bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient reaction deletion algorithms for redesign of constraint-based metabolic networks for metabolite production with weak coupling
Authors: Tamura Takeyuki 
Published: March 2019

AbstractBackgroundMetabolic network analysis through flux balance is an established method for the computational redesign of production strains in metabolic engineering. The computational redesign is often based on reaction deletions from the original wild type networks. A key principle often used in this method is the production of target metabolites as by-products of cell growth. From a viewpoint of bioinformatics, it is very important to prepare a set of algorithms that can determine reaction deletions that achieve growth coupling whatever network topologies, target metabolites and parameter values will be considered in the future. Recently, the strong coupling-based method was used to demonstrate that the coupling of growth and production is possible for nearly all metabolites through reaction deletions in genome-scale metabolic models of Escherichia coli and Saccharomyces cerevisiae under aerobic conditions. However, when growing S. cerevisiae under anaerobic conditions, deletion strategies using the strong coupling-based method were possible for only 3.9% of all metabolites. Therefore, it is necessary to develop algorithms that can achieve growth coupling by reaction deletions for the conditions that the strong coupling-based method was not efficient.ResultsWe developed an algorithm that could calculate the reaction deletions that achieve the coupling of growth and production for 91.3% metabolites in genome-scale models of S. cerevisiae under anaerobic conditions. This analysis was conducted for the worst-case-scenario using flux variability analysis. To demonstrate the feasibility of the coupling, we derived appropriate reaction deletions using the new algorithm for target production in which the search space was divided into small cubes (CubeProd).ConclusionsWe developed a novel algorithm, CubeProd, to demonstrate that growth coupling is possible for most metabolites in S.cerevisiae under anaerobic conditions. This may imply that growth coupling is possible by reaction deletions for most target metabolites in any genome-scale constraint-based metabolic networks. The developed software, CubeProd, implemented in MATLAB, and the obtained reaction deletion strategies are freely available.
Pharmacokinetics Modeling and Simulation of Voriconazole Dosing and Safety in Patients with Liver Cirrhosis
Authors: Wang Taotao , Yan Miao , Tang Dan , Dong Yuzhu , Zhu Li , Du Qian , Sun Dan , Xing Jianfeng , Dong Yalin 
Published: March 2019

AbstractVoriconazole is used to treat invasive fungal disease and the optimal dose regimens are still unknown in cirrhotic Patients. The aim of this study was to determine the safety, to describe pharmacokinetics characteristics, and to optimize dosage regimens of voriconazole in cirrhotic patients. Data pertaining to voriconazole were collected retrospectively and analyzed using a population pharmacokinetics model. A total of 219 trough concentrations (Cmin) from 120 patients were analyzed. Voriconazole-related adverse events developed in 29 patients, with 69.0% of AEs developing within the first week after voriconazole treatment. The threshold Cmin for AEs was 5.12 mg/L. A one-compartment model with first-order absorption and elimination adequately described the data. The Child-Pugh class was the only covariate in final model. Voriconazole clearance in patients with Child-pugh A and B cirrhosis (CP-A/CP-B) and Child-pugh C cirrhosis (CP-C) were 1.79 L/h and 0.99 L/h, respectively, the volume of distribution was 159.6 L, and the oral bioavailability was 91.8%. The elimination half-life was significantly extended for up to 61.8 – 111.7 h in cirrhotic patients. Model-based simulations showed that the appropriate maintenance doses are 75 mg/12 h and 150 mg/24 h intravenously or orally for CP-A/CP-B patients, and 50 mg/12 h and 100 mg/24 h intravenously or orally for CP-C patients. The results support voriconazole maintenance doses in LC patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/CP-B patients compared to that for patients with normal liver function. Monitoring Cmin early could be a useful strategy to ensure the safety.
Ecological strategy and genetic load in the shepherd’s purse (Capsella bursa-pastoris) from the core and the limit of its natural range
Authors: Orsucci Marion , Milesi Pascal , Hansen Johanna , Girodolle Johanna , Glémin Sylvain , Lascoux Martin 
Published: March 2019

AbstractSpecies range expansion is a complex process whose outcome depends on the interplay of demographic, environmental and genetic factors. In plants, self-fertilizing species that do not require a mate to reproduce usually show higher invasive ability. However, this comes at a cost as both selfing and bottlenecks occurring during colonization lead to an increase in deleterious mutations accumulation (genetic load). Although they are theoretically clearly spelled out, the relationships between genomic and phenotypic characteristics of expanding populations have hitherto rarely been characterized.In the present study we analyzed how different accessions of the shepherd’s purse, C. bursa-pastoris, coming from the front of colonization or from the core of the natural range performed under increasing density of competitors. We first showed that, as expected, accessions from the front of colonization performed the worst for most life history traits compared with accessions from core populations. Second, competitor density had a negative impact on both vegetative growth and reproductive output in term of fruits production for all accessions. However, somewhat unexpectedly given their higher genetic load and their lower absolute performance, accessions from the front of colonization were less affected by competition than accessions from the core of the species range. This could be due to phenotypic tradeoffs and a shift in phenology that allow the accessions from the front of colonization to avoid competition. These results are discussed in terms of ecological strategies of expanding populations.
Islands in the desert: Environmental distribution modelling of endemic flora reveals the extent of Pleistocene tropical relict vegetation in southern Arabia
Authors: Borrell James S. , Issaey Ghudaina Al , Lupton Darach A. , Starnes Thomas , Hinai Abdulrahman Al , Hatmi Saif Al , Senior Rebecca A. , Wilkinson Tim , Milborrow Jo L.H. , Stokes-Rees Andrew , Patzelt Annette 
Published: March 2019

ABSTRACTBackground and AimsSouthern Arabia is a global biodiversity hotspot with a high proportion of endemic desert-adapted plants. Here we examine evidence for a Pleistocene climate refugium in the southern Central Desert of Oman, and its role in driving biogeographical patterns of endemism.MethodsDistribution data for seven narrow-range endemic plants were collected systematically across 195 quadrats, together with incidental and historic records. Important environmental variables relevant to arid coastal areas, including night time fog and cloud cover were developed for the study area. Environmental niche models were built and tuned for each species and spatial overlap examined.Key ResultsA region of the Jiddat Al Arkad reported independent high model suitability for all species. Examination of environmental data across southern Oman indicates that the Jiddat Al Arkad displays a regionally unique climate with higher intra-annual stability, due in part to the influence of the southern monsoon. Despite this, relative importance of environmental variables was highly differentiated among species, suggesting characteristic variables such as coastal fog are not major cross-species predictors at this scale.ConclusionsThe co-occurrence of a high number of endemic study species within a narrow monsoon-influenced region is indicative of a refugium with low climate change velocity. Combined with climate analysis, our findings provide strong evidence for a southern Arabian Pleistocene refugium in the Oman’s Central Desert. We suggest this refugium has acted as an isolated temperate and mesic island in the desert, resulting in the evolution of these narrow-range endemic flora. Based on the composition of species, this system may represent the northernmost remnant of a continuous belt of mesic vegetation formerly ranging from Africa to Asia, with close links to the flora of East Africa. This has significant implications for future conservation of endemic plants in an arid biodiversity hotspot.
Time-Invariant Working Memory Representations in the Presence of Code-Morphing in the Lateral Prefrontal Cortex
Authors: Parthasarathy Aishwarya , Tang Cheng , Herikstad Roger , Cheong Loong Fah , Yen Shih-Cheng , Libedinsky Camilo 
Published: March 2019

AbstractEndogenous processes allow the maintenance of working memories. These processes presumably involve prefrontal networks with strong recurrent connections. Distractors evoke a morphing of the population code, even when memories are stable. But it is unclear whether these dynamic population responses contain stable memory information. Here we show that dynamic prefrontal activity contains stable memory information, and the stability depends on parallel movement of trajectories associated with different memories in state space. We used an optimization algorithm to find a subspace with stable memory information. In correct trials the stability extended to periods that were not used to find the subspace, but in error trials the information and the stability were reduced. A bump attractor model was able to replicate these behaviors. The model provided predictions that could be confirmed with the neural data. We conclude that downstream regions could read memory information from a stable subspace.
A conserved requirement forFbxo7during male germ cell cytoplasmic remodelling
Authors: Rathje Claudia C , Randle Suzanne J , Rawi Sara Al , Skinner Benjamin M , Johnson Emma EP , Bacon Joanne , Vlazaki Myrto , Affara Nabeel A , Ellis Peter J , Laman Heike 
Published: March 2019

Summary statementFbxo7 is the substrate-recognition subunit of an SCF-type ubiquitin E3 ligase complex. It has physiologically important functions in regulating mitophagy, proteasome activity and the cell cycle in multiple cell types, like neurons, lymphocytes and erythrocytes. Here we show that in addition to the previously-known Parkinsonian and haematopoietic phenotypes, Fbxo7-deficient male mice are completely sterile. In these males, despite successful meiosis, nuclear elongation and eviction of histones from chromatin, the developing spermatids are phagocytosed by Sertoli cells during late spermiogenesis, as the cells undergo cytoplasmic remodelling. Surprisingly, despite the loss of all germ cells, there was no evidence of the symplast formation and cell sloughing that is typically associated with spermatid death in other mouse sterility models, suggesting that novel cell death and/or cell disposal mechanisms may be engaged in Fbxo7-deficient males. Mutation of theDrosophilaFbxo7 orthologue,nutcracker(ntc) was previously shown to cause sterility at a similar stage of germ cell development, indicating that the requirement for Fbxo7 is conserved. Thentcphenotype was attributed to proteasome mis-regulation via an interaction with the proteasome regulator, DmPI31. Our data suggest rather that in mice, the requirement for Fbxo7 is either independent of its interaction with PI31, or relates specifically to cytoplasmic proteasome activity during spermiogenesis.
Heart development in the lizards (Varanidae) with the greatest extent of ventricular septation
Authors: Hanemaaijer Jermo , Gregorovicova Martina , Nielsen Jan M. , Moorman Antoon FM , Wang Tobias , Planken R. Nils , Christoffels Vincent M , Sedmera David , Jensen Bjarke 
Published: March 2019

AbstractAmong lizards, only monitor lizards (Varanidae) have a functionally divided cardiac ventricle. This enables them to sustain higher systemic blood pressures and higher metabolic rates than other reptiles of similar size. The division results from the concerted action of three partial septa, which may have homology to the full ventricular septum of mammals and archosaurs. Homology, however has only been inferred from anatomical comparisons of hearts of adult monitors whereas gene expression during heart development has not been studied. We show in developing monitors that the partial septa that separate the left and right ventricle, the ‘muscular ridge’ and ‘bulbuslamelle’, express the evolutionary conserved transcription factorsTbx5, Irx1andIrx2, orthologues of which mark the full ventricular septum. Compaction of embryonic trabeculae contributes to the formation of these septa. The septa are positioned, however, to the right of the atrioventricular junction and they do not partake in the separation of incoming atrial blood streams. Instead, the ‘vertical septum’ within the left ventricle separates the atrial blood streams. It expressesTbx3andTbx5, which orchestrate the formation of the electrical conduction axis of the full ventricular septum. These patterns of expression are more pronounced in monitors than in other lizards, and are associated with a deep electrical activation near the vertical septum, contrasting the primitive base-to-apex activation of other lizards. We conclude that current concepts of ventricular septum formation apply well to the monitor septa and that there is evolutionary conservation of ventricular septum formation among amniote vertebrates.
Definitely saw it coming? An ERP study on the role of article gender and definiteness in predictive processing
Authors: Fleur Damien S. , Flecken Monique , Rommers Joost , Nieuwland Mante S. 
Published: March 2019

ABSTRACTPeople sometimes anticipate specific words during language comprehension. Consistent with word anticipation, pre-nominal articles elicit differential neural activity when they mismatch the gender of a predictable noun compared with when they match. However, the functional significance of this pre-nominal effect is unclear: Do people only predict the noun or do they predict the entire article-noun combination? We addressed this question in an event-related potential study (N=48) with pre-registered data acquisition and analyses, capitalizing on gender-marking on Dutch definite articles and the lack thereof on indefinite articles. Participants read mini-story contexts that strongly suggested either a definite or indefinite noun phrase (e.g., ‘het/een boek’, the/a book) as its best continuation, followed by a definite noun phrase with the expected noun or an unexpected, different gender noun (‘het boek/de roman’, the book/the novel). We observed an enhanced negativity (N400) for articles that were unexpectedly definite or mismatched the expected gender, with the former effect being strongest. Pre-registered analyses and exploratory Bayesian analyses did not yield convincing evidence that the effect of gender-mismatch depended on expected definiteness. While prediction of article form cannot be excluded, it may not be required to elicit pre-nominal effects.
EMULSION: transparent and flexible multiscale stochastic models in epidemiology
Authors: Picault Sébastien , Huang Yu-Lin , Sicard Vianney , Arnoux Sandie , Beaunée Gaël , Ezanno Pauline 
Published: March 2019

AbstractStochastic mechanistic models are essential to predictive epidemiology, to better explore biological assumptions and anticipate effects of control measures on pathogen spread. Their development is usually long and iterative, involving multi-disciplinary knowledge integration. However, knowledge often becomes lost in model code, hindering late changes in assumptions and often making models appearing as black boxes to end-users. We introduce here EMULSION, an artificial intelligence-based software intended to help modellers focus on model design rather than programming. EMULSION defines a domain-specific language to make all components of an epidemiological model (structure, processes, parameters…) explicit as a structured text file. This file is readable by scientists from other fields (epidemiologists, biologists, economists), who can contribute to validate or revise assumptions at any stage of model development. It is then automatically processed by EMULSION generic simulation engine, preventing any discrepancy between model description and implementation. The modelling language and simulation architecture both rely on the combination of advanced artificial intelligence methods (knowledge representation and multi-level agent-based simulation), allowing several modelling paradigms (from compartment- to individual-based models) at several scales (up to metapopulations). The flexibility of EMULSION and its capability to support iterative modelling are illustrated here through examples of progressive complexity, including late revisions of core model assumptions. EMULSION is also currently used to model the spread of several diseases in real pathosystems (zoonoses such as Q fever or the vector-borne Rift Valley fever; or bovine respiratory diseases, with a focus on detection and treatment protocols). EMULSION provides a command-line tool for checking models, producing model diagrams, running simulations, and plotting outputs. Implemented in Python 3, EMULSION runs on Linux, MacOS, and soon Windows. It is released under Apache-2.0 license. A comprehensive documentation with installation instructions, tutorial and examples is available from:https://sourcesup.renater.fr/emulsion-public.
Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment
Authors: Leo Federica De , Quilici Giacomo , Tirone Mario , Mannella Valeria , Marchis Francesco De , Preti Alessandro , Gori Alessandro , Casalgrandi Maura , Mezzapelle Rosanna , Bianchi Marco E. , Musco Giovanna 
Published: March 2019

AbstractExtracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.
Transcriptome Profiling of Mouse Brain and Lung under Dip2A Regulation Using RNA-Sequencing
Authors: sah Rajiv kumar , Yang Anlan , Bah Fatoumata Binta , Adlat Salah , Bohio Ameer Ali , Oo Zin Mar , Wang Chenhao , Myint May zun Zaw , Bahadar Noor , Zhang Luqing , Feng Xuechao , Zheng Yaowu 
Published: March 2019

AbstractDisconnected interacting 2 homolog A (DIP2A) gene is highly expressed in nervous system and respiratory system of developing embryos. However, genes regulated by Dip2a in developing brain and lung have not been systemically studied. Transcriptome of brain and lung in embryonic 19.5 day (E19.5) were compared between wild type and Dip2a-/- mice. Total RNAs were extracted from brain and lung of E19.5 embryos for RNA-Seq. Clean reads were mapped to mouse reference sequence (mm9) using Tophat and assembled into transcripts by Cufflinks. Edge R and DESeq were applied to identify differentially expressed genes (DEGs) and annotated under GO, COG, KEGG and TF. An average of 50 million reads per sample was mapped to the reference sequence. A total of 214 DEGs were detected in brain (82 up and 132 down) and 1900 DEGs in lung (1259 up and 641 down). GO enrichment analysis indicated that DEGs in both Brain and Lung were mainly enriched in biological processes ‘DNA-templated transcription and Transcription from RNA polymerase II promoter’, ‘multicellular organism development’, ‘cell differentiation’ and ‘apoptotic process’. In addition, COG classification showed that both were mostly involved in ‘Replication, Recombination and Repair’, ‘Signal transduction and mechanism’, ‘Translation, Ribosomal structure and Biogenesis’ and ‘Transcription’. KEGG enrichment analysis showed that brain was mainly enriched in ‘Thryoid cancer’ pathway whereas lung in ‘Complement and Coagulation Cascades’ pathway. Transcription factor (TF) annotation analysis identified Zinc finger domain containing (ZF) proteins were mostly regulated in lung and brain. Interestingly, study identified genes Skor2, Gpr3711, Runx1, Erbb3, Frmd7, Fut10, Sox11, Hapln1, Tfap2c and Plxnb3 from brain that play important roles in neuronal cell maturation, differentiation and survival; genes Hoxa5, Eya1, Ctsh, Erff1, Lama1, Lama2, Rspo2, Sox11, Spry4, Shh, Igf1 and Wnt7a from lung are important in lung development and morphogenesis. Expression levels of the candidate genes were validated by qRT-PCR. Genome wide transcriptional analysis using wild type and Dip2a knockout mice in brain and lung at embryonic day 19.5 (E19.5) provided a genetic basis of molecular function of these genes.
Repeatability of adaptive radiation depends on spatial scale: regional versus global replicates of stickleback in lake versus stream habitats
Authors: Paccard Antoine , Hanson Dieta , Stuart Yoel E. , von Hippel Frank A. , Kalbe Martin , Klepaker Tom , Skúlason Skúli , Kristjánsson Bjarni K. , Bolnick Daniel I. , Hendry Andrew P. , Barrett Rowan D.H. 
Published: March 2019

ABSTRACTThe repeatability of adaptive radiation is expected to be scale dependent, with determinism decreasing as greater spatial separation among “replicates” leads to their increased genetic and ecological independence. Threespine stickleback (Gasterosteus aculeatus) provide an opportunity to test whether this expectation holds for the early stages of adaptive radiation - their diversification in freshwater ecosystems has been replicated many times. To better understand the repeatability of that adaptive radiation, we examined the influence of geographic scale on levels of parallel evolution by quantifying phenotypic and genetic divergence between lake and stream stickleback pairs sampled at regional (Vancouver Island) and global (North America and Europe) scales. We measured phenotypes known to show lake-stream divergence and used reduced representation genome-wide sequencing to estimate genetic divergence. We assessed the scale-dependence of parallel evolution by comparing effect sizes from multivariate models and also the direction and magnitude of lake-stream divergence vectors. At the phenotypic level, parallelism was greater at the regional than the global scale. At the genetic level, putative selected loci showed greater lake-stream parallelism at the regional than the global scale. Generally, the level of parallel evolution was low at both scales, except for some key univariate traits. Divergence vectors were often orthogonal, highlighting possible ecological and genetic constraints on parallel evolution at both scales. Overall, our results confirm that the repeatability of adaptive radiation decreases at increasing spatial scales. We suggest that greater environmental heterogeneity at larger scales imposes different selection regimes, thus generating lower repeatability of adaptive radiation at larger spatial scales.