bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of nanobody-recognition of grapevine fanleaf virus and of virus resistance loss
Authors: Orlov Igor , Hemmer Caroline , Ackerer Léa , Lorber Bernard , Ghannam Ahmed , Poignavent Vianney , Hleibieh Kamal , Sauter Claude , Schmitt-Keichinger Corinne , Belval Lorène , Hily Jean-Michel , Marmonier Aurélie , Komar Véronique , Gersch Sophie , Schellenberger Pascale , Bron Patrick , Vigne Emmanuelle , Muyldermans Serge , Lemaire Olivier , Demangeat Gérard , Ritzenthaler Christophe , Klaholz Bruno P. 
Published: August 2019

AbstractGrapevine fanleaf virus (GFLV) is a picorna-like plant virus transmitted by nematodes that affects vineyards worldwide. Nanobody (Nb)-mediated resistance against GFLV has been created recently and shown to be highly effective in plants including grapevine, but the underlying mechanism is unknown. Here we present the high-resolution cryo-EM structure of the GFLV-Nb23 complex which provides the basis for the molecular recognition by the nanobody. The structure reveals a composite binding site bridging over 3 domains of the capsid protein (CP) monomer. The structure provides a precise mapping of the Nb23 epitope on the GFLV capsid in which the antigen loop is accommodated through an induced fit mechanism. Moreover, we uncover and characterize several resistance-breaking GFLV isolates with amino acids mapping within this epitope, including C-terminal extensions of the CP, which would sterically interfere with Nb binding. Escape variants with such extended CP fail to be transmitted by nematodes linking Nb-mediated resistance to vector transmission. Together, these data provide insights into the molecular mechanism of Nb23-mediated recognition of GFLV and of virus resistance loss.SignificanceGrapevine fanleaf virus (GFLV) is a picorna-like plant virus that severely impacts vineyards worldwide. While Nanobodies (Nb) confer resistance to GFLV in plants the underlying molecular mechanism of action is unknown. Here we present the high-resolution cryo-EM structure of the GFLV-Nb complex. It uncovers the conformational epitope on the capsid surface which is a composite binding site into which the antigen loop is accommodated through an induced fit mechanism. Furthermore, we describe several resistance-breaking isolates of GFLV with reduced Nb binding capacity. Those that carry a C-terminal extension also fail to be transmitted by nematodes. Together, these data provide structure-function insights into the Nb-GFLV recognition and the molecular mechanism leading to loss of resistance.
Large-scale pan-cancer analysis reveals broad prognostic association between TGF-β ligands, not Hedgehog, and GLI1/2 expression in tumors
Authors: de Reyniès Aurélien , Javelaud Delphine , Elarouci Nabila , Marsaud Véronique , Gilbert Cristèle , Mauviel Alain 
Published: August 2019

AbstractGLI1expression is broadly accepted as a marker of Hedgehog pathway activation in tumors. Efficacy of Hedgehog inhibitors is essentially limited to tumors bearing activating mutations of the pathway. GLI2, a critical Hedgehog effector, is necessary forGLI1expression and is a direct transcriptional target of TGF-β/SMAD signaling. We examined the expression correlations of GLI1/2 withTGFBandHHgenes in 152 distinct transcriptome datasets totaling over 23,500 patients and representing 37 types of neoplasms. Their prognostic value was measured in over 15,000 clinically annotated tumor samples from 26 tumor types. In most tumor types,GLI1andGLI2follow a similar pattern of expression and are equally correlated withHHandTGFBgenes. However,GLI1/2broadly share prognostic value withTGFBgenes and a mesenchymal/EMT signature, not withHHgenes. Our results provide a likely explanation for the frequent failure of anti-Hedgehog therapies in tumors, as they suggest a key role for TGF-β, not Hedgehog, ligands, in tumors with elevatedGLI1/2-expression.
Density-dependent effects of mortality on the optimal body size of a habitat shift: Why smaller is better despite increased mortality risk?
Authors: Chaparro-Pedraza P. Catalina , de Roos André M. 
Published: August 2019

AbstractMany animal species across different taxa change their habitat during their development. An ontogenetic habitat shift enables the development of early vulnerable-to-predation stages in a safe ‘nursery’ habitat with reduced predation mortality, while less vulnerable stages can exploit a more risky, rich feeding habitat. Therefore, the timing of the habitat shift is crucial for individual fitness. We investigate the effect that size-selectivity in mortality in the rich feeding habitat has on the optimal timing of the habitat shift using a population model and the adaptive dynamics approach. We show that the size-selective nature of mortality in this habitat affects density-dependent body growth rate in the nursery habitat and thus the optimal timing of the habitat shift. This is caused by the effect exerted by size-dependent mortality on the size distribution of the population that results in strong competition in the nursery habitat. We furthermore find that, as a consequence of this effect, increased size-selectivity in mortality in the rich feeding habitat causes the optimal body size to shift habitat to decrease. Our results reveal the interdependence between population structure and life history traits, and highlight the need for integrating ecological interactions in the study of the evolution of life histories.
Complete genome assemblies for three variants of the Wolbachia endosymbiont of Drosophila melanogaster
Authors: Basting Preston J. , Bergman Casey M. 
Published: August 2019

ABSTRACTHere we report genome assemblies for three strains of Wolbachia pipientis assembled from unenriched, unfiltered long-read shotgun sequencing data of geographically distinct strains of Drosophila melanogaster. Our simple methodology can be applied to long-read datasets of other Wolbachia-infected species to produce complete assemblies for this important model symbiont.
AAV-mediated gene augmentation therapy restores critical functions in mutant iPSC-derived PRPF31+/- cells
Authors: Brydon Elizabeth M. , Bronstein Revital , Buskin Adriana , Lako Majlinda , Pierce Eric A. , Fernandez-Godino Rosario 
Published: August 2019

ABSTRACTRetinitis pigmentosa (RP) is the most common form of inherited vision loss and is characterized by degeneration of retinal photoreceptor cells and the retinal pigment epithelium (RPE). Mutations in pre-mRNA processing factor 31 (PRPF31) cause dominant RP via haploinsufficiency with incomplete penetrance. There is good evidence that the diverse severity of this disease is a result of differing levels of expression of the wild type allele among patients. Thus, we hypothesize that PRPF31-related RP will be amenable to treatment by adeno-associated virus (AAV)-mediated gene augmentation therapy. To test this hypothesis, we used induced pluripotent stem cells (iPSC) with mutations in PRPF31 and differentiated them into RPE cells. The mutant PRPF31 iPSC-RPE cells recapitulate the cellular phenotype associated with the PRPF31 pathology, including defective cell structure, diminished phagocytic function, defects in ciliogenesis, and compromised barrier function. Treatment of the mutant PRPF31 iPSC-RPE cells with AAV-PRPF31 restored normal phagocytosis and cilia formation, and partially restored structure and barrier function. These results provide proof-of concept that AAV-based gene therapy can be used to treat patients with PRPF31-related RP.
A Sense of Place: Transcriptomics Identifies Environmental Signatures in Cabernet Sauvignon Berry Skins in the Late Stages of Ripening
Authors: Cramer Grant R. , Cochetel Noé , Ghan Ryan , Destrac-Irvine Agnès , Delrot Serge 
Published: August 2019

AbstractBackgroundGrape berry ripening is influenced by climate, the main component of the “terroir” of a place. Light and temperature are major factors in the vineyard that affect berry development and fruit metabolite composition.ResultsTo better understand the effect of “place” on transcript abundance during the late stages of berry ripening, Cabernet Sauvignon berries grown in Bordeaux and Reno were compared at similar sugar levels (19 to 26 °Brix (total soluble solids)). Day temperatures were warmer and night temperatures were cooler in Reno. °Brix was lower in Bordeaux berries compared to Reno at maturity levels considered optimum for harvest. RNA-Seq analysis identified 5528 differentially expressed genes between Bordeaux and Reno grape skins at 22°Brix. Weighted Gene Coexpression Network Analysis for all expressed transcripts for all four °Brix levels measured indicated that the majority (75%) of transcript expression differed significantly between the two locations. Top gene ontology categories for the common transcript sets were translation, photosynthesis, DNA metabolism and catabolism. Top gene ontology categories for the differentially expressed genes at 22°Brix involved response to stimulus, biosynthesis and response to stress. Some differentially expressed genes encoded terpene synthases, cell wall enzymes, kinases, transporters, transcription factors and photoreceptors. Most circadian clock genes had higher transcript abundance in Bordeaux. Bordeaux berries had higher transcript abundance with differentially expressed genes associated with seed dormancy, light, auxin, ethylene signaling, powdery mildew infection, phenylpropanoid, carotenoid and terpenoid metabolism, whereas Reno berries were enriched with differentially expressed genes involved in water deprivation, cold response, ABA signaling and iron homeostasis.ConclusionsTranscript abundance profiles in the berry skins at maturity were highly dynamic. RNA-Seq analysis identified a smaller (25% of total) common core set of ripening genes that appear not to depend on rootstock, vineyard management, plant age, soil and climatic conditions. Much of the gene expression differed between the two locations and could be associated with multiple differences in environmental conditions that may have affected the berries in the two locations; some of these genes may be potentially controlled in different ways by the vinegrower to adjust final berry composition and reach a desired result.
Small molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease
Authors: Heller Gabriella T. , Aprile Francesco A. , Michaels Thomas C. T. , Limbocker Ryan , Perni Michele , Ruggeri Francesco Simone , Mannini Benedetta , Löhr Thomas , Bonomi Massimiliano , Camilloni Carlo , De Simone Alfonso , Felli Isabella C. , Pierattelli Roberta , Knowles Tuomas P. J. , Dobson Christopher M. , Vendruscolo Michele 
Published: August 2019

AbstractDisordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that has been shown to modify the properties of their monomeric states. Here, we identify a small molecule capable of binding and sequestering the amyloid-β peptide (Aβ) in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterise this interaction using biophysical experiments and integrative structural ensemble determination methods. We thus observe that this small molecule has the remarkable effect of increasing the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. We then show that this small molecule rescues a Caenorhabditis elegans model of Aβ-associated toxicity in a manner consistent with the mechanism of action identified from the in silico and in vitro studies. These results provide an illustration of the strategy of targeting the monomeric states of disordered proteins with small molecules to alter their behaviour for therapeutic purposes.
Volatile molecules secreted by the wheat pathogenParastagonospora nodorumare involved in development and phytotoxicity
Authors: Muria-Gonzalez M. Jordi , Yeannie Yap Hui Yeng , Breen Susan , Mead Oliver , Wang Chen , Chooi Yit-Heng , Barrow Russell A. , Solomon Peter S. 
Published: August 2019

AbstractSeptoria nodorum blotch is a major disease of wheat caused by the fungusParastagonospora nodorum. Recent studies have demonstrated that secondary metabolites, including polyketides and non-ribosomal peptides, produced by the pathogen play important roles in disease and development. However, there is currently no knowledge on the composition or biological activity of the volatile organic compounds (VOCs) secreted byP. nodorum. To address this, we undertook a series of growth and phytotoxicity assays and demonstrated thatP. nodorumVOCs inhibited bacterial growth, were phytotoxic and suppressed self-growth. Mass spectrometry analysis revealed that 3-methyl-1-butanol, 2-methyl-1-butanol, 2-methyl-1-propanol and 2-phenylethanol were dominant in the VOC mixture and phenotypic assays using these short chain alcohols confirmed that they were phytotoxic. Further analysis of the VOCs also identified the presence of multiple sesquiterpenes of which four were identified via mass spectrometry and nuclear magnetic resonance as β-elemene, α-cyperone, eudesma-4,11-diene and acora-4,9-diene. Subsequent reverse genetics studies were able to link these molecules to corresponding sesquiterpene synthases in theP. nodorumgenome. However, despite extensive testing, these molecules were not involved in either of the growth inhibition or phytotoxicity phenotypes previously observed. Plant assays using mutants of the pathogen lacking the synthetic genes revealed that the identified sesquiterpenes were not required for disease formation on wheat leaves. Collectively, these data have significantly extended our knowledge of the VOCs in fungi and provided the basis for further dissecting the roles of sesquiterpenes in plant disease.
Difference in context-dependency between orienting and defense-like responses induced by the superior colliculus
Authors: Isa Kaoru , Sooksawate Thongchai , Kobayashi Kenta , Kobayashi Kazuto , Redgrave Peter , Isa Tadashi 
Published: August 2019

AbstractPrevious electrical stimulation and lesion experiments have suggested that the crossed descending output pathway from the deeper layers (SCd) of superior colliculus (SC) controls orienting responses, while the uncrossed pathway mediates defense-like behavior. Here we extended these investigations by using selective optogenetic activation of each pathway in mice with channelrhodopsin 2 expression by double viral vector techniques. Brief photo-stimulation of the crossed pathway evoked short latency contraversive orienting-like head turns, while extended stimulation induced contraversive circling responses. In contrast, stimulation of uncrossed pathway induced short-latency upward head movements followed by longer-latency defense-like behaviors including retreat and flight. The novel discovery was that the evoked defense-like responses varied depending on the environment, suggesting that uncrossed output can be influenced by top-down modification of the SC or its downstream. This further suggests that the SCd-defense system can be profoundly modulated by non-motor, affective and cognitive components, in addition to direct sensory inputs.
Differential detection of Entamoeba species in stool samples collected from children in District Swat, Khyber Pakhtunkhwa Pakistan
Authors: Khan Muhammad Iftikhar , Shams Sumaira , Khan Asar , Akbar Ali , Muhammad Ijaz , Ullah Atta , Inam Muhammad , Ali Abid 
Published: August 2019

AbstractBackgroundAmoebiasis is an intestinal disease caused by enteric protozoan called Entamoeba histolytica belongs to the Genus Entamoeba. The main reason of infection is the contamination of food and water due to the poor sanitation. Among Entamoeba species, Entamoeba histolytica is highly pathogenic while the other species are non-pathogenic and needs no medical treatment.MethodologyA total of 400 stool samples were collected from different areas of district Swat and were processed for screening of amoebic cells. Microscopically identified samples containing amoebic cells were stored at −20 °C till DNA extraction. Extracted DNA was used in a PCR reaction with specific reference primers to amplify the target DNA.ResultsOut of all 400 stool samples 111 (27.7%) were found positive through microscopy while PCR reaction confirmed 80 out of microscope positive samples. Among 80 PCR positive samples, the infection with Entamoeba dispar was most common (57.5%) followed by E. histolytica (47.5%) and Entamoeba moshkovskii (20%). The positive cases for mono-infection of E. dispar were 33 (41.25%), followed by E.histolytica 25 (31.25%) and E. moshkovskii 7 (8.75%). The co-infection of E. histolytica with E. dispar and E. moshkovskii was 6 (7.5%) and 2 (2.5%), respectively. Similarly the co-infection of Entamoeba dispar with Entamoeba moshkovskii was also 2 (2.5%) while 5 (6.25%) samples were observed with mixed infection of E. histolytica, E. dispar and E. moshkovskii.Significance of the studyThe aim of the study was to detect and differentiate the E. histolytica, Entamoeba dispar and Entamoeba moshkovskii using conventional microscopy and polymerase chain reaction. The results suggested that the use of PCR is necessary to differentiate E. histolytica from E. dispar and E. moshkovskii and therefore, to avoid unnecessary treatment the present study recommend the use of PCR for the routine diagnosis of amoebiasis in the study area. It is also suggested that further studies from this area may also facilitate the understanding of genetic diversity of these pathogens.
Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine
Authors: de Pins Benoit , Montalban Enrica , Vanhoutte Peter , Giralt Albert , Girault Jean-Antoine 
Published: August 2019

AbstractThe striatum is a critical brain region for locomotor response to cocaine. Although the D1 receptor-expressing neurons are centrally involved in mediating the locomotor effects of cocaine, the molecular pathways controlling this response are not fully understood. Here we studied the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase, in striatum-related functions. We discovered that cocaine injection increases Pyk2 phosphorylation in the striatum of mice in vivo. Pyk2-deficient mice displayed an altered locomotor response to acute cocaine injection. In contrast, they developed normal locomotor sensitization and cocaine-conditioned place preference. Accordingly, a cocaine-activated signaling pathway essential for these late responses, ERK phosphorylation, was not altered. Specific deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced this phenotype, whereas deletion of Pyk2 in the dorsal striatum or in A2A receptor-expressing neurons did not. Mice lacking Pyk2 in D1-neurons also displayed lower locomotor response to the D1 receptor agonist SKF-81297 but not to an anticholinergic drug. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action.
Domain model explains propagation dynamics and stability of K27 and K36 methylation landscapes
Authors: Alabert C. , Loos C. , Voelker-Albert M. , Graziano S. , Forné I. , Reveron-Gomez N. , Schuh L. , Hasenauer J. , Marr C. , Imhof A. , Groth A. 
Published: August 2019

SUMMARYChromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle and the principles governing heritability remain unclear. Here, we take a quantitative computational modeling approach to describes propagation of K27 and K36 methylation states. We measure combinatorial K27 and K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that K27me3 on pre-existing histones stimulates the rate of de novo K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed, quantitative picture of the mutual antagonism between K27 and K37 methylation, and propose that it stabilizes epigenetic states across cell division.
Seeking an ecologically defensible calculation of net loss/gain of biodiversity
Authors: Cuckston Thomas 
Published: August 2019

PurposeThe purpose of this paper is to explain how proponents of biodiversity offsetting have sought to produce an ecologically defensible mechanism for reconciling economic development and biodiversity conservation.Design/methodology/approachThe paper analyses a case study biodiversity offsetting mechanism in New South Wales, Australia. Michel Callon’s framing and overflowing metaphor is used to explain how accounting devices are brought into the mechanism, to (re)frame a space of calculability and address anxieties expressed by conservationists about calculations of net loss/gain of biodiversity.FindingsThe analysis shows that the offsetting mechanism embeds a form of accounting for biodiversity that runs counter to the prevailing dominant anthropocentric approach. Rather than accounting for the biodiversity of a site in terms of the economic benefits it provides to humans, the mechanism accounts for biodiversity in terms of its ecological value. This analysis, therefore, reveals a form of accounting for biodiversity that uses numbers to provide valuations of biodiversity, but these numbers are ecological numbers, not economic numbers. So this is a calculative, and also ecocentric, approach to accounting for, and valuing, biodiversity.Originality/valueThis paper contributes to the extant literature on accounting for biodiversity by revealing a novel conceptualisation of the reconciliation of economic development and biodiversity conservation, producing an ecologically defensible form of sustainable development. The paper also makes a methodological contribution by showing how Callon’s framing and overflowing metaphor can be used to enable the kind of interdisciplinary engagement needed for researchers to address sustainable development challenges.