bluuebunny/crossref_metadata_2025_split huggingface dataset:
DHX9-dependent recruitment of BRCA1 to RNA is required to promote DNA end resection in homologous recombination
Authors: Chakraborty Prasun , Hiom Kevin 
Published: December 2019

AbstractDExD/H-box helicase 9 (DHX9/RNA helicaseA) is ubiquitously expressed ATP-dependent helicase that unwinds a variety of complex DNA and RNA secondary structures, suggesting it might have a role in DNA replication and the repair of DNA damage. Here we identify a pivotal role for DHX9 in homologous recombination (HR). Cells that are deficient in DHX9 are impaired in the generation of single stranded DNA (ssDNA) by DNA end resection. Consequently these cells fail to recruit RPA and RAD51 to sites of DNA damage and are hypersensitive to treatment with the DNA damaging agents camptothecin and Olaparib. A critical early step in the initiation of HR is the recruitment of BRCA1 mediator protein to DNA damage to promote DNA resection. We show here that recruitment of BRCA1 to DNA damage foci is dependent on its interaction with DHX9 to form the BRCA1-D complex, which binds to nascent RNA. Together our data identify a pivotal role for DHX9 in homologous recombination and highlight the important contribution of RNA in the recruitment of BRCA1 to DNA damage for the repair of DNA breaks
Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome
Authors: Iqbal Anila , Baldrighi Marta , Murdoch Jennifer N. , Fleming Angeleen , Wilkinson Christopher J. 
Published: December 2019

AbstractProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the Lewy bodies found in Parkinson’s disease. Aggresomes are closely-related cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede the organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since dopaminergic neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to loss of dopaminergic function and neuronal cell death in Parkinson’s disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.
Vargas: heuristic-free alignment for assessing linear and graph read aligners
Authors: Darby Charlotte A. , Gaddipati Ravi , Schatz Michael C. , Langmead Ben 
Published: December 2019

AbstractRead alignment is central to many aspects of modern genomics. Most aligners use heuristics to accelerate processing, but these heuristics can fail to find the optimal alignments of reads. Alignment accuracy is typically measured through simulated reads; however, the simulated location may not be the (only) location with the optimal alignment score. Vargas implements a heuristic-free algorithm guaranteed to find the highest-scoring alignment for real sequencing reads to a linear or graph genome. With semiglobal and local alignment modes and affine gap and quality-scaled mismatch penalties, it can implement the scoring functions of commonly used aligners to calculate optimal alignments. While this is computationally intensive, Vargas uses multi-core parallelization and vectorized (SIMD) instructions to make it practical to optimally align large numbers of reads, achieving a maximum speed of 456 billion cell updates per second. We demonstrate how these “gold standard” Vargas alignments can be used to improve heuristic alignment accuracy by optimizing command-line parameters in Bowtie 2, BWA-MEM, and vg to align more reads correctly. Source code implemented in C++ and compiled binary releases are available athttps://github.com/langmead-lab/vargasunder the MIT license.
A community-maintained standard library of population genetic models
Authors: Adrion Jeffrey R. , Cole Christopher B. , Dukler Noah , Galloway Jared G. , Gladstein Ariella L. , Gower Graham , Kyriazis Christopher C. , Ragsdale Aaron P. , Tsambos Georgia , Baumdicker Franz , Carlson Jedidiah , Cartwright Reed A. , Durvasula Arun , Gronau Ilan , Kim Bernard Y. , McKenzie Patrick , Messer Philipp W. , Noskova Ekaterina , Ortega-Del Vecchyo Diego , Racimo Fernando , Struck Travis J. , Gravel Simon , Gutenkunst Ryan N. , Lohmueller Kirk E. , Ralph Peter L. , Schrider Daniel R. , Siepel Adam , Kelleher Jerome , Kern Andrew D. 
Published: December 2019

AbstractThe explosion in population genomic data demands ever more complex modes of analysis, and increasingly these analyses depend on sophisticated simulations. Recent advances in population genetic simulation have made it possible to simulate large and complex models, but specifying such models for a particular simulation engine remains a difficult and error-prone task. Computational genetics researchers currently re-implement simulation models independently, leading to inconsistency and duplication of effort. This situation presents a major barrier to empirical researchers seeking to use simulations for power analyses of upcoming studies or sanity checks on existing genomic data. Population genetics, as a field, also lacks standard benchmarks by which new tools for inference might be measured. Here we describe a new resource,stdpopsim, that attempts to rectify this situation.Stdpopsimis a community-driven open source project, which provides easy access to a growing catalog of published simulation models from a range of organisms and supports multiple simulation engine backends. This resource is available as a well-documented python library with a simple command-line interface. We share some examples demonstrating howstdpopsimcan be used to systematically compare demographic inference methods, and we encourage a broader community of developers to contribute to this growing resource.
A full-proteome, interaction-specific characterization of mutational hotspots across human cancers
Authors: Chen Siwei , Liu Yuan , Zhang Yingying , Wierbowski Shayne D. , Lipkin Steven M. , Wei Xiaomu , Yu Haiyuan 
Published: December 2019

AbstractRapid accumulation of cancer genomic data has led to the identification of an increasing number of mutational hotspots with uncharacterized significance. Here we present a biologically-informed computational framework that characterizes the functional relevance of all 1,107 published mutational hotspots identified in ∼25,000 tumor samples across 41 cancer types in the context of a human 3D interactome network, in which the interface of each interaction is mapped at residue resolution. Hotspots reside in network hub proteins and are enriched on protein interaction interfaces, suggesting that alteration of specific protein-protein interactions is critical for the oncogenicity of many hotspot mutations. Our framework enables, for the first time, systematic identification of specific protein interactions affected by hotspot mutations at the full proteome scale. Furthermore, by constructing a hotspot-affected network that connects all hotspot-affected interactions throughout the whole human interactome, we uncover genome-wide relationships among hotspots and implicate novel cancer proteins that do not harbor hotspot mutations themselves. Moreover, applying our network-based framework to specific cancer types identifies clinically significant hotspots that can be used for prognosis and therapy targets. Overall, we demonstrate that our framework bridges the gap between the statistical significance of mutational hotspots and their biological and clinical significance in human cancers.
Transfer of antigen-encoding bone marrow under immune-preserving conditions deletes mature antigen-specific B cells in recipients and inhibits antigen-specific antibody production
Authors: Brooks Jeremy F. , Davies Janet M. , Wells James W. , Steptoe Raymond J. 
Published: December 2019

SummaryPathological activation and collaboration of T and B cells underlies pathogenic autoantibody responses. Existing treatments for autoimmune disease cause non-specific immunosuppression and induction of antigen-specific tolerance remains an elusive goal. Many immunotherapies aim to manipulate the T-cell component of T-B interplay but few directly target B cells. One possible means to specifically target B cells is the transfer of gene-engineered BM that, once engrafted, gives rise to widespread specific and tolerogenic antigen expression within the hematopoietic system. Gene-engineered bone marrow encoding ubiquitous ovalbumin expression was transferred after low-dose (300cGy) immune-preserving irradiation. B-cell responsiveness was monitored by analyzing ovalbumin-specific antibody production after immunization with ovalbumin/complete Freund’s adjuvant. Ovalbumin-specific B cells and their response to immunization were analyzed using multi-tetramer staining. When antigen-encoding bone marrow was transferred under immune-preserving conditions, cognate antigen-specific B cells were purged from the recipient’s pre-existing B cell repertoire as well as the repertoire that arose after bone marrow transfer. OVA-specific B-cell deletion was apparent within the established host B-cell repertoire as well as that developing after gene-engineered bone marrow transfer. OVA-specific antibody production was substantially inhibited by transfer of OVA-encoding BM and activation of OVA-specific B cells, germinal centre formation and subsequent OVA-specific plasmablast differentiation were all inhibited. Low levels of gene-engineered bone marrow chimerism were sufficient to limit antigen-specific antibody production. These data show that antigen-specific B cells within an established B-cell repertoire are susceptible tode novotolerance induction and this can be achieved by transfer of gene-engineered bone marrow. This adds further dimensions to the utility of antigen-encoding bone marrow transfer as an immunotherapeutic tool.
Compensatory guaiacyl lignin biosynthesis at the expense of syringyl lignin in4CL1-knockout poplar
Authors: Tsai Chung-Jui , Xu Peng , Xue Liang-Jiao , Hu Hao , Nyamdari Batbayar , Naran Radnaa , Zhou Xiaohong , Goeminne Geert , Gao Ruili , Gjersing Erica , Dahlen Joseph , Pattathil Sivakumar , Hahn Michael G. , Davis Mark F. , Ralph John , Boerjan Wout , Harding Scott A. 
Published: December 2019

AbstractThe lignin biosynthetic pathway is highly conserved in angiosperms, yet pathway manipulations give rise to a variety of taxon-specific outcomes. Knockout of lignin-associated4-coumarate:CoA ligases(4CLs) in herbaceous species mainly reduces guaiacyl (G) lignin and enhances cell wall saccharification. Here we show that CRISPR-knockout of4CL1inPopulus tremula×albapreferentially reduced syringyl (S) lignin, with negligible effects on biomass recalcitrance. Concordant with reduced S-lignin was downregulation offerulate 5-hydroxylases(F5Hs). Lignification was largely sustained by 4CL5, a low-affinity paralog of 4CL1 typically with only minor xylem expression or activity. Levels of caffeate, the preferred substrate of 4CL5, increased in line with significant upregulation ofcaffeoyl shikimate esterase1. Upregulation ofcaffeoyl-CoA O-methyltransferase1and downregulation ofF5Hsare consistent with preferential funneling of 4CL5 products toward G-lignin biosynthesis at the expense of S-lignin. Thus, transcriptional and metabolic adaptations to4CL1-knockout appear to have enabled 4CL5 catalysis at a level sufficient to sustain lignification. Finally, genes involved in sulfur assimilation, the glutathione-ascorbate cycle and various antioxidant systems were upregulated in the mutants, suggesting cascading responses to perturbed thioesterification in lignin biosynthesis.One sentence summaryKnockout of lignin-associated4CL1inPopulusreveals a 4CL5-dependent, caffeate-modulated compensatory pathway for lignification with links to thiol redox balance and sulfur assimilation.
Self-regulation of single-stranded DNA wrapping dynamics byE. coliSSB promotes both stable binding and rapid dissociation
Authors: Naufer M. Nabuan , Morse Michael , Möller Guðfríður Björg , McIsaac James , Rouzina Ioulia , Beuning Penny J. , Williams Mark C. 
Published: December 2019

AbstractE. coliSSB (EcSSB) is a model protein for studying functions of single-stranded DNA (ssDNA) binding proteins (SSBs), which are critical in genome maintenance.EcSSB forms homotetramers that wrap ssDNA in multiple conformations in order to protect these transiently formed regions during processes such as replication and repair. Using optical tweezers, we measure the binding and wrapping of a single long ssDNA substrate under various conditions and free protein concentrations. We show thatEcSSB binds in a biphasic manner, where initial wrapping events are followed by unwrapping events as protein density on the substrate passes a critical saturation. Increasing freeEcSSB concentrations increase the fraction ofEcSSBs in less-wrapped conformations, including a previously uncharacterizedEcSSB8bound state in which ∼8 nucleotides of ssDNA are bound by a single domain of the tetramer with minimal substrate deformation. When the ssDNA is over-saturated withEcSSB, stimulated dissociation rapidly removes excessEcSSB, leaving an array of stably-wrappedEcSSB-ssDNA complexes. We develop a multi-step kinetic model in whichEcSSB tetramers transition through multiple wrapped conformations which are regulated through nearest neighbor interactions and ssDNA occupancy. These results provide a mechanism through which otherwise stably bound and wrappedEcSSB tetramers can be rapidly removed from an ssDNA substrate to allow for DNA maintenance and replication functions while still fully protecting ssDNA over a wide range of protein concentrations.
HSI2/VAL1 and HSL1/VAL2 function redundantly to regulate seed dormancy by controllingDOG1expression in Arabidopsis
Authors: Chen Naichong , Wang Hui , Abdelmageed Haggag , Veerappan Vijaykumar , Tadege Million , Allen Randy D. 
Published: December 2019

ABSTRACTDELAY OF GERMINATION1(DOG1) represents a major quantitative locus for the genetic regulation of seed dormancy in Arabidopsis. Accumulation of DOG1 in seeds leads to deep dormancy and delayed germination. Here, we report that the conserved B3 DNA binding domains of the transcriptional repressors HIGH-LEVEL EXPRESSION OF SUGAR INDICIBLE GENE2/ VIVIPAROUS-1/ABSCISIC ACID INSENSITIVE 3-LIKE1 (HSI2/VAL1) and HSI2-LIKE1/ VIVIPAROUS-1/ABSCISIC ACID INSENSITIVE 3-LIKE2 (HSL1/VAL2), which play critical roles in the developmental transition from seed maturation to seedling growth, interact with RY elements in theDOG1proximal promoter leading to repression ofDOG1transcription during germination and seedling establishment.DOG1expression is partially de-repressed inhsi2/val1(hsi2-2) but not inhsl1/val2(hsl1-1) knockout mutants and is strongly upregulated in ahsi2/val1 hsl1/val2double mutant, indicating that HSI2/VAL1 and HSL1/VAL2 act redundantly to repressDOG1expression. HSI2/VAL1 and HSL1/VAL2 form homo- and hetero-dimersin vivo, and dimerization is dependent on the HSI2/VAL1 PHD-like domain. Complementation ofhsi2-2with HSI2/VAL1 harboring a disrupted plant homeodomain (PHD)-like domain results in stronger de-repression ofDOG1expression than thehsi2-2knockout, indicating that the PHD-like domain plays a critical role in mediating functional interactions between HSI2/VAL1 and HSL1/VAL2. Both HSI2/VAL1 and HSL1/VAL2 interact with components of polycomb repressive complex 2 (PRC2), including CURLY LEAF and MULTICOPY SUPPRESSOR OF IRA1 (MSI1), along with LIKE HETERCHROMATIN PROTEIN 1 (LHP1), which are involved in the deposition and expansion of histone H3 lysine 27 trimethylation (H3K27me3) marks in repressive chromatin. Thus, HSI2/VAL1 HSL1/VAL2-dependent recruitment of PRC2 leads to silencing ofDOG1through the deposition of H3K27me3.
Coarse-Grained Modelling of DNA Plectoneme Pinning in the Presence of Base-Pair Mismatches
Authors: Desai Parth Rakesh , Brahmachari Sumitabha , Marko John F. , Das Siddhartha , Neuman Keir C. 
Published: December 2019

ABSTRACTDamaged or mismatched DNA bases result in the formation of physical defects in double-stranded DNA.In vivo, defects in DNA must be rapidly and efficiently repaired to maintain cellular function and integrity. Defects can also alter the mechanical response of DNA to bending and twisting constraints, both of which are important in defining the mechanics of DNA supercoiling. Here, we use coarse-grained molecular dynamics (MD) simulation and supporting statistical-mechanical theory to study the effect of mismatched base pairs on DNA supercoiling. Our simulations show that plectoneme pinning at the mismatch site is deterministic under conditions of relatively high force (> 2 pN) and high salt concentration (> 0.5 M NaCl). Under physiologically relevant conditions of lower force (0.3 pN) and lower salt concentration (0.2 M NaCl), we find that plectoneme pinning becomes probabilistic and the pinning probability increases with the mismatch size. These findings are in line with experimental observations. The simulation framework, validated with experimental results and supported by the theoretical predictions, provides a way to study the effect of defects on DNA supercoiling and the dynamics of supercoiling in molecular detail.
A burst in T cell receptor translation mediated by eIF3 interactions with T cell receptor mRNAs
Authors: De Silva Dasmanthie , Ferguson Lucas , Smith Benjamin E. , Chin Grant H. , Apathy Ryan A. , Roth Theodore L. , Kudla Marek , Marson Alexander , Ingolia Nicholas T. , Cate Jamie H. D. 
Published: December 2019

AbstractActivation of T cells requires a global surge in cellular protein synthesis, accompanied by a large increase in translation initiation1–4. A central component of the translation initiation machinery–the multi-subunit eukaryotic initiation factor 3 (eIF3)–is rapidly turned on when quiescent T cells are stimulated3. However, the precise role eIF3 plays in activated T cells is not known. Using a global transcriptome crosslinking approach, we show human eIF3 interacts with a distinct set of mRNAs in activated Jurkat cells. A subset of these mRNAs, including those encoding the T cell receptor (TCR) subunits TCRA and TCRB, crosslink to eIF3 across the entire length of the mRNA. TheTCRAandTCRBmRNAs do not co-localize with translationally repressed environments of P-bodies or stress granules but form distinct granules, potentially acting as translation “hot-spots.” T cell activation through CD28 causes a burst of TCR translation controlled by elements in the 3’-untranslated regions (3’-UTRs) of theTCRAandTCRBmRNAs that directly contact eIF3 and that are required for T cell activity. These results highlight a new role for eIF3 in regulating the translation dynamics of the TCR and provide insights that can guide the engineering of T cells used in cell immunotherapy applications.
Regionally divergent drivers of historical diversification in the late Quaternary in a widely distributed generalist species, the common pheasantPhasianus colchicus
Authors: Liu Simin , Liu Yang , Jelen Edouard , Alibadian Mansour , Yao Cheng-Te , Li Xintong , Kayvanfar Nasrin , Wang Yutao , Vahidi Farhad , Han Jianlin , Sundev Gombobaatar , Zhang Zhengwang , Schweizer Manuel 
Published: December 2019

ABSTRACTAimHistorical factors such as Pleistocene climate cycles and associated environmental changes have influenced the phylogeographic structure and demographic dynamics of many species. Resulting patterns not only depend on species’ life-history but also vary regionally. Consequently, different populations of species with large ranges over different biomes might have experienced divergent drivers of diversification and show different population histories. Such a representative species is the common pheasantPhasianus colchicus, an ecological generalist with a wide distribution in the Palearctic and at the edge of the Oriental region. We aimed at identifying distinct phylogeographic lineages of the common pheasant and investigating their evolutionary trajectories.Study locationAsiaMethodsWe used coalescent approaches to describe the phylogeographic structure and to reconstruct the spatio-temporal diversification and demographic history of the common pheasant based on a comprehensive geographic sampling of 265 individuals genotyped at seven nuclear and two mitochondrial loci.ResultsThe common pheasant diversified during the late Pleistocene into eight distinct evolutionary lineages which only partly correspond to traditional morphological groups. It originated at the edge of the Qinghai-Tibetan plateau and spread from there to East and Central Asia. Only the widely distributed genetically uniform lowland lineage of East Asia showed a recent range and population expansion, starting during last glacial. More phylogeographic structure was found elsewhere with lineages showing no signs of recent range expansions. One lineage of subtropical south-central China this is the result of long-term isolation in a climatically stable and topographically complex region. In others from arid Central Asia and China, demographic and range expansions were impeded by repeated population fragmentation during dry glacial and recent aridification. Given such a phylogeographic structure and demographic scenarios among lineages, we proposed split the range-wide common pheasant into three species.Main conclusionsSpatio-temporal phylogeographic frameworks of widespread species complexes such as the common pheasant provide valuable opportunities to identify regionally divergent drivers of diversification.
Elongation of stigmatic papillae induced by heat stress is associated with disturbance of pollen attachment inArabidopsis thaliana
Authors: Katano Kazuma , Oi Takao , Suzuki Nobuhiro 
Published: December 2019

ABSTRUCTHeat stress can seriously impact on yield production and quality of crops. Many studies uncovered the molecular mechanisms that regulate heat stress responses in plants. Nevertheless, effects of heat stress on the morphology of plants were still not extensively studied. In this study, we observed the detailed morphological changes of reproductive organs inArabidopsis thalianacaused by heat stress. Larger area of stigma, and shorter length of anthers, filaments and petals were observed in plants subjected to heat stress compared to those under controlled conditions. Scanning electron microscopy (SEM) observation showed that length of stigmatic papillae without pollens seemed to be longer than that with pollens. In addition, classification of stigmas based on pollen attachment patterns together with artificial pollination assay revealed that pollen attachment onto stigma was clearly decreased by heat stress, and indicated that heat induced elongation of stigmatic papillae might be associated with disturbance of pollen attachment onto stigma. Furthermore, histochemical staining experiments revealed that crosstalk between Ca2+and NO derived from pollens and O2−derived from stigma might be associated with morphological alteration of stigma.