bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enabling Semantic Queries Across Federated Bioinformatics Databases
Authors: Sima Ana Claudia , de Farias Tarcisio Mendes , Zbinden Erich , Anisimova Maria , Gil Manuel , Stockinger Heinz , Stockinger Kurt , Robinson-Rechavi Marc , Dessimoz Christophe 
Published: June 2019

MotivationData integration promises to be one of the main catalysts in enabling new insights to be drawn from the wealth of biological data available publicly. However, the heterogeneity of the different data sources, both at the syntactic and the semantic level, still poses significant challenges for achieving interoperability among biological databases.ResultsWe introduce an ontology-based federated approach for data integration. We applied this approach to three heterogeneous data stores that span different areas of biological knowledge: 1) Bgee, a gene expression relational database; 2) OMA, a Hierarchical Data Format 5 (HDF5) orthology data store, and 3) UniProtKB, a Resource Description Framework (RDF) store containing protein sequence and functional information. To enable federated queries across these sources, we first defined a new semantic model for gene expression called GenEx. We then show how the relational data in Bgee can be expressed as a virtual RDF graph, instantiating GenEx, through dedicated relational-to-RDF mappings. By applying these mappings, Bgee data are now accessible through a public SPARQL endpoint. Similarly, the materialised RDF data of OMA, expressed in terms of the Orthology ontology, is made available in a public SPARQL endpoint. We identified and formally described intersection points (i.e. virtual links) among the three data sources. These allow performing joint queries across the data stores. Finally, we lay the groundwork to enable nontechnical users to benefit from the integrated data, by providing a natural language template-based search interface.Project URLhttp://biosoda.expasy.org, https://github.com/biosoda/bioquery
Molecular and cellular correlates of human nerve regeneration: ADCYAP1 encoding PACAP enhances sensory neuron outgrowth
Authors: Schmid Annina B , Baskozos Georgios , Windsor Katherine , Karlsson Pall , Sandy-Hindmarch Oliver , Weir Greg A , McDermott Lucy A , Clark Alex J , Burchall Joanna , Wiberg Akira , Furniss Dominic , Bennett David LH 
Published: June 2019

AbstractWe only have a rudimentary understanding of the molecular and cellular determinants of human nerve regeneration. Here, we use carpal tunnel syndrome (CTS) as a human model system to prospectively evaluate correlates of neural regeneration and their relationship with clinical recovery after decompression surgery. At 6 months post-surgery, we noted a significant improvement of median nerve neurophysiological and somatosensory function. Serial skin biopsies revealed a partial recovery of intraepidermal innervation, whose extent correlated with symptom improvement. In myelinated afferents, nodal length increased postoperatively. Transcriptional profiling of the skin revealed 23 differentially expressed genes following decompression, with ADCYAP1 (encoding PACAP) being the most strongly upregulated and showing an association with regeneration of intraepidermal nerve fibres. Using human induced pluripotent stem cell-derived sensory neurons, we confirmed that PACAP significantly enhances axon outgrowth in vivo. Since PACAP signals through G-protein receptors, this pathway provides an interesting therapeutic target for human sensory nerve regeneration.
Mouse retinal cell behaviour in space and time using light sheet fluorescence microscopy
Authors: Prahst Claudia , Ashrafzadeh Parham , Harrington Kyle , Venkatraman Lakshmi , Richards Mark , Russo Ana Martins , Cho Kin-Sang , Chang Karen , Mead Thomas , Chen Dong Feng , Richardson Douglas , Claesson-Welsh Lena , Franco Claudio , Bentley Katie 
Published: June 2019

AbstractAs the general population ages and the incidence of diabetes increases epidemically, more people are affected by eye diseases, such as retinopathies. It is therefore critical to improve imaging of eye disease mouse models. Here, we demonstrate that 1) rapid, quantitative 3D and 4D (time lapse) imaging of cellular and subcellular processes in the murine eye is feasible, with and without tissue clearing, using light-sheet fluorescent microscopy (LSFM) and 2) LSFM readily reveals new features of even well studied eye disease mouse models, such as the Oxygen-Induced Retinopathy (OIR) model. Through correlative LSFM-Confocal imaging we find that flat-mounting retinas for confocal microscopy significantly distorts tissue morphology. The minimized distortion with LSFM dramatically improved analysis of pathological vascular tufts in the OIR model revealing “knotted” morphologies, leading to a proposed new tuft nomenclature. Furthermore, live-imaging of OIR tuft formation revealed abnormal cell motility and altered filopodia dynamics. We conclude that quantitative 3D/4D LSFM imaging and analysis has the potential to advance our understanding of pathological processes in the eye, in particular neuro-vascular degenerative processes.
Direct evidence for transport of RNA from the mouse brain to the germline and offspring
Authors: O’Brien Elizabeth A. , Ensbey Kathleen S. , Day Bryan W. , Baldock Paul A. , Barry Guy 
Published: June 2019

AbstractBackgroundThe traditional concept that heritability occurs exclusively from the transfer of germline-restricted genetics is being challenged by the increasing accumulation of evidence confirming the existence of experience-dependent transgenerational inheritance. However, questions remain unanswered as to how heritable information can be passed from somatic cells. Previous studies have implicated the critical involvement of RNA in heritable transgenerational effects and the high degree of mobility and genomic impact of RNAs in all organisms is an attractive model for the efficient transfer of genetic information.ResultsWe hypothesized that RNA may be transported from a somatic tissue, in this case the brain, of an adult male mouse to the germline, and subsequently to offspring. To investigate this, we injected one hemisphere of the male mouse striatum with an AAV1/9 virus expressing human pre-MIR941 (MIR941). After 2, 8 and 16 weeks following injection, we used an LNA-based qPCR system to detect the presence of virus and human MIR941 in brain, peripheral tissues and offspring, from injected male mice mated with uninjected females. Virus was never detected outside of the brain. Verification of single bands of the correct size for MIR941 was performed using Sanger sequencing while quantitation demonstrated that a small percentage (∼ 1-8%) of MIR941 is transported to the germline and to offspring in about a third of the cases.ConclusionsWe show that somatic RNA can be transported to the germline and passed on to offspring, thereby providing additional evidence of a role for RNA in somatic cell-derived transgenerational effects.
Single-particle measurements of filamentous influenza virions reveal damage induced by freezing
Authors: Hirst Jack C. , Hutchinson Edward C. 
Published: June 2019

AbstractClinical isolates of influenza virus produce pleiomorphic virions, ranging from small spheres to elongated filaments. The filaments are seemingly adaptive in natural infections, but their basic functional properties are poorly understood and functional studies of filaments often report contradictory results. This may be due to artefactual damage from routine laboratory handling, an issue which has been noted several times without being explored in detail. To determine whether standard laboratory techniques could damage filaments, we used immunofluorescence microscopy to rapidly and reproducibly quantity and characterise the dimensions of filaments. Most of the techniques we tested had minimal impact on filaments, but freezing to -70°C, a standard storage step before carrying out functional studies on influenza viruses, severely reduced both their concentration and median length. We noted that damage from freezing is likely to have affected most of the functional studies of filaments performed to date, and to address this we show that it can be mitigated by using the cryoprotectant DMSO. We recommend that functional studies of filaments characterise virion populations prior to analysis to ensure reproducibility, and that they use unfrozen samples if possible and cryoprotectants if not. These basic measures will support the robust functional characterisations of filaments that are required to understand their roles in natural influenza virus infections.
PDXGEM: Patient-Derived Tumor Xenograft based Gene Expression Model for Predicting Clinical Response to Anticancer Therapy in Cancer Patients
Authors: Kim Youngchul , Kim Daewon , Cao Biwei , Carvajal Rodrigo , Kim Minjung 
Published: June 2019

AbstractBackgroundCancer is a highly heterogeneous disease and shows varying responses to anti-cancer drugs. Although several approaches have been attempted to predict the drug responses by analyzing molecular profiling data of tumors from preclinical cancer models or cancer patients, there is still a great need of developing highly accurate prediction models of response to the anti-cancer drugs for clinical applications toward personalized medicine. Here, we present PDXGEM pipeline to build a predictive gene expression model (GEM) for cancer patients’ drug responses on the basis of data on gene expression and drug activity in patient-derived xenograft (PDX) models.ResultsDrug sensitivity biomarkers were identified by an association analysis between gene expression levels and post-treatment tumor volume changes in PDX models. Only biomarkers with concordant co-expression patterns between the PDX and cancer patient tumors were used in random-forest algorithm to build a drug response prediction model, so called PDXGEM. We applied PDXGEM to several cytotoxic chemotherapy as well as targeted therapy agents that are used to treat breast cancer, pancreatic cancer, colorectal cancer, or non-small cell lung cancer. Significantly accurate predictions of PDXGEM for pathological and survival outcomes were observed through extensive validation analyses of multiple independent cancer patient datasets obtained from retrospective observational study and prospective clinical trials.ConclusionOur results demonstrated a strong potential of utilizing molecular profiles and drug activity data of PDX tumors for developing a clinically translatable predictive cancer biomarkers for cancer patients. PDXGEM web application is publicly available athttp://pdxgem.moffitt.org.
Stress- and pathway-specific impacts of impaired jasmonoyl-isoleucine (JA-Ile) catabolism on defense signaling and biotic stress resistance in Arabidopsis
Authors: Marquis Valentin , Smirnova Ekaterina , Poirier Laure , Zumsteg Julie , Schweizer Fabian , Reymond Philippe , Heitz Thierry 
Published: June 2019

ABSTRACTJasmonate (JA) synthesis and signaling are essential for plant defense upregulation upon herbivore or microbial attacks. Stress-induced accumulation of jasmonoyl-isoleucine (JA-Ile), the bioactive hormonal form triggering major transcriptional changes, is often dynamic and transient, due to the existence of potent removal mechanisms. Two distinct but interconnected JA-Ile turnover pathways have been described in Arabidopsis, either via cytochrome P450 (CYP94)-mediated oxidation, or through deconjugation by the amidohydrolases (AH) IAR3 and ILL6. Their impact was not well known because of gene redundancy and compensation mechanisms when each pathway was partially impaired. Here we address the consequences of fully blocking either or both pathways on JA homeostasis and defense signaling in three mutant backgrounds: a doubleiar3 ill6(2ah) mutant, a triplecyp94b1 b3 c1mutant (3cyp), and a newly generated quintuple (5ko) mutant deficient in all known JA-Ile-degrading activities. These lines behaved very differently in response to either mechanical wounding, insect attack or fungal infection, highlighting the stress-specific contributions and impacts of JA-Ile catabolic pathways. Deconjugation and oxidative pathways contributed additively to JA-Ile removal upon wounding, but their genetic impairement had opposite impacts onSpodoptera littoralislarvae feeding:2ahline was more resistant whereas3cypwas more susceptible to insect attack. In contrast,2ah, 5kobut not3cypoveraccumulated JA-Ile upon inoculation byBotrytis cinerea, yet3cypwas most resistant to the fungus. Despite of building-up unprecedented JA-Ile levels,5kodisplayed near WT levels of resistance in both bioassays. Molecular and metabolic analysis indicated that restrained JA-Ile catabolism resulted in enhanced defense and resistance levels only if genes encodingJAZorJAMnegative regulators were not simultaneously overstimulated. Our data demonstrate that despite of acting on a shared hormonal substrate, AH or/and CYP94 deficiency differentially impacts JA homeostasis, responses and tolerance to related biotic stresses.
Sexual selection does not increase the rate of compensatory adaptation to a mutation influencing a secondary sexual trait inDrosophila melanogaster
Authors: Chandler Christopher H. , Mammel Anna , Dworkin Ian 
Published: June 2019

AbstractTheoretical work predicts that sexual selection can enhance natural selection, increasing the rate of adaptation to new environments and helping purge harmful mutations. While some experiments support these predictions, remarkably little work has addressed the role of sexual selection on compensatory adaptation—populations’ ability to compensate for the costs of deleterious alleles that are already present. We tested whether sexual selection, as well as the degree of standing genetic variation, affect the rate of compensatory evolution via phenotypic suppression in experimental populations ofDrosophila melanogaster. These populations were fixed for a spontaneous mutation causing mild abnormalities in the male sex comb, a structure important for mating success. We fine-mapped this mutation to an ∼85 kb region on the X chromosome containing three candidate genes, showed that the mutation is deleterious, and that its phenotypic expression and penetrance vary by genetic background. We then performed experimental evolution, including a treatment where opportunity for mate choice was limited by experimentally enforced monogamy. Although evolved populations did show some phenotypic suppression of the morphological abnormalities in the sex comb, the amount of suppression did not depend on the opportunity for sexual selection. Sexual selection, therefore, may not always enhance natural selection; instead, the interaction between these two forces may depend on additional factors.
Functional ultrasound speckle decorrelation-based velocimetry of the brain
Authors: Tang Jianbo , Postnov Dmitry D. , Kilic Kivilcim , Erdener Sefik Evren , Lee Blaire , Giblin John T. , Szabo Thomas L. , Boas David A. 
Published: June 2019

AbstractA high-speed, contrast free, quantitative ultrasound velocimetry (vUS) for blood flow velocity imaging throughout the rodent brain is developed based on the normalized first order temporal autocorrelation function of the ultrasound field signal. vUS is able to quantify blood flow velocity in both transverse and axial directions, and is validated with numerical simulation, phantom experiments, and in vivo measurements. The functional imaging ability of vUS is demonstrated by monitoring blood flow velocity changes during whisker stimulation in awake mice. Compared to existing power Doppler and color Doppler-based functional ultrasound imaging techniques, vUS shows quantitative accuracy in estimating both axial and transverse flow speeds and resistance to acoustic attenuation and high frequency noise.
HP1γ binding pre-mRNA at intronic repeats increases splicing fidelity and regulates alternative exon usage
Authors: Rachez Christophe , Legendre Rachel , Costallat Mickaël , Varet Hugo , Yi Jia , Kornobis Etienne , Muchardt Christian 
Published: June 2019

ABSTRACTHP1 proteins are best known as markers of heterochromatin and gene silencing. Yet, they are also RNA-binding proteins and the HP1γ/Cbx3 family member is present on transcribed genes together with RNA polymerase II, where it regulates co-transcriptional processes such as alternative splicing. To gain insight in the role of the RNA binding activity of HP1γ in transcriptionally active chromatin, we have captured and analyzed RNAs associated with this protein. We find that HP1γ specifically recognizes hexameric RNA motifs and coincidentally transposable elements of the SINE family. As these elements are abundant in introns, while essentially absent from exons, the HP1γ RNA binding activity tethers unspliced pre-mRNA to chromatin via the intronic region and limits the usage of intronic cryptic splice sites. Thus, our data unveil novel determinants in the relationship between chromatin and co-transcriptional splicing.
Molecular estimation of neurodegeneration pseudotime in older brains
Authors: Mukherjee Sumit , Heath Laura , Preuss Christoph , Jayadev Suman , Garden Gwenn A. , Greenwood Anna K , Sieberts Solveig K , De Jager Phillip L , Ertekin-Taner Nilufer , Carter Gregory W , Mangravite Lara M , Logsdon Benjamin A 
Published: June 2019

AbstractThe temporal molecular changes that lead to disease onset and progression in Alzheimer’s disease are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage – or disease pseudotime - for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0×10−5), Aβ (CERAD score, P = 1.8×10−5), and cognitive diagnosis (P = 3.5×10−7) of LOAD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data.
Regulation of Numb during planar cell polarity establishment in the Drosophila eye
Authors: Domingos Pedro M , Jenny Andreas , del Alamo David , Mlodzik Marek , Steller Hermann , Mollereau Bertrand 
Published: June 2019

ABSTRACTThe establishment of planar cell polarity (PCP) in theDrosophilaeye requires correct specification of the R3/R4 pair of photoreceptor cells, determined by a Frizzled mediated signaling event that specifies R3 and induces Delta to activate Notch signaling in the neighboring cell, specifying it as R4. Here, we investigated the role of the Notch signaling negative regulator Numb in the specification of R3/R4 fates and PCP establishment in theDrosophilaeye. We observed that Numb is transiently upregulated in R3 at the time of R3/R4 specification. This regulation of Numb levels in developing photoreceptors occurs at the post-transcriptional level and is dependent on Dishevelled, an effector of Frizzled signaling, and Lethal Giant Larva. We detected PCP defects in cells homozygous fornumb15, but these defects were due to a loss of function mutation infat(fatQ805*) being present in thenumb15chromosome. However, mosaic overexpression of Numb in R4 precursors (only) caused PCP defects andnumbloss-of-function had a modifying effect on the defects found in a hypomorphicdishevelledmutation. Our results suggest that Numb levels are upregulated to reinforce the bias of Notch signaling activation in the R3/R4 pair, two post-mitotic cells that are not specified by asymmetric cell division.
IPCO: Inference of Pathways from Co-variance analysis
Authors: Das Mrinmoy , Ghosh Tarini Shankar , Jeffery Ian B. 
Published: June 2019

AbstractKey aspects of microbiome research are accurate identification of taxa followed by the profiling of their functionality. Amplicon profiling based on the 16S ribosomal DNA sequence is a ubiquitous technique to identify and profile the abundances of the various taxa. However, it does not provide information on their encoded functionality. Predictive tools which can accurately extrapolate the functional information of a microbiome based on taxonomic profile composition is essential. At present the applicability of these tools is however limited due to requirement of reference genomes from known species. We present IPCO (Inference of Pathways from Co-variance analysis), a new method of inferring functionality for 16S-based microbiome profiles independent of reference genomes. IPCO utilises the biological co-variance observed between paired taxonomic and functional profiles and co-varies it with the queried dataset. It outperforms other established methods both in terms of sample and feature profile prediction. Validation results confirmed that IPCO can replicate observed biological signals seen within shotgun and metabolite profiles. Comparative analysis of predicted functionality profiles with other popular 16S-based functional prediction tools indicates significantly lower performance with predicted functionality showing little to no correlation with paired shotgun features across samples. IPCO is implemented in R and available fromhttps://github.com/IPCO-Rlibrary/IPCO.
Survival of prey growing through gape-limited and apex predators
Authors: Anderson James J. 
Published: June 2019

ABSTRACTA mechanistic model based on first principles of growth and predator-prey behavior introduces the effects of a predator size distribution on the survival of rapidly growing prey. The model, fit to Chinook salmon data, can explain the observed increase in ocean survival with smolt ocean entrance length using different predator size-frequency distributions. The model introduces new dimensions to theories on predator-prey interactions and population recruitment and suggests the possibility that fish recruitment control can be highly variable; sometimes dominated by juvenile growth and encounters with gape-limited predators and other times dominated by adult encounters with apex predators. Additionally, a sensitivity analysis suggests that scale and otolith circuli spacing are insensitive indicators of size-selective mortality but the profile of adult survival with juvenile length provides information on the balance of size-dependent and size-independent mortality processes.
Mouse CHD4-NURD is required for neonatal spermatogonia survival and normal gonad development
Authors: de Castro Rodrigo O. , Previato Luciana , Carbajal Agustin , Goitea Victor , Griffin Courtney T. , Pezza Roberto J. 
Published: June 2019

AbstractTestis development and sustained germ cell production in adults rely on the establishment and maintenance of spermatogonia stem cells and their proper differentiation into spermatocytes. Chromatin remodeling complexes regulate critical processes during gamete development by restricting or promoting accessibility of DNA repair and gene expression machineries to the chromatin. Here, we investigated the role of CHD4 and CHD3 catalytic subunits of the NURD complex during spermatogenesis. Germ cell-specific deletion of Chd4 early in gametogenesis, but not Chd3, resulted in arrested early gamete development due to failed cell survival of neonate undifferentiated spermatogonia stem cell population. Candidate assessment revealed that CHD4 controls expression of Dmrt1 and its downstream target Plzf, both described as prominent regulators of spermatogonia stem cell maintenance. Our results show the requirement of CHD4 in mammalian gametogenesis pointing to functions in gene expression early in the process.