bluuebunny/crossref_metadata_2025_split huggingface dataset:
RUNX1/RUNX1T1 controls alternative splicing in the t(8;21)-positive acute myeloid leukemia cells
Authors: Grinev Vasily , Ilyushonak Ilia , Clough Richard , Nakjang Sirintra , Smink Job , Martinez-Soria Natalia , Ramanouskaya Tatsiana , Bonifer Constanze , Heidenreich Olaf 
Published: May 2019

SUMMARYThe fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of the t(8;21)-positive acute myeloid leukemia. Here we show that this oncogene is a regulator of the alternative RNA splicing for a sub-set of genes in the leukemia cells. We found two primary mechanisms underlying changes in the production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start sites selection in target genes, and (ii) direct or indirect control of the expression of the genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5’-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals a novel layer of RUNX1/RUNX1T1-dependent transcriptome organization in t(8;21)-positive acute myeloid leukemia.
DEN-IM: Dengue Virus identification from shotgun and targeted metagenomics
Authors: Mendes C I , Lizarazo E , Machado M P , Silva D N , Tami A , Ramirez M , Couto N , Rossen J W A , Carriço J A 
Published: May 2019

AbstractDengue virus (DENV) represents a public health and economic burden in affected countries. The availability of genomic data is key to understand viral evolution and dynamics, supporting improved control strategies. Currently, the use of High Throughput Sequencing (HTS) technologies, which can be applied both directly to patient samples (shotgun metagenomics) and to PCR amplified viral sequences (targeted metagenomics), is the most informative approach to monitor the viral dissemination and genetic diversity.Despite many advantages, these technologies require bioinformatics expertise and appropriate infrastructure for the analysis and interpretation of the resulting data. In addition, the many software solutions available can hamper reproducibility and comparison of results.Here we present DEN-IM, a one-stop, user-friendly, containerised and reproducible workflow for the analysis of DENV sequencing data, both from shotgun and targeted metagenomics approaches. It is able to infer DENV coding sequence (CDS), identify serotype and genotype, and generate a phylogenetic tree. It can easily be run on any UNIX-like system, from local machines to high-performance computing clusters, performing a comprehensive analysis without the requirement of extensive bioinformatics expertise.Using DEN-IM, we successfully analysed two DENV datasets. The first comprised 25 shotgun metagenomic sequencing samples of varying serotype and genotype, including a spiked sample containing the existing four serotypes. The second dataset consisted of 106 targeted metagenomics samples of DENV 3 genotype III where DEN-IM allowed detection of the intra-genotype diversity.The DEN-IM workflow, parameters and execution configuration files, and documentation are freely available athttps://github.com/B-UMMI/DEN-IM.
Protein Expression Patterns in ovarian cancer cells Associated with Monofunctional Platinums Treatment
Authors: Arzuman Laila , Moni Mohammad Ali , Beale Philip , Yu Jun Q. , Molloy Mark , Quinn Julian M.W. , Huq Fazlul 
Published: May 2019

ABSTRACTPlatinum drugs cisplatin and carboplatin, given in combination with paclitaxel, constitute the standard chemotherapy against ovarian cancer (OC). Oc chemoresistance is a major obstacle to effective treatment, but knowledge of the mechanisms that underlie it remains incomplete. We thus sought to discover key proteins associated with platinum resistance by comparing A2780 OC cells with A2780cisR cells (resistant cells derived from the A2780 line) to identify proteins with markedly altered expression levels in the resistant cells. We also determined which proteins in these cells had altered expression in response to treatment with either designed monofunctional platinum alone or a combination with cisplatin with selected phytochemical therapeutic agents.We thus performed proteomic analysis using 2D-gel electrophoresis A2780 and A2780cisR to identify proteins with differential expression; these were eluted and analysed by mass spectrometry to identify them. A total of 122 proteins were found to be differentially expressed between A2780 and A2780cisR cell lines in the absence of any drug treatment. Among them, levels of 27 proteins in A2780cisR cell line were further altered (up-or down-regulated) in response to one or more of the drug treatments. We then investigated primary OC tissue RNA expression levels (compared to l ovarian tissue) of genes coding for these candidate 27 proteins using publically available datasets (The Cancer Genome Atlas). We assessed how expression of these genes in OC tissue associates with patient survival using Cox Proportional Hazard (PH) regression models to determine relative risk of death associated with each factor. Our Cox PH regression-based machine learning method confirmed a significant relationship of mortality with altered expression of ARHGDIA, CCT6A and HISTIH4F genes. This indicated that these genes affect OC patient survival, i.e., provided mechanistic evidence, in addition to that of the clinical traits, that these genes may be critical mediators of the processes that underlie OC progression and mortality.Thus, we identified differentially expressed proteins that are implicated in platinum-based chemotherapy resistance mechanisms which may serve as resistance biomarkers. These drug resistance associated proteins may also serve as potential OC therapeutic targets whose blockade may enhance the effectiveness of platinum based drugs.
Different energetic diets affect the maintenance of Apis mellifera L. colonies during off-season
Authors: de Oliveira Gabriela Pinto , Kadri Samir Moura , Emilio Benaglia Bruno Giovane , Martins Ribolla Paulo Eduardo , de Oliveira Orsi Ricardo 
Published: May 2019

AbstractThe aim of this study wasto evaluate the best energetic foodforuse in the maintenance of honey bee colonies during the off-season. To do this, 20Apis mellifera beehives were used(with five beehives per treatment): CTL,control (without feeding); SJ,sugarcane juice; SS,sugar syrup; and IS,inverted sugar. We evaluated the food consumption, population development, and physiological state (expression of vitellogenin and hexamerin 70agenes)of eachcolony.The results showed that the supplementation of colonieswith sugar syrup resulted in an intermediateconsumption and thebetter development of the colony.In addition, this diet ensured that the colonies were in a good physiological state,as beesfed this diet presentedthe highest relative expression levels of vitellogenin and hexamerin 70ameasuredamong all thediets tested.Therefore, sugar syrup was concluded to be the best artificial energetic food for use in thesupplementation of honey bee colonies during the off-season.
Model-based control of individual finger movements for prosthetic hand function
Authors: Blana Dimitra , van den Bogert Antonie J. , Murray Wendy M. , Ganguly Amartya , Krasoulis Agamemnon , Nazarpour Kianoush , Chadwick Edward K. 
Published: May 2019

AbstractProsthetic devices for hand difference have advanced considerably in recent years, to the point where the mechanical dexterity of a state-of-the-art prosthetic hand approaches that of the natural hand. Control options for users, however, have not kept pace, meaning that the new devices are not used to their full potential. Promising developments in control technology reported in the literature have met with limited commercial and clinical success. We have previously described a biomechanical model of the hand that could be used for prosthesis control. In this study, we report on three key elements of the biomechanical simulations relevant to prosthesis control: we show the performance of the model in replicating recorded hand kinematics and find average correlations of 0.89 between modelled and recorded motions; we show that the computational performance of the simulations is fast enough to achieve real-time control with a robotic hand in the loop; and we describe the use of the model for controlling object gripping. Despite some limitations in accessing sufficient driving signals, the model performance shows promise as a controller for prosthetic hands when driven with recorded EMG signals. We identify areas for future work to address these limitations.
The L1 stalk is required for efficient export of nascent large ribosomal subunits in yeast
Authors: Musalgaonkar Sharmishtha , Black Joshua J. , Johnson Arlen W. 
Published: May 2019

AbstractThe ribosomal protein Rpl1 (uL1 in universal nomenclature) is essential in yeast and constitutes part of the L1 stalk which interacts with E site ligands on the ribosome. Structural studies of nascent pre-60S complexes in yeast have shown that a domain of the Crm1-dependent nuclear export adapter Nmd3, binds in the E site and interacts with Rpl1, inducing closure of the L1 stalk. Based on this observation, we decided to reinvestigate the role of the L1 stalk in nuclear export of pre-60S subunits despite previous work showing that Rpl1-deficient ribosomes are exported from the nucleus and engage in translation. Large cargoes, such as ribosomal subunits, require multiple export factors to facilitate their transport through the nuclear pore complex. Here, we show that pre-60S subunits lacking Rpl1 or truncated for the RNA of the L1 stalk are exported inefficiently. Surprisingly, this is not due to a measurable defect in recruitment of Nmd3 but appears to result from inefficient recruitment of the Mex67-Mtr2 heterodimer.
Rapid functionalisation and detection of viruses via a novel Ca2+-mediated virus-DNA interaction
Authors: Robb Nicole C. , Taylor Jonathan M. , Kent Amy , Pambos Oliver J. , Gilboa Barak , Kapanidis Achillefs N. 
Published: May 2019

ABSTRACTCurrent virus detection methods often take significant time or can be limited in sensitivity and specificity. The increasing frequency and magnitude of viral outbreaks in recent decades has resulted in an urgent need for diagnostic methods that are facile, sensitive, rapid and inexpensive. Here, we describe and characterise a novel, calcium-mediated interaction of the surface of enveloped viruses with DNA, that can be used for the functionalisation of intact virus particles via chemical groups attached to the DNA. Using DNA modified with fluorophores, we have demonstrated the rapid and sensitive labelling and detection of influenza and other viruses using single-particle tracking and particle-size determination. With this method, we have detected clinical isolates of influenza in just one minute, significantly faster than existing rapid diagnostic tests. This powerful technique is easily extendable to a wide range of other enveloped pathogenic viruses and holds significant promise as a future diagnostic tool.
Noncanonical scaffolding of Gαiand β-arrestin by G protein-coupled receptors
Authors: Smith Jeffrey S. , Pack Thomas F. , Inoue Asuka , Lee Claudia , Xiong Xinyu , Zheng Kevin , Kahsai Alem W. , Choi Issac , Ma Zhiyuan , Levitan Ian M. , Rochelle Lauren K. , Staus Dean P. , Snyder Joshua C. , Caron Marc G. , Rajagopal Sudarshan 
Published: May 2019

SummaryG-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct Gαproteins, such as Gαs, Gαi, Gαqor Gα12/13, as well as β-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of Gαproteins to directly interact with β-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gαiprotein family members and β-arrestin. Gαi:β-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gαi:β-arrestin scaffolds enhances our understanding of GPCR signalling.
PROMO: An interactive tool for analyzing clinically-labeled multi-omic cancer datasets
Authors: Netanely Dvir , Stern Neta , Laufer Itay , Shamir Ron 
Published: May 2019

AbstractBackgroundAnalysis of large genomic datasets along with their accompanying clinical information has shown great promise in cancer research over the last decade. Such datasets typically include thousands of samples, each measured by one or several high-throughput technologies (‘omics’) and annotated with extensive clinical information. While instrumental for fulfilling the promise of personalized medicine, the analysis and visualization of such large datasets is challenging and necessitates programming skills and familiarity with a large array of software tools to be used for the various steps of the analysis.ResultsWe developed PROMO (Profiler of Multi-Omic data), a friendly, fully interactive stand-alone software for analyzing large genomic cancer datasets together with their associated clinical information. The tool provides an array of built-in methods and algorithms for importing, preprocessing, visualizing, clustering, clinical label enrichment testing and survival analysis that can be performed on a single or multi-omic dataset. The tool can be used for quick exploration and for stratification of tumor samples taken from patients into clinically significant molecular subtypes. Identification of prognostic biomarkers and generation of simple subtype classifiers are additional important features. We review PROMO’s main features and demonstrate its analysis capabilities on a breast cancer cohort from TCGA.ConclusionsPROMO provides a single integrated solution for swiftly performing a complete analysis of cancer genomic data for subtype discovery and biomarker identification without writing a single line of code, and can, therefore, make the analysis of these data much easier for cancer biologists and biomedical researchers. PROMO is freely available for download at http://acgt.cs.tau.ac.il/promo/.
Calcium entry does not drive fast mechanotransduction adaptation in cochlear hair cells
Authors: Caprara Giusy A. , Mecca Andrew A. , Wang Yanli , Ricci Anthony J. , Peng Anthony W. 
Published: May 2019

AbstractSound detection in auditory sensory hair cells depends on the deflection of the stereocilia hair bundle, which opens mechano-electric transduction (MET) channels. Adaptation is hypothesized to be a critical property of MET that contributes to the wide dynamic range and sharp frequency selectivity of the auditory system. Historically, adaptation was hypothesized to have multiple mechanisms, all of which require calcium entry through MET channels. Our recent work using a stiff probe to displace hair bundles showed that the fastest adaptation mechanism (fast adaptation) does not require calcium entry. Using a fluid-jet stimulus, others obtained data showing only a calcium-dependent fast adaptation response. Here, we identified the source of this discrepancy. Because the hair cell response to a hair bundle stimulus depends critically on the magnitude and time course of the hair bundle deflection, we developed a high-speed imaging technique to quantify this deflection. The fluid jet delivers a force stimulus, and step-like force stimuli lead to a complex time course of hair bundle displacement (mechanical creep), which affects the hair cell’s macroscopic MET current response by masking the time course of the fast adaptation response. Modifying the fluid-jet stimulus to generate a step-like hair bundle displacement produced rapidly adapting currents that did not depend on membrane potential. This indicated that fast adaptation does not depend on calcium entry. We also confirmed the presence of a calcium-dependent slow adaptation process. These results confirm the existence of multiple adaptation processes: a fast adaptation that is not driven by calcium entry and a slower calcium-dependent process.Significance StatementMechanotransduction by sensory hair cells represents a key first step for the sound sensing ability in vertebrates. The sharp frequency tuning and wide dynamic range of sound sensation are hypothesized to require a mechanotransduction adaptation mechanism. For decades, it had been accepted that all adaptation mechanisms require calcium entry into hair cells. However, more recent work indicated that the apparent calcium dependence of the fastest adaptation differs with the method of cochlear hair cell stimulation. Here, we reconcile existing data and show that calcium entry does not drive the fastest adaptation process, independent of the stimulation method.
A highly-selective chloride microelectrode based on a mercuracarborand anion carrier
Authors: DiFranco Marino , Quinonez Marbella , Dziedzic Rafal M. , Spokoyny Alexander M. , Cannon Stephen C. 
Published: May 2019

ABSTRACTThe chloride gradient plays an important role in regulating cell volume, membrane potential, pH, secretion, and the reversal potential of inhibitory GABAA receptors. Measurement of intracellular chloride activity, , using liquid membrane ion-selective microelectrodes (ISM), however, has been limited by the physiochemical properties of Cl ionophores which have caused poor stability, drift, sluggish response times, and interference from other biologically relevant anions. Most importantly, intracellular HCO3− may be up to 4 times more abundant than Cl− (e.g. skeletal muscle) which places severe constraints on the required selectivity of a Cl – sensing ISM.Previously, a sensitive and highly-selective Cl sensor was developed in a polymeric membrane electrode (Badr et al. 1999) using a trinuclear Hg(II) complex containing carborane-based ligands, [9]-mercuracarborand-3, or MC3 for short. Here, we have adapted the use of the MC3 anion carrier in a liquid membrane ion-selective microelectrode and show the MC3-ISM has a linear Nernstian response over a wide range of aCl (0.1 mM to 100 mM), is highly selective for Cl over other biological anions or inhibitors of Cl transport, and has a response time of less than 5 sec. Importantly, over the physiological range of aCl (1 mM to 100 mM) the potentiometric response of the MC3-ISM is insensitive to HCO3− or changes in pH. Finally, we demonstrate the biological application of an MC3-ISM by measuring intracellular aCl, and the response to an external Cl-free challenge, for an isolated skeletal muscle fiber.
Variable prediction accuracy of polygenic scores within an ancestry group
Authors: Mostafavi Hakhamanesh , Harpak Arbel , Conley Dalton , Pritchard Jonathan K , Przeworski Molly 
Published: May 2019

AbstractFields as diverse as human genetics and sociology are increasingly using polygenic scores based on genome-wide association studies (GWAS) for phenotypic prediction. However, recent work has shown that polygenic scores have limited portability across groups of different genetic ancestries, restricting the contexts in which they can be used reliably and potentially creating serious inequities in future clinical applications. Using the UK Biobank data, we demonstrate that even within a single ancestry group, the prediction accuracy of polygenic scores depends on characteristics such as the age or sex composition of the individuals in which the GWAS and the prediction were conducted, and on the GWAS study design. Our findings highlight both the complexities of interpreting polygenic scores and underappreciated obstacles to their broad use.
Relationships between MA-RNA binding in cells and suppression of HIV-1 Gag mislocalization to intracellular membranes
Authors: Thornhill Dishari , Olety Balaji , Ono Akira 
Published: May 2019

ABSTRACTThe HIV-1 Gag matrix (MA) domain mediates localization of Gag to the plasma membrane (PM), the site for infectious virion assembly. The MA highly basic region (HBR) interacts with phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2], a PM-specific acidic lipid. MA-HBR also binds RNAs. To test whether acidic lipids alone determine PM-specific localization of Gag or whether MA-RNA binding also plays a role, we compared a panel of MA-HBR mutants that contain two types of substitutions at MA residues 25/26 or 29/31: Lys->Arg (KR) (25/26KR and 29/31KR) and Lys->Thr (KT) (25/26KT and 29/31KT). Consistent with the importance of the HBR charge in RNA binding, both KT mutants failed to bind RNA via MA efficiently unlike the corresponding KR mutants. Both 25/26KT Gag-YFP and 29/31KT Gag-YFP bound non-specifically to PM and intracellular membranes, presumably via the myristoyl moiety and remaining MA basic residues. In contrast, 25/26KR Gag-YFP bound specifically to the PM, suggesting a role for the total positive charge and/or MA-bound RNA in navigating Gag to the PM. Unlike 29/31KT Gag-YFP, 29/31KR Gag-YFP was predominantly cytosolic and showed little intracellular membrane binding despite having a higher HBR charge. Therefore, it is likely that MA-RNA binding blocks promiscuous Gag membrane binding in cells. Notably, introduction of a heterologous multimerization domain restored PI(4,5)P2-dependent PM-specific localization for 29/31KR Gag-YFP, suggesting that the blocking of PM binding is more readily reversed than that of intracellular membrane binding. Altogether, these cell-based data support a model in which MA-RNA binding ensures PM-specific localization of Gag via suppression of non-specific membrane binding.IMPORTANCEThe PM-specific localization of HIV-1 Gag is a crucial early step in the infectious progeny production. The interaction between the MA highly basic region (HBR) of Gag and the PM-specific lipid PI(4,5)P2 is critical for Gag localization to the PM. Additionally,in vitroevidence has indicated that MA-RNA binding prevents non-specific binding of Gag to non-PI(4,5)P2-containing membranes. However, cell-based evidence supporting a role for HIV-1 MA-RNA binding in PM-specific subcellular localization has been scarce; thus, it remained possible that in cells, just the high basic charge or the PI(4,5)P2-binding ability is sufficient for MA to direct Gag specifically to the PM. The current study revealed for the first time an excellent correlation between RNA binding of MA-HBR and inhibition of promiscuous Gag localization, both within the cells, and thereby provided cell-based evidence supporting a mechanism in which HIV-1 MA binding to RNA ensures specific localization of Gag to the PM.
Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan
Authors: Ghodousi Arash , Rizvi Alamdar Hussain , Baloch Aurangzaib Quadir , Ghafoor Abdul , Khanzada Faisal Masood , Qadir Mehmood , Borroni Emanuele , Trovato Alberto , Tahseen Sabira , Cirillo Daniela Maria 
Published: May 2019

AbstractWe report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential culture isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimen were tested for minimum inhibitory concentration (MIC) and whole genome sequencing. An increase in MICs associated with cross-resistance to clofazimine and appearance of specific mutations was documented in six cases. The study underlines that appropriate monitoring is mandatory for the introduction of new drugs.