bluuebunny/crossref_metadata_2025_split huggingface dataset:
SIZ1-mediated SUMOylation of ROS1 Enhances Its Stability and Positively Regulates Active DNA Demethylation inArabidopsis
Authors: Kong Xiangfeng , Hong Yechun , Hsu Yi-Feng , Huang Huan , Liu Xue , Song Zhe , Zhu Jian-Kang 
Published: March 2020

AbstractThe 5-methylcytosine DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1)-mediated active DNA demethylation is critical for shaping the genomic DNA methylation landscape inArabidopsis. Whether and how the stability of ROS1 may be regulated by post-translational modifications is unknown. Using a methylation-sensitive PCR (CHOP-PCR)-based forward genetic screen forArabidopsisDNA hypermethylation mutants, we identified the SUMO E3 ligase SIZ1 as a critical regulator of active DNA demethylation. Dysfunction of SIZ1 leads to hyper-methylation at approximately one thousand genomic regions. SIZ1 physically interacts with ROS1 and mediates the SUMOylation of ROS1. The SUMOylation of ROS1 is reduced insiz1mutant plants. Compared to that in wild type plants, the protein level of ROS1 is significantly decreased, even though there is an increased level ofROS1transcripts insiz1mutant plants. Our results suggest that SIZ1 positively regulates active DNA demethylation by promoting the stability of ROS1 protein through SUMOylation.Short SummaryThe 5-methylcytosine DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1) is indispensable for proper DNA methylation landscape inArabidopsis. Whether and how the stability of ROS1 may be regulated by post-translational modifications is unknown. Here, we show that SIZ1-mediated SUMOylation of ROS1 enhances its stability and positively regulates active DNA demethylation.
Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia
Authors: Wang Ping , Tang Zhonghui , Lee Byoungkoo , Zhu Jacqueline Jufen , Cai Liuyang , Szalaj Przemyslaw , Tian Simon Zhongyuan , Zheng Meizhen , Plewczynski Dariusz , Ruan Xiaoan , Liu Edison T. , Wei Chia-Lin , Ruan Yijun 
Published: March 2020

AbstractBackgroundAcute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML/RARα in leukemogenesis remains largely unknown.ResultsUsing an inducible system, we comprehensively analyzed the 3D genome organization in myeloid cells and its reorganization after PML/RARα induction, and performed additional analyses in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediates extensive chromatin interactions genome-wide. Globally, it redefines the chromatin topology of the myeloid genome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated interaction domains, interrupts myeloid-specific transcription factors binding at enhancers and super-enhancers, and leads to transcriptional repression of genes critical for myeloid differentiation and maturation.ConclusionsOur results not only provide novel topological insights for the roles of PML/RARα in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.
Bayesian Genome-wide TWAS method to leverage both cis- and trans- eQTL information through summary statistics
Authors: Luningham Justin M. , Chen Junyu , Tang Shizhen , De Jager Philip L. , Bennett David A. , Buchman Aron S. , Yang Jingjing 
Published: March 2020

AbstractTranscriptome-wide association studies (TWAS) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans- expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian Genome-wide TWAS (BGW-TWAS) method which leverages both cis- and trans- eQTL information for TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans- eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWAS achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N=∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of geneZC3H12Band Alzheimer’s dementia (AD) (p-value= 5.42 × 10−13), neurofibrillary tangle density (p-value= 1.89 ×10−6), and global measure of AD pathology (p-value=9.59 × 10−7). These associations for geneZC3H12Bwere completely driven by trans-eQTL. Additionally, the GReX of geneKCTD12was found to be significantly associated withβ-amyloid (p-value= 3.44 ×10−8) which was driven by both cis- and trans- eQTL. Four of the top driven trans-eQTL ofZC3H12Bare located within geneAPOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N=∼54K), we identified 13 significant genes including known GWAS risk genesHLA-DRB1andAPOC1, as well asZC3H12B.
Cell-free styrene biosynthesis at high titers
Authors: Grubbe William S. , Rasor Blake J. , Krüger Antje , Jewett Michael C. , Karim Ashty S. 
Published: March 2020

AbstractStyrene is an important petroleum-derived molecule that is polymerized to make versatile plastics, including disposable silverware and foamed packaging materials. Finding more sustainable methods, such as biosynthesis, for producing styrene is essential due to the increasing severity of climate change as well as the limited supply of fossil fuels. Recent metabolic engineering efforts have enabled the biological production of styrene inEscherichia coli, but styrene toxicity and volatility limit biosynthesis in cells. To address these limitations, we have developed a cell-free styrene biosynthesis platform. The cell-free system provides an open reaction environment without cell viability constraints, which allows exquisite control over reaction conditions and greater carbon flux toward product formation rather than cell growth. The two biosynthetic enzymes required for styrene production were generated via cell-free protein synthesis and mixed in defined ratios with supplemented L-phenylalanine and buffer. By altering the time, temperature, pH, and enzyme concentrations in the reaction, this approach increased the cell-free titer of styrene from 5.36 ± 0.63 mM to 40.33 ± 1.03 mM, an order of magnitude greater than cellular synthesis methods. Cell-free systems offer a complimentary approach to cellular synthesis of small molecules, which can provide particular benefits for producing toxic molecules.HighlightsA cell-free system for styrene biosynthesis was established. Thisin vitrosystem achieved styrene titers an order of magnitude greater than the highest reported concentrationin vivo.
Improved stability of an engineered function using adapted bacterial strains
Authors: Tack Drew S. , Tonner Peter D. , Musteata Elena , Paralanov Vanya , Ross David 
Published: March 2020

AbstractEngineering useful functions into cells is one of the primary goals of synthetic biology. However, engineering novel functions that remain stable for multiple generations remains a significant challenge. Here we report the importance of host fitness on the stability of an engineered function. We find that the initial fitness of the host cell affects the stability of the engineered function. We demonstrate that adapting a strain to the intended growth condition increases fitness and in turn improves the stability of the engineered function over hundreds of generations. This approach offers a simple and effective method to increase the stability of engineered functions without genomic modification or additional engineering and will be useful in improving the stability of novel, engineered functions in living cells.Abstract Figure
Discovery and Predictive Modeling of Urine Microbiome, Metabolite and Cytokine Biomarkers in Hospitalized Patients with Community Acquired Pneumonia
Authors: Pierre Joseph F. , Akbilgic Oguz , Smallwood Heather , Cao Xueyuan , Fitzpatrick Elizabeth A. , Pena Senen , Furmanek Stephen P. , Ramirez Julio A. , Jonsson Colleen B 
Published: March 2020

AbstractPneumonia is the leading cause of infectious related death costing 12 billion dollars annually in the United States alone. Despite improvements in clinical care, total mortality remains around 4%, with inpatient mortality reaching 5-10%. For unknown reasons, mortality risk remains high even after hospital discharge and there is a need to identify those patients most at risk. Also of importance, clinical symptoms alone do not distinguish viral from bacterial infection which may delay appropriate treatment and may contribute to short-term and long-term mortality. Biomarkers have the potential to provide point of care diagnosis, identify high-risk patients, and increase our understanding of the biology of disease. However, there have been mixed results on the diagnostic performance of many of the analytes tested to date. Urine represents a largely untapped source for biomarker discovery and is highly accessible. To test this hypothesis, we collected urine from hospitalized patients with community-acquired pneumonia (CAP) and performed a comprehensive screen for urinary tract microbiota signatures, metabolite, and cytokine profiles. CAP patients were diagnosed with influenza or bacterial (S. aureusandS. pneumoniae) etiologies and compared with healthy volunteers. Microbiome signatures showed marked shifts in taxonomic levels in patients with bacterial etiology versus influenza and CAP versus normal. Predictive modeling of 291 microbial and metabolite values achieved a +90% accuracy with LASSO in predicting specific pneumonia etiology. This study demonstrates that urine from patients hospitalized with pneumonia may serve as a reliable and accessible sample to evaluate biomarkers that may diagnose etiology and predict clinical outcomes.Author SummaryUrine has been classically considered sterile since most microorganisms are not readily culturable under healthy circumstances. Further, many pneumonia patients are immediately placed on antibiotics rendering culture-based techniques useless. However, the advent of next generation sequencing has enabled unprecedented analysis of the microbial communities – living or detected as free DNA – found in many niches of the human body. Here, we describe a urine microbiome as well as metabolites and cytokines measured in patients newly admitted to the hospital diagnosed with influenza or bacterial (S. aureusandS. pneumoniae) infection pneumonia, compared with healthy controls. Using these parameters alone, we were able to achieve high success in predicting patient pneumonia. This study provides a proof of concept that urine samples, which are easily accessible in outpatient and inpatient settings, could provide additional diagnostic insights to patient infectious status and future risk factor for complication.
Neurons in the ventral striatopallidal complex modulate lateral hypothalamic orexin/hypocretin neuron activity: Implications for reward-seeking
Authors: Mitchell Caitlin S. , Mohammadkhani Aida , Manning Elizabeth E. , Campbell Erin J. , Fisher Simon D , Yeoh Jiann W. , Pearl Amy J. , Burton Nicholas J. , Qiao Min , Iredale Jacqueline A. , Bains Jaideep S. , McNally Gavan P. , Andrews Zane A. , Graham Brett A. , Scammell Thomas E. , Lowell Bradford B. , Kong Dong , Borgland Stephanie L. , Dayas Christopher V. 
Published: March 2020

AbstractReward-seeking involves the engagement and computation of multiple physiological and motivational parameters. The lateral hypothalamus (LH) is a necessary node in the circuits that control food-seeking and motivation. One group of cells that plays an important yet incompletely understood role in these processes are the orexin/hypocretin (OX/HT) neurons. OX/HT cells are located exclusively within the LH and are implicated in feeding, arousal, and reward-seeking behavior. Importantly, the role of OX/HT neurons in consummatory versus reward-seeking actions is not fully defined, nor are the circuits that control the activity of these neurons under different behavioral states. Here we show that OX/HT neurons respond in real time to food presentation and that this response is modulated by differences in metabolic state. We observed increased OX/HT neuron activity on approach to food, but this activity trended towards pre-approach levels by the start of the consummatory phase. Next, we studied ventrostriatopallidal (VSP) inputs to the OX/HT neurons. Using optogenetics and cell type-specific electrophysiology, we found that ventral pallidum inputs onto OX/HT neurons exert strong inhibitory (and weak excitatory) effects whereas the lateral nucleus accumbens shell provides weaker direct inhibitory connections with OX/HT neurons. These findings reveal that the activity of OX/HT neurons is strongly modulated by metabolic and hedonic state. Further, OX/HT neurons is primarily associated with food approach and that the effect of VSP-terminal output is to suppress OX/HT activity.
A high-resolution map of bacteriophage øX174 transcription
Authors: Logel Dominic Y. , Jaschke Paul R. 
Published: March 2020

AbstractBacteriophage øX174 is a model virus for studies across the fields of structural biology, genetics, gut microbiome, and synthetic biology, but did not have a high-resolution transcriptome until this work. In this study we used next-generation sequencing to measure the RNA produced from øX174 while infecting its hostE. coli C.We broadly confirm the past transcriptome model while revealing several interesting deviations from previous knowledge. Additionally, we measure the strength of canonical øX174 promoters and terminators and discover both a putative new promoter that may be activated by heat shock sigma factors, as well as rediscover a controversial Rho-dependent terminator. We also provide evidence for the first antisense transcription observed in theMicroviridaefamily, identify two promoters that may be involved in generating this transcriptional activity, and discuss possible reasons why this RNA may be produced.
The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes
Authors: Williams Graham D. , Gokhale Nandan S. , Snider Daltry L. , Horner Stacy M. 
Published: March 2020

AbstractType I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection is unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2’O methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2’O methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.ImportanceInduction of an efficient type I IFN response is important to control viral infection. We show that the host 2’O methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of these mRNAs lacking cap 2’O methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.
Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes
Authors: Seyres Denis , Cabassi Alessandra , Lambourne John J , Burden Frances , Farrow Samantha , McKinney Harriet , Batista Joana , Kempster Carly , Pietzner Maik , Slingsby Oliver , Cao Thong Huy , Quinn Paulene A , Stefanucci Luca , Sims Matthew C , Rehnstrom Karola , Adams Claire L , Frary Amy , Ergüener Bekir , Kreuzhuber Roman , Mocciaro Gabriele , D’Amore Simona , Koulman Albert , Grassi Luigi , Griffin Julian L , Ng Leong Loke , Park Adrian , Savage David B , Langenberg Claudia , Bock Christoph , Downes Kate , Wareham Nicholas J , Allison Michael , Vacca Michele , Kirk Paul DW , Frontini Mattia 
Published: March 2020

AbstractImproving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis are ongoing healthcare challenges. Using plasma biomarkers analysis coupled with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (obese and lipodystrophy) and comparing these to lean individuals and blood donors, the present study identifies the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells and shows that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, six months after bariatric surgery shows the loss of the patterns of abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurs via the establishment of novel gene expression landscapes. Netosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Taken together, by integrating across data layers, the observed molecular and metabolic differences form a disease signature that is able to discriminate, amongst the blood donors, those individuals with a higher likelihood of having cardiometabolic syndrome, even when not presenting with the classic features.
Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFβ1
Authors: Chong Deborah. L. W. , Mikolasch Theresia A. , Sahota Jagdeep , Rebeyrol Carine , Garthwaite Helen S. , Booth Helen L. , Heightman Melissa , José Ricardo J. , Khawaja Akif A. , Labelle Myriam , Scotton Christopher J. , Porter Joanna C. 
Published: March 2020

AbstractTransforming growth factor-β1 (TGFβ1) is the key pro-fibrotic cytokine implicated in the interstitial lung diseases (ILD), including idiopathic pulmonary fibrosis (IPF), but the primary source of TGFβ1 in these diseases is unknown. Platelets have abundant TGFβ1 stores, however their role in IPF is ill-defined. We sought to investigate whether platelets or platelet-derived TGFβ1 mediate IPF disease progression.ILD/IPF and non-ILD patients were recruited to determine platelet reactivity and followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis, mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1fl/fl.PF4-Cre) were used in the bleomycin-induced PF model.We found a significantly higher mortality in IPF patients with elevated platelet counts, along with significantly increased platelets, neutrophils, TGFβ1 and CCL5 in the lung and bronchoalveolar lavage (BAL) of ILD patients. Despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation or fibrosis were significantly different between TGFβ1fl/fl.PF4-Cre and control mice.Our results demonstrate for the first-time that platelet-derived TGFβ1 is redundant in driving pulmonary fibrosis in an animal model. However, platelets can predict mortality in IPF implicating other platelet-derived mediators, such as CCL5, in promoting human IPF disease.
Technology usage for teaching and learning law in open and distance learning: a Sri Lankan perspective
Authors: Selvaras Janaka 
Published: March 2020

PurposeThe Open University of Sri Lanka (OUSL) is the only institution to deliver legal education through Open and Distance Learning (ODL) in Sri Lanka. This study aims to analyze technology usage in learning and teaching law in the ODL under OUSL to evaluate the accessibility and also challenges.Design/methodology/approachA combination of qualitative and quantitative methodologies has been used for the study. This includes both interviews with teachers and surveying among students on the usage of technology in learning and teaching law at OUSL. Since the LL.B Degree Programme of OUSL delivered at six regional centres in Sri Lanka, this study also includes the comparative analysis of technology usage in teaching and learning at selected regional centres.FindingsThe findings indicate that the majority of students have access to technology through mobile phones and are aware of blended learning. Even though they prefer to integrate blended learning with learning law, they do not prefer learning entirely online. Social media and mobile applications are the most preferred modes of blended learning by students. It is also acknowledged that the internal staff has knowledge and access to the use of technology in teaching law while the external staff faces challenges and is in need of adequate training.Originality/valueThe original contribution of this article provides insightful guidelines not only to the OUSL of Sri Lanka but also to the institutions offering similar disciplines through ODL to understand lecturers, learners in the future integration of technology.
Digital engagement strategies and tactics in social media marketing
Authors: Drummond Conor , O'Toole Thomas , McGrath Helen 
Published: March 2020

Purpose
Digitalisation has increased the importance of online forms of marketing, including social media (SM) marketing, for entrepreneurial firms. This paper aims to identify digital engagement strategies and tactics in developing SM marketing capability.

Design/methodology/approach
The study uses ethnographic content analysis of an entrepreneurial firm and a network of business-to-business (B2B) actors to classify 1,248 B2B Facebook posts and Twitter tweets from a case of an artisan food producer in addition to semi-structured interviews with 26 networked actors.

Findings
The authors derive a range of digital engagement strategies (8 in total) and tactics (15 in total) for the four defining layers of SM marketing capability, namely, connect, engage, co-ordinate and collaborate.

Research limitations/implications
This research focuses on a case study and a network of B2B actors within the artisan food sector. However, the strategies and tactics are applicable to other entrepreneurial firms and contexts.

Practical implications
The digital engagement strategies and tactics are of direct practical benefit to entrepreneurial firms willing to learn and develop SM marketing capability in interaction with their B2B partners.

Originality/value
This study investigates three under-researched areas, SM as it relates to B2B relationships, and entrepreneurship, and marketing capability gaps in an era of rapid digitalisation. The definition of SM marketing capability and associated digital engagement strategies and tactics are new to the extant literature moving forward the understanding of SM B2B marketing in theory and practice.