bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNOT1 mediates phosphorylation via Protein kinase A on the circadian clock
Authors: Zhang Yunfeng , Qin Haitang , Feng Yongjie , Gao Peng , Zhong Yingbin , Tan Yicheng , Wang Han , Xu Ying , Takahashi Joseph S. , Huang Guocun 
Published: May 2019

AbstractAt the core of the mammalian circadian feedback loop, CLOCK (NPAS2)-BMAL1 is the positive element to activate transcription of downstream genes encoding the negative elements PERs and CRYs. Here we show that CNOT1 associates with both CLOCK and BMAL1, promotes their phosphorylation and increases their protein stability, and in turn inhibits the transcriptional activity of CLOCK-BMAL1. Expression of either CLOCK, BMAL1 or CNOT1 could interact with endogenous Protein Kinase A (PKA) as assessed by co-immunoprecipitation (Co-IP) and kinase assays. PKA could phosphorylate CLOCK and BMAL1 and this was promoted by CNOT1. Genetic deletion of PKA-Cα by CRISPR-Cas9 results in a longer period of the circadian rhythm; while overexpression of PKA-Cα induces a shorter period. Furthermore, we demonstrate that CNOT1 associates with CLOCK and BMAL1 in the mouse liver and promotes their phosphorylation. PER2, but not CRY2, is also a PKA target. Our results suggest that CNOT1 and PKA play a critical role in the mammalian circadian clock, revealing a conserved function in eukaryotic circadian regulations.
Viral infection causes sex-specific changes in fruit fly social aggregation behaviour
Authors: Siva-Jothy Jonathon A. , Vale Pedro F. 
Published: May 2019

AbstractHost behavioural changes following infection are common and could be important determinants of host behavioural competence to transmit pathogens. Identifying potential sources of variation in sickness behaviours is therefore central to our understanding of disease transmission. Here, we test how group social aggregation and individual locomotor activity vary between different genotypes of male and female fruit flies (Drosophila melanogaster) following septic infection with Drosophila C Virus. We find genetic-based variation in both locomotor activity and social aggregation but we did not detect an effect of DCV infection on fly activity or sleep patterns within the initial days following infection. However, DCV infection caused sex-specific effects on social aggregation, as male flies in most genetic backgrounds increased the distance to their nearest neighbour when infected. We discuss possible causes for these differences in the context of individual variation in immunity and their potential consequences for disease transmission.
Set1/COMPASS repels heterochromatin invasion at euchromatic sites by disrupting Suv39/Clr4 activity and nucleosome stability
Authors: Greenstein R.A. , Barrales Ramon R. , Sanchez Nicholas A. , Bisanz Jordan E. , Braun Sigurd , Al-Sady Bassem 
Published: May 2019

ABSTRACTProtection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While hetero- and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary, using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Interestingly, this effect can be gene orientation dependent. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. At least two independent pathways direct this Set1 activity–inhibition of catalysis by Suv39/Clr4 and disruption of nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion.
Host-Microbial Interactions in Systemic Lupus Erythematosus and Periodontitis
Authors: Pessoa L.C. , Aleti G. , Choudhury S. , Nguyen D. , Yaskell T. , Zang Y. , Weizhong L. , Nelson K.E. , Santos Neto L. L. , Sant’Ana A.C.P. , Freire M. 
Published: May 2019

AbstractSystemic lupus erythematosus (SLE) is a potentially fatal complex autoimmune disease, that is characterized by widespread inflammation manifesting tissue damage and comorbidities across the human body including heart, blood vessels, joints, skin, liver, kidneys, and periodontal tissues. The etiology of SLE is partially attributed to a deregulated inflammatory response to microbial dysbiosis and environmental changes. In the mouth, periodontal environment provides an optimal niche to assay local dynamic microbial ecological changes in health and disease important to systemic inflammation in SLE subjects. Our aim was to evaluate the reciprocal impact of periodontal subgingival microbiota on SLE systemic inflammation. Ninety-one female subjects were recruited, including healthy (n=31), SLE-inactive (n=29), and SLE-active (n=31). Patients were screened for probing depth (PD), bleeding on probing (BOP), clinical attachment level (CAL), and classified with or without periodontal dysbiosis, periodontitis. Serum inflammatory cytokines were measured by human cytokine panel and subgingival biofilm was examined by DNA-DNA checkerboard. The results showed significant upregulation of proinflammatory cytokines in individuals with SLE when compared to controls. Stratification of subject’s into SLE-inactive (I) and SLE-active (A) phenotypes or periodontitis and non-periodontitis groups provided new insights into SLE pathophysiology. While low-grade inflammation was found in SLE-I subjects, a potent anti-inflammatory cytokine, IL-10 was found to control clinical phenotypes. Out of twenty-four significant differential oral microbial abundances found in SLE, fourteen unique subgingival bacteria profiles were found to be elevated in SLE. Pathogens from periodontal disease sites (Treponema denticola and Tannerella forsythia) showed increase abundance in SLE-A subjects when compared to controls. Cytokine-microbial correlations showed that periodontal pathogens dominating the environment increased proinflammatory cytokines systemically. Deeper clinical attachment loss and periodontal pathogens were found in SLE subjects, especially on SLE-I, likely due to long-term chronic and low-grade inflammation. Altogether, local periodontal pathogen enrichment was positively associated with high systemic inflammatory profiles, relevant to the overall health and SLE disease pathogenesis.
Computationally Enhanced Quantitative Phase Microscopy Reveals Autonomous Oscillations in Mammalian Cell Growth
Authors: Liu Xili , Oh Seungeun , Peshkin Leonid , Kirschner Marc W. 
Published: May 2019

AbstractThe fine balance of growth and division is a fundamental property of the physiology of cells and one of the least understood. Its study has been thwarted by difficulties in the accurate measurement of cell size and the even greater challenges of measuring growth of a single-cell over time. We address these limitations by demonstrating a new computationally enhanced methodology for Quantitative Phase Microscopy (ceQPM) for adherent cells, using improved image processing algorithms and automated cell tracking software. Accuracy has been improved more than two-fold and this improvement is sufficient to establish the dynamics of cell growth and adherence to simple growth laws. It is also sufficient to reveal unknown features of cell growth previously unmeasurable. With these methodological and analytical improvements, we document a remarkable oscillation in growth rate in several different cell lines, occurring throughout the cell cycle, coupled to cell division or birth, and yet independent of cell cycle progression. We expect that further exploration with this improved tool will provide a better understanding of growth rate regulation in mammalian cells.Significance StatementIt has been a long-standing question in cell growth studies that whether the mass of individual cell grows linearly or exponentially. The two models imply fundamentally distinct mechanisms, and the discrimination of the two requires great measurement accuracy. Here, we develop a new method of computationally enhanced Quantitative Phase Microscopy (ceQPM), which greatly improves the accuracy and throughput of single-cell growth measurement in adherent mammalian cells. The measurements of several cell lines indicate that the growth dynamics of individual cells cannot be explained by either of the simple models but rather present an unanticipated and remarkable oscillatory behavior, suggesting more complex regulation and feedbacks.
The evolution of nitroimidazole antibiotic resistance in Mycobacterium tuberculosis
Authors: Lee Brendon M. , Almeida Deepak V. , Afriat-Jurnou Livnat , Aung Htin Lin , Forde Brian M. , Hards Kiel , Pidot Sacha J. , Ahmed F. Hafna , Mohamed A. Elaaf , Taylor Matthew C. , West Nicholas P. , Stinear Timothy P. , Greening Chris , Beatson Scott A. , Cook Gregory M. , Nuermberger Eric L. , Jackson Colin J. 
Published: May 2019

AbstractOur inability to predict whether certain mutations will confer antibiotic resistance has made it difficult to rapidly detect the emergence of resistance, identify pre-existing resistant populations and manage our use of antibiotics to effective treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is important in aerobic respiration and essential for emergence from dormancy, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, even though it was never exposed to pretomanid. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.
Unbiased identification of trans regulators of ADAR and A-to-I RNA editing
Authors: Freund Emily C. , Sapiro Anne L. , Li Qin , Linder Sandra , Moresco James J. , Yates John R. , Li Jin Billy 
Published: May 2019

AbstractAdenosine-to-Inosine RNA editing is catalyzed by ADAR enzymes that deaminate adenosine to inosine. While many RNA editing sites are known, few trans regulators have been identified. We perform BioID followed by mass-spectrometry to identify trans regulators of ADAR1 and ADAR2 in HeLa and M17 neuroblastoma cells. We identify known and novel ADAR-interacting proteins. Using ENCODE data we validate and characterize a subset of the novel interactors as global or site-specific RNA editing regulators. Our set of novel trans regulators includes all four members of the DZF-domain-containing family of proteins: ILF3, ILF2, STRBP, and ZFR. We show that these proteins interact with each ADAR and modulate RNA editing levels. We find ILF3 is a global negative regulator of editing. This work demonstrates the broad roles RNA binding proteins play in regulating editing levels and establishes DZF-domain containing proteins as a group of highly influential RNA editing regulators.
Individual difference in serial dependence results from opposite influences of perceptual choices and motor responses
Authors: Zhang Huihui , Alais David 
Published: May 2019

AbstractNatural image statistics exhibit temporal regularities of slow changes and short-term correlations and visual perception, too, is biased towards recently seen stimuli, i.e., a positive serial dependence. Some studies report strong individual differences in serial dependence in perceptual decision making: some observers show positive serial effects, others repulsive effects, and some show no bias. To understand these contrasting results, this study separates the influences of physical stimuli per se, perceptual choices and motor responses on serial dependence in perceptual decision making. In two experiments, human observers reported which orientation (45° or −45°, at threshold contrast) they perceived. Experiment 1, used a consistent mapping between stimulus and response buttons while in Experiment 2, observers did two tasks: one with a consistent stimulus-response mapping, the other with a random stimulus-response mapping (perceptual choice and motor response unrelated). Results show that the stimulus percept (not the physical stimulus per se) affected subsequent perceptual choices in an attractive way, and that motor responses produced a repulsive serial effect. When the choice-response mapping was consistent (inseparable choice and response, typical of most experiments), individual differences in the overall serial effect was observed: some were positive, some repulsive, and some were bias-free. These individual differences likely reflect different relative weightings in individuals of a positive choice bias and a repulsive motor bias.
BOCS: DNA k-mer content and scoring for rapid genetic biomarker identification at low coverage
Authors: Korshoj Lee E. , Nagpal Prashant 
Published: May 2019

AbstractA single, inexpensive diagnostic test capable of rapidly identifying a wide range of genetic biomarkers would prove invaluable in precision medicine. Previous work has demonstrated the potential for high-throughput, label-free detection of A-G-C-T content in DNA k-mers, providing an alternative to single-letter sequencing while also having inherent lossy data compression and massively parallel data acquisition. Here, we apply a new bioinformatics algorithm – block optical content scoring (BOCS) – capable of using the high-throughput content k-mers for rapid, broad-spectrum identification of genetic biomarkers. BOCS uses content-based sequence alignment for probabilistic mapping of k-mer contents to gene sequences within a biomarker database, resulting in a probability ranking of genes on a content score. Simulations of the BOCS algorithm reveal high accuracy for identification of single antibiotic resistance genes, even in the presence of significant sequencing errors (100% accuracy for no sequencing errors, and > 90% accuracy for sequencing errors at 20%), and at well below full coverage of the genes. Simulations for detecting multiple resistance genes within a methicillin-resistant Staphylococcus aureus (MRSA) strain showed 100% accuracy at an average gene coverage of merely 0.515, when the k-mer lengths were variable and with 4% sequencing error within the k-mer blocks. Extension of BOCS to cancer and other genetic diseases met or exceeded the results for resistance genes. Combined with a high-throughput content-based sequencing technique, the BOCS algorithm potentiates a test capable of rapid diagnosis and profiling of genetic biomarkers ranging from antibiotic resistance to cancer and other genetic diseases.
Electroporated recombinant proteins as tools forin vivofunctional complementation, imaging, and chemical biology
Authors: Alex Amal , Piano Valentina , Polley Soumitra , Stuiver Marchel , Voss Stephanie , Ciossani Giuseppe , Overlack Katharina , Voss Beate , Wohlgemuth Sabine , Petrovic Arsen , Wu Yao-Wen , Selenko Philipp , Musacchio Andrea , Maffini Stefano 
Published: May 2019

AbstractDelivery of native or chemically modified recombinant proteins into mammalian cells shows promise for functional investigations and various technological applications, but concerns that sub-cellular localization and functional integrity of delivered proteins may be affected remain high. Here, we surveyed batch electroporation as a delivery tool for single polypeptides and multi-subunit protein assemblies of kinetochores, a spatially confined and well-studied subcellular structures. After electroporation in human cells, recombinant fluorescent Ndc80 and Mis12 multi-subunit complexes displayed native localization, physically interacted with endogenous binding partners, and functionally complemented depleted endogenous counterparts to promote mitotic checkpoint signaling and chromosome segregation. Farnesylation is required for kinetochore localization of the Dynein adaptor Spindly. In cells with chronically inhibited farnesyl transferase activity,in vitrofarnesylation and electroporation reconstituted robust kinetochore localization of Spindly. Thus, electroporation is uniquely versatile for delivering synthetic and, as required, chemically modified functional mimics of endogenous proteins, and is therefore a promising tool for chemical and synthetic biology.
In situabundance and carbon fixation activity of distinct anoxygenic phototrophs in the stratified seawater lake Rogoznica
Authors: Pjevac Petra , Dyksma Stefan , Goldhammer Tobias , Mujakić Izabela , Koblížek Michal , Mussmann Marc , Amann Rudolf , Orlić Sandi 
Published: May 2019

AbstractSulfide-driven anoxygenic photosynthesis is an ancient microbial metabolism that contributes significantly to inorganic carbon fixation in stratified, sulfidic water bodies. Methods commonly applied to quantify inorganic carbon fixation by anoxygenic phototrophs, however, cannot resolve the contributions of distinct microbial populations to the overall process. We implemented a straightforward workflow, consisting of radioisotope labeling and flow cytometric cell sorting based on the distinct autofluorescence of bacterial photo pigments, to discriminate and quantify contributions of co-occurring anoxygenic phototrophic populations toin situinorganic carbon fixation in environmental samples. This allowed us to assign 89.3 ±7.6% of daytime inorganic carbon fixation by anoxygenic phototrophs in Lake Rogoznica (Croatia) to an abundant chemocline-dwelling population of green sulfur bacteria (dominated byChlorobium phaeobacteroides), whereas the co-occurring purple sulfur bacteria (Halochromatiumsp.) contributed only 1.8 ±1.4%. Furthermore, we obtained two metagenome assembled genomes of green sulfur bacteria and one of a purple sulfur bacterium which provides the first genomic insights into the genusHalochromatium, confirming its high metabolic flexibility and physiological potential for mixo-and heterotrophic growth.
Cellular precision of orientation and spatial frequency maps in macaque V1
Authors: Ju Nian-Sheng , Guan Shu-Chen , Tang Shi-Ming , Yu Cong 
Published: May 2019

AbstractFunctional organization of neuronal response properties along the surface of the neocortex is a fundamental guiding principle of neural computation in the brain. Despite this importance, the cellular precision of functional maps is still largely unknown. We address the challenge by using two-photon calcium imaging to measure cell-specific orientation and spatial frequency (SF) responses across fields of macaque V1 superficial layers. The cellular orientation maps confirm iso-orientation domains, but rarely show pinwheels. Pinwheels obtained through conventional Gaussian smoothing and vector summation of orientation responses mostly overlap with blood vessel regions, suggesting false singularities. Cellular SF maps clarify existing controversies by showing weak iso-frequency clusters, which also suggests a weak geometric relationship between orientation and SF maps. Most neurons are tuned to medium frequencies, but the tuning functions are often asymmetric with a wider low- or high-frequency branch, which may help encode low or high SF information for later decoding.
Epithelial Modelling Platform: A Tool for Model Discovery and Assembly with the Physiome Model Repository
Authors: Sarwar Dewan M. , Munarko Yuda , Nickerson David P. 
Published: May 2019

ABSTRACTIn this paper we present a web-based platform enabling scientists to construct a novel epithelial transport model to investigate their hypotheses, aided by building on existing models discovered in the Physiome Model Repository (PMR). We have comprehensively annotated a cohort of epithelial transport models deposited in the PMR as a seeding collection of building blocks that are freely available for reuse. On the platform, users are able to semantically display models for visualization, graphical editing, and model assembly. In addition, we leverage web services from the European Bioinformatics Institute (EBI) to help rank similar models based on the suggestions provided by the platform. In addition to potential use in biomedical and clinical research, novice modellers could use our platform as a learning tool. The source code and links to a live demonstration of the platform are available at https://github.com/dewancse/ epithelial-modelling-platform.
D-alanylation of Teichoic Acids in Bacilli impedes the immune sensing of peptidoglycan in Drosophila
Authors: Attieh Zaynoun , Kallassy Awad Mireille , Rejasse Agnès , Courtin Pascal , Gomperts Boneca Ivo , Chapot-Chartier Marie-Pierre , Sanchis Borja Vincent , El Chamy Laure 
Published: May 2019

AbstractModification of cell wall components is a prominent mean for pathogens to hinder host immune defenses. Here, using the Drosophila model, we aimed at characterizing the role of D-alanine esterification of teichoic acids (TAs) in the resistance of Bacillus thuringiensis to host defenses in vivo. We show that, by preventing cationic antimicrobial effectors-mediated bacterial lysis, this cell wall modification also limits the release of peptidoglycan immunostimulatory fragments thus impeding their sensing and the subsequent induction of the IMD- NF-κB pathway. Interestingly, we show that this strategy is also adopted by Lactobacillus plantarum, a bona fide commensal, to fine-tune its immunomodulatory potential in the Drosophila gut. Markedly, we show that the D-alanylation of TAs is essential for the resistance of L. plantarum to gut lysozyme. Altogether our data shed light on the mechanism underlying the persistence and the low immunostimulatory potential of L. plantarum in the Drosophila gut.