bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sick plants in grassland communities: a growth-defense trade-off is the main driver of fungal pathogen abundance and impact
Authors: Cappelli Seraina L. , Pichon Noémie A. , Kempel Anne , Allan Eric 
Published: October 2019

ABSTRACTAboveground fungal pathogens can substantially reduce biomass production in grasslands. However, we lack a mechanistic understanding of the drivers of fungal infection and impact. Using a global change biodiversity experiment we show that the trade-off between plant growth and defense is the main determinant of fungal infection in grasslands. Nitrogen addition only indirectly increased infection via shifting plant communities towards more fast growing species. Plant diversity did not decrease infection, likely because the spillover of generalist pathogens or dominance of susceptible species counteracted dilution effects. There was also evidence that fungal pathogens reduced biomass more strongly in diverse communities. Further, fungicide altered plant-pathogen interactions beyond just removing pathogens, probably by removing certain fungi more efficiently than others. Our results show that fungal pathogens have large effects on plant functional composition and biomass production and highlight the importance of considering changes in pathogen community composition to understand their effects.
Succession of physiological stages hallmarks the transcriptomic response of fungusAspergillus nigerto lignocellulose
Authors: van Munster Jolanda M. , Daly Paul , Blythe Martin J. , Ibbett Roger , Kokolski Matt , Gaddipati Sanyasi , Lindquist Erika , Singan Vasanth R. , Barry Kerrie W. , Lipzen Anna , Ngan Chew Yee , Petzold Christopher J. , Chan Leanne Jade G. , Arvas Mikko , Raulo Roxane , Pullan Steven T. , Delmas Stéphane , Grigoriev Igor V. , Tucker Gregory A. , Simmons Blake A. , Archer David B. 
Published: October 2019

AbstractBackgroundUnderstanding how fungi degrade lignocellulose is a cornerstone of improving renewables-based biotechnology, in particular for the production of hydrolytic enzymes. Considerable progress has been made in investigating fungal degradation during time-points where CAZyme expression peaks. However, a robust understanding of the fungal survival strategies over its life time on lignocellulose is thereby missed. Here we aimed to uncover the physiological responses of the biotechnological workhorse and enzyme producerAspergilllus nigerover its life time to six substrates important for biofuel production.ResultsWe analysed the response ofA. nigerto the feedstockMiscanthusand compared it with our previous study on wheat straw, alone or in combination with hydrothermal or ionic liquid feedstock pretreatments. Conserved (substrate-independent) metabolic responses as well as those affected by pretreatment and feedstock were identified via multivariate analysis of genome-wide transcriptomics combined with targeted transcript and protein analyses and mapping to a metabolic model. Initial exposure to all substrates increased fatty acid beta-oxidation and lipid metabolism transcripts. In a strain carrying a deletion of the ortholog of theAspergillus nidulansfatty acid beta-oxidation transcriptional regulatorfarA, there was a reduction in expression of selected lignocellulose degradative CAZyme-encoding genes suggesting that beta-oxidation contributes to adaptation to lignocellulose. Mannan degradation expression was wheat straw feedstock-dependent and pectin degradation was higher on the untreated substrates. In the later life stages, known and novel secondary metabolite gene clusters were activated, which are of high interest due to their potential to synthesize bioactive compounds.ConclusionIn this study, which includes the first transcriptional response of Aspergilli toMiscanthus, we highlighted that life time as well as substrate composition and structure (via variations in pretreatment and feedstock) influence the fungal responses to lignocellulose. We also demonstrated that the fungal response contains physiological stages that are conserved across substrates and are typically found outside of the conditions with high CAZyme expression, as exemplified by the stages that are dominated by lipid and secondary metabolism.
Studying POU2F1 to Unveil the Structural Facet for Pan-Cancer Analysis Considering the Functional Annotations and Sequence-Structure Space Paradigm
Authors: Dey A. , Sen S. , Maulik U. 
Published: October 2019

ABSTRACTPOU domain class 2 homebox 1 (POU2F1) is largely known for its transcription factor(TF) activity. Due to its association with different types of malignancies, POU2F1 becomes one of the key factors in pan-cancer analysis. However, in spite of understanding it as a potential drug target, none of the drug has been designed till date due to its extreme dynamicity. In this article, we have proposed a three fold comprehensive framework for understanding the structural conservation and co-variation of POU2F1. Firstly, a gene regulatory network based non-pathogenic and pathogenic study have been performed to understand the strong association between cancers and POU2F1. After that, based on evolutionary sequence space study, the comparative sequential dynamicity of the protein members of POU domain family has been observed mostly between non-human and human samples. Subsequently, the reciprocity effect of the residual co-variation has been identified through direct coupling analysis. Along with that, the structure of POU2F1 has been analysed depending on quality assessment and normal mode based structure network. Comparing the sequence and structure space information, the most significant set of residue viz., 3, 9, 13, 17, 20, 21, 28, 35, 36 have been identified as structural facet for stable binding. It is observed that targeting these residues can help to prevent the monomeric aggregations. This study demonstrates-the observed malleability of POU2F1 is one of the prime reason behind its functional multiplicity in terms of protein moonlighting.SIGNIFICANCEPOU2F1 is one of the important TFs associated with several malignancies. In spite of orderly stable structure in primitive family proteins, this protein is highly unstable at the monomeric stage. Previous studies show that POU2F1 has a clear association with 121 different diseases. Therefore, it becomes one of the important links in the pan-cancer study. Interestingly, TFs can be considered as a potential drug target. However, it is hardly possible to control the extreme dynamicity of TFs. In this regard, protein moonlighting plays an important role. We have tried to provide a theoretical frame to build understanding on POU2F1. The study provides pathogenic and non-pathogenic connections of the protein in terms of comprehensive and precise Gene Regulatory Network. Subsequently, the instability has been unveiled and the structural facet has been identified. Finally, the specified set of function for a suitable session to target the protein is analyzed based on protein moonlighting properties.
Association between DNA methylation and ADHD symptoms from birth to school age: A prospective meta-analysis
Authors: Neumann Alexander , Walton Esther , Alemany Silvia , Cecil Charlotte , González Juan Ramon , Jima Dereje D. , Lahti Jari , Tuominen Samuli T. , Barker Edward D. , Binder Elisabeth , Caramaschi Doretta , Carracedo Ángel , Czamara Darina , Evandt Jorunn , Felix Janine F. , Fuemmeler Bernard F. , Gutzkow Kristine B. , Hoyo Cathrine , Julvez Jordi , Kajantie Eero , Laivuori Hannele , Maguire Rachel , Maitre Léa , Murphy Susan K. , Murcia Mario , Villa Pia M. , Sharp Gemma , Sunyer Jordi , Raikkönen Katri , Bakermans-Kranenburg Marian , van IJzendoorn Marinus , Guxens Mònica , Relton Caroline L. , Tiemeier Henning 
Published: October 2019

ABSTRACTAttention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is not known. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school-age. We examined associations of DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age range 4-15 years) in 2477 children from five cohorts and DNA methylation at school-age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from ten cohorts. CpGs identified with nominal significance (p<0.05) in either of the EWAS were correlated between timepoints (ρ=0.30), suggesting overlap in associations, however, top signals were very different. At birth, we identified nine CpGs that were associated with later ADHD symptoms (P<1*10−7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 located in the promotor region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which was associated with neurite outgrowth and an ADHD diagnosis in previous studies. In contrast, at school-age, no CpGs were associated with ADHD with P<1*10−7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.
Presynaptic inhibition of cutaneous afferents prevents self-generated itch
Authors: Escalante Augusto , Klein Rüdiger 
Published: October 2019

SummaryChronic itch represents an incapacitating burden on patients suffering a wide spectrum of diseases. Despite recent advances in our understanding of the cells and circuits implicated in the processing of itch information, chronic itch often presents itself without apparent cause. Here, we identify a spinal subpopulation of inhibitory neurons defined by the expression of Ptf1a involved in gating mechanosensory information self-generated during movement. These neurons receive tactile and motor input and establish presynaptic inhibitory contacts on mechanosensory afferents. Loss of Ptf1a neurons leads to increased hairy skin sensitivity and chronic itch, at least partially mediated through the classic itch pathway involving gastrin releasing peptide receptor (GRPR) spinal neurons. Conversely, chemogenetic activation of GRPR neurons elicits itch which is suppressed by concomitant activation of Ptf1a neurons. These findings shed new light on the circuit mechanisms implicated in chronic itch and open novel targets for therapy developments.Highlights*Ptf1a specifies adult spinal presynaptic neurons contacting cutaneous afferents*Loss of spinal Ptf1a+ neurons leads to self-generated itch and excessive grooming*Absence of Ptf1a+ neurons increases hairy skin sensitivity which triggers scratching*GRPR+ neurons act downstream of Ptf1a+ neurons in spontaneous itch
Deaminase associated single nucleotide variants in blood and saliva-derived exomes from healthy subjects
Authors: Hall Nathan E. , Mamrot Jared , Frampton Christopher M.A. , Read Prue , Steele Edward J. , Bischof Robert J. , Lindley Robyn A. 
Published: October 2019

AbstractBackgroundDeaminases play an important role in shaping inherited and somatic variants. Disease related SNVs are associated with deaminase mutagenesis and genome instability. Here, we investigate the reproducibility and variance of whole exome SNV calls in blood and saliva of healthy subjects and analyze variants associated with AID, ADAR, APOBEC3G and APOBEC3B deaminase sequence motifs.MethodsSamples from twenty-four healthy Caucasian volunteers, allocated into two groups, underwent whole exome sequencing. Group 1 (n=12) analysis involved one blood and four saliva replicates. A single saliva sample was sequenced for Group 2 subjects (n=12). Overall, a total of 72 whole exome datasets were analyzed. Biological (Group 1 & 2) and technical (Group 1) variance of SNV calls and deaminase metrics were calculated and analyzed using intraclass correlation coefficients. Candidate somatic SNVs were identified and evaluated.ResultsWe report high blood-saliva concordance in germline SNVs from whole exome sequencing. Concordant SNVs, found in all subject replicates, accounted for 97% of SNVs located within the protein coding sequence of genes. Discordant SNVs have a 30% overlap with variants that fail gnomAD quality filters and are less likely to be found in dbSNP. SNV calls and deaminase-associated metrics were found to be reproducible and robust (intraclass correlation coefficients >0.95). No somatic SNVs were conclusively identified when comparing blood and saliva samples.ConclusionsSaliva and blood both provide high quality sources of DNA for whole exome sequencing, with no difference in ability to resolve SNVs and deaminase-associated metrics. We did not identify somatic SNVs when comparing blood and saliva of healthy individuals, and we conclude that more specialized investigative methods are required to comprehensively assess the impact of deaminase activity on genome stability in healthy individuals.
Genetic design automation for autonomous formation of multicellular shapes from a single cell progenitor
Authors: Appleton Evan , Mehdipour Noushin , Daifuku Tristan , Briers Demarcus , Haghighi Iman , Moret Michael , Chao George , Wannier Timothy , Chiappino-Pepe Anush , Huang Jeremy , Belta Calin , Church George 
Published: October 2019

AbstractMulti-cellular organisms originate from a single cell, ultimately giving rise to mature organisms of heterogeneous cell type composition in complex structures. Recent work in the areas of stem cell biology and tissue engineering have laid major groundwork in the ability to convert certain types of cells into other types, but there has been limited progress in the ability to control the morphology of cellular masses as they grow. Contemporary approaches to this problem have included the use of artificial scaffolds, 3D bioprinting, and complex media formulations, however, there are no existing approaches to controlling this process purely through genetics and from a single-cell starting point. Here we describe a computer-aided design approach for designing recombinase-based genetic circuits for controlling the formation of multi-cellular masses into arbitrary shapes in human cells.
High throughput CRISPR screening identifies genes involved in macrophage viability and inflammatory pathways
Authors: Covarrubias Sergio , Vollmers Apple , Capili Allyson , Boettcher Michael , Robinson Elektra K. , O’Briain Laura , Vollmers Christopher , Blau James , McManus Michael , Carpenter Susan 
Published: October 2019

AbstractMacrophages are critical cells of the innate immune system involved in the recognition and destruction of invading microbes in addition to the resolution of inflammation and maintenance of homeostasis. Understanding the genes involved in all aspects of macrophage biology is essential to gaining new insights into immune system dysregulation during diseases that range from autoinflammatory to cancer. Here we utilize high throughput clustered regularly interspaced short palindromic repeats (CRISPR) screening to generate a resource that identifies genes required for macrophage viability and function. First, we employ a pooled based CRISPR/Cas nuclease active screening approach to identify essential genes required for macrophage viability by targeting genes within coding exons. In addition, we also target 3’UTRs to gain insights into newcis-regulatory regions that control expression of these essential genes. Second, using our recently generated NF-κB reporter macrophage line, we perform a fluorescence-activated cell sorting (FACS)-based high-throughput genetic screen to identify regulators of inflammation. We identify a number of novel positive and negative regulators of the NF-κB pathway as well as unraveling complexities of the TNF signaling cascade showing it can function in an autocrine manner to negatively regulate the pathway. Utilizing a single complex library design we are capable of interrogating various aspects of macrophage biology, generating a resource for future studies.Author SummaryExcess inflammation is associated with a variety of autoimmune diseases and cancers. Macrophages are important mediators of this inflammatory response. Defining the genes involved in their viability and effector function is needed to completely understand these two important aspects of macrophage biology. Here we screened over 21,000 genes and generated a resource guide of genes required for macrophage viability as well as novel positive and negative regulators of NF-κB signaling.
Using transcranial magnetic stimulation to map the cortical representation of lower-limb muscles
Authors: Davies Jennifer L 
Published: October 2019

AbstractThe aim of this study was to evaluate the extent to which transcranial magnetic stimulation (TMS) can identify discrete cortical representation of lower-limb muscles in healthy individuals. Data were obtained from 16 young healthy adults (12 women, four men; mean [SD] age 23.0 [2.6] years). Motor evoked potentials were recorded from the resting vastus medialis, rectus femoris, vastus lateralis, medial and lateral hamstring, and medial and lateral gastrocnemius muscles on the right side of the body using bipolar surface electrodes. TMS was delivered through a 110-mm double-cone coil at 63 sites over the left hemisphere. Location and size of the cortical representation and the number of discrete peaks were quantified for each muscle. Within the quadriceps muscle group there was a main effect of muscle on anterior-posterior centre of gravity (p = 0.010), but the magnitude of the difference was very small. Within the quadriceps there was a main effect of muscle on medial-lateral hotspot (p = 0.027) and map volume (p = 0.047), but no post-hoc tests were significant. The topography of each lower-limb muscle was complex, displaying multiple peaks that were present across the stimulation grid, and variable across individuals. The results of this study indicate that TMS delivered with a 110-mm double-cone coil could not reliably identify discrete cortical representations of resting lower-limb muscles when responses were measured using bipolar surface electromyography. The characteristics of the cortical representation of lower-limb muscles reported here provide a basis against which to evaluate cortical reorganisation in clinical populations.
LITESEC-T3SS - Light-controlled protein delivery into eukaryotic cells with high spatial and temporal resolution
Authors: Lindner Florian , Milne-Davies Bailey , Langenfeld Katja , Diepold Andreas 
Published: October 2019

AbstractMany bacteria employ a type III secretion system (T3SS), also called injectisome, to translocate proteins into eukaryotic host cells through a hollow extracellular needle. The system can efficiently transport heterologous cargo, which makes it a uniquely suited tool for the translocation of proteins into eukaryotic cells. However, the injectisome indiscriminately injects proteins into any adjoining eukaryotic cell, and this lack of target specificity currently limits its application in biotechnology and healthcare. In this study, we exploit the dynamic nature of the T3SS to control protein secretion and translocation into eukaryotic cells by light. By combining optogenetic interaction switches with the dynamic cytosolic T3SS component SctQ, the cytosolic availability of SctQ and in consequence T3SS-dependent effector secretion can be regulated by external light. The resulting system, which we call LITESEC-T3SS (Light-inducedtranslocation ofeffectors throughsequestration ofendogenouscomponents of theT3SS), allows rapid, specific, and reversible activation or deactivation of the T3SS upon illumination. We demonstrate the application of the system for light-regulated translocation of a heterologous reporter protein into cultured eukaryotic cells. LITESEC-T3SS represents a new method to achieve unparalleled spatial and temporal resolution for the controlled protein translocation into eukaryotic host cells.
Functionally-informed fine-mapping and polygenic localization of complex trait heritability
Authors: Weissbrod Omer , Hormozdiari Farhad , Benner Christian , Cui Ran , Ulirsch Jacob , Gazal Steven , Schoech Armin P. , van de Geijn Bryce , Reshef Yakir , Márquez-Luna Carla , O’Connor Luke , Pirinen Matti , Finucane Hilary K. , Price Alkes L. 
Published: October 2019

AbstractFine-mapping aims to identify causal variants impacting complex traits. Several recent methods improve fine-mapping accuracy by prioritizing variants in enriched functional annotations. However, these methods can only use information at genome-wide significant loci (or a small number of functional annotations), severely limiting the benefit of functional data. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy using genome-wide functional data for a broad set of coding, conserved, regulatory and LD-related annotations. PolyFun prioritizes variants in enriched functional annotations by specifying prior causal probabilities for fine-mapping methods such as SuSiE or FINEMAP, employing special procedures to ensure robustness to model misspecification and winner’s curse. In simulations with in-sample LD, PolyFun + SuSiE and PolyFun + FINEMAP were well-calibrated and identified >20% more variants with posterior causal probability >0.95 than their non-functionally informed counterparts (and >33% more fine-mapped variants than previous functionally-informed fine-mapping methods). In simulations with mismatched reference LD, PolyFun + SuSiE remained well-calibrated when reducing the maximum number of assumed causal SNPs per locus, which reduces absolute power but still produces large relative improvements. In analyses of 49 UK Biobank traits (average N=318K) with in-sample LD, PolyFun + SuSiE identified 3,025 fine-mapped variant-trait pairs with posterior causal probability >0.95, a >32% improvement vs. SuSiE; 223 variants were fine-mapped for multiple genetically uncorrelated traits, indicating pervasive pleiotropy. We used posterior mean per-SNP heritabilities from PolyFun + SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 28 (hair color) to 3,400 (height) to 2 million (number of children). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures.
Pseudomonas two-partner secretion toxin Exolysin contributes to insect killing
Authors: Job Viviana , Bouillot Stéphanie , Gueguen Erwan , Robert-Genthon Mylène , Panchev Peter , Elsen Sylvie , Attrée Ina 
Published: October 2019

AbstractPseudomonas chlororaphis is a promising biocontrol agent promoting plant-growth and providing protection against pest insects and phytopathogenic fungi. We have identified in the genome of P. chlororaphis PA23 an operon encoding the toxin Exolysin (ExlA) and its outer-membrane transporter, ExlB. We found that P. chlororaphis producing ExlA (ExlAPch) is cytotoxic towards murine macrophages and human epithelial cells at 30 °C. P. chlororaphis PA23 provoked shrinkage of epithelial cell, leakage of cytoplasmic components and subsequent cell death. During infection, ExlAPch incorporated into epithelial cell membranes within detergent-resistant lipid rafts, suggesting the same mechanisms of cell destruction by pore-formation as reported for P. aeruginosa toxin. ExlAPch was not involved in the capacity of the strain to kill fungi, amoeba or other bacteria. The contribution of ExlA in insecticidal activity of P. chlororaphis was evaluated in the wax moth larvae Galleria mallonella and in Drosophila melanogaster flies. The impact of the deletion of a gene encoding exlA homologue was tested in the natural fly pathogen P. entonomophila. In both models, the ExlA absence delayed killing, suggesting the contribution of the toxin in bacteria-insect pathogenic interactions.