bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two pathways of p27Kip1degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A
Authors: Sora Richard P. , Ikeda Masato , Longnecker Richard 
Published: March 2019

AbstractEpstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV latency, contributes to Burkitt Lymphoma (BL) development in a murine model by acting as a constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A andMYCtransgenes (LMP2A/λ-MYC) develop tumors significantly faster than mice only expressingMYC(λ-MYC). Previously, we demonstrated the cell cycle inhibitor p27Kip1is present at significantly lower levels in LMP2A/λ-MYCmice due to increased post-translational degradation. P27Kip1degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10), or in the nucleus via the SCFSkp2complex, which depends on Cks1. We previously demonstrated a S10A knock-in of p27Kip1(p27S10A/S10A), which prevented S10 phosphorylation, failed to significantly delay tumor onset in LMP2A/λ-MYCmice. We also previously demonstrated that aCks1knockout partially delayed tumor onset in LMP2A/λ-MYCmice, but onset was still significantly faster than in λ-MYCmice. Here, we have combined both genetic manipulations in what we call p27Supermice. LMP2A/λ-MYC/p27Supermice and λ-MYC/p27Supermice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/λ-MYC/p27Supermice was later than in λ-MYCmice and not significantly different from λ-MYC/p27Supermice. The p27Supergenotype also normalized G1-S phase cell cycle progression, spleen size, and splenic architecture in LMP2A/λ-MYCmice. Our results reveal both major pathways of p27Kip1degradation are required for the accelerated BL development driven by LMP2A in our BL model and that blocking both degradation pathways is sufficient to delay Myc-driven tumor development with or without LMP2A.ImportanceBurkitt lymphoma (BL) is a cancer that primarily affects children. The side effects of chemotherapy highlight the need for better BL treatments. Many BL tumors contain Epstein-Barr virus (EBV) and our goal is to determine what makes EBV-positive BL different from EBV-negative BL. This may lead to more specific treatments for both types. All cases of BL require overexpression ofMYC. Mice engineered to express an EBV LMP2A along withMYC(LMP2A/λ-MYCmice) develop tumors much more quickly than mice only expressing MYC (λ-MYCmice). Blocking degradation of the cell cycle inhibitor protein p27Kip1in LMP2A/λ-MYCmice causes tumors to develop later than in λ-MYCmice, showing that p27Kip1degradation may play a larger role in EBV-positive BL than EBV-negative. Furthermore, our studies suggest the cell cycle may be an attractive target as a treatment option for LMP2A positive cancers in humans.
A high-fat high-sugar diet in adolescent rats impairs social memory and alters chemical markers characteristic of atypical neuroplasticity and GABAergic neurodevelopment in the medial prefrontal cortex
Authors: Reichelt Amy C , Gibson Gabrielle D , Abbott Kirsten N , Hare Dominic J 
Published: March 2019

AbstractBrain plasticity is a multifaceted process that is dependent on both neurons and extracellular matrix (ECM) structures, including perineuronal nets (PNNs). In the medial prefrontal cortex (mPFC) PNNs primarily surround fast-spiking parvalbumin (PV)-containing GABAergic interneurons and are central to regulation of neuroplasticity. In addition to the development of obesity, high-fat and high-sugar (HFHS) diets are also associated with alterations in brain plasticity and emotional behaviours in humans. To examine the underlying involvement of PNNs and cortical plasticity in the mPFC in diet-evoked social behaviour deficits (in this case social recognition), we exposed adolescent (postnatal days P28-P56) rats to a HFHS-supplemented diet. At P56 HFHS-fed animals and age-matched controls fed standard chow were euthanized and co-localization of PNNs with PV neurons in the prelimbic (PrL) and infralimbic (IL) and anterior cingulate (ACC) sub regions of the PFC were examined by dual fluorescence immunohistochemistry. ΔFosB expression was also assessed as a measure of chronic activity and behavioural addiction marker. Consumption of the HFHS diet reduced the number of PV+ neurons and PNNs in the infralimbic (IL) region of the mPFC by −21.9% and −16.5%, respectively. While PV+ neurons and PNNs were not significantly decreased in the ACC or PrL, the percentage of PV+ and PNN co-expressing neurons was increased in all assessed regions of the mPFC in HFHS-fed rats (+33.7% to +41.3%). This shows that the population of PV neurons remaining are those surrounded by PNNs, which may afford some protection against HFHS diet-induced mPFC-dysregulation. ΔFosB expression showed a 5-10-fold increase (p< 0.001) in each mPFC region, supporting the hypothesis that a HFHS diet induces mPFC dysfunction and subsequent behavioural deficits. The data presented shows a potential neurophysiological mechanism and response to specific diet-evoked social recognition deficits as a result of hypercaloric intake in adolescence.
Gene expression profiles and pathway enrichment analysis to identification of differentially expressed gene and signaling pathways in epithelial ovarian cancer based on high-throughput RNA-seq data
Authors: Siavoshi A , Taghizadeh M , Dookhe E , Piran M 
Published: March 2019

ABSTRACTEpithelial ovarian cancer (EOC) can be considered as a stressful and challenging disease among all women in the world, which has been associated with a poor prognosis and its molecular pathogenesis has remained unclear. In recent years, RNA Sequencing (RNA-seq) has become a functional and amazing technology for profiling gene expression. In the present study, RNA-seq raw data from Sequence Read Archive (SRA) of six tumor and normal ovarian sample was extracted, and then analysis and statistical interpretation was done with Linux and R Packages from the open-source Bioconductor. Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied for the identification of key genes and pathways involved in EOC. We identified 1091 Differential Expression Genes (DEGs) which have been reported in various studies of ovarian cancer as well as other types of cancer. Among them, 333 genes were up-regulated and 273 genes were down-regulated. In addition, Differentially Expressed Genes (DEGs) including RPL41, ALDH3A2, ERBB2, MIEN1, RBM25, ATF4, UPF2, DDIT3, HOXB8 and IL17D as well as Ribosome and Glycolysis/Gluconeogenesis pathway have had the potentiality to be used as targets for EOC diagnosis and treatment. In this study, unlike that of any other studies on various cancers, ALDH3A2 was most down-regulated gene in most KEGG pathways, and ATF4 was most up-regulated gene in leucine zipper domain binding term. In the other hand, RPL41 as a regulatory of cellular ATF4 level was up-regulated in many term and pathways and augmentation of ATF4 could justify the increase of RPL41 in the EOC. Pivotal pathways and significant genes, which were identified in the present study, can be used for adaptation of different EOC study. However, further molecular biological experiments and computational processes are required to confirm the function of the identified genes associated with EOC.
Integrating behaviour and ecology into global biodiversity conservation strategies
Authors: Tobias Joseph A. , Pigot Alex L. 
Published: March 2019

SummaryInsights into animal behaviour play an increasingly central role in species-focused conservation practice. However, progress towards incorporating behaviour into regional or global conservation strategies has been far more limited, not least because standardised datasets of behavioural traits are generally lacking at wider taxonomic or spatial scales. Here we make use of the recent expansion of global datasets for birds to assess the prospects for including behavioural traits in systematic conservation priority-setting and monitoring programmes. Using IUCN Red List classification for >9500 bird species, we show that the incidence of threat can vary substantially across different behavioural syndromes, and that some types of behaviour—including particular foraging, mating and migration strategies—are significantly more threatened than others. When all factors are included in a combined model, behavioural traits have a weaker effect than well-established geographical and ecological factors, including range size, body mass and human population pressures. We also show that the association between behavior and extinction risk is partly driven by correlations with these underlying factors. Overall, these results suggest that a multi-species approach at the scale of communities, continents and ecosystems can be used to identify and monitor threatened behaviours, and to flag up cases of latent extinction risk, where threatened status may currently be underestimated. Our findings also highlight the importance of comprehensive standardized descriptive data for ecological and behavioural traits, and point the way forward to a deeper integration of behaviour into quantitative conservation assessments.
Functional dissection of TADs reveals non-essential and instructive roles in regulating gene expression
Authors: Despang Alexandra , Schöpflin Robert , Franke Martin , Ali Salaheddine , Jerkovic Ivana , Paliou Christina , Chan Wing-Lee , Timmermann Bernd , Wittler Lars , Vingron Martin , Mundlos Stefan , Ibrahim Daniel M. 
Published: March 2019

AbstractThe genome is organized in megabase-sized three-dimensional units, called Topologically Associated Domains (TADs), that are separated by boundaries. TADs bring distant cis-regulatory elements into proximity, a process dependent on the cooperative action of cohesin and the DNA binding factor CTCF. Surprisingly, genome-wide depletion of CTCF has little effect on transcription, yet structural variations affecting TADs have been shown to cause gene misexpression and congenital disease. Here, we investigate TAD functionin vivoin mice by systematically editing components of TAD organization at theSox9/Kcnjlocus. We find that TADs are formed by a redundant system of CTCF sites requiring the removal of all major sites within the TAD and at the boundary for two neighboring TADs to fuse. TAD fusion resulted in leakage of regulatory activity from theSox9to theKcnjTAD, but no major changes in gene expression. This indicates that TAD structures provide robustness and precision, but are not essential for developmental gene regulation. Gene misexpression and resulting disease phenotypes, however, were attained by re-directing regulatory activity through inversions and/or the re-positioning of boundaries. Thus, efficient re-wiring of enhancer promoter interaction and aberrant disease causing gene activation is not induced by a mere loss of insulation but requires the re-direction of contacts.
Reconstructing the ecology of a Jurassic pseudoplanktonic megaraft colony
Authors: Hunter Aaron W. , Casenove David , Mitchell Emily G. , Mayers Celia 
Published: March 2019

AbstractPseudoplanktonic crinoid megaraft colonies are an enigma of the Jurassic. They are among the largest in-situ invertebrate accumulations ever to exist in the Phanerozoic fossil record. These megaraft colonies and are thought to have developed as floating filter-feeding communities due to an exceptionally rich relatively predator free oceanic niche, high in the water column enabling them to reach high densities on these log rafts. However, this pseudoplanktonic hypothesis has never actually been quantitatively tested and some researchers have cast doubt that this mode of life was even possible. The ecological structure of the crinoid colony is resolved using spatial point process techniques and its longevity using moisture diffusion models. Using spatial analysis we found that the crinoids would have trailed preferentially positioned at the back of migrating structures in the regions of least resistance, consistent with a floating, not benthic ecology. Additionally, we found using a series of moisture diffusion models at different log densities and sizes that ecosystem collapse did not take place solely due to colonies becoming overladen as previously assumed. We have found that these crinoid colonies studied could have existed for greater than 10 years, even up to 20 years exceeding the life expectancy of modern documented megaraft systems with implications for the role of modern raft communities in the biotic colonisation of oceanic islands and intercontinental dispersal of marine and terrestrial species.Significance statementTransoceanic rafting is the principle mechanism for the biotic colonisation of oceanic island ecosystems. However, no historic records exist of how long such biotic systems lasted. Here, we use a deep-time example from the Early Jurassic to test the viability of these pseudoplanktonic systems, resolving for the first time whether these systems were truly free floating planktonic and viable for long enough to allow its inhabitants to grow to maturity. Using spatial methods we show that these colonies have a comparable structure to modern marine pesudoplankton on maritime structures, whilst the application of methods normally used in commercial logging is used to demonstrate the viability of the system which was capable of lasting up to 20 years.
Nanopore sequencing of full-length circRNAs in human and mouse brains reveals circRNA-specific exon usage and intron retention
Authors: Rahimi Karim , Venø Morten T. , Dupont Daniel M. , Kjems Jørgen 
Published: March 2019

AbstractCircular RNA (circRNA) is a poorly understood class of non-coding RNAs, some of which have been shown to be functional important for cell proliferation and development. CircRNAs mainly derive from back splicing events of coding mRNAs, making it difficult to distinguish the internal exon composition of circRNA from the linearly spliced mRNA. To examine the global exon composition of circRNAs, we performed long-read sequencing of single molecules using nanopore technology for human and mouse brain-derived RNA. By applying an optimized circRNA enrichment protocol prior to sequencing, we were able to detect 7,834 and 10,975 circRNAs in human and mouse brain, respectively, of which 2,945 and 7,052 are not currently found in circBase. Alternative splicing was more prevalent in circRNAs than in linear spliced transcripts, and notably >200 not previously annotated exons were used in circRNAs. This suggests that properties associated with circRNA- specific features, e.g. the unusual back-splicing step during biogenesis, increased stability and /or their lack of translation, alter the general exon usage at steady state. We conclude that the nanopore sequencing technology provides a fast and reliable method to map the specific exon composition of circRNA.
Insights into an alternative pathway for glycerol metabolism in a glycerol kinase deficientPseudomonas putidaKT2440
Authors: Walsh Meg , Casey William , Kenny Shane T. , Narancic Tanja , Blank Lars M. , Wierckx Nick , Ballerstedt Hendrik , Connor Kevin E O 
Published: March 2019

AbstractPseudomonas putidaKT2440 is known to metabolise glycerol via glycerol-3-phosphate using glycerol kinase an enzyme previously described as critical for glycerol metabolism (1). However, when glycerol kinase was knocked out inP. putidaKT2440 it retained the ability to use glycerol as the sole carbon source, albeit with a much-extended lag period and 2 fold lower final biomass compared to the wild type strain. A metabolomic study identified glycerate as a major and the most abundant intermediate in glycerol metabolism in this mutated strain with levels 21-fold higher than wild type. Erythrose-4-phosphate was detected in the mutant strain, but not in the wild type strain. Glyceraldehyde and glycraldehyde-3-phosphate were detected at similar levels in the mutant strain and the wild type. Transcriptomic studies identified 191 genes that were more than 2-fold upregulated in the mutant compared to the wild type and 175 that were down regulated. The genes involved in short chain length fatty acid metabolism were highly upregulated in the mutant strain. The genes encoding 3-hydroxybutyrate dehydrogenase were 5.8-fold upregulated and thus the gene was cloned, expressed and purified to reveal it can act on glyceraldehyde but not glycerol as a substrate.
Application of Global Metabolomics to the Identification of Complex Counterfeit Medicinal Products
Authors: Jenkins Conor , Orsburn Ben 
Published: March 2019

AbstractFood fraud and drug counterfeiting are of increasingly large concern to both global economics and to public health and safety. Simple medicinal products consisting of single synthesized or purified compounds can be tested for purity and authenticity rapidly with established assays such as chromatography and UV absorbance. Drugs derived from natural sources may contain hundreds or thousands of distinct chemical compounds and require correspondingly complex analytical methods. In this study we explore the use of methods developed for global metabolic profiling toward the identification of unknown complex medicinal products. By utilizing rapid solvent extraction followed by ultrahigh pressure high performance liquid chromatography (UHPLC) coupled to high resolution accurate mass spectrometry (HRAM-MS/MS), we can reliably obtain a profile of the sample’s molecular makeup. After profiling plant material to the depth of over 1,000 distinct molecules identified and quantified, we utilize these profiles to identify separately prepared and individually assayed blinded samples. We conclude that once a comprehensive library of small molecules has been acquired for each sample, identical preparations of products of unknown origin may be identified using simple statistical tools such as principal component analysis. We also conclude that these tools will be a valuable resource in affordably identified contaminated, adulterated and counterfeit products.Abstract Graphic
The Paf1 complex broadly impacts the transcriptome ofSaccharomyces cerevisiae
Authors: Ellison Mitchell A. , Lederer Alex R. , Warner Marcie H. , Mavrich Travis , Raupach Elizabeth A. , Heisler Lawrence E. , Nislow Corey , Lee Miler T. , Arndt Karen M. 
Published: March 2019

ABSTRACTThe Polymerase Associated Factor 1 complex (Paf1C) is a multifunctional regulator of eukaryotic gene expression important for the coordination of transcription with chromatin modification and post-transcriptional processes. In this study, we investigated the extent to which the functions of Paf1C combine to regulate theSaccharomyces cerevisiaetranscriptome. While previous studies focused on the roles of Paf1C in controlling mRNA levels, here we took advantage of a genetic background that enriches for unstable transcripts and demonstrate that deletion ofPAF1affects all classes of Pol II transcripts including multiple classes of noncoding RNAs. By conducting ade novodifferential expression analysis independent of gene annotations, we found that Paf1 positively and negatively regulates antisense transcription at multiple loci. Comparisons with nascent transcript data revealed that many, but not all, changes in RNA levels detected by our analysis are due to changes in transcription instead of post-transcriptional events. To investigate the mechanisms by which Paf1 regulates protein-coding genes, we focused on genes involved in iron and phosphate homeostasis, which were differentially affected byPAF1deletion. Our results indicate that Paf1 stimulates phosphate gene expression through a mechanism that is independent of any individual Paf1C-dependent histone modification. In contrast, the inhibition of iron gene expression by Paf1 correlates with a defect in H3 K36 tri-methylation. Finally, we showed that one iron regulon gene,FET4, is coordinately controlled by Paf1 and transcription of upstream noncoding DNA. Together these data identify roles for Paf1C in controlling both coding and noncoding regions of the yeast genome.
A Comparison of Non-human Primate and Deep Reinforcement Learning Agent Performance in a Virtual Pursuit-Avoidance Task
Authors: Willke Theodore L. , Yoo Seng Bum M. , Capotă Mihai , Musslick Sebastian , Hayden Benjamin Y. , Cohen Jonathan D. 
Published: March 2019

AbstractWe compare the performance of non-human primates and deep reinforcement learning agents in a virtual pursuit-avoidance task, as part of an effort to understand the role that cognitive control plays in the deeply evolved skill of chase and escape behavior. Here we train two agents, a deep Q network and an actor-critic model, on a video game in which the player must capture a prey while avoiding a predator. A previously trained rhesus macaque performed well on this task, and in a manner that obeyed basic principles of Newtonian physics. We sought to compare the principles learned by artificial agents with those followed by the animal, as determined by the ability of one to predict the other. Our findings suggest that the agents learn primarily 1st order physics of motion, while the animal exhibited abilities consistent with the 2nd order physics of motion. We identify scenarios in which the actions taken by the animal and agents were consistent as well as ones in which they differed, including some surprising strategies exhibited by the agents. Finally, we remark on how the differences between how the agents and the macaque learn the task may affect their peak performance as well as their ability to generalize to other tasks.
MRI and cognitive scores complement each other to accurately predict Alzheimer’s dementia 2 to 7 years before clinical onset
Authors: Zandifar Azar , Fonov Vladimir S. , Ducharme Simon , Belleville Sylvie , Collins D. Louis ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: March 2019

AbstractBackgroundPredicting cognitive decline and the eventual onset of dementia in patients with Mild Cognitive Impairment (MCI) is of high value for patient management and potential cohort enrichment in pharmaceutical trials. We used cognitive scores and MRI biomarkers from a single baseline visit to predict the onset of dementia in an MCI population over a nine-year follow-up period.MethodAll MCI subjects from ADNI1, ADNI2, and ADNI-GO with available baseline cognitive scores and T1w MRI were included in the study (n=756). We built a Naïve Bayes classifier for every year over a 9-year follow-up period and tested each one with Leave one out cross validation.ResultsWe reached 87% prediction accuracy at five years follow-up with an AUC>0.85 from two to seven years (peaking at 0.92 at five years). Both cognitive test scores and MR biomarkers were needed to make the prognostic models highly sensitive and specific, especially for longer follow-ups. MRI features are more sensitive, while cognitive features bring specificity to the prediction.ConclusionCombining cognitive scores and MR biomarkers yield accurate prediction years before onset of dementia. Such a tool may be helpful in selecting patients that would most benefit from lifestyle changes, and eventually early treatments that would slow cognitive decline and delay the onset of dementia.