bluuebunny/crossref_metadata_2025_split huggingface dataset:
Streptomycesendophytes promote the growth ofArabidopsis thaliana
Authors: Worsley Sarah F. , Newitt Jake , Rassbach Johannes , Batey Sibyl F. D. , Holmes Neil A. , Murrell J. Colin , Wilkinson Barrie , Hutchings Matthew I. 
Published: January 2019

AbstractStreptomycesbacteria are ubiquitous in soils and are well-known for producing secondary metabolites, including antimicrobials. Increasingly, they are being isolated from plant roots and several studies have shown they are specifically recruited to the rhizosphere and the endosphere of the model plantArabidopsis thaliana. Here we test the hypothesis thatStreptomycesbacteria have a beneficial effect onA. thalianagrowth and could potentially be used as plant probiotics. To do this, we selectively isolated streptomycetes from surface washedA. thalianaroots and generated high quality genome sequences for five strains which we named L2, M2, M3, N1 and N2. Re-infection ofA. thalianaplants with L2, M2 and M3 significantly increased plant biomass individually and in combination whereas N1 and N2 had a negative effect on plant growth, likely due to their production of polyene natural products which can bind to phytosterols and reduce plant growth. N2 exhibits broad spectrum antimicrobial activity and makes filipin-like polyenes, including 14-hydroxyisochainin which inhibits the Take-all fungus,Gaeumannomyces graminisvar.tritici. N2 antifungal activity as a whole was upregulated ~2-fold in response to indole-3-acetic acid (IAA) suggesting a possible role during competition in the rhizosphere. Furthermore, coating wheat seeds with N2 spores protected wheat seedlings against Take-all disease. We conclude that at least some soil dwelling streptomycetes confer growth promoting benefits onA. thalianawhile others might be exploited to protect crops against disease.ImportanceIt is vital that we reduce our reliance on agrochemicals and there is increasing interest in using bacterial strains to promote plant growth and protect against disease. Our study follows up reports thatArabidopsis thalianaspecifically recruitsStreptomycesbacteria to its roots. In particular, we test the hypothesis that these bacteria can offer benefits to theirA. thalianahosts and that strains isolated from these plants might be used as probiotics. We isolatedStreptomycesstrains from surface washedA. thalianaroots and genome sequenced five phylogenetically distinct strains. Genome mining and bioassays indicated that all five strains have plant growth promoting properties, including production of IAA, siderophores and ACC deaminase activity. Three strains significantly increasedA. thalianagrowthin vitroand when applied in combination in soil. Another produces potent filipin-like antifungal metabolites and we used it as a seed coating to protect germinating wheat seeds against the fungal pathogenGaeumannomyces graminisvar.tritici(wheat Take-all fungus). We conclude that introducing an optimal combination ofStreptomycesstrains into the root microbiome can provide significant benefits to plants.
Yorkie controls tube length and apical barrier integrity in the developingDrosophilaairways
Authors: Papadopoulos Dimitrios K. , Tomancak Pavel , Tsarouhas Vasilios , Samakovlis Christos , Knust Elisabeth , Skouloudaki Kassiani 
Published: January 2019

AbstractEpithelial organ size and shape depend on cell shape changes, cell-matrix communication and apical membrane growth. TheDrosophilaembryonic tracheal network is an excellent model to study these processes. Here, we show that the transcriptional co-activator of the Hippo pathway, Yorkie (YAP in vertebrates), plays distinct roles in the developingDrosophilaairways. Yorkie exerts a cytoplasmic function by bindingDrosophilaTwinstar, the orthologue of the vertebrate actin-severing protein Cofilin, to regulate F-actin levels and apical cell membrane size, which are required for proper tracheal tube elongation. Second, Yorkie controls water-tightness of tracheal tubes by transcriptional regulation of the enzymeδ-aminolevulinate synthase(Alas). We conclude that Yorkie has a dual role in tracheal development to ensure proper tracheal growth and functionality.Short SummaryThis work identified an alternative role of the transcriptional co-activator Yorkie (Yki) in controlling water impermeability and tube size of the developingDrosophilaairways. Tracheal impermeability is triggered by Yki-mediated transcriptional regulation ofδ-aminolevulinate synthase,Alas, whereas tube elongation is controlled by binding of Yki to the actin severing factor Twinstar.
Disease-associated scaffold protein CNK2 modulates PSD size and influences trafficking of new synaptic binding partner TNIK
Authors: Zieger Hanna L. , Kunde Stella-Amrei , Rademacher Nils , Schmerl Bettina , Shoichet Sarah A. 
Published: January 2019

AbstractScaffold proteins are responsible for structural organisation within cells; they form complexes with other proteins to facilitate signalling pathways and catalytic reactions. The scaffold protein connector enhancer of kinase suppressor of Ras 2 (CNK2) is predominantly expressed in neural tissues and was recently implicated in X-linked intellectual disability (ID). We have investigated the role of CNK2 in neurons in order to contribute to our understanding of how CNK2 alterations might cause developmental defects, and we have elucidated a functional role for CNK2 in the molecular processes that govern morphology of the postsynaptic density (PSD). We have also identified novel CNK2 interaction partners and explored their functional interdependency with CNK2. We focussed on the novel interaction partner TRAF2- and NCK-interacting kinase TNIK, which is also associated with ID. Both CNK2 and TNIK are expressed in neuronal dendrites and concentrated in dendritic spines, and staining with synaptic markers indicates a clear postsynaptic localisation. Importantly, our data highlight that CNK2 plays a role in directing TNIK subcellular localisation, and in neurons, CNK2 participates in ensuring that this multifunctional kinase is present at desirable levels at synaptic sites. In summary, our data indicate that CNK2 expression is critical for modulating PSD morphology; moreover, our study highlights a role for CNK2 in directing the localisation of regulatory proteins within the cell. Importantly, we describe a novel link between CNK2 and the regulatory kinase TNIK, and provide evidence supporting the idea that these proteins play complementary roles in the regulation of dendritic spine growth and maintenance.
Sequence-dependent trafficking of GDE2, a GPI-specific phospholipase promoting neuronal differentiation
Authors: Salgado-Polo Fernando , van Veen Michiel , van den Broek Bram , Leyton-Puig Daniela , Baas Roy , Perrakis Anastassis , Moolenaar Wouter H. , Matas-Rico Elisa 
Published: January 2019

SummaryGDE2 is a six-transmembrane glycerophosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby influences biological signaling cascades. GDE2 promotes neuronal differentiation cell-autonomously through glypican cleavage and is a prognostic marker in neuroblastoma, while GDE2 deficiency causes progressive neurodegeneration in mice and developmental defects in zebrafish. However, the regulation of GDE2 remains unclear. Here we show that in undifferentiated neuronal cells, GDE2 undergoes constitutive internalization and traffics back along both fast and slow recycling routes, while a small percentage is sorted to late endosomes. GDE2 trafficking is dictated by distinctive C-terminal tail sequences that determine secretion, endocytosis and recycling preference, respectively, and thereby regulate GDE2 function both positively and negatively. Our study reveals the sequence determinants of GDE2 trafficking and surface localization, and provides insight into the control of GPI-anchored protein activities with potential implications for nervous system disorders associated with impaired trafficking and beyond.
RE-EVALUATION OF MEFV GENE VARIANTS: UTILITY OF A GENE SPECIFIC THRESHOLD IN REDUCING THE NUMBER OF VARIANTS OF UNKNOWN SIGNIFICANCE
Authors: Accetturo Matteo , D’Uggento Angela Maria , Portincasa Piero , Stella Alessandro 
Published: January 2019

AbstractFamilial Mediterranean Fever (FMF) is an inherited autoinflammatory syndrome caused by mutations in the MEFV gene. MEFV variants are still in large part classified as variant of uncertain significance (VOUS), or with classification unresolved, posing significant challenges in the clinical diagnosis of Familial Mediterranean Fever (FMF). REVEL is a recently developed variant metapredictor tool. To reduce the number of MEFV variants with ambiguous classification we extracted the REVEL score for all missense variants reported at the locus specific database INFEVERS, and analyzed its correlation with expert-based classification and localization in the MEFV-encoded pyrin protein functional domains.The data set of 216 missense variants was divided in four classification categories (BENIGN, VOUS, PATHOGENIC and UNRESOLVED). MEFV variants were plotted onto the pyrin protein, the distribution of REVEL scores in each category was computed and means, confidence intervals, and area under the receiver operating curve were calculated.We observed a non-random distribution of pathogenic variants along the functional domains of the pyrin protein. The REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases (INSAID). Sensitivity, specificity, and accuracy were calculated for different cutoff values of REVEL scores and a gene-specific threshold was computed with confidence boundary limits. A REVEL score of 0.298 was the best performing cut-off to reclassify 96 MEFV gene variants previously of uncertain significance or unsolved thus reducing their proportion from 61.6% to 17.6%.In conclusion, the combination of available expert information with highly sensitive predictor tools yields to more accurate interpretation of clinical consequences of MEFV gene variants. This approach should bring to a better genetic counseling and patient management.Author summaryWe aimed to refine MEFV gene variants classification using the metapredictor REVEL. We demonstrate that a gene-specific threshold is effective for accurate variants’ classification. Using this threshold, we reduced significantly the proportion of MEFV variants with an ambiguous classification. The proposed classification could represent a useful resource for variant interpretation in the context of FMF diagnosis.
The SUMO ligase Su(var)2-10 controls eu- and heterochromatic gene expression via establishment of H3K9 trimethylation and negative feedback regulation
Authors: Ninova Maria , Godneeva Baira , Ariel Chen Yung-Chia , Luo Yicheng , Prakash Sharan J. , Jankovics Ferenc , Erdélyi Miklós , Tóth Katalin Fejes , Aravin Alexei A. 
Published: January 2019

AbstractChromatin is critical for genome compaction and gene expression. On a coarse scale, the genome is divided into euchromatin, which harbors the majority of genes and is enriched in active chromatin marks, and heterochromatin, which is gene-poor but repeat-rich. The conserved molecular hallmark of heterochromatin is the H3K9me3 modification, which is associated with gene silencing. We found that inDrosophiladeposition of most of the H3K9me3 mark depends on SUMO and the SUMO-ligase Su(var)2-10, which recruits the histone methyltransferase complex SetDB1/Wde. In addition to repressing repeats, H3K9me3 also influences expression of both hetero- and euchromatic host genes. High H3K9me3 levels in heterochromatin are required to suppress spurious non-canonical transcription and ensure proper gene expression. In euchromatin, a set of conserved genes is repressed by Su(var)2-10/SetDB1-induced H3K9 trimethylation ensuring tissue-specific gene expression. Several components of heterochromatin are themselves repressed by this pathway providing a negative feedback mechanism to ensure chromatin homeostasis.Highlights-Proper expression of host genes residing in heterochromatin requires Su(var)2-10-dependent installation of the H3K9me3 mark to suppress spurious non-canonical transcription.-A set of euchromatic host genes is repressed by transposon-independent installation of H3K9me3 in a process that depends on Su(var)2-10 and SUMO.-Installation of H3K9me3 via Su(var)2-10 ensures tissue-specific gene expression.-H3K9me3-dependent silencing of genes encoding proteins involved in heterochromatin formation provides negative feedback regulation to maintain heterochromatin homeostasis.
Neanderthal introgression reintroduced functional alleles lost in the human out of Africa bottleneck
Authors: Rinker David C. , Simonti Corinne N. , McArthur Evonne , Shaw Douglas , Hodges Emily , Capra John A. 
Published: January 2019

ABSTRACTNeanderthal ancestry remains across modern Eurasian genomes, and introgressed sequences influence diverse phenotypes, including immune, skin, and neuropsychiatric diseases. Interpretation of introgressed sequences has focused on alleles derived in the Neanderthal lineage. Here, we demonstrate that Neanderthal introgression also reintroduced thousands of ancestral hominin alleles lost in the Eurasian out of Africa bottleneck. Combining evolutionary simulations, expression quantitative trait loci (eQTL), massively parallel reporter assay (MPRA) data, and in vitro validation, we show that reintroduced alleles (RAs) have different fitness effects than Neanderthal-derived alleles (NDAs) and that some RAs regulate gene expression independent of NDAs. Illustrating the broad potential influence of RAs, we find that over 70% of known phenotype associations with NDAs are equally associated with RAs. Finally, we discover enrichment for RA eQTL activity in several tissues, with strongest enrichment in the brain. In summary, our study reveals that Neanderthal introgression supplied Eurasians with many lost functional variants and demonstrates that RAs must be considered when evaluating the effects of introgression.ONE SENTENCE SUMMARYNeanderthal interbreeding with modern humans restored to Eurasians, hundreds of thousands of ancient alleles that were lost in the out of Africa bottleneck.
High-speed device synchronization in optical microscopy with an open-source hardware control platform
Authors: Colville Marshall J. , Park Sangwoo , Zipfel Warren R. , Paszek Matthew J. 
Published: January 2019

AbstractRecent advances in fluorescence microscopy have enabled the visualization of subcellular structures at unprecedented resolution. However, the complexity of state-of-the-art microscopes has increased considerably, often requiring the precise control and synchronization of multiple peripheral devices at high speeds. Drawing inspiration from open-source prototyping systems, like the Arduino, we describe the development of a new control platform that adopts the best features of these systems – affordability, facile programmability, and flexible connectivity – but with the scientific-grade inputs and outputs (I/O) and built-in routines that are necessary to control peripherals in advanced microscopy applications. Notably, our platform includes waveform generators and I/O for point-and azimuthal-scanning of excitation in laser-based applications. As a proof of concept, we show how the integration of waveform generation, multiplexed analog outputs, and native hardware triggers into a single central hub provides a versatile platform for performing fast circle-scanning acquisitions, including ring scanning-angle interference microscopy (SAIM), total internal reflection fluorescence (TIRF and ring TIRF) microscopy, and multiangle TIRF (MA-TIRF). We also demonstrate how the low communication latency of our hardware platform can reduce image intensity and reconstruction artifacts arising from synchronization errors produced by software control. Our complete platform, including hardware design files, firmware, API, software, and all associated source code, will be hosted for community-based development and collaboration.
Interacting cells driving the evolution of multicellular life cycles
Authors: Gao Yuanxiao , Traulsen Arne , Pichugin Yuriy 
Published: January 2019

AbstractEvolution of complex multicellular life begun from the emergence of life cycle involving formation of cell clusters. Opportunity for cells to interact within clusters provided them an advantage over unicellular life forms. However, what kind of interactions may lead to the evolution of multicellular life cycles? Here, we combine evolutionary game theory with a model for the emergence of multicellular groups to investigate how cell interactions can influence reproduction modes during the early stages of the evolution of multicellularity. We identify evolutionary optimal life cycles as those which maximize the population growth rate. Among all interactions captured by two-player games, only eight life cycles were found to be evolutionarily optimal. Moreover, the vast majority of games promotes either of two classes of life cycles: (i) splitting into unicellular propagules or (ii) fragmentation into two offspring clusters of equal (or almost equal) size. Our findings indicate that the three most important characteristics, determining whether multicellular life cycles will evolve, are average performance of homogeneous groups, heterogeneous groups, and solitary cells.
Tubulin as a sensitive target of nanosecond-scale intense electric field: quantitative insights from molecular dynamics simulations
Authors: Marracino Paolo , Havelka Daniel , Průša Jiří , Liberti Micaela , Tuszynski Jack A. , Ayoub Ahmed T. , Apollonio Francesca , Cifra Michal 
Published: January 2019

AbstractIntense pulsed electric fields are known to act at the cell membrane level and are already being exploited in biomedical and biotechnological applications. However, it is not clear if intra-cellular components such as cytoskeletal proteins could be directly influenced by electric pulses within biomedically-attainable parameters. If so, a molecular mechanism of action could be uncovered for therapeutic applications of such electric fields. To help clarify this question, we first identified that a tubulin heterodimer is a natural biological target for intense electric fields due to its exceptional electric properties and crucial roles played in cell division. Using molecular dynamics simulations, we then demonstrated that an intense - yet experimentally attainable - electric field of nanosecond duration can affect the β-tubulin’s C-terminus conformations and also influence local electrostatic properties at the GTPase as well as the binding sites of major tubulin drugs site. Our results suggest that intense nanosecond electric pulses could be used for physical modulation of microtubule dynamics. Since a nanosecond pulsed electric field can penetrate the tissues and cellular membranes due to its broadband spectrum, our results are also potentially significant for the development of novel therapeutic protocols.Author summaryα/β-tubulin heterodimers are the basic building blocks of microtubules, that form diverse cellular structures responsible for essential cell functions such as cell division and intracellular transport. The ability of tubulin protein to adopt distinct conformations contributes to control the architecture of microtubule networks, microtubule-associated proteins, and motor proteins; moreover, it regulates microtubule growth, shrinkage, and the transitions between these states. Previous recent molecular dynamics simulations demonstrated that the interaction of the tubulin protein macrodipole with external electric field modifies orientation and conformations of key loops involved in lateral contacts: as a result, the stability of microtubules can be modulated by such fields. In this study, we seek to exploit these findings by investigating the possibility of fine-tuning the dipolar properties of binding sites of major drugs, by means of the action of electric fields. This may open the way to control tubulin-drug interactions using electric fields, thus modulating and altering the biological functions relative to the molecular vectors of microtubule assembly or disassembly. The major finding of our study reveals that intense (> 20 MV/m) ultra-short (30 ns) electric fields induce changes in the major residues of selected binding sites in a field strength-dependent manner.
Maximum Parsimony Interpretation of Chromatin Capture Experiments
Authors: Homouz Dirar , Kudlicki Andrzej 
Published: January 2019

AbstractWe present a new approach to inferring global geometric state of chromatin from Hi-C data. Chromatin conformation capture techniques (3C, and its variants: 4C, 5C, Hi-C, etc.) probe the spatial structure of the genome by identifying physical contacts between genomic loci within the nuclear space. In whole-genome conformation capture (Hi-C) experiments, the signal can be interpreted as spatial proximity between genomic loci and physical distances can be estimated from the data. However, the results of these estimations suffer from internal geometric inconsistencies, notoriously violating the triangle inequality. Here we propose that the inconsistencies may be caused not by experimental artifacts but rather by a mixture of cells, each in one of several conformational states, contained in the sample. We have developed and implemented a graph-theoretic approach that identifies the properties of these subpopulations. We show that the geometrical conflicts in a standard yeast HiC dataset, can be explained by only a small number of homogeneous populations of cells (4 populations are sufficient to reconcile 95,000 most prominent impossible triangles, 8 populations can explain 375,000 top geometric conflicts). Finally, we analyze the functional annotations of genes differentially interacting between the populations, suggesting that each inferred subpopulation may be involved in a functionally different transcriptional program.Author SummaryThe global conformation of chromatin within a nucleus plays an important role in regulation of genes. The Hi-C technique can detect proximity between genomic loci, but attempts to use Hi-C data to infer the global conformation lead to hundreds of thousands of impossible geometries, violating the triangle inequality. To date, there was no explanation for this phenomenon. Here, we resolve these discrepancies by modeling the sample as a mixture of nuclei in several conformation states. We have developed a graph-theoretic approach to characterize the shape of chromatin in each of these states. In a real-life situation, as few as 4-5 discrete subpopulations can resolve all spatial inconsistencies in the data. Moreover, the results suggest that each subpopulation is associated with a functionally specific transcriptional program.