bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell transcriptional diversity is a hallmark of developmental potential
Authors: Gulati Gunsagar S. , Sikandar Shaheen S. , Wesche Daniel J. , Manjunath Anoop , Bharadwaj Anjan , Berger Mark J. , Ilagan Francisco , Kuo Angera H. , Hsieh Robert W. , Cai Shang , Zabala Maider , Scheeren Ferenc A. , Lobo Neethan A. , Qian Dalong , Yu Feiqiao B. , Dirbas Frederick M. , Clarke Michael F. , Newman Aaron M. 
Published: May 2019

AbstractSingle-cell RNA-sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation without prior knowledge has remained challenging. Here we describe a simple yet robust determinant of developmental potential—the number of detectably expressed genes per cell— and leverage this measure of transcriptional diversity to develop a new framework for predicting ordered differentiation states from scRNA-seq data. When evaluated on ~150,000 single-cell transcriptomes spanning 53 lineages and five species, our approach, called CytoTRACE, outperformed previous methods and ~19,000 molecular signatures for resolving experimentally-confirmed developmental trajectories. In addition, it enabled unbiased identification of tissue-resident stem cells, including cells with long-term regenerative potential. When used to analyze human breast tumors, we discovered candidate genes associated with less-differentiated luminal progenitor cells and validated GULP1 as a novel gene involved in tumorigenesis. Our study establishes a key RNA-based correlate of developmental potential and provides a new platform for robust delineation of cellular hierarchies (https://cytotrace.stanford.edu).
Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors
Authors: Tillage Rachel P. , Sciolino Natale R. , Plummer Nicholas W. , Lustberg Daniel , Liles L. Cameron , Hsiang Madeline , Powell Jeanne M. , Smith Kathleen G. , Jensen Patricia , Weinshenker David 
Published: May 2019

ABSTRACTAccumulating evidence indicates that disruption of galanin signaling is associated with neuropsychiatric disease, but the precise functions of this neuropeptide remain largely unresolved due to lack of tools for experimentally disrupting its transmission in a cell type-specific manner. To examine the function of galanin in the noradrenergic system, we generated and crossed two novel knock-in mouse lines to create animals lacking galanin specifically in noradrenergic neurons (GalcKO-Dbh). We observed reduced levels of galanin peptide in pons, hippocampus, and prefrontal cortex of GalcKO-Dbh mice, indicating that noradrenergic neurons are a significant source of galanin to those brain regions, while midbrain and hypothalamic galanin levels were comparable to littermate controls. In these same brain regions, we observed no change in levels of norepinephrine or its major metabolite at baseline or after an acute stressor, suggesting that loss of galanin does not affect noradrenergic synthesis or turnover. GalcKO-Dbh mice had normal performance in tests of depression, learning, and motor-related behavior, but had an altered response in some anxiety-related tasks. Specifically, GalcKO-Dbh mice showed increased marble and shock probe burying and had a reduced latency to eat in a novel environment, indicative of a more proactive coping strategy. Together, these findings indicate that noradrenergic neurons provide a significant source of galanin to discrete brain areas, and noradrenergic-specific galanin opposes adaptive coping responses.
miRDriver: A Tool to Infer Copy Number Derived miRNA-Gene Networks in Cancer
Authors: Bose Banabithi , Bozdag Serdar 
Published: May 2019

ABSTRACTCopy number aberration events such as amplifications and deletions in chromosomal regions are prevalent in cancer patients. Frequently aberrated copy number regions include regulators such as microRNAs (miRNAs), which regulate downstream target genes that involve in the important biological processes in tumorigenesis and proliferation. Many previous studies explored the miRNA-gene interaction networks but copy number-derived miRNA regulations are limited. Identifying copy number-derived miRNA-target gene regulatory interactions in cancer could shed some light on biological mechanisms in tumor initiation and progression. In the present study, we developed a computational pipeline, called miRDriver which is based on the hypothesis that copy number data from cancer patients can be utilized to discover driver miRNAs of cancer. miRDriver integrates copy number aberration, DNA methylation, gene and miRNA expression datasets to compute copy number-derived miRNA-gene interactions in cancer. We tested miRDriver on breast cancer and ovarian cancer data from the Cancer Genome Atlas (TCGA) database. miRDriver discovered some of the known miRNAs, such as miR-125b, mir-320d, let-7g, and miR-21, which are known to be in copy number aberrated regions in breast cancer. We also discovered some potentially novel miRNA-gene interactions. Also, several miRNAs such as miR-127, miR-139 and let-7b were found to be associated with tumor survival and progression based on Cox proportional hazard model. We compared the enrichment of known miRNA-gene interactions computed by miRDriver with the enrichment of interactions computed by the state-of-the-art methods and miRDriver outperformed all the other methods.CCS CONCEPTSBioinformaticsComputational GenomicsBiological Networks
Large-scale Analyses of Disease Biomarkers and Apremilast Pharmacodynamic Effects
Authors: Medvedeva Irina V. , Stokes Matthew E. , Eisinger Dominic , LaBrie Samuel T. , Ai Jing , Trotter Matthew W. B. , Schafer Peter , Yang Robert 
Published: May 2019

ABSTRACTFinding biomarkers that provide shared link between disease severity, drug-induced pharmacodynamic effects and response status in human trials can provide number of values for patient benefits: elucidating current therapeutic mechanism-of-action, and, back-translating to fast-track development of next-generation therapeutics. Both opportunities are predicated on proactive generation of human molecular profiles that capture longitudinal trajectories before and after pharmacological intervention. Here, we present the largest plasma proteomic biomarker dataset available to-date and the corresponding analyses from placebo-controlled Phase III clinical trials of the phosphodiesterase type 4 inhibitor apremilast in psoriasis (PSOR), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from 526 subjects overall. Using approximately 150 plasma analytes tracked across three time points, we identified IL-17A and KLK-7 as biomarkers for disease severity and apremilast pharmacodynamic effect in psoriasis patients. Combined decline rate of KLK-7, PEDF, MDC and ANGPTL4 by Week 16 represented biomarkers for the responder subgroup, shedding insights into therapeutic mechanisms. In ankylosing spondylitis patients, IL-6 and LRG-1 were identified as biomarkers with concordance to disease severity. Apremilast-induced LRG-1 increase was consistent with the overall lack of efficacy in ankylosing spondylitis. Taken together, these findings expanded the mechanistic knowledge base of apremilast and provided translational foundations to accelerate future efforts including compound differentiation, combination, and repurposing.
A fitness cost resulting fromHamiltonella defensainfection is associated with altered probing and feeding behaviour inRhopalosiphum padi
Authors: Leybourne Daniel. J. , Valentine Tracy. A. , Bos Jorunn. I. B. , Karley Alison. J. 
Published: May 2019

AbstractAphids frequently associate with facultative endosymbiotic bacteria which influence aphid physiology in myriad ways. Endosymbiont infection can increase aphid resistance against parasitoids and pathogens, modulate plant responses to aphid feeding, and promote aphid virulence. These endosymbiotic relationships can also decrease aphid fitness in the absence of natural enemies or when feeding on less suitable plant types. Here, we use the Electrical Penetration Graph (EPG) technique to monitor feeding behaviour of four genetically-similar clonal lines of a cereal-feeding aphid,Rhopalosiphum padi, differentially infected (+/−) with the facultative protective endosymbiont,Hamiltonella defensa, to understand how physiological processes at the aphid-plant interface are affected by endosymbiont infection. Endosymbiont-infected aphids exhibited altered probing and feeding patterns compared with uninfected aphids, characterised by a two-fold increase in the number of plant cell punctures, a 50% reduction in the duration of each cellular puncture, and a greater probability of achieving sustained ingestion of plant phloem. Feeding behaviour was altered further by host plant identity: endosymbiont-infected aphids spent less time probing into plant tissue, required twice as many probes into plant tissue to reach plant phloem, and showed a 44% reduction in phloem ingestion when feeding on the partially-resistant wild relative of barley,Hordeum spontaneum5, compared with a commercial barley cultivar. These observations might explain reduced growth ofH. defensa-infected aphids on the former host plant. This study is the first to demonstrate a physiological mechanism at the aphid-plant interface contributing to endosymbiont effects on aphid fitness on different quality plants through altered aphid feeding behaviour.SummaryReduced performance of aphids infected with a common facultative endosymbiont on poor quality plants may be explained by changes in aphid probing behaviour and decreased phloem sap ingestion.
Dense neuronal reconstruction through X-ray holographic nano-tomography
Authors: Pacureanu Alexandra , Maniates-Selvin Jasper , Kuan Aaron T. , Thomas Logan A. , Chen Chiao-Lin , Cloetens Peter , Lee Wei-Chung Allen 
Published: May 2019

AbstractElucidating the structure of neuronal networks provides a foundation for understanding how the nervous system processes information to generate behavior. Despite technological breakthroughs in visible light and electron microscopy, imaging dense nanometer-scale neuronal structures over millimeter-scale tissue volumes remains a challenge. Here, we demonstrate that X-ray holographic nano-tomography is capable of imaging large tissue volumes with sufficient resolution to disentangle dense neuronal circuitry in Drosophila melanogaster and mammalian central and peripheral nervous tissue. Furthermore, we show that automatic segmentation using convolutional neural networks enables rapid extraction of neuronal morphologies from these volumetric datasets. The technique we present allows rapid data collection and analysis of multiple specimens, and can be used correlatively with light microscopy and electron microscopy on the same samples. Thus, X-ray holographic nano-tomography provides a new avenue for discoveries in neuroscience and life sciences in general.
Haptic metameric textures
Authors: Kuroki Scinob , Sawayama Masataka , Nishida Shin’ya 
Published: May 2019

AbstractHumans sense spatial patterns through their eyes and hands. Past studies have revealed differences (as well as similarities) between vison and touch in texture processing (e.g., eye is good at detecting texture boundaries, while hand can discriminate subtle texture differences), but the underlying computational differences remains poorly understood. Here we transcribed various textures as surface relief patterns by 3D-printing, and analyzed the tactile discrimination performance regarding the sensitivity to image statistics. The results suggest that touch is sensitive to texture differences in lower-order statistics (e.g., statistics of local amplitude spectrum), while may not to those in the higher-order statistics (e.g., joint statistics of local orientations). In agreement with this, we found that pairs of synthesized textures differing only in higher-order statistics were nearly indiscriminable (metameric) by touch, while easily discriminable by vision. Our findings show that touch and vision sense spatial information using different and complementary computational strategies.
Endocardial differentiation in zebrafish occurs during early somitogenesis and is dependent on BMP andetv2signalling
Authors: Capon Samuel J , Smith Kelly A 
Published: May 2019

AbstractThe endocardium and adjacent vascular endothelial network share a number of molecular markers however there are distinct physiological functions of these tissues. What distinguishes these lineages on a molecular level remains an important, unanswered question in cardiovascular biology. We have identified theGt(SAGFF27C); Tg(4xUAS:egfp)line as a marker of early endocardial development and used this line to examine endocardial differentiation. Our results show that the endocardium emerges from the anterior lateral plate mesoderm at the 8-somite stage (13 hpf). Analysis in a number of loss-of-function models showed that whilstnkx2.5,hand2andtal1loss-of-function have no effect on the endocardial progenitor domain, bothetv2loss-of-function and inhibition of BMP signalling reduce the endocardial domain. Furthermore, manipulating BMP signalling altersetv2expression. Together, these results describe the onset of endocardial molecular identity and suggest a signalling cascade whereby BMP signalling acts upstream ofetv2to direct differentiation of endocardial progenitors.
DiADeM: differential analysis via dependency modelling of chromatin interactions with robust generalized linear models
Authors: Zaborowski Rafał , Wilczyński Bartek 
Published: May 2019

AbstractHigh throughput Chromosome Conformation Capture experiments have become the standard technique to assess the structure and dynamics of chromosomes in living cells. As any other sufficiently advanced biochemical technique, Hi-C datasets are complex and contain multiple documented biases, with the main ones being the non-uniform read coverage and the decay of contact coverage with genomic distance. Both of these effects have been studied and there are published methods that are able to normalize different Hi-C data to mitigate these biases to some extent. It is crucial that this is done properly, or otherwise the results of any comparative analysis of two or more Hi-C experiments are bound to be biased. In this paper we study both mentioned biases present in the Hi-C data and show that normalization techniques aimed at alleviating the coverage bias are at the same time exacerbating the problems with contact decay bias. We also postulate that it is possible to use generalized linear models to directly compare non-normalized data an that it is giving better results in identification of differential contacts between Hi-C matrices than using the normalized data.
The development of cooperative channels explains the maturation of hair cell’s mechanotransduction
Authors: Gianoli Francesco , Risler Thomas , Kozlov Andrei S. 
Published: May 2019

ABSTRACTHearing relies on the conversion of mechanical stimuli into electrical signals. In vertebrates, this process of mechano-electrical transduction (MET) is performed by specialized receptors of the inner ear, the hair cells. Each hair cell is crowned by a hair bundle, a cluster of microvilli that pivot in response to sound vibrations, causing the opening and closing of mechanosensitive ion channels. Mechanical forces are projected onto the channels by molecular springs called tip links. Each tip link is thought to connect to a small number of MET channels that gate cooperatively and operate as a single transduction unit. Pushing the hair bundle in the excitatory direction opens the channels, after which they rapidly reclose in a process called fast adaptation. It has been experimentally observed that the hair cell’s biophysical properties mature gradually during postnatal development: the maximal transduction current increases, sensitivity sharpens, transduction occurs at smaller hair-bundle displacements, and adaptation becomes faster. Similar observations have been reported during tip-link regeneration after acoustic damage. Moreover, when measured at intermediate developmental stages, the kinetics of fast adaptation varies in a given cell depending on the magnitude of the imposed displacement. The mechanisms underlying these seemingly disparate observations have so far remained elusive. Here, we show that these phenomena can all be explained by the progressive addition of MET channels of constant properties, which populate the hair bundle first as isolated entities, then progressively as clusters of more sensitive, cooperative MET channels. As the proposed mechanism relies on the difference in biophysical properties between isolated and clustered channels, this work highlights the importance of cooperative interactions between mechanosensitive ion channels for hearing.SIGNIFICANCEHair cells are the sensory receptors of the inner ear that convert mechanical stimuli into electrical signals transmitted to the brain. Sensitivity to mechanical stimuli and the kinetics of mechanotransduction currents change during hair-cell development. The same trend, albeit on a shorter timescale, is also observed during hair-cell recovery from acoustic trauma. Furthermore, the current kinetics in a given hair cell depends on the stimulus magnitude, and the degree of that dependence varies with development. These phenomena have so far remained unexplained. Here, we show that they can all be reproduced using a single unifying mechanism: the progressive formation of channel pairs, in which individual channels interact through the lipid bilayer and gate cooperatively.
Neurogenin regulates effectors of migratory neuron cell behaviors in Ciona
Authors: Gibboney Susanne , Kim Kwantae , Razy-Krajka Florian , Wang Wei , Stolfi Alberto 
Published: May 2019

AbstractThe bipolar tail neurons (BTNs) of Ciona develop according to a highly dynamic, yet highly stereotyped developmental program and thus could serve as an accessible model system for neuronal delamination, migration, and polarized axon outgrowth. Here we used FACS/RNAseq to profile the transcriptional output of Neurogenin in the BTNs, searching for candidate effectors of BTN cell behaviors. We identified several candidate genes that might play conserved roles in similar cell behaviors in other animals, including mammals. Among the more interesting candidates were several microtubule-binding proteins and TGFβ pathway antagonists. A small Gαi subunit was also found to be upregulated in migrating BTNs, and interfering with its function through expression of a dominant negative inhibited delamination and a complete epithelial-to-mesenchymal transition. We propose models for the regulation of BTN behaviors by the identified candidate effectors, establishing a foundation for testing effector gene functions that might be conserved in chordate neurodevelopment.
Phosphorylation by CK2 increases the SUMO-dependent activity of Cytomegalovirus transactivator IE2
Authors: Tripathi Vasvi , Chatterjee Kiran Sankar , Das Ranabir 
Published: May 2019

AbstractViral factors manipulate the host post-translational modification (PTM) machinery for replication. Distinctly, phosphorylation and SUMOylation can regulate the activity of human cytomegalovirus (HCMV) protein IE2. However, the molecular mechanism of this process is unknown. Taking a structural, biochemical and cellular approach, we uncover a cross-talk of phosphorylation and SUMOylation exploited by IE2. A scan for the SUMO Interacting Motifs (SIMs) revealed two SIMs in IE2. A real-time SUMOylation assay indicated that the N-terminal SIM (IE2-SIM1) enhanced IE2 SUMOylation up to 4-fold. Kinetic analysis and structural studies proved that IE2 is a SUMO cis-E3 ligase. Two putative CK2 sites adjacent to IE2-SIM1 are phosphorylated in-vitro and in cellular conditions. Phosphorylation drastically increased the IE2/SUMO affinity, IE2-SUMOylation and cis-E3 activity of IE2. Additional salt-bridges between the phosphoserines and SUMO account for the higher IE2/SUMO affinity. Phosphorylation also enhances the SUMO-dependent transactivation activity and auto-repression activity of IE2. Together, our findings highlight a novel mechanism where SUMOylation and phosphorylation of the viral cis-E3 ligase and transactivator protein IE2, works in tandem to enable transcriptional regulation of viral genes.Author summaryThe host protein SUMO is a crucial regulator of cellular processes. Conjugation of other proteins to SUMO by a process called SUMOylation, can change the protein’s function or localization and regulate downstream cellular events. The SUMO pathway is exploited by viruses to transcribe viral genes and replicate the viral genome. IE2 is an essential gene of human Cytomegalovirus (HCMV), which acts as a transactivator and helps to transcribe other viral proteins required for viral genome replication and viral assembly. SUMOylation of IE2 is necessary for its function. Here, we have uncovered that IE2 functions as a cis-SUMO-E3 ligase, where a SUMO-Interacting Motif (SIM) in IE2 enhances its SUMOylation. Interestingly, phosphorylation of the SIM in IE2 augments its cis-E3 activity to further increase SUMOylation. Moreover, SIM phosphorylation also enhances the interaction between IE2 and SUMOylated binding partners. Thus, we uncover an exciting process, where phosphorylation enhances both covalent and non-covalent interaction of a protein (IE2) and SUMO. We also observe that the cross-talk of phosphorylation and SUMOylation has significant effects on the transactivation function of IE2. Overall, we discover how a viral protein IE2 exploits crosstalk between SUMOylation and Phosphorylation to enhance its activity and in turn, ensure efficient viral replication.
The effect of alien species on plant-pollinator network structure across a gradient of plant species invasion
Authors: Parra-Tabla Víctor , Angulo-Pérez Diego , Albor Cristopher , Campos-Navarrete María José , Tun-Garrido Juan , Sosenski Paula , Alonso Conchita , Ashman Tia-Lynn , Arceo-Gómez Gerardo 
Published: May 2019

AbstractThe interactions between pairs of native and alien plants via shared use of pollinators have been widely studied. Studies of invasive species effects at the community level on the other hand are still scarce. Few community level studies, however, have considered how differences in the intensity of invasion, and degree of floral trait similarity between native and invasive species, can mediated effects on native plant-pollinator communities. Here, we evaluated the effect of alien species on overall plant-pollinator network structure, and species-level network parameters, across nine coastal communities distributed along 205 km at Yucatán, México that vary in alien species richness and flower abundance. We further assessed the effect of alien plant species on plant-pollinator network structure and robustness via computational simulation of native and invasive plant extinction scenarios. We did not find significant differences between native and alien species in functional floral phenotypes, the visitation rate and species composition of the pollinator community. Variation in the proportion of alien plant species and flower abundance across sites did not affect plant-pollinator networks structure. Species-level network parameters (i.e., normalized degree and nestedness contribution) did not differ between native and alien species. Furthermore, our simulation analyses revealed that alien species are functionally equivalent to native species and contribute equally to network structure and robustness. Overall, our results suggest that alien species are well integrated into native coastal plant-pollinator networks which may be facilitated by high levels of floral trait similarity and pollinator use overlap. As a result, alien species may play a similar role than that of natives in the structure and stability of native plant and pollinator communities in the studied coastal sand dune ecosystem.