bluuebunny/crossref_metadata_2025_split huggingface dataset:
Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth
Authors: Cox Andrew G. , Tsomides Allison , Yimlamai Dean , Hwang Katie L. , Miesfeld Joel , Galli Giorgio G. , Fowl Brendan H. , Fort Michael , Ma Kimberly Y. , Sullivan Mark R. , Hosios Aaron M. , Snay Erin , Yuan Min , Brown Kristin K. , Lien Evan C. , Chhangawala Sagar , Steinhauser Matthew L. , Asara John M. , Houvras Yariv , Link Brian , Heiden Matthew G. Vander , Camargo Fernando D. , Goessling Wolfram 
Published: April 2018

AbstractThe Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis: transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improved Yap-deficiency phenotypes, indicating functional importance of glucose-fuelled nucleotide biosynthesis. Yap-regulated Glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signalling in metabolic homeostasis.
Predicting the time needed to conduct an environmental systematic review or systematic map: analysis and decision support tool
Authors: Haddaway Neal R , Westgate Martin J 
Published: April 2018

AbstractSystematic reviews aim to maximise transparency and comprehensiveness, whilst also minimising subjectivity and sources of bias. Because of these time-consuming and complex tasks, systematic reviews are perceived as being resource-intensive. To date, published estimates of systematic review resource requirements have been largely anecdotal, being imprecise and not based on evidence. However, it is valuable to provide reliable means of estimating the resource and time requirements of systematic reviews and maps. We analysed all CEE systematic reviews (n=66) and maps (n=20) published or registered between 2012 and 2017 to estimate the average time needed to complete a systematic review and map. We then surveyed 33 experienced systematic reviewers to collate information on time needed for each stage of the review process. Our results show that the average CEE systematic review takes 157 days (SD; ±22), whilst the average CEE systematic map takes 209 days (SD; ±53). While screening of titles and abstracts is widely accepted to be time-consuming, in practice meta-data extraction and critical appraisal can take as long (or even longer) to complete, especially when producing systematic maps. Finally, we present a tool that allows the user to predict the time requirements of a review or map given information known about the planned methods and evidence base likely to be identified. Our tool uses evidence-based defaults as a useful starting point for those wishing to predict the time requirements for a particular review. Our analyses shed light on the most time-consuming stages of the systematic review and map process, and highlight key bottlenecks from the perspective of time requirements, helping future reviewers to plan their time accordingly. Future predictions of effort required to complete systematic reviews and maps could be improved if CEE and CEE review authors provided more detailed reporting of the methods and results of their reviewing processes.
Characterisation and functional predictions of canine long non-coding RNAs
Authors: Le Béguec Céline , Wucher Valentin , Lagoutte Lætitia , Cadieu Edouard , Botherel Nadine , Hédan Benoît , De Brito Clotilde , Anne-Sophie Guillory , André Catherine , Derrien Thomas , Hitte Christophe 
Published: April 2018

AbstractLong non-coding RNAs (lncRNAs) are a family of heterogeneous RNAs that play major roles in multiple biological processes. We recently identified an extended repertoire of more than 10,000 lncRNAs of the domestic dog however, predicting their biological functionality remains challenging. In this study, we have characterised the expression profiles of 10,444 canine lncRNAs in 26 distinct tissue types, representing various anatomical systems. We showed that lncRNA expressions are mainly clustered by tissue type and we highlighted that 44% of canine lncRNAs are expressed in a tissue-specific manner. We further demonstrated that tissue-specificity correlates with specific families of canine transposable elements. In addition, we identified more than 900 conserved dog-human lncRNAs for which we show their overall reproducible expression patterns between dog and humans through comparative transcriptomics. Finally, co-expression analyses of lncRNA and neighbouring protein-coding genes identified more than 3,400 canine lncRNAs, suggesting that functional roles of these lncRNAs act as regulatory elements. Altogether, this genomic and transcriptomic integrative study of lncRNAs constitutes a major resource to investigate genotype to phenotype relationships and biomedical research in the dog species.
Nuclear import ofArabidopsisPOLY(ADP-RIBOSE) POLYMERASE 2 is mediated by importin-α and a nuclear localization sequence located between the predicted SAP domains
Authors: Chen Chao , Lintermann Ruth , Wirthmueller Lennart 
Published: April 2018

AbstractProteins of the poly(ADP-ribose) polymerase (PARP) family modify target proteins by covalent attachment of ADP-ribose moieties onto amino acid side chains. InArabidopsis, PARP proteins contribute to repair of DNA lesions and modulate plant responses to various abiotic and biotic stressors.ArabidopsisPARP1 and PARP2 are nuclear proteins and given that their molecular weights exceed the diffusion limit of nuclear pore complexes, an active import mechanism into the nucleus is likely. Here we use confocal microscopy of fluorescent protein-taggedArabidopsisPARP2 and PARP2 deletion constructs in combination with site-directed mutagenesis to identify a nuclear localization sequence in PARP2 that is required for nuclear import. We report that in co-immunoprecipitation assays PARP2 interacts with several isoforms of the importin-α group of nuclear transport adapters and that PARP2 binding to IMPORTIN-α2 is mediated by the identified nuclear localization sequence. Our results demonstrate that PARP2 is a cargo protein of the canonical importin-α/β nuclear import pathway.
Neuromesodermal Progenitors are a Conserved Source of Spinal Cord with Divergent Growth Dynamics
Authors: Attardi Andrea , Fulton Timothy , Florescu Maria , Shah Gopi , Muresan Leila , Huisken Jan , van Oudenaarden Alexander , Steventon Benjamin 
Published: April 2018

AbstractDuring gastrulation, embryonic cells become specified into distinct germ layers. In mouse, this continues throughout somitogenesis from a population of bipotent stem cells called neuromesodermal progenitors (NMps). However, the degree self-renewal is associated with NMps in the fast-developing zebrafish embryo is unclear. With a genetic clone tracing method, we labelled early embryonic progenitors and find a strong clonal similarity between spinal cord and mesoderm tissues. We then followed individual cell lineages by light-sheet imaging and reveal a common neuromesodermal lineage contribution to a subset of spinal cord tissue across the anterior-posterior body axis. An initial population subdivides at mid gastrula stages and is directly allocated to neural and mesodermal compartments during gastrulation. A second population in the tailbud undergoes delayed allocation to contribute to the neural and mesodermal compartment only at late somitogenesis. We suggest that NMps undergo vastly different rates of differentiation and growth in a species-specific manner.
Relative evolutionary rates in proteins are largely insensitive to the substitution model
Authors: Spielman Stephanie J. , Kosakovsky Pond Sergei L. 
Published: April 2018

AbstractThe relative evolutionary rates at individual sites in proteins are informative measures of conservation or adaptation. Often used as evolutionarily-aware conservation scores, relative rates reveal key functional or strongly-selected residues. Estimating rates in a phylogenetic context requires specifying a protein substitution model, which is typically a phenomenological model trained on a large empirical dataset. A strong emphasis has traditionally been placed on selecting the “best-fit” model, with the implicit understanding that suboptimal or otherwise ill-fitting models can potentially bias inferences. However, the pervasiveness and degree of such bias has not been systematically examined. We investigated how model choice impacts site-wise relative rates from a large set of empirical protein alignments. We compared models designed for use on any general protein, models designed for specific domains of life, and the simple equal-rates Jukes Cantor-style model (JC). As expected, information theoretic measures showed overwhelming evidence that some models fit the data decidedly better than others. By contrast, estimates of site-specific evolutionary rates were impressively insensitive to the substitution model used, revealing an unexpected degree of robustness to potential model misspecification. A deeper examination of the fewer than 5% of sites for which model inferences differed in a meaningful way showed that the JC model can uniquely identify rapidly-evolving sites that models with empirically-derived exchangeabilities fail to detect. We conclude that relative protein rates appear robust to the applied substitution model, and any sensible model of protein evolution, regardless of its fit to the data, should produce broadly consistent evolutionary rates.
Probiotics enhance susceptibility of mice to cryptosporidiosis
Authors: Oliveira Bruno C. M. , Widmer Giovanni 
Published: April 2018

AbstractCryptosporidiosis is a leading cause of diarrhea in infants and immune-compromised individuals. The lack of effective drugs against this enteric infection is motivating research to develop alternative treatments. To this aim, the impact of probiotics on the course of cryptosporidiosis was explored. The native intestinal microbiota of specific pathogen-free immunosuppressed mice was initially depleted with orally administered antibiotics. Then, a commercially available probiotic product intended for human consumption was added (or not) to the drinking water. Probiotic treated and untreated mice were orally infected withCryptosporidium parvumoocysts. On average, mice treated with probiotic excreted more oocysts, indicative of a more severe infection. The probiotic treatment significantly altered the fecal microbiota, but taxonomic analyses showed no direct association between ingestion of probiotic bacteria and their abundance in fecal microbiota. These results suggest that probiotics indirectly alter the intestinal microenvironment in such a way that favors proliferation ofC. parvum. The increase in the relative abundance of facultative anaerobes observed in mice with severe cryptosporidiosis indicates that dysbiosis is a consequence of severe cryptosporidiosis. The increase in the abundance of facultative anaerobes observed in severely infected animals is consistent with analyses of microbiota from individuals infected with other enteric pathogens. The results are significant because they show thatC. parvumresponds to changes in the intestinal microenvironment induced by a nutritional supplement.One Sentence SummaryMice treated with probiotics develop more severe symptoms of cryptosporidiosis.
Persistence of Resident and Transplanted Genotypes of the Undomesticated Yeast, Saccharomyces paradoxus in Forest Soil
Authors: Anderson James B. , Kasimer Dahlia , Xia Clara , Shröeder Nicolas C. H. , Cichowicz Patrick , Lioniello Silvio , Chakrabarti Rudrackshi , Mohan Eashwar , Kohn Linda M. 
Published: April 2018

ABSTRACTOne might expect yeasts in soil to be highly dispersed via water or insects, forming ephemeral, genetically heterogeneous populations subject to competition and environmental stochasticity. Here, we report years-long persistence of genotypes of the yeast Sacchaormyces paradoxus in space and time. Within 1 km2 in a mixed hardwood forest on scales from centimeters to tens of meters, we detect persistence over 3 years of native genotypes, identified by SNPs genome-wide, of the wild yeast, Saccharomyces paradoxus around Quercus rubra and Q. alba. Yeasts were recovered by enrichment in ethanol-containing medium, which measures only presence or absence, not abundance. Additional transplantation experiments employed strains marked with spontaneous defects in the URA3 gene, which also confer resistance to 5-Fluoroorotic acid (5FOA). Plating soil suspensions from transplant sites on 5FOA medium permitted one-step quantification of yeast colony-forming units, with no interference from other unmarked yeasts or microorganisms. After an initial steep decrease in abundance, the yeast densities fluctuated over time, increasing in association with rainfall and decreasing in association with drought. After 18 months, the transplanted yeasts remain in place on the nine sites. In vitro transplantation experiments into non-sterile soil in petri dishes showed similar patterns of persistence and response to moisture and drought. To determine whether S. cerevisiae, not previously recovered from soils regionally, can persist in our cold-climate sites, we transplanted marked S. cerevisiae alone and in mixture with S. paradoxus in fall, 2017. Five months on, S. cerevisiae persist to the same extent as S. paradoxus.
In vivo Chemical Reprogramming of Astrocytes into Functional Neurons
Authors: Ma Yantao , Xie Handan , Du Xiaomin , Wang Lipeng , Jin Xueqin , Sun Shicheng , Han Yanchuang , Han Yawen , Xu Jun , Huang Zhuo , Chai Zhen , Dengi Hongkui 
Published: April 2018

AbstractMammals lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced reprogramming is a spatiotemporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for the in vivo reprogramming in organs with poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram resident astrocytes into functional neurons. The in situ chemically induced neurons (CiNs) resemble endogenous neurons in terms of neuron-specific marker expression and electrophysiological properties. Importantly, these CiNs can integrate into the mouse brain. Our study, for the first time, demonstrates in vivo chemical reprogramming in the adult brain, which could be a novel path for generating desired cells in situ for regenerative medicine.
CHOP: Haplotype-aware path indexing in population graphs
Authors: Mokveld Tom , Linthorst Jasper , Al-Ars Zaid , Holstege Henne , Reinders Marcel 
Published: April 2018

AbstractThe practical use of graph-based reference genomes depends on the ability to align reads to them. Performing substring queries to paths through these graphs lies at the core of this task. The combination of increasing pattern length and encoded variations inevitably leads to a combinatorial explosion of the search space. We propose CHOP a method that uses haplotype information to prevent this from happening. We show that CHOP can be applied to large and complex datasets, by applying it on a graph-based representation of the human genome encoding all 80 million variants reported by the 1000 Genomes project.
EGF signalling in epithelial carcinoma cells utilizes preformed receptor homoclusters, with larger heteroclusters post activation
Authors: Fournier Charlotte , Wollman Adam J. M. , Llorente-Garcia Isabel , Harriman Oliver , Ouarat Djamila , Wilding Jenny , Bodmer Walter , Leake Mark C. 
Published: April 2018

AbstractEpidermal growth factor (EGF) signalling regulates cell growth, differentiation and proliferation in epithelium and EGF receptor (EGFR) overexpression has been reported in several carcinoma types. Structural and biochemical evidence suggests EGF binding stimulates EGFR monomer-dimer transitions, activating downstream signalling. However, mechanistic details of ligand binding to functional receptors in live cells remain contentious. We report real time single-molecule TIRF of human epithelial carcinoma cells with negligible native EGFR expression, transfected with GFP-tagged EGFR, before and after receptor activation with TMR-labelled EGF ligand. Fluorescently labelled EGFR and EGF are simultaneously tracked to 40nm precision to explore stoichiometry and spatiotemporal dynamics upon EGF binding. Using inhibitors that block binding to EGFR directly, or indirectly through HER2, our results indicate that pre-activated EGFR consists of preformed homoclusters, while larger heteroclusters including HER2 form upon activation. The relative stoichiometry of EGFR to EGF after binding peaks at 2, indicating negative cooperativity of EGFR activation.
Inference of significant microbial interactions from longitudinal metagenomics sequencing data
Authors: Gao Xuefeng , Huynh Bich-Tram , Guillemot Didier , Glaser Philippe , Opatowski Lulla 
Published: April 2018

AbstractData of next-generation sequencing (NGS) and their analysis have been facilitating advances in our understanding of microbial ecosystems such as human gut microbiota. However, inference of microbial interactions occurring within an ecosystem is still a challenge mainly due to metagenomics sequencing (e.g., 16S rDNA sequences) providing relative abundance of microbes instead of absolute cell count. In order to describe the population dynamics in microbial communities and estimate the involved microbial interactions, we introduce a procedure by integrating generalized Lotka-Volterra equations, forward stepwise regression and bootstrap aggregation. First, we successfully identify experimentally confirmed microbial interactions with relative abundance data of a cheese microbial community. Then, we apply the procedure to time-series of 16S rDNA sequences of gut microbiomes of children who were progressing to Type 1 diabetes (T1D progressors), and compare their gut microbial interactions to a healthy control group. Our results suggest that the number of inferred microbial interactions increased over time during the first three years of life. More microbial interactions are found in the gut flora of healthy children than the T1D progressors. The inhibitory effects from Actinobacteria and Bacilli to Bacteroidia, from Bacteroidia to Clostridia, and the benifit effect from Clostridia to Bacteroidia are shared between healthy children and T1D progressors. An inhibition of Clostridia by Gammaproteobacteria is found in healthy children that maintains through their first three years of life. This suppression appears in T1D progressors during the first year of life, which transforms to a commensalism relationship at the age of three years old. Gammaproteobacteria is found exerting an inhibition on Bacteroidia in the T1D progressors, which is not identified in the healthy controls.
A novel panel of short mononucleotide repeats linked to informative polymorphisms enabling effective high volume low cost discrimination between mismatch repair deficient and proficient tumours
Authors: Redford Lisa , Alhilal Ghanim , Needham Stephanie , O’Brien Ottie , Coaker Julie , Tyson John , Amorim Leonardo Maldaner , Middleton Iona , Sheth Harsh , Izuogu Osagi , Arends Mark , Oniscu Anca , Alonso Ángel Miguel , Laguna Sira Moreno , Santibanez-Koref Mauro , Jackson Michael S. , Burn John 
Published: April 2018

AbstractSomatic mutations in mononucleotide repeats are commonly used to assess the mismatch repair status of tumours. Current tests focus on repeats with a length above 15bp, which tend to be somatically more unstable than shorter ones. These longer repeats also have a substantially higher PCR error rate and tests that use capillary electrophoresis for fragment size analysis often require expert interpretation. In this communication, we present a panel of 17 short repeats (length 7–12bp) for sequence-based microsatellite instability (MSI) testing. Using a simple scoring procedure that incorporates the allelic distribution of the mutant repeats, and analysis of two cohort of tumours totalling 209 samples, we show that this panel is able to discriminate between MMR proficient and deficient tumours, even when constitutional DNA is not available. In the training cohort, the method achieved 100% concordance with fragment analysis, while in the testing cohort, 4 discordant samples were observed (corresponding to 97% concordance). Of these, 2 showed discrepancies between fragment analysis and immunohistochemistry and one was reclassified after re-testing using fragment analysis. These results indicate that our approach offers the option of a reliable, scalable routine test for MSI.
CXXC1 is redundant for normal DNA double-strand break formation and meiotic recombination in mouse
Authors: Tian Hui , Billings Timothy , Petkov Petko M. 
Published: April 2018

AbstractIn most mammals, including mice and humans, meiotic recombination is determined by the meiosis specific histone methytransferase PRDM9, which binds to specific DNA sequences and trimethylates histone 3 at lysine-4 and lysine-36 at the adjacent nucleosomes. These actions ensure successful DNA double strand break initiation and repair that occur on the proteinaceous structure forming the chromosome axis. The process of hotspot association with the axis after their activation by PRDM9 is poorly understood. Previously, we and others have identified CXXC1, an ortholog ofS. cerevisiaeSpp1 in mammals, as a PRDM9 interactor. In yeast, Spp1 is a histone methyl reader that links H3K4me3 sites with the recombination machinery, promoting DSB formation. Here we investigated whether CXXC1 has a similar function in mouse meiosis. We found that CXXC1 is co-expressed and interacts with PRDM9 in mouse spermatocytes. To investigate the meiotic function of CXXC1, we created aCxxc1conditional knockout mouse to deplete CXXC1 before the onset of meiosis. Surprisingly, knockout mice were fertile, and the loss of CXXC1 in spermatocytes had no effect on hotspot trimethylation activity, double-strand break formation or repair. Our results demonstrate that CXXC1 is not an essential link between recombination hotspot sites and DSB machinery and that the hotspot recognition pathway in mouse is independent of CXXC1.Author SummaryMeiotic recombination increases genetic diversity by ensuring novel combination of alleles passing onto the next generation correctly. In most mammals, the meiotic recombination sites are determined by histone methyltransferase PRDM9. These sites subsequently become associated with the chromosome axis with the participation of additional proteins and undergo double strand breaks, which are repaired by homologous recombination. InSaccharomyces cerevisiae, Spp1 (ortholog of CXXC1) binds to methylated H3K4 and connects these sites with chromosome axis promoting DSB formation. However, our data suggest that even though CXXC1 interacts with PRDM9 in male germ cells, it does not play a crucial role in mouse meiotic recombination. These results indicate that, unlike inS. cerevisiae, a recombination initiation pathway that includes CXXC1 could only serve as a non-essential pathway in mouse meiotic recombination.