bluuebunny/crossref_metadata_2025_split huggingface dataset:
The flagellar substrate specificity switch protein FlhB assembles onto the extra-membrane export gate to regulate type three secretion
Authors: Kuhlen Lucas , Johnson Steven , Zeitler Andreas , Bäurle Sandra , Deme Justin C. , Debo Rebecca , Fisher Joseph , Wagner Samuel , Lea Susan M. 
Published: July 2019

AbstractExport of proteins through type three secretion systems (T3SS) is critical for motility and virulence of many major bacterial pathogens. Proteins are transported through an export gate complex consisting of three proteins (FliPQR in flagellar systems, SctRST in virulence systems) that were initially annotated as membrane proteins, but which we have recently shown assemble into an extra-membranous helical assembly. A fourth putative membrane protein (FlhB/SctU) is essential to the export process, and also functions to “switch” secretion substrate specificity once the growing hook/needle structures reach their determined length. Here we present the structure of an export gate containing the switch protein from a Vibrio polar flagellar system at 3.2 Å resolution by cryo-electron microscopy. The structure reveals that the FlhB/SctU further extends the helical export gate assembly with its four putative transmembrane helices adopting an out-of-membrane location, wrapped around the other export gate components at the base of the structure. The unusual topology of the switch protein helices creates a loop that wraps around the bottom of the closed export gate complex. Structure-informed mutagenesis suggests that this loop is critical in gating secretion and we propose that a series of conformational changes in the type 3 secretion system trigger opening of the export gate through the interactions between FlhB/SctU and FliPQR/SctRST.
Ploidy determines the consequences of antifungal-induced mutagenesis in Candida albicans, a human fungal pathogen
Authors: Avramovska Ognenka , Hickman Meleah A. 
Published: July 2019

AbstractOrganismal ploidy state and environmental stress impact the mutational spectrum and the mutational rate. The human fungal pathogenCandida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and stress-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploidC. albicansfollowing exposure to two classes of antifungal drugs, azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-of-heterozygosity (LOH), and genome size changes in cells treated with fluconazole and caspofungin. We find that caspofungin induced higher rates of mutation than fluconazole, likely an indirect result from the stress associated with cell wall perturbations rather than an inherent genotoxicity. Furthermore, we found disproportionately elevated rates of LOH and genome size changes in response to both antifungals in tetraploidC. albicanscompared to diploidC. albicans, suggesting that the magnitude of stress-induced mutagenesis results from an interaction between ploidy state and the environment. These results have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress, and may facilitate the emergence of antifungal resistance.
Low level of expression of C-terminally truncated human FUS causes extensive changes in spinal cord transcriptome of asymptomatic transgenic mice
Authors: Lysikova Ekaterina A. , Funikov Sergei , Rezvykh Alexander P. , Chaprov Kirill D. , Kukharsky Michail S. , Ustyugov Alexey A. , Deykin Alexey V. , Flyamer Ilya. A. , Boyle Shelagh , Bachurin Sergey O. , Ninkina Natalia , Buchman Vladimir L. 
Published: July 2019

AbstractMutations in a gene encoding RNA-binding protein FUS was linked to familial forms of amyotrophic lateral sclerosis (ALS). C-terminal truncations of FUS are associated with aggressive forms of ALS. However, motor neurons are able to tolerate permanent production of pathogenic truncated form of FUS protein until its accumulation in the cytoplasm of neurones does not reach a critical threshold.In order to identify how the nervous system responds to pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1-359], with a low level of neuronal expression of a highly aggregation prone and pathogenic form of C-terminally truncated FUS. In contrast to mice with substantially higher level of expression of the same FUS variant that develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any sign of pathology even at old age. Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice comparing to the wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating to potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective target for therapy of FUS-ALS and possibly, other forms of ALS.
Epigenetic signatures of chronic social stress in stress-susceptible animals
Authors: O’Toole Nicholas , Zhang Tie-Yuan , Wen Xianglan , Diorio Josie , Silveira Patricia P. , Labonté Benoit , Nestler Eric J. , Meaney Michael J. 
Published: July 2019

AbstractExposure of mice to chronic social defeat stress (CSDS) produces depressive- and anxiety-like behaviors and widespread transcriptomic changes in several brain regions in susceptible animals. Here we present the first study of genome-wide cytosine methylation patterns of mice susceptible to CSDS using whole-genome bisulfite sequencing on DNA from the nucleus accumbens, a critical region for CSDS effects on behavior. We found extensive evidence for differential methylation following exposure to CSDS in susceptible animals, with a greater proportion of CG hypermethylation than hypomethylation in CSDS-susceptible mice compared to non-stressed controls; non-CG methylation shows the opposite trend. Several genes previously implicated in the effects of CSDS are among those with the greatest number of differentially methylated sites, including estrogen receptor alpha (Esr1), the deleted in colorectal cancer (Dcc) gene andCacna1c, which has been associated with a range of psychiatric conditions. Informatic analysis of DM sites revealed a gene network with ß-catenin as the hub gene of a network that included the ß-catenin-related WNT/frizzled signaling pathway as well as bothEsr1andDcc. Finally, we found considerable overlap between DM genes associated with CSDS in susceptible animals and those associated with human neuroticism in a genome-wide association study. Analysis of these overlapping genes revealed ‘WNT signaling’ as the top pathway, which features ß-catenin as the primary hub gene. These findings reveal a striking convergence between the molecular pathways identified through either transcriptional or epigenomic analyses of the mouse model of susceptibility to chronic stress and the genomic architecture of increased stress susceptibility reflected in neuroticism in humans.
A non-acidic method using hydroxyapatite and phosphohistidine monoclonal antibodies allows enrichment of phosphopeptides containing non-conventional phosphorylations for mass spectrometry analysis
Authors: Adam K. , Fuhs S. , Meisenhelder J. , Aslanian A. , Diedrich J. , Moresco J. , La Clair J. , Yates J.R. , Hunter T. 
Published: July 2019

AbstractFour types of phosphate-protein linkage generate nine different phosphoresidues in living organisms. Histidine phosphorylation is a long-time established but largely unexplored post-translational modification, mainly because of the acid-lability of the phosphoramidate bonds. This lability means that standard phosphoproteomic methods used for conventional phosphate esters (phospho-Ser/Thr/Tyr) must be modified to analyze proteins containing the phosphoramidate-amino acids - phospho-His/Arg/Lys. We show that a non-acidic method allows enrichment of non-conventional phosphoresidue-containing peptides from tryptic digests of human cell lines, using hydroxyapatite binding and/or immobilized 1-pHis and 3-pHis monoclonal antibodies for enrichment. 425 unique non-conventional phosphorylation sites (i.e. pHis, pLys and pArg) were detected with a high probability of localization by LC-MS/MS analysis and identified using a customized MaxQuant configuration, contributing to a new era of study in post-translational modification and cell signaling in humans. This is the first fully non-acidic method for phosphopeptide enrichment which uses immunoaffinity purification and remains compatible with mass spectrometry analysis for a wider coverage of potential protein phosphorylation events.
Myf6/MRF4 is a Myogenic Niche Regulator Required for the Maintenance of the Muscle Stem Cell Pool
Authors: Lazure Felicia , Blackburn Darren M. , Karam Nabila , Sahinyan Korin , Sharanek Ahmad , Nguyen Duy , Corchado Aldo H. , Lepper Christoph , Najafabadi Hamed S. , Perkins Theodore J. , Jahani-Asl Arezu , Soleimani Vahab 
Published: July 2019

AbstractIn metazoans, skeletal muscle evolved to contract and produce force. However, recent experimental evidence suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 transcriptionally regulates a broad spectrum of myokines and muscle-secreted proteins, including ligands for downstream activation of key signaling pathways such as EGFR, STAT3 and VEGFR. Homozygous deletion of Myf6 causes a significant reduction in the ability of muscle to produce key myokines such as EGF, VEGFA and LIF. Consequently, although Myf6 knockout mice are born with a normal muscle stem cell compartment, they undergo progressive reduction in their stem cell pool during postnatal life. Mechanistically, muscle stem cells from the Myf6 knockout animals show defects in activation of EGFR and STAT3 signaling, upregulate the p38 MAP kinase pathway and spontaneously break from quiescence. Exogenous application of recombinant EGF and LIF rescue the defects in the muscle stem cell pool of Myf6 knockout animals. Finally, skeletal muscles of mice lacking Myf6 have a significantly reduced ability to sustain donor-engrafted muscle stem cells. Taken together, our data uncovers a novel role for Myf6 in regulating the expression of niche factors and myokines to maintain the skeletal muscle stem cell pool in adult mice.
Continuous Endoglin (CD105) Overexpression Disrupts Angiogenesis and Facilitates Tumor Cell Metastasis
Authors: Ollauri-Ibáñez Claudia , Núñez-Gómez Elena , Egido-Turrión Cristina , Silva-Sousa Laura , Rodríguez-Barbero Alicia , López-Novoa José M. , Pericacho Miguel 
Published: July 2019

ABSTRACTAngiogenesis is a complex process essential for tumor growth. For this reason, high levels of pro-angiogenic molecules, such as endoglin (CD105), are supposed to be related to greater tumor growth that lead to a poor cancer prognosis. However, we demonstrate here that defects in angiogenesis that can be attributed to high levels of endoglin, lead to development and worsening of cancer disease. Steady endoglin overexpression disrupts the correct stabilization of the endothelium and the recruitment of mural cells. In consequence, endoglin overexpression gives rise to altered vessels that promote the intravasation of tumor cells, the subsequent development of metastases and, thus, a worse cancer prognosis.
Tumors Exploit Dedicated Intracellular Vesicles to Program T cell Responses
Authors: Roberts Edward W. , Ruhland Megan K. , Cai En , Mujal Adriana M. , Marchuk Kyle , Beppler Casey , Nam David , Serwas Nina K. , Binnewies Mikhail , Krummel Matthew F. 
Published: July 2019

AbstractIn order to drive productive tumor-infiltrating lymphocyte (TIL) function, myeloid populations must direct antigens to the lymph node, including to resident antigen-presenting cells (APCs) that have never touched the tumor. It has long been supposed that APCs trade antigens with one another, but the dominant cell biology underlying that remains unknown. We used in vitro and in vivo assays together with lattice light sheet and multiphoton imaging to show that myeloid cells carry tumor antigen-laden vesicles that they ‘trade’ with one another as they reach distant sites. This accounts for the majority of antigen displayed to T cells and provides tumors with a mechanism to access APCs that differentially direct T cell activation away from memory phenotypes. This work defines efficient cell biology that drives the first steps of TIL generation and represents a new frontier for engineering tumoral immunity.
Hemispheric asymmetries in resting-state EEG and fMRI are related to approach and avoidance behaviour, but not to eating behaviour or BMI
Authors: Morys Filip , Janssen Lieneke , Cesnaite Elena , Beyer Frauke , Garcia-Garcia Isabel , Kube Jana , Kumral Deniz , Liem Franziskus , Mehl Nora , Mahjoory Keyvan , Schrimpf Anne , Gaebler Michael , Margulies Daniel , Villringer Arno , Neumann Jane , Nikulin Vadim , Horstmann Annette 
Published: July 2019

AbstractMuch of our behaviour is driven by two motivational dimensions – approach and avoidance. These have been related to frontal hemispheric asymmetries in clinical and resting-state EEG studies: approach was linked to higher activity of the left relative to the right hemisphere, while avoidance was related to the opposite pattern. Increased approach behaviour, specifically towards unhealthy foods, is also observed in obesity and has been linked to asymmetry in the framework of the right-brain hypothesis of obesity. Here, we aimed to replicate previous EEG findings of hemispheric asymmetries for self-reported approach/avoidance behaviour and to relate them to eating behaviour. Further, we assessed whether resting fMRI hemispheric asymmetries can be detected and whether they are related to approach/avoidance, eating behaviour, and BMI. We analysed 3 samples: Sample 1 (n=117) containing EEG and fMRI data from lean participants, and Samples 2 (n=89) and 3 (n=152) containing fMRI data from lean, overweight, and obese participants. While in Sample 1 approach in women was related to EEG and fMRI hemispheric asymmetries, in Samples 2 and 3 this effect was not significant. Here, hemispheric asymmetries were neither related to BMI nor eating behaviour. Our study partly replicates previous EEG findings regarding hemispheric asymmetries and indicates that this relationship could also be captured using fMRI. Our findings suggest that eating behaviour and obesity are likely to be mediated by mechanisms not directly relating to frontal asymmetries in neuronal activation quantified with EEG and fMRI.
Spatially-extended nucleation-aggregation-fragmentation models for the dynamics of prion-like neurodegenerative protein-spreading in the brain and its connectome
Authors: Fornari Sveva , Schäfer Amelie , Kuhl Ellen , Goriely Alain 
Published: July 2019

AbstractThe prion-like hypothesis of neurodegenerative diseases states that the accumulation of misfolded proteins in the form of aggregates is responsible for tissue death and its associated neurodegenerative pathology and cognitive decline. Some disease-specific misfolded proteins can interact with healthy proteins to form long chains that are transported through the brain along axonal pathways. Since aggregates of different sizes have different transport properties and toxicity, it is important to follow independently their evolution in space and time. Here, we model the spreading and propagation of aggregates of misfolded proteins in the brain using the general Smoluchowski theory of nucleation, aggregation, and fragmentation. The transport processes considered here are either anisotropic diffusion along axonal bundles or discrete Laplacian transport along a network. In particular, we model the spreading and aggregation of both amyloid-βandτmolecules in the brain connectome. We show that these two models lead to different size distributions and different propagation along the network. A detailed analysis of these two models reveals the existence of four different stages with different dynamics and invasive properties.
CELLULOSE SYNTHASE INTERACTIVE1- and Microtubule-Dependent Cell Wall Architecture Is Required for Acid Growth inArabidopsis Hypocotyls
Authors: Xin Xiaoran , Lei Lei , Zheng Yunzhen , Zhang Tian , Pingali Sai Venkatesh , O’Neill Hugh , Cosgrove Daniel J. , Li Shundai , Gu Ying 
Published: July 2019

AbstractAuxin-induced cell elongation relies in part on the acidification of the cell wall, a process known as acid growth that presumably triggers expansin-mediated wall loosening via altered interactions between cellulose microfibrils. Cellulose microfibrils are a major determinant for anisotropic growth and they provide the scaffold for cell wall assembly. Little is known about how acid growth depends on cell wall architecture. To explore the relationship between acid growth-mediated cell elongation and plant cell wall architecture, two mutants (jia1-1andcsi1-3) that are defective in cellulose biosynthesis and cellulose microfibril organization were analyzed. The study revealed that cell elongation is dependent on CSI1-mediated cell wall architecture but not on the overall crystalline cellulose content. We observed a correlation between loss of crossed-polylamellate walls and loss of auxin- and fusicoccin-induced cell growth incsi1-3. Furthermore, induced loss of crossed-polylamellate walls via disruption of cortical microtubule mimics the effect ofcsi1in acid growth. We hypothesize that CSI1- and microtubule-dependent crossed-polylamellate walls are required for acid growth inArabidopsishypocotyls.
Variation and inheritance of small RNAs in maize inbreds and F1 hybrids
Authors: Crisp Peter A. , Hammond Reza , Zhou Peng , Vaillancourt Brieanne , Lipzen Anna , Daum Chris , Barry Kerrie , de Leon Natalia , Buell C. Robin , Kaeppler Shawn M. , Meyers Blake C. , Hirsch Candice N. , Springer Nathan M. 
Published: July 2019

AbstractSmall RNAs (sRNAs) regulate gene expression, play important roles in epigenetic pathways, and have been hypothesised to contribute to hybrid vigor in plants. Prior investigations have provided valuable insights into associations between sRNAs and heterosis, often using a single hybrid genotype or tissue. However, our understanding of the role of sRNAs and their potential value to plant breeding are limited by an incomplete picture of sRNA variation between diverse genotypes and development stages. Here, we provide a deep exploration of sRNA variation and inheritance among a panel of 108 maize samples spanning five tissues from eight inbred parents and 12 hybrid genotypes, covering a spectrum of heterotic groups, genetic variation, and levels of heterosis for various traits. We document substantial developmental and genotypic influences on sRNA expression, with varying patterns for 21-nt, 22-nt and 24-nt sRNAs. We provide a detailed view of the distribution of sRNAs in the maize genome, revealing a complex make-up that also shows developmental plasticity, particularly for 22-nt sRNAs. sRNAs exhibited substantially more variation between inbreds as compared to observed variation for gene expression. In hybrids, we identify locus-specific examples of non-additive inheritance, mostly characterised as partial or complete dominance, but rarely outside the parental range. However, the global abundance of 21-nt, 22-nt and 24-nt sRNAs varies very little between inbreds and hybrids, suggesting that hybridization affects sRNA expression principally at specific loci rather than on a global scale. This study provides a valuable resource for understanding the potential role of sRNAs in hybrid vigor.One-sentence summaryCharacterizing the roles of development and genotype in driving expression variation of different small RNA populations in maize inbreds and their F1 hybrids.
Induced and primed defence responses of Fragaria vesca to Botrytis cinerea infection
Authors: Badmi Raghuram , Zhang Yupeng , Tengs Torstein , Brurberg May Bente , Krokene Paal , Fossdal Carl Gunnar , Hytönen Timo , Thorstensen Tage 
Published: July 2019

1.SummaryStrawberry is a high-value crop that suffers huge losses from diseases such as grey mould caused by the necrotrophic fungal pathogen Botrytis cinerea. Pesticides are heavily used to protect the strawberry crop, which raises environmental and human health concerns and promotes the evolution of pesticide resistant strains. Upregulating or priming the plants’ defences may be a more environmentally sustainable way of increasing disease resistance. Using Fragaria vesca as a model for the commercially grown octaploid strawberry Fragaria × ananassa, we investigated the transcriptional reprogramming of strawberry upon B. cinerea infection and the effectiveness of four priming chemicals in protecting strawberry against grey mould. First, we found that the transcriptional reprogramming of strawberry upon B. cinerea infection overlapped substantially with the transcriptome responses induced by Phytophthora cactorum (Toljamo et al., 2016), including the genes involved in jasmonic acid (JA), salicylic acid (SA), ethylene (ET) and terpenoid pathways. Furthermore, we investigated the effectiveness of previously identified priming chemicals in protecting strawberry against B. cinerea. The level of upregulated or primed resistance depended on the priming chemical itself (β-aminobutyric acid (BABA), methyl jasmonate (MeJ), (R)-β-homoserine (RBH), prohexadione-calcium (ProCa)) and the application method used (foliar spray, soil drench, seed treatment). Overall, RBH effectively primed strawberry defences against B. cinerea, whereas BABA and ProCa were not effective and MeJ showed mixed effects. Our results not only identify ways to effectively upregulate or prime strawberry defences against B. cinerea, but also provide novel insights about strawberry defences that may be applied in future crop protection schemes.