this apparent flexibility may allow for greater anti-viral activities with a larger number of viruses.