bluuebunny/crossref_metadata_2025_split huggingface dataset:
KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity
Authors: Turberfield Anne H. , Kondo Takashi , Nakayama Manabu , Koseki Yoko , King Hamish W. , Koseki Haruhiko , Klose Robert J. 
Published: March 2019

ABSTRACTCpG islands (CGI) are associated with the majority of mammalian gene promoters and function to recruit chromatin modifying enzymes. It has therefore been proposed that CGIs regulate gene expression through chromatin-based mechanisms, however in most cases this has not been directly tested. Here, we reveal that the histone H3 lysine 36 (H3K36) demethylase activity of the CGI-binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. Instead, we discover that KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. We further show that KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters. Together this reveals a demethylase-independent role for KDM2 proteins in transcriptional repression and uncovers a new function for CGIs in constraining gene expression.
Hidden Rice Diversity in the Guianas
Authors: Andel Tinde van , Veltman Margret , Bertin Alice , Maat Harro , Polime Thomas , Ris Lambers Derk Hille , Awie Jerry Tjoe , Boer Hugo de , Manzanilla Vincent 
Published: March 2019

AbstractTraditional crop varieties are an important source of genetic diversity for crop adaptation and modern breeding. Landraces of Asian (Oryza sativa) and African (Oryza glaberrima) rice have been well studied on the continents where they were domesticated. However, their history of cultivation in northern South America is poorly understood. Here we reveal the rice diversity that is maintained by Maroons, descendants of enslaved Africans who fled to the interior forests of the Guianas ca. 300 years ago. We interviewed subsistence farmers who practice shifting cultivation along the Maroni and Lawa rivers that form the natural border between French Guiana and Suriname, and used ethnobotanical and morphological methods to identify around 50 varieties, of which 15 were previously undocumented. The genetic origin of these varieties was explored using the Angiosperms-353 universal probe set. Despite the large distances between sites and relative inaccessibility of the area, phenotypic and genetic diversity did not display any geographic structure, which is consistent with knowledge of seed exchange among members of the same ethnolinguistic group. Although improved US cultivars were introduced in Maroon villages in the 1940s, these have not displaced the traditional landraces, which are cherished for their taste and nutritious qualities and for their importance in Maroon spiritual life. The unique agricultural and ritual practices of Maroons confirm their role as custodians of rice diversity, a role that is currently under threat from external pressures and encroaching globalization. We expect that the rice diversity uncovered in this study represents only a fraction of the total diversity in the Guianas and may constitute a large untapped resource that holds promise for future rice improvement. Further efforts to inventory and preserve these landraces will help to protect a precious cultural heritage and local food security.
Alanine Metabolism inBacillus subtilis
Authors: Sidiq Karzan R. , Zhao Zhao , Daniel Richard A. 
Published: March 2019

AbstractDespite a long history of genetic manipulation ofBacillus subtilisusing auxotrophic markers in genetic manipulation, the genes involved in alanine metabolism have not been characterised fully. Here we show thatB. subtilisexpresses an alanine uptake permease, YtnA (DatA), that has a major role in the assimilation of D-alanine from the environment. Since this isomer of the amino acid is not normally abundant it likely source is form the cells own cell wall probably through the action of carboxypeptidases and/or the spontaneous release of D-alanine from the teichoic acids. Also in this work we clarify the synthetic pathways acting in the biosynthesis of alanine. Genetically we show that, unlikeE. coliwhere multiple enzymes have a biochemical activity that can generate alanine, inB. subtilisthe primary synthetic enzyme for alanine is encoded byalaT, although a second gene,dat, is present that can support slow growth of an alanine auxotroph however our data suggests that this enzyme probably synthesises D-alanine. In summary this work has provided an explanation of the observation that growth ofB. subtilisis linked with an efficient recycling system for D-alanine that is released from the cell as the cell envelope is processed to permit cell enlargement. The results also suggest that the relative abundance of D- and L-alanine that might be linked with cytosolic pool of D and L-glutamate, and so enabling tight coupling protein and cell envelope synthesis with the metabolic status of the cell.
Combinations ofSpokgenes create multiple meiotic drivers inPodospora
Authors: Vogan Aaron A. , Ament-Velásquez S. Lorena , Granger-Farbos Alexandra , Svedberg Jesper , Bastiaans Eric , Debets Alfons J. M. , Coustou Virginie , Yvanne Hélène , Clavé Corinne , Saupe Sven J. , Johannesson Hanna 
Published: March 2019

AbstractMeiotic drive is the preferential transmission of a particular allele at a given locus during sexual reproduction. The phenomenon is observed as spore killing in a variety of fungal lineages, includingPodospora. In natural populations ofPodospora anserina, seven spore killers (Psks) have been identified through classical genetic analyses. Here we show that theSpokgene family underlie thePskspore killers. The combination of the variousSpokgenes at different chromosomal locations defines the spore killers and creates a killing hierarchy within the same population. We identify two novelSpokhomologs that are located within a complex region (theSpokblock) that reside in different chromosomal locations in given natural strains. We confirm that the individual SPOK proteins perform both the killing and resistance functions and show that these activities are dependent on distinct domains, a nuclease and a kinase domain respectively. Genomic data and phylogenetic analysis across ascomycetes suggest that theSpokgenes disperse via cross-species transfer, and evolve by duplication and diversification within several lineages.
Stochastic gene expression influences the selection of antibiotic resistance mutations
Authors: Sun Lei , Ashcroft Peter , Ackermann Martin , Bonhoeffer Sebastian 
Published: March 2019

AbstractBacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically simulates multiple biochemical processes in the cell and we observe the growth and survival dynamics of the cell population. Resistance-enhancing mutations are introduced by varying parameters that control the enzyme expression or efficacy. We find that stochastic gene expression can cause complex dynamics in terms of survival and extinction for these mutants. Regulatory mutations, which augment the frequency and duration of resistance gene transcription, can provide limited resistance by increasing mean expression. Structural mutations, which modify the enzyme or efflux efficacy, provide most resistance by improving the binding affinity of the resistance protein to the antibiotic; increasing the enzyme’s catalytic rate alone does not contribute to resistance. Overall, we identify conditions where regulatory mutations are selected over structural mutations, and vice versa. Our findings show that stochastic gene expression is a key factor underlying efflux and enzymatic resistances and should be taken into consideration in future antibiotic research.
Comment on ‘Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size’
Authors: Gapsys Vytautas , de Groot Bert L. 
Published: March 2019

AbstractA recent molecular dynamics investigation into the stability of hemoglobin concluded that the unliganded protein is only stable in the T state when a solvent box is used in the simulations that is ten times larger than what is usually employed. Here, we express three main concerns about that study. In addition, we show that with an order of magnitude more statistics, the reported box size dependence is not reproducible. Overall, no significant effects on the kinetics or thermodynamics of conformational transitions were observed.
Challenges and opportunities in population monitoring of cheetahs
Authors: Linden Daniel W. , Green David S. , Chelysheva Elena V. , Mandela Salim , Dloniak Stephanie M. 
Published: March 2019

AbstractPopulation monitoring is key to wildlife conservation and management but is challenging at the spatial and temporal extents necessary for understanding changes. Non-invasive survey methods and spatial capture-recapture (SCR) models have revolutionized wildlife monitoring by providing the means to more easily acquire data at large scales and the framework to generate spatially-explicit predictions, respectively. Despite the opportunities for improved monitoring, challenges can remain in the study design and model fitting phases of an SCR approach. Here, we used a search-encounter design with multi-session SCR models to collect spatially-indexed photographs and estimate the changes in density of cheetahs between 2005 and 2013–2016 in the Masai Mara National Reserve (MMNR) in southwestern Kenya. Our SCR models of cheetah encounters suggested little change in cheetah density from 2005 to 2013–2016, though there was some evidence that density fluctuated annually in the MMNR. The sampling period length (5 vs. 10 months) and timing (early, late, full year) over which spatial encounters were included in the modeling did not substantially alter inferences about density when sample sizes were adequate (>20 spatially distinct encounters). We estimated an average cheetah density of ~1.2 cheetahs/100 km2, consistent with the impression that the MMNR provides important habitat for cheetahs in Africa. During most years and seasonal periods, the spatial distribution of vegetation greenness (a proxy for ungulate habitat quality) accounted for important variation in encounter rates. The search-encounter design used here could be applied to other regions for the purposes of cheetah monitoring. While snap-shot estimates of population size across time are useful for wildlife monitoring, open population models could identify the mechanisms behind changes and further facilitate better conservation and management decision making.
Transcranial Alternating Current Stimulation (tACS) Entrains Alpha Oscillations by Preferential Phase Synchronization of Fast-Spiking Cortical Neurons to Stimulation Waveform
Authors: Negahbani Ehsan , Stitt Iain M. , Davey Marshall , Doan Thien T. , Dannhauer Moritz , Hoover Anna C. , Peterchev Angel V. , Radtke-Schuller Susanne , Fröhlich Flavio 
Published: March 2019

SummaryModeling studies predict that transcranial alternating current stimulation (tACS) entrains brain oscillations, yet direct examination has been lacking or potentially contaminated by stimulation artefact. Here we first demonstrate how the posterior parietal cortex drives primary visual cortex and thalamic LP in the alpha-band in head-fixed awake ferrets. The spike-field synchrony is maximum within alpha frequency, and more prominent for narrow-spiking neurons than broad-spiking ones. Guided by a validated model of electric field distribution, we produced electric fields comparable to those in humans and primates (< 0.5 mV/mm). We found evidence to support the model-driven predictions of how tACS entrains neural oscillations as explained by the triangular Arnold tongue pattern. In agreement with the stronger spike-field coupling of narrow-spiking cells, tACS more strongly entrained this cell population. Our findings provide the firstin vivoevidence of how tACS with electric field amplitudes used in human studies entrains neuronal oscillators.
Comments on the recent crystal structure of TsaBDE complex of bacterial t6A biosynthesis system and its significance for understanding TC-AMP processing
Authors: Stec Boguslaw 
Published: March 2019

ABSTRACTThe N(6)-threonylcarbamoyl adenosine (t6A) modification at position 37 of a tRNA of the anticodon loop is universal and central to the translational fidelity of all known organisms. The ternary complex of TsaBDE is the central and essential workstation for t6A biosynthesis in bacteria. The recently published crystal structure of Thermotoga maritima (T.maritima) TsaBDE complex (Missoury et al., 2018) has ~15% incorrectly-placed, misplaced/mistraced, or missing residues. These structural errors have precipitated incorrect conclusions about the disordering of the active site and inferred action of the TsaE element. In this report, we rectify the published structural model of the T.maritima TsaBDE complex. In stark contrast, a corrected structural model of TsaBDE shows that both active sites of the TsaD element are fully occupied with threonylcarbamoyladenosine (TC-AMP), an unstable intermediate chemical moiety of the t6A biosynthesis pathway. This observation has profound implications for understanding the funneling of intermediates in the t6A pathway and also in helping to elucidate tRNA binding modes. Based on the structural details described in here we propose a unifying principle for binding the tRNA to the TsaD subunit of the complex which is universally required in all known t6A modification pathways.
Combining amoxicillin and relebactam provides new therapeutic potential for Mycobacterium abscessus infection
Authors: Lopeman Rose C. , Harrison James , Desai Maya , Lambert Peter , Cox Jonathan A. G. 
Published: March 2019

AbstractInfections caused by the opportunistic pathogen Mycobacterium abscessus are increasing in prevalence within the cystic fibrosis population. Our limited understanding of this ubiquitous environmental microorganism matched with its intrinsic resistance to most classes of antibiotic, including β-lactams, has left us with an urgent demand for new, more effective therapeutic interventions. De novo antimicrobial drug discovery is a lengthy process and so we have taken the approach of repurposing known antibiotics in order to provide a rapidly implementable solution to a current problem. Here we report a significant step forward in treatment potential for M. abscessus infection by sensitising the organism to the broad spectrum β-lactam antibiotic, amoxicillin, using the non-competitive β-lactamase inhibitor, relebactam. We demonstrate by disk diffusion and broth microdilution assay that this combination works synergistically to inhibit M. abscessus. We also demonstrate the direct non-competitive inhibition of the M. abscessus β-lactamase, BlaMab using a novel thin-layer chromatography-based assay for β-lactamase inhibition, which is subsequently kinetically validated by spectrophotometric assay using the nitrocefin reporter assay. Finally, we demonstrate the in vitro efficacy of this combination against a collection of M. abscessus clinical isolates, demonstrating the significant therapeutic potential of the amoxicillin and relebactam combination.
Predicting vaccine effectiveness in livestock populations: a theoretical framework applied to PRRS virus infections in pigs
Authors: Bitsouni Vasiliki , Lycett Samantha , Opriessnig Tanja , Doeschl-Wilson Andrea 
Published: March 2019

AbstractVaccines remain one of the main tools to control infectious diseases in domestic livestock. Although a plethora of veterinary vaccines are on the market and routinely applied to protect animals against infection with particular pathogens, the disease in question often continues to persist, sometimes at high prevalence. The limited effectiveness of certain vaccines in the field leaves open questions regarding the required properties that an effective vaccine should have, as well as the most efficient vaccination strategy for achieving the intended goal of vaccination programmes. To date a systematic approach for studying the combined effects of different types of vaccines and vaccination strategies is lacking. In this paper, we develop a theoretical framework for modelling the epidemiological consequences of vaccination with imperfect vaccines of various types, administered using different strategies to herds with different replacement rates and heterogeneity in vaccine responsiveness. Applying the model to the Porcine Reproductive and Respiratory Syndrome (PRRS), which despite routine vaccination remains one of the most significant endemic swine diseases worldwide, we then examine the influence of these diverse factors alone and in combination, on within-herd virus transmission. We derive threshold conditions for preventing infection invasion in the case of imperfect vaccines inducing limited sterilizing immunity. The model developed in this study has practical implications for the development of vaccines and vaccination programmes in livestock populations not only for PRRS, but also for other viral infections.
A Multiplex Pharmacogenetics Assay using the MinION Nanopore Sequencing Device
Authors: Liau Yusmiati , Cree Simone L. , Maggo Simran , Miller Allison L. , Pearson John F. , Gladding Patrick A. , Kennedy Martin A. 
Published: March 2019

AbstractAimThe MinION nanopore sequencing device opens the opportunity to cost-effective and point-of-care DNA sequencing. We developed a multiplex assay targeting pharmacogenetic variants related to clopidogrel and warfarin, two commonly used drugs that show response variability due to genetic polymorphisms.Materials & MethodsSix reference and 78 clinical DNA samples were amplified by PCR to generate 15 amplicons targeting key variants. These products were then barcoded to enable sample multiplexing. Three variant calling tools were used to compare genotyping accuracy.Results and ConclusionsAll but three samples were successfully sequenced and genotyped. Nanopolish software achieved accuracy > 90 % for all except one variant. While minor mis-genotyping issues exist, this work demonstrates that drug-specific or broad pharmacogenetic screening assays are possible on the MinION sequencing device.
An Integrated Framework for Genome Analysis Reveals Numerous Previously Unrecognizable Structural Variants in Leukemia Patients’ Samples
Authors: Xu Jie , Song Fan , Schleicher Emily , Pool Christopher , Bann Darrin , Hennessy Max , Sheldon Kathryn , Batchelder Emma , Annageldiyev Charyguly , Sharma Arati , Chang Yuanyuan , Hastie Alex , Miller Barbara , Goldenberg David , Mineishi Shin , Claxton David , Moldovan George-Lucian , Yue Feng , Broach James R. 
Published: March 2019

AbstractWhile genomic analysis of tumors has stimulated major advances in cancer diagnosis, prognosis and treatment, current methods fail to identify a large fraction of somatic structural variants in tumors. We have applied a combination of whole genome sequencing and optical genome mapping to a number of adult and pediatric leukemia samples, which revealed in each of these samples a large number of structural variants not recognizable by current tools of genomic analyses. We developed computational methods to determine which of those variants likely arose as somatic mutations. The method identified 97% of the structural variants previously reported by karyotype analysis of these samples and revealed an additional fivefold more such somatic rearrangements. The method identified on average tens of previously unrecognizable inversions and duplications and hundreds of previously unrecognizable insertions and deletions. These structural variants recurrently affected a number of leukemia associated genes as well as cancer driver genes not previously associated with leukemia and genes not previously associated with cancer. A number of variants only affected intergenic regions but caused cis-acting alterations in expression of neighboring genes. Analysis of TCGA data indicates that the status of several of the recurrently mutated genes identified in this study significantly affect survival of AML patients. Our results suggest that current genomic analysis methods fail to identify a majority of structural variants in leukemia samples and this lacunae may hamper diagnostic and prognostic efforts.
Effects of topical PaiTeLing in nude mice implanted with human condyloma acuminatum tissue infected with HPV 6, 31, and 81: comparison with imiquimod and interferon-α-2b
Authors: Xu Rong , Wang Li , Hou Jianmei , Li Jun , Fan Zhiyan , Wu Liangcai , Zhu Congzhong , Ma Miaomiao , Wang Huiping , Hou Shuping 
Published: March 2019

AbstractBACKGROUNDThe standard treatment for condyloma acuminatum is topical imiquimod. In the current study, we used a mouse model to compare the effects of an herbal medication PaiTeLing.METHODSLesion tissue was obtained from a woman with genital condyloma acuminatum. DNA genotyping revealed HPV6, 31, and 81. Tissue prism (0.5 cm3) was implanted to BALB/C nude mice, 22 days after the implantation, mice began to receive topical treatment with imiquimod, interferon-α-2b gel, or PaiTeLing over the site of implantation for 2 consecutive weeks. Mice receiving tissue implantation but no other intervention was included as a control. Skin tissue was collected for H&E staining and anti-CD207 immunohistochemistry. Blood was collected to determine a panel of cytokines.RESULTSH&E staining showed lower number of koilocytes and higher number of Langerhans cells in the treatment groups, particularly in mice receiving imiquimod or PaiTeLing. Blood levels of TNFα, IL-2, INF-γ and IL-12p70 were increased in the treatment groups, particularly in mice receiving imiquimod or PaiTeLing.CONCLUSIONImmune response in nude mice infected with HPV6, 31, and 81 is enhanced by treatment with imiquimod, interferon-α-2b and PaiTeLing. Effects of imiquimod and PaiTeLing seems to be stronger than interferon-α-2b.
Deep learning in bioinformatics: introduction, application, and perspective in big data era
Authors: Li Yu , Huang Chao , Ding Lizhong , Li Zhongxiao , Pan Yijie , Gao Xin 
Published: March 2019

AbstractDeep learning, which is especially formidable in handling big data, has achieved great success in various fields, including bioinformatics. With the advances of the big data era in biology, it is foreseeable that deep learning will become increasingly important in the field and will be incorporated in vast majorities of analysis pipelines. In this review, we provide both the exoteric introduction of deep learning, and concrete examples and implementations of its representative applications in bioinformatics. We start from the recent achievements of deep learning in the bioinformatics field, pointing out the problems which are suitable to use deep learning. After that, we introduce deep learning in an easy-to-understand fashion, from shallow neural networks to legendary convolutional neural networks, legendary recurrent neural networks, graph neural networks, generative adversarial networks, variational autoencoder, and the most recent state-of-the-art architectures. After that, we provide eight examples, covering five bioinformatics research directions and all the four kinds of data type, with the implementation written in Tensorflow and Keras. Finally, we discuss the common issues, such as overfitting and interpretability, that users will encounter when adopting deep learning methods and provide corresponding suggestions. The implementations are freely available athttps://github.com/lykaust15/Deep_learning_examples.