bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic and phenotypic evolution ofEscherichia coliin a novel citrate-only resource environment
Authors: Blount Zachary D. , Maddamsetti Rohan , Grant Nkrumah A. , Ahmed Sumaya T. , Jagdish Tanush , Sommerfeld Brooke A. , Tillman Alice , Moore Jeremy , Slonczewski Joan L. , Barrick Jeffrey E. , Lenski Richard E. 
Published: January 2020

ABSTRACTEvolutionary innovations allow populations to colonize new, previously inaccessible ecological niches. We previously reported that aerobic growth on citrate (Cit+) evolved in a population ofEscherichia coliduring adaptation to a minimal glucose medium containing citrate (DM25). Cit+can grow in citrate-only medium (DM0), which is a novel environment forE. coli. To study adaptation to this new niche, we evolved one set of Cit+populations for 2,500 generations in DM0 and a control set in DM25. We identified numerous parallel mutations, many mediated by transposable elements. Several lineages evolved multi-copy amplifications containing themaeAgene, constituting up to ∼15% of the genome. We also found substantial cell death in ancestral and evolved clones. Our results demonstrate the importance of copy-number variation and transposable elements in the refinement of the Cit+trait. However, the observed mortality suggests a persistent evolutionary mismatch betweenE. coliphysiology and a citrate-only environment.
AmpliconReconstructor: Integrated analysis of NGS and optical mapping resolves the complex structures of focal amplifications in cancer
Authors: Luebeck Jens , Coruh Ceyda , Dehkordi Siavash R. , Lange Joshua T. , Turner Kristen M. , Deshpande Viraj , Pai Dave A. , Zhang Chao , Rajkumar Utkrisht , Law Julie A. , Mischel Paul S. , Bafna Vineet 
Published: January 2020

AbstractOncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary mechanism driving focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA’s structure is a first step in deciphering the mechanisms of its genesis and the subsequent biological consequences. Here, we introduce a powerful new computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating performance by extensive simulations, we used AR to reconstruct fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, breakage-fusion-bridge cycles, and other complex rearrangements. By distinguishing between chromosomal and extrachromosomal origins, and by reconstructing the rearrangement signatures associated with a given fCNA’s generative mechanism, AR enables a more thorough understanding of the origins of fCNAs, and their functional consequences.
High-throughput screens of PAM-flexible Cas9 variants for gene knock-out and transcriptional modulation
Authors: Legut Mateusz , Daniloski Zharko , Xue Xinhe , McKenzie Dayna , Guo Xinyi , Wessels Hans-Hermann , Sanjana Neville E. 
Published: January 2020

AbstractA key limitation of the commonly-used CRISPR enzymeS. pyogenesCas9 is the strict requirement of an NGG protospacer-adjacent motif (PAM) at the target site, which reduces the number of accessible genomic loci. This constraint can be limiting for genome editing applications that require precise Cas9 positioning. Recently, two Cas9 variants with a relaxed PAM requirement (NG) have been developed (xCas9 and Cas9-NG) but their activity has been measured at only a small number of endogenous sites. Here we devised a high-throughput Cas9 pooled competition screen to compare the performance of both PAM-flexible Cas9 variants and wild-type Cas9 at thousands of genomic loci and across 3 modalities (gene knock-out, transcriptional activation and suppression). We show that PAM flexibility comes at a substantial cost of decreased DNA targeting and cutting. Of the PAM-flexible variants, we found that Cas9-NG outperforms xCas9 regardless of genome engineering modality or PAM. Finally, we combined xCas9 mutations with those of Cas9-NG, creating a stronger transcriptional modulator than existing PAM-flexible Cas9 variants.
S-adenosylhomocysteine hydrolase regulates anterior patterning inDugesia japonica
Authors: Reinmets Kristina , Bischof Johanna , Taketa Emily , Levin Michael , Fuchs Stephen M. 
Published: January 2020

AbstractBackgroundBiological methylation requires S-adenosylmethionine (SAM) and participates in a range of processes from modulation of gene expression via histone modifications to neurotransmitter synthesis. An important factor in all methylation reactions is the concentration ratio of SAM to methylation byproduct S-adenosylhomocysteine (SAH). SAH hydrolase, also known as adenosylhomocysteinase, depletes SAH and thereby facilitates metabolite recycling and maintains the methylation permissive SAM/SAH ratio. While the importance of SAH hydrolase in sustaining methylation is obvious on the cellular level, the function of this metabolic process on the organismal scale is not clear.ResultsWe used planarianDugesia japonicato investigate the role SAH hydrolase in physiological homeostasis on the body-wide scale. Remarkably, pharmacological inhibition of the SAH hydrolase results in regression of anterior tissues and is accompanied by extensive apoptosis throughout the planarian body. Moreover, exposure to the SAHH inhibitor AdOx leads to changes in brain morphology and spatial shift in the expression of Wnt-modulatorNotum. Strikingly, planarians are able to overcome these destructive patterning defects through regeneration of the anterior tissues and adaptation to the used inhibitor. Transcriptome analysis indicates that resistance to the SAHH inhibitor is at least partly mediated by changes in folate cycle and lipid metabolism.ConclusionsSAH hydrolase plays a critical role in planarian homeostasis and anterior patterning potentially through modulation of Wnt signaling. Moreover, planarian adaptation to the SAHH inhibitor via metabolic reprogramming suggests potential targets for addressing methylation-related human conditions.
From graph topology to ODE models for gene regulatory networks
Authors: Kang Xiaohan , Hajek Bruce , Hanzawa Yoshie 
Published: January 2020

AbstractA gene regulatory network can be described at a high level by a directed graph with signed edges, and at a more detailed level by a system of ordinary differential equations (ODEs). The former qualitatively models the causal regulatory interactions between ordered pairs of genes, while the latter quantitatively models the time-varying concentrations of mRNA and proteins. This paper clarifies the connection between the two types of models.We propose a property, called the constant sign property, for a general class of ODE models. The constant sign property characterizes the set of conditions (system parameters, external signals, or internal states) under which an ODE model is consistent with a signed, directed graph. If the constant sign property for an ODE model holds globally for all conditions, then the ODE model has a single signed, directed graph. If the constant sign property for an ODE model only holds locally, which may be more typical, then the ODE model corresponds to different graphs under different sets of conditions. In addition, two versions of constant sign property are given and a relationship between them is proved.As an example, the ODE models that capture the effect ofcis-regulatory elements involving protein complex binding, based on the model in the GeneNetWeaver source code, are described in detail and shown to satisfy the global constant sign property with a unique consistent gene regulatory graph. Even a single gene regulatory graph is shown to have many ODE models of GeneNetWeaver type consistent with it due to combinatorial complexity and continuous parameters.Finally the question of how closely data generated by one ODE model can be fit by another ODE model is explored. It is observed that the fit is better if the two models come from the same graph.
Probing multi-way chromatin interaction with hypergraph representation learning
Authors: Zhang Ruochi , Ma Jian 
Published: January 2020

AbstractAdvances in high-throughput mapping of 3D genome organization have enabled genome-wide characterization of chromatin interactions. However, proximity ligation based mapping approaches for pairwise chromatin interaction such as Hi-C cannot capture multi-way interactions, which are informative to delineate higher-order genome organization and gene regulation mechanisms at single-nucleus resolution. The very recent development of ligation-free chromatin interaction mapping methods such as SPRITE and ChIA-Drop has offered new opportunities to uncover simultaneous interactions involving multiple genomic loci within the same nuclei. Unfortunately, methods for analyzing multi-way chromatin interaction data are significantly underexplored. Here we develop a new computational method, called MATCHA, based on hypergraph representation learning where multi-way chromatin interactions are represented as hyperedges. Applications to SPRITE and ChIA-Drop data suggest that MATCHA is effective to denoise the data and makede novopredictions of multi-way chromatin interactions, reducing the potential false positives and false negatives from the original data. We also show that MATCHA is able to distinguish between multi-way interaction in a single nucleus and combination of pairwise interactions in a cell population. In addition, the embeddings from MATCHA reflect 3D genome spatial localization and function. MATCHA provides a promising framework to significantly improve the analysis of multi-way chromatin interaction data and has the potential to offer unique insights into higher-order chromosome organization and function.
Antigens in water-in-oil emulsion: a simple antigen extraction method for analysis and proof of equal antigen distribution in vaccination syringe after mixture
Authors: Ghosh Michael , Gauger Marion , Denk Monika , Rammensee Hans-Georg , Stevanović Stefan 
Published: January 2020

AbstractTherapeutic vaccination of antigens in oil emulsions is an approach becoming increasingly popular. Water-in-oil emulsions enable the formation of a depot, a slow passive antigen release and a decelerated antigen degradation. Furthermore, particularly advantageous for peptide vaccinations with a low clinical response rate is the increased immunogenicity and activation of CD8+and CD4+T-cells. Therefore, the use of personalized peptide vaccination cocktails in oil emulsions are tested in the treatment of cancer patients. An equal peptide distribution in the emulsion is striking for a successful depot effect to ensure the optimal efficacy and additionally, to enable reliable drug release analytics. First, the stability of the generated peptide-Montanide ISA™51 emulsion was demonstrated with a cocktail of heterogeneous peptides for 24 h in room temperature. Furthermore, we developed a simple peptide extraction method to investigate the equal peptide distribution in a Montanide ISA™51 emulsion in the syringe after mixing. Peptides were successfully extracted from a peptide-Montanide ISA™51 vaccination cocktail in sufficient volume for analysis and an equal peptide distribution in the syringe was verified via HPLC.
Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and enhanced mitochondrial biogenesis in human fibroblasts
Authors: Takenaka Yasuhiro , Inoue Ikuo , Nakano Takanari , Ikeda Masaaki , Kakinuma Yoshihiko 
Published: January 2020

AbstractProteolytic activities decline with age, resulting in the accumulation of aggregated proteins in aged organisms. To investigate how disturbance in proteostasis causes cellular senescence, we developed a stress-induced premature senescence (SIPS) model, in which normal human fibroblast MRC-5 cells were treated with either the proteasome inhibitor MG132 or the V-ATPase inhibitor bafilomycin A1 (BAFA1) for 5 days. Time-course studies revealed significant increase in intracellular and mitochondrial reactive oxygen species (ROS) during and after drug treatment. Mitochondrial membrane potential initially decreased, but recovered along with PGC-1α-mediated mitochondrial biogenesis, especially after drug treatment. Mitochondrial antioxidant enzymes SOD2 and GPx4 were temporally depleted in mitochondria on day 1 of the treatment, which in turn could cause excess production of mitochondrial ROS. Extra-mitochondrial SOD2 colocalized with protein aggregates and lysosomes in MG132-treated cells on day 1. SOD2 partially interacted with HSC70 and LAMP2, implying that dysfunctional SOD2 was degraded through chaperon-mediated autophagy (CMA) and caused SOD2 depletion in mitochondria. SIPS induction by MG132 or BAFA1 was partially attenuated by co-treatment with rapamycin, in which generation of excess ROS and mitochondrial biogenesis were suppressed. Rapamycin co-treatment also augmented the upregulation of HSP70 and decreased protein aggregates after drug treatment. Our study proposes a possible pathway from the disturbance of proteostasis to cellular senescence via functional changes in mitochondria.
Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions
Authors: Read Jonathan M. , Bridgen Jessica R.E. , Cummings Derek A.T. , Ho Antonia , Jewell Chris P. 
Published: January 2020

AbstractSince first identified, the epidemic scale of the recently emerged novel coronavirus (2019-nCoV) in Wuhan, China, has increased rapidly, with cases arising across China and other countries and regions. using a transmission model, we estimate a basic reproductive number of 3.11 (95%CI, 2.39–4.13); 58–76% of transmissions must be prevented to stop increasing; Wuhan case ascertainment of 5.0% (3.6–7.4); 21022 (11090–33490) total infections in Wuhan 1 to 22 January.Changes to previous versioncase data updated to include 22 Jan 2020; we did not use cases reported after this period as cases were reported at the province level hereafter, and large-scale control interventions were initiated on 23 Jan 2020;improved likelihood function, better accounting for first 41 confirmed cases, and now using all infections (rather than just cases detected) in Wuhan for prediction of infection in international travellers;improved characterization of uncertainty in parameters, and calculation of epidemic trajectory confidence intervals using a more statistically rigorous method;extended range of latent period in sensitivity analysis to reflect reports of up to 6 day incubation period in household clusters;removed travel restriction analysis, as different modelling approaches (e.g. stochastic transmission, rather than deterministic transmission) are more appropriate to such analyses.
Machine-learning forecasting for Dengue epidemics - Comparing LSTM, Random Forest and Lasso regression
Authors: Mussumeci Elisa , Coelho Flávio Codeço 
Published: January 2020

AbstractEffective management of seasonal diseases such as dengue fever depends on timely deployment of control measures prior to the high transmission season. As the epidemic season fluctuates from year to year, the availability of accurate forecasts of incidence can be decisive in attaining control of such diseases. Obtaining such forecasts from classical time series models has proven a difficult task. Here we propose and compare machine learning models incorporating feature selection,such as LASSO and Random Forest regression with LSTM a deep recurrent neural network, to forecast weekly dengue incidence in 790 cities in Brazil. We use multivariate time-series as predictors and also utilize time series from similar cities to capture the spatial component of disease transmission. Among the compared models, the LSTM recurrent neural network model displayed the smallest predictive errors in predicting incidence of dengue out of sample, in cities of different sizes.
Large-scale DNA-based phenotypic recording and deep learning enable highly accurate sequence-function mapping
Authors: Höllerer Simon , Papaxanthos Laetitia , Gumpinger Anja Cathrin , Fischer Katrin , Beisel Christian , Borgwardt Karsten , Benenson Yaakov , Jeschek Markus 
Published: January 2020

AbstractPredicting quantitative effects of gene regulatory elements (GREs) on gene expression is a longstanding challenge in biology. Machine learning models for gene expression prediction may be able to address this challenge, but they require experimental datasets that link large numbers of GREs to their quantitative effect. However, current methods to generate such datasets experimentally are either restricted to specific applications or limited by their technical complexity and error-proneness. Here we introduce DNA-based phenotypic recording as a widely applicable and practical approach to generate very large datasets linking GREs to quantitative functional readouts of high precision, temporal resolution, and dynamic range, solely relying on sequencing. This is enabled by a novel DNA architecture comprising a site-specific recombinase, a GRE that controls recombinase expression, and a DNA substrate modifiable by the recombinase. Both GRE sequence and substrate state can be determined in a single sequencing read, and the frequency of modified substrates amongst constructs harbouring the same GRE is a quantitative, internally normalized readout of this GRE’s effect on recombinase expression. Using next-generation sequencing, the quantitative expression effect of extremely large GRE sets can be assessed in parallel. As a proof of principle, we apply this approach to record translation kinetics of more than 300,000 bacterial ribosome binding sites (RBSs), collecting over 2.7 million sequence-function pairs in a single experiment. Further, we generalize from these large-scale datasets by a novel deep learning approach that combines ensembling and uncertainty modelling to predict the function of untested RBSs with high accuracy, substantially outperforming state-of-the-art methods. The combination of DNA-based phenotypic recording and deep learning represents a major advance in our ability to predict quantitative function from genetic sequence.
Multiple streams of genetic diversity in Japonica rice
Authors: Santos João D. , Billot Claire , Chebotarov Dmytro , Droc Gaëtan , Lorieux Mathias , McNally Kenneth L. , Glaszmann Jean Christophe 
Published: January 2020

AbstractIn-depth studies on the genetic diversity of crops indicate that domestication is likely a drawn-out process that differs from the traditional representation of a simple rapid bottleneck. Asian cultivated rice provides a clear picture of multiple foundations of crop diversity. Among them, Japonica rice is likely the group derived from the first human manipulations of this species. We make use of the 3,000 Rice Genomes (3K RG) data set, first described in 2018, to explore the genetic diversity of traditional Japonica rice. After delineating introgressions from the Indica andcAus cultivar groups, we mask these traces to analyse Japonica diversity in more depth. We find differentiation between the established “temperate”, “subtropical” and “tropical” subgroups, and identify stream-like traces of highly divergent sources from broad geographic ranges and subgroups. We characterize five such streams, most visible respectively in: 1) Indonesia, 2) continental Southeast Asia, 3) China, 4) uplands of Japan, and 5) Bhutan. These streams likely consist of ancient alien introgressions propagated through geneflow to different degrees. They currently appear as long genome segments conserved among specific germplasm groups, as well as shorter segments more broadly distributed across diverse germplasm along what could be adaptive corridors. They are all represented in the Japonica component ofcBasmati varieties, thought to have emerged over two millennia ago. We thus provide strong evidence that Japonica, the group posited as being the most direct product of a simple domestication process in China, is an aggregate derived from multiple waves of admixture and represents a composite gene pool with ancient Asia-wide population dynamics.
Establishment gaps in species-poor grasslands: artificial biodiversity hotspots to support the colonization of target species
Authors: Kiss Réka , Deák Balázs , Tóthmérész Béla , Miglécz Tamás , Tóth Katalin , Török Péter , Lukács Katalin , Godó Laura , Körmöczi Zsófia , Radócz Szilvia , Kelemen András , Sonkoly Judit , Kirmer Anita , Tischew Sabine , Švamberková Eva , Valkó Orsolya 
Published: January 2020

AbstractSowing of grass seed mixtures is a feasible and cost-effective method for landscape-scale grassland restoration. However, sowing only grasses usually leads to species-poor and dense grass sward, where the establishment of target forbs is hampered both by microsite and propagule limitation. To overcome these limitations and increase the diversity of species-poor sown grasslands we developed a novel method by creating ‘establishment gaps’. We used tillage to open gaps of 1 m2, 4 m2and 16 m2size in the dense grass sward of six species-poor sown grasslands in the Great Hungarian Plain. We sowed high-diversity seed mixtures of 35 native species into all gaps. We analyzed vegetation development during the first five years after setting up the trial. We also studied the colonization dynamics of the sown species along four 20-m transects around each gap, resulting in a total of 1440 plots of 1 m2size that were studied. Our results indicated that most of the sown species were able to establish permanently in the establishment gaps. The total cover and the cover of perennial sown species increased independently of gap size. Meanwhile the cover of short-lived sown species decreased during the five years. There was only a moderate level of weed abundance in the gaps, and weed cover decreased over the years. The sown target species started to colonize the species-poor grasslands surrounding the establishment gaps within five years. The highest number of species and individuals dispersed from the 4 m2-sized gaps, as they had a more stable development than small gaps and were exposed to lower grazing pressure than large ones.Implications for practiceEstablishment gaps are widely applicable tools to increase the diversity of species-poor grasslands. Gaps of 4 m2represent a more feasible solution compared to larger openings also for the farmers, because there is only a moderate level of weed encroachment and smaller soil disturbance occurs during their creation.We recommend sowing high-diversity seed mixtures containing both short-lived species that can establish in the first year and perennial species, which guarantee a high cover of target species later on.Gaps sown with high-diversity seed mixture are highly resistant to unfavorable climatic conditions: increasing grass abundance in dry years does not hamper the recovery of target grassland species in the following years.