bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR17~92 is essential for the survival of hematopoietic stem and progenitor cells by restraining pro-apoptotic BIM
Authors: Brinkmann Kerstin , Hyland Craig , de Graaf Carolyn A , Strasser Andreas , Alexander Warren S , Herold Marco J 
Published: June 2018

SummaryThe micro RNA cluster miR17~92, also known as oncomiR-1, impacts diverse cellular processes, such as cell survival and proliferation. Constitutive loss of miR17~92 in mice causes severe defects in skeletal development, organ development and hematopoiesis, resulting in early post-natal lethality. The critical functions of miR17~92 in a fully developed animal have not yet been explored. Here we show that deletion of miR17~92 in adult mice had no impact on their lifespan or general well-being. However, detailed analysis of the hematopoietic system in mice, revealed a dramatic reduction in all mature hematopoietic lineages, which was due to the loss of early hematopoietic stem/progenitor cells (HSPCs). Strikingly, the concomitant loss of the pro-apoptotic BH3-only protein BIM rescued the loss of the HSPCs and all of their differentiated progeny that was caused by the deletion of miR17~92. These findings demonstrate that miR17~92 is critical for the survival of HSPCs by restraining the activity of the pro-apoptotic BH3-only protein BIM.
The non-canonical SMC protein SmcHD1 antagonises TAD formation on the inactive X chromosome
Authors: Gdula Michal R , Nesterova Tatyana B , Pintacuda Greta , Godwin Jonathan , Zhan Ye , Ozadam Hakan , McClellan Michael , Moralli Daniella , Krueger Felix , Green Catherine M , Reik Wolf , Kriaucionis Skirmantas , Heard Edith , Dekker Job , Brockdorff Neil 
Published: June 2018

AbstractThe inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), and formation of two mega-domains. In this study we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 null cells revealed the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred in an acute SmcHD1 knockout model, but in this case, independent of Xi gene de-repression. We conclude that SmcHD1 is a key factor in antagonising TAD formation on Xi.
Context-dependent spatial sorting of dispersal-related traits in the invasive starlings (Sturnus vulgaris) of South Africa and Australia
Authors: Phair David J. , Roux Johannes J. Le , Berthouly-Salazar Cecile , Visser Vernon , Jansen van Vuuren Bettine , Cardilini Adam P.A. , Hui Cang 
Published: June 2018

AbstractSpecies undergoing range expansion frequently experience increased dispersal rates, especially among invasive alien species. Such increased dispersal rates have been attributed to ‘spatial sorting’, where traits enhancing dispersal assort towards the expanding range edge while traits enhacing competitiveness are favoured within the core range. To date no single study has compared patterns of spatial sorting across multiple continents for the same species. Here we compared patterns of spatial sorting in Sturnus vulgaris, the European starling (hereafter referred to as starlings), in its invasive ranges in South Africa and Australia. Starlings have experienced similar residence times in these two countries. Using multi-scale pattern analyses and generalized additive models, we determine whether dispersal and foraging traits (i.e. the morphological attributes of wings and bills) were sorted along the distance from introduction site. We found apparent patterns of spatial sorting in Australia, but not in South Africa. This difference may be attributed to differences in dispersal rates, clinal variation, environmental heterogeneity, and thus population demography on the two continents. Genetic data suggests that starlings in South Africa have experienced frequent long distance dispersal events, which could have diluted or overridden patterns of spatial sorting.
Mapping of TNTs using Correlative Cryo-Electron Microscopy Reveals a Novel Structure
Authors: Sartori-Rupp Anna , Cervantes Diégo Cordero , Pepe Anna , Delage Elise , Gousset Karine , Corroyer-Dulmont Simon , Schmitt Christine , Krijnse-Locker Jacomina , Zurzolo Chiara 
Published: June 2018

AbstractThe harmonious orchestration of intercellular communication is essential for multicellular organisms. One mechanism by which cells communicate is through long, actin-rich membranous protrusions, called tunneling nanotubes, that allow for the intercellular transport of various cargoes, including viruses, organelles, and proteins between the cytoplasm of distant cells in vitro and in vivo. Over the last decade, studies have focused on their functional role but information regarding their structure and the differences with other cellular protrusions such as filopodia, is still lacking. Here, we report the structural characterization of tunneling nanotubes using correlative light- and cryo-electron microscopy approaches. We demonstrate their structural identity compared to filopodia by showing that they are comprised of a bundle of functional individual Tunneling Nanotubes containing membrane-bound compartments and allowing organelle transfer.
Decoupling tRNA promoter and processing activities enables specific Pol-II Cas9 guide RNA expression
Authors: Knapp David JHF , Michaels Yale S , Jamilly Max , Ferry Quentin RV , Barbosa Hector , Milne Thomas A , Fulga Tudor A 
Published: June 2018

ABSTRACTSpatial/temporal control of Cas9 guide RNA expression could considerably expand the utility of CRISPR-based technologies. Current approaches based on tRNA processing offer a promising strategy but suffer from high background. Here we developed a variant screening platform to identify differential sequence determinants of human tRNA promoter and processing activities. Rational design based on the ensuing principles allowed us to engineer an improved tRNA scaffold that enabled highly specific guide RNA production from a Pol-II promoter.
Low-Cost Solution for Rodent Home-Cage Behaviour Monitoring
Authors: Singh Surjeet , Contreras Edgar Bermudez , Nazari Mojtaba , Sutherland Robert J. , Mohajerani Majid H. 
Published: June 2018

AbstractIn the current research on measuring complex behaviours/phenotyping in rodents, most of the experimental design requires the experimenter to remove the animal from its home-cage environment and place it in an unfamiliar apparatus (novel environment). This interaction may influence behaviour, general well-being, and the metabolism of the animal, affecting the phenotypic outcome even if the data collection method is automated. Most of the commercially available solutions for home-cage monitoring are expensive and usually lack the flexibility to be incorporated with existing home-cages. Here we present a low-cost solution for monitoring home-cage behaviour of rodents that can be easily incorporated to practically any available rodent home-cage. To demonstrate the use of our system, we reliably predict the sleep/wake state of mice in their home-cage using only video. We validate these results using hippocampal local field potential (LFP) and electromyography (EMG) data. Our approach provides a low-cost flexible methodology for high-throughput studies of sleep, circadian rhythm and rodent behaviour with minimal experimenter interference.
A novel amidase signature family amidase from the marine actinomyceteSalinispora arenicolaCNS-205
Authors: Yanling Ma , Xinfeng Zhang , Rong Zeng 
Published: June 2018

AbstractWe cloned a new gene from the amidase signature (AS) family, designatedam, from the marine actinomyceteSalinispora arenicolaCNS-205. As indicated by bioinformatics analysis and site-directed mutagenesis, the AM protein belonged to the AS family. AM was expressed, purified, and characterised inEscherichia coliBL21 (DE3), and the AM molecular mass was determined to be 51 kDa. The optimal temperature and pH were 40 °C and pH 8.0, respectively. AM exhibited a wide substrate spectrum and showed amidase, aryl acylamidase, and acyl transferase activities. AM had high activity towards aromatic and aliphatic amides. The AM substrate specificity for anilides was very narrow; only propanil could be used as an effective substrate. The extensive substrate range of AM indicates it may have broad potential applications in biosynthetic processes and biodegradation.
Impact of Bactrocera oleae on the fungal microbiota of ripe olive drupes
Authors: Abdelfattah Ahmed , Ruano-Rosa David , Cacciola Santa O. , Li Destri Nicosia Maria G. , Schena Leonardo 
Published: June 2018

AbstractThe olive fruit fly (OFF), Bactrocera oleae is the most devastating pest affecting olive fruit worldwide. Previous investigations have addressed the fungal microbiome associated with olive drupes or B. oleae, but the impact of the insect on fungal communities of olive fruit remains undescribed. In the present work, the fungal microbiome of olive drupes, infested and non-infested by the OFF, was investigated in four different localities and cultivars. Olive fruit fly infestations caused a general reduction of the fungal diversity, a higher quantity of the total DNA and an increase in taxa that remained unidentified or had unknown roles. The infestations led to imbalanced fungal communities with the growth of taxa that are usually outcompeted. While it was difficult to establish a cause-effect link between fly infestation and specific fungi, it is clear that the fly alters the natural microbial balance, especially the low abundant taxa. On the other hand, the most abundant ones, were not significantly influenced by the insect. In fact, despite the slight variation between the sampling locations, Aureobasidium, Cladosporium, and Alternaria, were the dominant genera, suggesting the existence of a typical olive fungal microbiome.
Microbial Dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer
Authors: Mendez Roberto , Kesh Kousik , Arora Nivedita , Di Martino Leá , McAllister Florencia , Merchant Nipun , Banerjee Sulagna , Banerjee Santanu 
Published: June 2018

AbstractPurposeThe lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated to the abysmal survival rate in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high-risk for PDAC.Experimental DesignA combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota was used in a spontaneous genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUmanN2 pipeline. Serum polyamine levels were measured from murine and patient samples using standard methods.ResultsResults showed a progressive Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentration. Therefore, at the early stages of tumorigenesis, the gut microbial composition changes in a way to release metabolites that foster host tumorigenesis, thereby fulfilling the ‘vicious cycle hypothesis’ of the role of the microbiome in health and disease states.ConclusionsOur results provide a potential, precise, non-invasive tool for early detection of PDAC, which will result in improved outcomes.SynopsisGut microbiota changes during early stages of pancreatic ductal adenocarcinoma (PDAC) progression and contributes towards host polyamine pool. Both changes can be used as an early predictive marker for PDAC.Translational RelevancePancreatic carcinogenesis progresses through pre-cancerous PanIN lesions to invasive cancer. Even though these morphological changes are histologically distinct, imaging techniques are not able to distinguish the pre-invasive PanINs from normal pancreas, making detection of a tumor at a precancerous stage impossible. Thus, majority of cases (85–90%) present with advanced pancreatic cancer at the time of diagnosis. This contributes to the dismal survival rate in this disease. Our study of gut microbiome analysis on KPC mice during tumor progression followed by metabolic reconstruction and experimental validation in human samples indicate that gut-microbiome analysis along with an analysis of the microbial metabolites can be developed as potential biomarkers for detection of PDAC at early stages when histological changes are not yet grossly apparent.
Large-scale, quantitative protein assays on a high-throughput DNA sequencing chip
Authors: Layton Curtis J , McMahon Peter L , Greenleaf William J 
Published: June 2018

SummaryHigh-throughput DNA sequencing techniques have enabled diverse approaches for linking DNA sequence to biochemical function. In contrast, assays of protein function have substantial limitations in terms of throughput, automation, and widespread availability. We have adapted an Illumina high-throughput sequencing chip to display an immense diversity of ribosomally-translated proteins and peptides, and then carried out fluorescence-based functional assays directly on this flow cell, demonstrating that a single, widely-available high-throughput platform can perform both sequencing-by-synthesis and protein assays. We quantified the binding of the M2 anti-FLAG antibody to a library of 1.3×104 variant FLAG peptides, exploring non-additive effects of combinations of mutations and discovering a “superFLAG” epitope variant. We also measured the enzymatic activity of 1.56×105 molecular variants of full-length of human O6-alkylguanine-DNA alkyltransferase (SNAP-tag). This comprehensive corpus of catalytic rates linked to amino acid sequence perturbations revealed amino acid interaction networks and cooperativity, linked positive cooperativity to structural proximity, and revealed ubiquitous positively-cooperative interactions with histidine residues.
KH-type splicing regulatory protein controls colorectal cancer cell growth and modulates the tumor microenvironment
Authors: Caiazza Francesco , Oficjalska Katarzyna , Tosetto Miriam , Phelan James J. , Noonan Sinéad , Martin Petra , Killick Kate , Breen Laura , O’Neill Fiona , Nolan Blathnaid , Furney Simon , Power Robert , Fennelly David , Craik Charles S. , O’Sullivan Jacintha , Sheahan Kieran , Doherty Glen A. , Ryan Elizabeth J. 
Published: June 2018

ABSTRACTKH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination ofin silicoanalysis of large datasets,ex vivoanalysis of protein expression in patients, and mechanistic studies usingin vitromodels of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Elevated expression was found in tumor versus matched normal tissue, and we validated these findings in larger independent cohortsin silico.KHSRP expression was a prognostic indicator of worse overall survival (HR=3.74, 95% CI = 1.43-22.97, p=0.0138). Mechanistic data in CRC cell line models supported a role of KHSRP in driving epithelial cell proliferation in both a primary and metastatic setting, through control of the G1/S transition. Additionally, KHSRP promoted a pro-angiogenic extracellular environment by regulating the secretion of oncogenic proteins involved in diverse cellular processes such as migration and response to cellular stress. Our study provides novel mechanistic insight into the tumor-promoting effects of KHSRP in CRC.
A Visualization Tool to Evaluate Pairwise Protein Structure Alignment Algorithms
Authors: Bhattacharjee Shalini , Mukhopadhyay Asish 
Published: June 2018

AbstractThe alignment of two protein structures is a fundamental problem in structural bioinformatics. In this paper, we propose a novel approach to measure the effectiveness of a sample of three such algorithms, DALI, TM-align and EDAlignsse. The underlying premise of our approach is that structural proximity should translate into spatial proximity.
DataPackageR: Reproducible data preprocessing, standardization and sharing using R/Bioconductor for collaborative data analysis
Authors: Finak Greg , Mayer Bryan T. , Fulp William , Obrecht Paul , Sato Alicia , Chung Eva , Holman Drienna , Gottardo Raphael 
Published: June 2018

AbstractA central tenet of reproducible research is that scientific results are published along with the underlying data and software code necessary to reproduce and verify the findings. A host of tools and software have been released that facilitate such work-flows and scientific journals have increasingly demanded that code and primary data be made available with publications. There has been little practical advice on implementing reproducible research work-flows for large ‘omics’ or systems biology data sets used by teams of analysts working in collaboration. In such instances it is important to ensure all analysts use the same version of a data set for their analyses. Yet, instantiating relational databases and standard operating procedures can be unwieldy, with high “startup” costs and poor adherence to procedures when they deviate substantially from an analyst’s usual work-flow. Ideally a reproducible research work-flow should fit naturally into an individual’s existing work-flow, with minimal disruption. Here, we provide an overview of how we have leveraged popular open source tools, including Bioconductor, Rmarkdown, git version control, R, and specifically R’s package system combined with a new toolDataPackageR,to implement a lightweight reproducible research work-flow for preprocessing large data sets, suitable for sharing among small-to-medium sized teams of computational scientists. Our primary contribution is theDataPackageRtool, which decouples time-consuming data processing from data analysis while leaving a traceable record of how raw data is processed into analysis-ready data sets. The software ensures packaged data objects are properly documented and performs checksum verification of these along with basic package version management, and importantly, leaves a record of data processing code in the form of package vignettes. Our group has implemented this work-flow to manage, analyze and report on pre-clinical immunological trial data from multi-center, multi-assay studies for the past three years.
Transcriptional trajectories of human kidney disease progression
Authors: Cippà Pietro E , Sun Bo , Liu Jing , Chen Liang , Naesens Maarten , McMahon Andrew P 
Published: June 2018

AbstractOur molecular understanding of clinical conditions progressing from acute organ injury to irreversible dysfunction is limited. We used renal transplantation as a model to characterize the transcriptional response along the transition from acute kidney injury to allograft fibrosis in humans. The integrated analysis of 163 transcriptomes with machine learning techniques identified shared and divergent transcriptional trajectories determining distinct clinical outcomes in a heterogeneous population. The molecular map of renal responses to injury was validated in a mouse ischemia-reperfusion injury model and highlighted early markers of disease progression. This generally applicable approach opens the way for an unbiased analysis of progressive diseases.
Kinesin-Binding Protein (KBP) buffers the activity of KIF18A and KIF15 in mitosis to ensure accurate chromosome segregation
Authors: Malaby Heidi L. H. , Dumas Megan E. , Ohi Ryoma , Stumpff Jason 
Published: June 2018

ABSTRACTMitotic kinesins must be regulated to ensure a precise balance of spindle forces and accurate segregation of chromosomes into daughter cells. Here we demonstrate that Kinesin-Binding Protein (KBP) reduces the activity of KIF18A and KIF15 during metaphase. Overexpression of KBP disrupts the movement and alignment of mitotic chromosomes and decreases spindle length, a combination of phenotypes observed in cells deficient for KIF18A and KIF15, respectively. We show through gliding filament and microtubule co-pelleting assays that KBP directly inhibits KIF18A and KIF15 motor activity by preventing microtubule-binding. Consistent with these effects, the mitotic localizations of KIF18A and KIF15 are altered by overexpression of KBP. Cells depleted of KBP exhibit lagging chromosomes in anaphase, an effect that is recapitulated by KIF15 and KIF18A overexpression. Based on these data, we propose a model in which KBP acts as a protein buffer in mitosis, protecting cells from excessive KIF18A and KIF15 activity to promote accurate chromosome segregation.SUMMARYKinesin-Binding Protein (KBP) is identified as a regulator of the kinesins KIF18A and KIF15 during mitosis. KBP buffers the activity of these motors to control chromosome alignment and spindle integrity in metaphase and prevent lagging chromosomes in anaphase.
The expected time to cross extended fitness plateaus
Authors: Ghafari Mahan , Weissman Daniel 
Published: June 2018

AbstractFor a population to acquire a complex adaptation requiring multiple individually neutral mutations, it must cross a plateau in the fitness landscape. We consider plateaus involving three mutations, and show that large populations can cross them rapidly via lineages that acquire multiple mutations while remaining at low frequency. Plateau-crossing is fastest for very large populations. At intermediate population sizes, recombination can greatly accelerate adaptation by combining independent mutant lineages to form triple-mutants. For more frequent recombination, such that the population is kept near linkage equilibrium, we extend our analysis to find simple expressions for the expected time to cross plateaus of arbitrary width.
Co-simulation framework of discrete element method and multibody dynamics models
Authors: Lommen Stef , Lodewijks Gabriel , Schott Dingena L. 
Published: June 2018

Purpose
Bulk material-handling equipment development can be accelerated and is less expensive when testing of virtual prototypes can be adopted. However, often the complexity of the interaction between particulate material and handling equipment cannot be handled by a single computational solver. This paper aims to establish a framework for the development, verification and application of a co-simulation of discrete element method (DEM) and multibody dynamics (MBD).

Design/methodology/approach
The two methods have been coupled in two directions, which consists of coupling the load data on the geometry from DEM to MBD and the position data from MBD to DEM. The coupling has been validated thoroughly in several scenarios, and the stability and robustness have been investigated.

Findings
All tests clearly demonstrated that the co-simulation is successful in predicting particle–equipment interaction. Examples are provided describing the effects of a coupling that is too tight, as well as a coupling that is too loose. A guideline has been developed for achieving stable and efficient co-simulations.

Originality/value
This framework shows how to achieve realistic co-simulations of particulate material and equipment interaction of a dynamic nature.