bluuebunny/crossref_metadata_2025_split huggingface dataset:
TheDrosophila fusselgene is required for bitter gustatory neuron differentiation acting within an Rpd3 dependent chromatin modifying complex
Authors: Rass Mathias , Oestreich Svenja , Guetter Severin , Fischer Susanne , Schneuwly Stephan 
Published: November 2018

AbstractMembers of the Ski/Sno protein family are classified as proto-oncogenes and act as negative regulators of the TGF-ß/BMP-pathways in vertebrates and invertebrates. A newly identified member of this protein family isfussel(fuss), theDrosophilahomologue of the humanfunctional Smad suppressing elements(fussel-15andfussel-18). We and others have shown that Fuss interacts with SMAD4 and that overexpression leads to a strong inhibition of Dpp signaling. However, to be able to characterize the endogenous Fuss function inDrosophila melanogaster,we have generated a number of state of the art tools including anti-Fuss antibodies, specificfuss-Gal4 lines andfussmutant fly lines via the CRISPR/Cas9 system. Fuss is a predominantly nuclear, postmitotic protein, mainly expressed in interneurons andfussmutants are fully viable without any obvious developmental phenotype. To identify potential target genes or cells affected infussmutants, we conducted targeted DamID experiments in adult flies, which revealed the function offussin bitter gustatory neurons. We fully characterizedfussexpression in the adult proboscis and by using food choice assays we were able to show thatfussmutants display defects in detecting bitter compounds. This correlated with a reduction of gustatory receptor gene expression (Gr33a, Gr66a, Gr93a) providing a molecular link to the behavioral phenotype. In addition, Fuss interacts with Rpd3, and downregulation ofrpd3in gustatory neurons phenocopies the loss of Fuss expression. Surprisingly, there is no colocalization of Fuss with phosphorylated Mad in the larval central nervous system, excluding a direct involvement of Fuss in Dpp/BMP signaling.Here we provide a first and exciting link of Fuss function in gustatory bitter neurons. Although gustatory receptors have been well characterized, little is known regarding the differentiation and maturation of gustatory neurons. This work therefore reveals Fuss as a pivotal element for the proper differentiation of bitter gustatory neurons acting within a chromatin modifying complex.
Random Tanglegram Partitions (Random TaPas): An Alexandrian Approach to the Cophylogenetic Gordian Knot
Authors: Balbuena Juan Antonio , Pérez-Escobar Óscar Alejandro , Llopis-Belenguer Cristina , Blasco-Costa Isabel 
Published: November 2018

AbstractSymbiosis is a key driver of evolutionary novelty and ecological diversity, but our understanding of how macroevolutionary processes originate extant symbiotic associations is still very incomplete. Cophylogenetic tools are used to assess the congruence between the phylogenies of two groups of organisms related by extant associations. If phylogenetic congruence is higher than expected by chance, we conclude that there is cophylogenetic signal in the system under study. However, how to quantify cophylogenetic signal is still an open issue. We present a novel approach, Random Tanglegram Partitions (Random TaPas) that applies a given global-fit method to random partial tanglegrams of a fixed size to identify the associations, terminals and nodes that maximize phylogenetic congruence. By means of simulations, we show that the output value produced is inversely proportional to the number and proportion of cospeciation events employed to build simulated tanglegrams. In addition, with time-calibrated trees, Random TaPas is also efficient at distinguishing cospeciation from pseudocospeciation. Random TaPas can handle large tanglegrams in affordable computational time and incorporates phylogenetic uncertainty in the analyses. We demonstrate its application with two real examples: Passerine birds and their feather mites, and orchids and bee pollinators. In both systems, Random TaPas revealed low cophylogenetic signal, but mapping its variation onto the tanglegram pointed to two different coevolutionary processes. We suggest that the recursive partitioning of the tanglegram buffers the effect of phylogenetic nonindependence occurring in current global-fit methods and therefore Random TaPas is more reliable than regular global-fit methods to identify host-symbiont associations that contribute most to cophylogenetic signal. Random TaPas can be implemented in the public-domain statistical software R with scripts provided herein. A User’s Guide is also available at GitHub.
Yeast-to-hypha transition ofSchizosaccharomyces japonicusin response to natural stimuli
Authors: Kinnaer Cassandre , Dudin Omaya , Martin Sophie G 
Published: November 2018

AbstractMany fungal species are dimorphic, exhibiting both unicellular yeast-like and filamentous forms.Schizosaccharomyces japonicus, a member of the fission yeast clade, is one such dimorphic fungus. Here, we first identify fruit extracts as natural, stress-free, starvation-independent inducers of filamentation, which we use to describe the properties of the dimorphic switch. During the yeast-to-hypha transition, the cell evolves from a bipolar to a unipolar system with 10-fold accelerated polarized growth but constant width, vacuoles segregated to the non-growing half of the cell, and hyper-lengthening of the cell. We demonstrate unusual features ofS. japonicushyphae: these cells lack a Spitzenkörper, a vesicle distribution center at the hyphal tip, but display more rapid cytoskeleton-based transport than the yeast form, with actin cables being essential for the transition.S. japonicushyphae also remain mononuclear and undergo complete cell divisions, which are highly asymmetric: one daughter cell inherits the vacuole, the other the growing tip. We show these elongated cells scale their nuclear size, spindle length and elongation rates but display altered division size controls. This establishesS. japonicusas a unique system that switches between symmetric and asymmetric modes of growth and division.
Identification of biomarkers and pathways to identify novel therapeutic targets in Alzheimer’s disease: Insights from a systems biomedicine perspective
Authors: Rahman Md. Rezanur , Islam Tania , Zaman Toyfiquz , Shahjaman Md. , Karim Md. Rezaul , Huq Fazlul , Quinn Julian M.W. , Holsinger R. M. Damian , Moni Mohammad Ali 
Published: November 2018

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, there are no peripheral biomarkers available that can detect AD onset. This study aimed to identify such AD biomarkers through an integrative analysis of blood cell gene expression data. We used two microarray datasets (GSE4226 and GSE4229) comparing blood cell transcriptomes of AD patients and matched controls to identify differentially expressed genes (DEGs). Geneset and protein overrepresentation analysis, protein-protein interaction (PPI), DEGs-Transcription Factor interactions, DEGs-MicroRNAs interactions, protein-drug interactions, and protein subcellular localizations analyses were performed on DEGs common to the datasets. We identified 25 common DEGs between the two datasets. Integration of genome scale transcriptome datasets with biomolecular networks revealed hub genes (TUBB, ATF3, NOL6, UQCRC1, SND1, CASP2, BTF3, INPP5K, VCAM1, and CSTF1), common transcription factors (FOXC1, ZNF3, GEMIN7, and SMG9) and miRNAs (mir-20a-5p, mir-93-5p, mir-16-5p, let-7b-5p, mir-708-5p, mir-24-3p, mir-26b-5p, mir-17-5p, mir-4270, and mir-4441). These included 8 previously identified AD markers (BTF3, VCAM, FOXC1, mir-26b-5p, mir-20a-5p, mir-93-5p, let-7b-5p, mir-24-3p) and 13 novel AD biomarkers. Evaluation of histone modification revealed that hub genes and transcription factors possess several histone modification sites associated with AD. Protein-drug interactions revealed 10 compounds that affect the identified AD candidate markers, including anti-neoplastic agents (Vinorelbine, Vincristine, Vinblastine, Epothilone D, Epothilone B, CYT997, and ZEN-012), a dermatological (Podofilox) and an immunosuppressive agent (Colchicine). The subcellular localization of markers varied, including nuclear, plasma membrane and cytosolic proteins. This study identified blood-cell derived molecular biomarker signatures that might be useful as peripheral biomarkers in AD. This study also identified drug and epigenetic data associated with these molecules that may be useful in designing therapeutic approaches to ameliorate AD.
Vulnerability to climate change for narrowly ranged species: the case of Ecuadorian endemicMagnolia mercedesiarum
Authors: Shalisko V. , Vázquez-García J. A. , Villalobos-Arámbula A. R. , Muñiz-Castro M. A. 
Published: November 2018

AbstractSpecies vulnerability to climate change has been inferred using species distribution models from an example of the recently discoveredMagnolia mercedesiarum(sect.Talauma, Magnoliaceae), a narrowly ranged species endemic to moist tropical forests in the eastern Ecuadorian Andes. The environmental conditions within the current species distribution area has been compared with conditions projected to 2050 and 2070, using data from the HadGEM2-ES model in two CO2 emission scenarios: RCP4.5 and RCP8.5. The ecological niche modelling allowed determination of parameters of climatic environmental conditions that control current species distribution to produce a hypothesis on probable changes in spatial pattern of suitable habitats in future scenarios. Within the current species distribution area ofM. mercedesiarum, significant reduction of habitat suitability was projected for both emission scenarios, combined with a lack of nearby areas with adequate environmental conditions. Several disjunct sites of high habitat suitability were found to emerge in the Colombian Andes, but they seem unreachable by this tree species in the scope of a few decades, due to intrinsic dispersal limitations. The reduction of habitat suitability and improbability of distribution area shift to adjacent geographic locations could mean a high species vulnerability to climate change. The species could be at risk of extinction if it does not possess hidden phenotypical plasticity and potential for fast adaptation to climate change.
Waddington Revisited: Organ transformation by environmental disruption of epigenetic memory
Authors: Snir Orli , Elgart Michael , Ciabrelli Filippo , Dagan Shlomi , Aviezer Iris , Stoops Elizabeth , Cavalli Giacomo , Soen Yoav 
Published: November 2018

AbstractDespite major progress in mechanistic understanding of epigenetic reprogramming of cells, the basis of ‘organ reprograming’ by (epi-)gene-environment interactions remained largely obscured. Here we use the ether-induced haltere-to-wing transformations as a model for epigenetic “reprogramming” at the whole organism level. Our findings support a mechanistic chain of events explaining why and how brief embryonic exposure to ether leads to organ transformation manifested at the larval stage and on. We show that ether interferes with protein integrity in the egg leading to altered deployment of Hsp90 and repression of Trithorax-mediated establishment of H3K4 tri-methylations. This repression pre-disposes early methylated Ubx targets and wing genes for later up-regulation in the larval haltere disc, hence the wing-like outcome. Consistent with compromised protein integrity during the exposure, the severity of bithorax transformation is increased by genetic or chemical reduction of Hsp90 function. Moreover, a joint reduction inHsp90andtrxgene dosage can cause bithorax transformations without exposure to ether. These findings implicate environmental disruption of protein integrity at the onset of histone methylations with a modification of epigenetic memory, which in turn, supports a morphogenetic shift towards an ancestral-like body plan. The morphogenetic impact of chaperone response during a major setup of epigenetic patterns may be a general scheme for organ reprogramming by environmental cues.
ACAT: A Fast and Powerful P-value Combination Method for Rare-variant Analysis in Sequencing Studies
Authors: Liu Yaowu , Chen Sixing , Li Zilin , Morrison Alanna C. , Boerwinkle Eric , Lin Xihong 
Published: November 2018

ABSTRACTSet-based analysis that jointly tests the association of variants in a group has emerged as a popular tool for analyzing rare and low-frequency variants in sequencing studies. The existing set-based tests can suffer significant power loss when only a small proportion of variants are causal, and their powers can be sensitive to the number, effect sizes and effect directions of the causal variants and the choices of weights. Here we propose an Aggregated Cauchy Association Test (ACAT), a general, powerful and computationally efficient p-value combination method to boost power in sequencing studies. First, by combining variant-level p-values, we use ACAT to construct a set-based test (ACAT-V) that is particularly powerful in the presence of only a small number of casual variants in a variant set. Second, by combining different variant set-level p-values, we use ACAT to construct an omnibus test (ACAT-O) that combines the strength of multiple complimentary set-based tests including the burden test, Sequence Kernel Association Test (SKAT) and ACAT-V. Through analysis of extensively simulated data and the whole-genome sequencing data from the Atherosclerosis Risk in Communities (ARIC) study, we demonstrate that ACAT-V complements the SKAT and burden test, and that ACAT-O has a substantially more robust and higher power than the alternative tests.
Genetic differentiation and intrinsic genomic features explain variation in recombination hotspots among cocoa tree populations
Authors: Schwarzkopf Enrique J. , Motamayor Juan C. , Cornejo Omar E. 
Published: November 2018

AbstractOur study investigates the possible drivers of recombination hotspots inTheobroma cacaousing ten genetically differentiated populations. By comparing recombination patterns between multiple populations, we obtain a novel view of recombination at the population-divergence timescale. For each population, a fine-scale recombination map was generated using the coalescent with a standard method based on linkage disequilibrium (LD). These maps revealed higher recombination rates in a domesticated population and a population that has undergone a recent bottleneck. We inferred hotspots of recombination for each population and find that the genomic locations of hotspots correlate with genetic differentiation between populations (FST). We used randomization approaches to generate appropriate null models to understand the association between hotspots of recombination and both DNA sequence motifs and genomic features. We found that hotspot regions contained fewer known retroelement sequences than expected and were overrepresented near transcription start and termination sites. Our findings indicate that recombination hotspots are evolving in a way that is consistent with genetic differentiation but are also preferentially driven to near coding regions. We illustrate that, consistent with predictions in plant domestication, the recombination rate of the domesticated population is orders of magnitude higher than that of other populations. More importantly, we find two fixed mutations in the domesticated population’s FIGL1 protein. FIGL1 has been shown to increase recombination rates inArabidopsisby several orders of magnitude, suggesting a possible mechanism for the observed increased recombination rate in the domesticated population.
A Network based Approach to Identify the Genetic Influence Caused by Associated Factors and Disorders for the Parkinsons Disease Progression
Authors: Sakib Najmus , Chowdhury Utpala Nanda , Islam M. Babul , Quinn Julian M.W. , Moni Mohammad Ali 
Published: November 2018

AbstractActual causes of Parkinsons disease (PD) are still unknown. In any case, a better comprehension of genetic and ecological influences to the PD and their interaction will assist physicians and patients to evaluate individual hazard for the PD, and definitely, there will be a possibility to find a way to reduce the progression of the PD. We introduced quantitative frameworks to reveal the complex relationship of various biasing genetic factors for the PD. In this study, we analyzed gene expression microarray data from the PD, ageing (AG), severe alcohol consumption (AC), type II diabetes (T2D), high body fat (HBF), hypercholesterolemia (HC), high dietary fat (HDF), red meat dietary (RMD), sedentary lifestyle (SL), smoking (SM), and control datasets. We have developed genetic associations of various factors with the PD based on the neighborhood-based benchmarking and multilayer network topology.We identified 1343 significantly dysregulated genes in the PD patients compared to the healthy control, where we have 779 genes down regulated and 544 genes up regulated. 69 genes were highly expressed in both for the PD and alcohol consumption whereas the number of shared genes for the PD and the type II diabetes is 51. However, the PD shared 45, 43 and 42 significantly expressed genes with the ageing, high dietary fat and high body fat respectively. The PD shared less than 40 significant transcripts with other factors. Ontological and pathway analyses have identified significant gene ontology and molecular pathways that enhance our understanding of the fundamental molecular procedure of the PD progression. Therapeutic targets of the PD could be developed using these identified target genes, ontologies and pathways. Our formulated methodologies demonstrate a network-based approach to understand the disease mechanism and the causative reason of the PD, and the identification for therapeutic targets of the PD.
Molecular fingerprints for a novel glucosamine kinase family inActinobacteria
Authors: Manso José A , Nunes-Costa Daniela , Macedo-Ribeiro Sandra , Empadinhas Nuno , Pereira Pedro José Barbosa 
Published: November 2018

AbstractActinobacteriahave long been the main source of antibiotics, secondary metabolites with tightly controlled biosynthesis by environmental and physiological factors. Phosphorylation of exogenous glucosamine has been suggested as a mechanism for incorporation of this extracellular material into secondary metabolite biosynthesis, but experimental evidence of specific glucosamine kinases inActinobacteriais lacking. Here, we present the molecular fingerprints for the identification of a unique family of actinobacterial glucosamine kinases. Structural and biochemical studies on a distinctive kinase from the soil bacteriumStreptacidiphilus jiangxiensisunveiled its preference for glucosamine and provided structural evidence of a phosphoryl transfer to this substrate. Conservation of glucosamine-contacting residues across a large number of uncharacterized actinobacterial proteins unveiled a specific glucosamine-binding sequence motif. This family of kinases and their genetic context may represent the missing link for the incorporation of environmental glucosamine into the antibiotic biosynthesis pathways inActinobacteriaand can be explored to enhance antibiotic production.
Structural basis of Cullin-2 RING E3 ligase regulation by the COP9 signalosome
Authors: Faull Sarah V. , Lau Andy. M. C. , Martens Chloe , Ahdash Zainab , Yebenes Hugo , Schmidt Carla , Beuron Fabienne , Cronin Nora B. , Morris Edward P. , Politis Argyris 
Published: November 2018

SUMMARYCullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 (N8) from activated Cullins. The structure of stable CSN-CRL can be used to understand this mechanism of regulation. Here we present the first structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (MS). These structures reveal a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen deuterium exchange-MS we show that CRL2 binding and conformational activation of CSN5/CSN6 occur in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identified novel sensory regions of the CSN that mediate its stepwise activation mechanism and provide a framework for better understanding the regulatory mechanism of other Cullin family members.One sentence summaryStructure and dynamics of the CSN-CRL2 complexes assessed by cryo-electron microscopy and structural mass spectrometry.
The fine-scale landscape of immunity and parasitism in a wild ungulate population
Authors: Albery Gregory F. , Becker Daniel J. , Kenyon Fiona , Nussey Daniel H. , Pemberton Josephine M. 
Published: November 2018

AbstractSpatial heterogeneity in parasite susceptibility and exposure is a common source of confounding variation in disease ecology studies. However, it is not known whether spatial autocorrelation acts on immunity in particular at small scales, within wild animal populations, and whether this predicts spatial patterns in infection. Here we used a well-mixed wild population of individually recognised red deer (Cervus elaphus) inhabiting a heterogeneous landscape to investigate fine-scale spatial patterns of immunity and parasitism. We noninvasively collected 842 faecal samples from 141 females with known ranging behaviour over two years. We quantified total and helminth-specific mucosal antibodies and counted propagules of three gastrointestinal helminth taxa. These data were analysed with linear mixed models using the Integrated Nested Laplace Approximation (INLA), using a Stochastic Partial Differentiation Equation approach (SPDE) to control for and quantify spatial autocorrelation. We also investigated whether spatial patterns of immunity and parasitism changed seasonally. We discovered substantial spatial heterogeneity in general and helminth-specific antibody levels and parasitism with two helminth taxa, all of which exhibited contrasting seasonal variation in their spatial patterns. Notably, strongyle nematode intensity did not align with density hotspots, while Fasciola hepatica intensity appeared to be strongly influenced by the presence of wet grazing. In addition, antibody hotspots did not correlate with distributions of any parasites. Our results suggest spatial heterogeneity may be an important factor affecting immunity and parasitism in a wide range of study systems. We discuss these findings with regards to the design of sampling regimes and public health interventions, and suggest that disease ecology studies investigate spatial heterogeneity more regularly to enhance their results, even when examining small geographic areas.