bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia: a systematic review
Authors: Toksvang Linea Natalie , Schmidt Magnus Strøh , Arup Sofie , Larsen Rikke Hebo , Frandsen Thomas Leth , Schmiegelow Kjeld , Rank Cecilie Utke 
Published: January 2019

ABSTRACTBackgroundThe recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity.ObjectivesTo assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established.Data sourcesDatabases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018.MethodsWe included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included.Results and conclusionsWe included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9–25% of the ALL patients in two of the four included RCTs using 6TG doses of 40–60 mg/m2/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m2/day, NRH occurred in 14% of patients; SOS has not been reported. At a 6TG dose of approximately 12 mg/m2/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m2/day are rarely associated with notable hepatotoxicity and can probably be considered safe.
Interspecies bacterial competition determines community assembly in theC. elegansintestine
Authors: Lopez Anthony Ortiz , Vega Nicole M. , Gore Jeff 
Published: January 2019

AbstractFrom insects to mammals, a large variety of animals hold in their intestines complex bacterial communities that play an important role in health and disease. However, the complexity of these gut microbiomes and their hosts often constrains our ability to understand how these bacterial communities assemble and function. In order to elucidate basic principles of community assembly in a host intestine, we study the assembly of the microbiome ofCaenorhabditis eleganswith a bottom-up approach. We colonize the gut of the wormC. eleganswith 11 bacterial species individually, in all possible pairs, and in selected trios, and we find an organized mixture of coexistence and competitive exclusion that indicates a hierarchical structure in the bacterial interactions. The capacity of a bacterial species fed in monoculture to colonize theC. elegansintestine correlates with its average fraction in co-culture experiments, yet fails to predict its abundance in many two- and three-species microbiomes. Hence, the bacterial fractional abundances in co-culture experiments—pairwise outcomes—are influenced by interspecies interactions. These pairwise outcomes accurately predict the trio outcomes in the worm intestine, further highlighting the importance of pairwise interactions in determining community composition. We also find that theC. elegansgut environment influences the outcome of co-culture experiments, and demonstrate that the low intestinal pH is one of the causes. These results highlight that a bottom-up approach to microbiome community assembly may provide valuable insight into the structure and composition of complex microbial communities.
Chk1 Phosphorylates Cdh1 to Promote SCFβTRCP-Dependent Degradation of Cdh1 During S-Phase
Authors: Pal Debjani , Torres Adrian E. , Messina Abbey L. , Dickson Andrew , De Kuntal , Willard Belinda , Venere Monica , Summers Matthew K. 
Published: January 2019

ABSTRACTThe interplay of the Anaphase-Promoting Complex/Cyclosome (APC/C) and Skp1-Cul1-F-box (SCF) E3 ubiquitin ligases is necessary for controlling cell cycle transitions and checkpoint responses, which are critical for maintaining genomic stability. Yet, the mechanisms underlying the coordinated activity of these enzymes are not completely understood. Recently, Cyclin A- and Plk1- mediated phosphorylation of Cdh1 was demonstrated to trigger its ubiquitination by SCFβTRCPat the G1/S transition. However, Cyclin A-Cdk and Plk1 activities peak in G2 so it is unclear why Cdh1 is targeted at G1/S but not in G2. Here, we show that phosphorylation of Cdh1 by Chk1 contributes to its recognition by SCFβTRCP, promotes efficient S-phase entry, and is important for cellular proliferation. Conversely, Chk1 activity in G2 inhibits Cdh1 accumulation. Overall, these data suggest a model whereby the rise and fall of Chk1 activity is a key factor in the feedback loop between APC/CCdh1and the replication machinery that enhances the G1/S and S/G2 transitions, respectively.
Species abundance distributions should underpin ordinal cover-abundance transformations
Authors: McNellie Megan J , Dorrough Josh , Oliver Ian 
Published: January 2019

AbstractThe cover and abundance of individual plant species have been recorded on ordinal scales for millions of plots world-wide. Many ecological questions can be addressed using these data. However ordinal cover data may need to be transformed to a quantitative form (0 to 100%), especially when scrutinising summed cover of multiple species. Traditional approaches to transforming ordinal data often assume that data are symmetrically distributed. However, skewed abundance patterns are ubiquitous in plant community ecology. A failure to account for this skew will bias plant cover estimates, especially when cover of multiple species are summed. The questions this paper addresses are (i) how can we estimate transformation values for ordinal data that accounts for the underlying right-skewed distribution of plant cover; (ii) do different plant groups require different transformations and (iii) how do our transformations compare to other commonly used transformations within the context of exploring the aggregate properties of vegetation? Using a continuous cover dataset, each occurrence record was mapped to its commensurate ordinal value, in this case, the ubiquitous Braun-Blanquet cover-abundance (BBCA) scale. We fitted a Bayesian hierarchical beta regression to estimate the predicted mean (PM) cover of each of six plant growth forms within different ordinal classes. We illustrate our method using a case study of 2 809 plots containing 95 812 occurrence records with visual estimates of cover for 3 967 species. We compare the model derived estimates to other commonly used transformations. Our model found that PM estimates differed by growth form and that previous methods overestimated cover, especially of smaller growth forms such as forbs and grasses. Our approach reduced the cumulative compounding of errors when transformed cover data were used to explore the aggregate properties of vegetation and was robust when validated against an independent dataset. By accounting for the right-skewed distribution of cover data, our alternate approach for estimating transformation values can be extended to other ordinal scales. A more robust approach to transforming floristic data and aggregating cover estimates can strengthen ecological analyses to support biodiversity conservation and management.
Towards creating an extended metabolic model (EMM) for E. coli using enzyme promiscuity prediction and metabolomics data
Authors: Amin Sara A. , Chavez Elizabeth , Nair Nikhil U. , Hassoun Soha 
Published: January 2019

AbstractBackgroundMetabolic models are indispensable in guiding cellular engineering and in advancing our understanding of systems biology. As not all enzymatic activities are fully known and/or annotated, metabolic models remain incomplete, resulting in suboptimal computational analysis and leading to unexpected experimental results. We posit that one major source of unaccounted metabolism is promiscuous enzymatic activity. It is now well-accepted that most, if not all, enzymes are promiscuous – i.e., they transform substrates other than their primary substrate. However, there have been no systematic analyses of genome-scale metabolic models to predict putative reactions and/or metabolites that arise from enzyme promiscuity.ResultsOur workflow utilizes PROXIMAL – a tool that uses reactant-product transformation patterns from the KEGG database – to predict putative structural modifications due to promiscuous enzymes. Using iML1515 as a model system, we first utilized a computational workflow, referred to as Extended Metabolite Model Annotation (EMMA), to predict promiscuous reactions catalyzed, and metabolites produced, by natively encoded enzymes in E. coli. We predict hundreds of new metabolites that can be used to augment iML1515. We then validated our method by comparing predicted metabolites with the Escherichia coli Metabolome Database (ECMDB).ConclusionsWe utilized EMMA to augment the iML1515 metabolic model to more fully reflect cellular metabolic activity. This workflow uses enzyme promiscuity as basis to predict hundreds of reactions and metabolites that may exist in E. coli but have not been documented in iML1515 or other databases. Among these, we found that 17 metabolites have previously been documented in E. coli metabolomics studies. Further, 6 of these metabolites are not documented for any other E. coli metabolic model (e.g. KEGG, EcoCyc). The corresponding reactions should be added to iML1515 to create an Extended Metabolic Model (EMM). Other predicted metabolites and reactions can guide future experimental metabolomics studies. Further, our workflow can easily be applied to other organisms for which comprehensive genome-scale metabolic models are desirable.
Characterization of Sex Differences in Ocular HSV-1 Infection and Herpes Stromal Keratitis Pathogenesis of Wild Type and Herpesvirus Entry Mediator Knockout Mice
Authors: Riccio Rachel E , Park Seo J , Longnecker Richard M , Kopp Sarah J 
Published: January 2019

ABSTRACTSex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050-9, 2012). Herpes simplex virus type 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, J. E. Knickelbein, and E. Vilain, Prog Retin Eye Res 32:88-101, 2013). Our research focuses on the role of Herpes Viral Entry Mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM KO) exhibit lower immune cell infiltrates and less severe ocular disease in the cornea compared to wild type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested sex as a biological variable in the immune response to HSV-1 infection and Herpes Stromal Keratitis pathogenesis (HSK). Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers and immune cell infiltrates were collected and analyzed. Our results indicate no significant difference in viral titers in tear film or affected tissues; immune cell infiltration; or clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model, and that male and female mice can similarly be used in studies of ocular HSV-1 pathogenesis.IMPORTANCESex hormones have only recently been considered as an important factor for the development of certain diseases and as such should continue to be considered as a biological variable. Ocular Herpesvirus Type 1 (HSV-1), and the resulting Herpes Stromal Keratitis, is the leading cause of infectious blindness worldwide. We compared ocular HSV-1 infection and pathogenesis between sexes and found no significance difference between male and female wild type mice or herpesvirus entry mediator knockout mice. Therefore, male and female mice can be used interchangeably in studying ocular HSV-1 pathogenesis.
DypFISH: Dynamic Patterned FISH to Interrogate RNA and Protein Spatial and Temporal Subcellular Distribution
Authors: Savulescu Anca F. , Brackin Robyn , Bouilhol Emmanuel , Dartigues Benjamin , Warrell Jonathan H. , Pimentel Mafalda R. , Dallongeville Stephane , Schmoranzer Jan , Olivo-Marin Jean-Christophe , Gomes Edgar R. , Nikolski Macha , Mhlanga Musa M. 
Published: January 2019

SUMMARYAdvances in single cell RNA sequencing have allowed for the identification and characterization of cellular subtypes based on quantification of the number of transcripts in each cell. However, cells may differ not only in the number of mRNA transcripts that they exhibit, but also in their spatial and temporal distribution, intrinsic to the definition of their cellular state. Here we describe DypFISH, an approach to quantitatively investigate the spatial and temporal subcellular localization of RNA and protein, by combining micropatterning of cells with fluorescence microscopy at high resolution. We introduce a range of analytical techniques for quantitatively interrogating single molecule RNA FISH data in combination with protein immunolabeling over time. Strikingly, our results show that constraining cellular architecture reduces variation in subcellular mRNA and protein distributions, allowing the characterization of their localization and dynamics with high reproducibility. Many tissues contain cells that exist in similar constrained architectures. Thus DypFISH reveals reproducible patterns of clustering, strong correlative influences of mRNA-protein localization on MTOC orientation when they are present and interdependent dynamics globally and at specific subcellular locations which can be extended to physiological systems.
Tissue shape determines actin-dependent nuclear migration mechanisms in neuroepithelia
Authors: Yanakieva Iskra , Erzberger Anna , Matejčić Marija , Modes Carl D. , Norden Caren 
Published: January 2019

ABSTRACTCorrect nuclear position is crucial for cellular function. Depending on cell context however, cytoskeletal elements and force generation mechanisms vary. While these mechanisms have been intensely studied in single cells, how nuclear positioning is linked to tissue morphology is less clear. Here, we compare apical nuclear positioning in developing straight and curved neuroepithelia of zebrafish.Interestingly, in differently shaped neuroepithelia the kinetics of nuclear positioning differ and we find that distinct actin-dependent mechanisms are employed. In straight neuroepithelia nuclear positioning is controlled by Rho-ROCK-dependent myosin contractility. Curved neuroepithelia use a formin-dependent pushing mechanism for which we propose a force generation theory.We suggest that cytoskeleton adaptability to tissue shape ensures correct nuclear positioning and robust epithelial maturation across different geometries. We further speculate that different mechanisms arise due to differences in actin arrangements during development, a theme highlighting the importance of developmental context for the execution of intracellular processes.
Hydrogen Bond Donors and Acceptors are Generally Depolarized in α-Helices as Revealed by a Molecular Tailoring Approach
Authors: Kondo Hiroko X. , Kusaka Ayumi , Kitakawa Colin K. , Onari Jinta , Yamanaka Shusuke , Nakamura Haruki , Takano Yu 
Published: January 2019

AbstractHydrogen-bond (H-bond) interaction energies in α-helices of short alanine peptides were systematically examined by precise DFT calculations, followed by a molecular tailoring approach (MTA). The contribution of each H-bond interaction in α-helices was estimated in detail from the entire conformation energies, and the results were compared with those in the minimal H-bond models, in which only H-bond donors and acceptors exist with the capping methyl groups. Consequently, the former interaction energies were always significantly weaker than the latter energies, when the same geometries of the H-bond donors and acceptors were applied. The chemical origin of this phenomenon was investigated by analyzing the differences among the electronic structures of the local peptide backbones of the α-helices and those of the minimal H-bond models. Consequently, we found that the reduced H-bond energy originated from the depolarizations of both the H-bond donor and acceptor groups, due to the repulsive interactions with the neighboring polar peptide groups in the α-helix backbone. The classical force-fields provide similar H-bond energies to those in the minimal H-bond models, which ignore the current depolarization effect, and thus they overestimate the actual H-bond energies in α-helices.
Multilevel regulation of the glass locus during Drosophila eye development
Authors: Fritsch Cornelia , Bernardo-Garcia F. Javier , Humberg Tim-Henning , Miellet Sara , Almeida Silvia , Huber Armin , Sprecher Simon G. 
Published: January 2019

ABSTRACTDevelopment of eye tissue is initiated by a conserved set of transcripton factors termed retinal determination network (RDN). In the fruit fly Drosophila melanogaster, the zinc-finger transcription factor Glass acts directly downstream of the RDN to control idendity of photoreceptor as well as non-photoreceptors cells. Tight control of spatial and temporal gene expression is a critical feature during development, cell-fate determination as well as maintainance of differentiated tissues. The molecular mechanisms that control expression of glass, however remain largely unknown. We here identify complex regulatory mechanisms controlling expression of the glass locus. All information to recapitulate glass expression are contained in a compact 5.2 kb cis-acting genomic element by combining different cell-type specific and general enhancers with repressor elements. Moreover, the immature RNA of the locus contains an alterantive small open reading frame (smORF) upstream of the actual glass translation start, resulting in a small peptide instead of the three possible glass protein isoforms. CRISPR/Cas9-based mutagenesis shows that the smORF is not required for the formation of functioning photoreceptors, but to attenuate effects of glass misexpression. Furthermore, editing the genome to generate glass loci eliminating either one or two isoforms shows that only one of the three proteins is critical for formation of functioning photoreceptors, while removing the two other isoforms did not cause defects in developmental or photoreceptor function. Our results show that eye development and function is surprisingly robust and appears buffered to targeted manipulations of critical features of the glass transcript, suggesting a strong selection pressure to allow the formation of a functioning eye.
Divergence-based introgression polarization
Authors: Forsythe Evan S. , Sloan Daniel B. , Beilstein Mark A. 
Published: February 2019

ABSTRACTIntrogressive hybridization results in the transfer of genetic material between species, often with fitness implications for the recipient species. The development of statistical methods for detecting the signatures of historical introgression (IG) in whole-genome data has been a major area of focus. While existing techniques are able to identify the taxa that exchanged genes during IG using a four-taxon system, most methods do not explicitly distinguish which taxon served as donor and which as recipient during IG (i.e. polarization of IG directionality). The existing methods that do polarize IG are only able to do so when there is a fifth taxon available and that taxon is sister to one of the taxa involved in IG. Here, we presentDivergence-based Introgression Polarization(DIP), a method for polarizing IG using patterns of sequence divergence across whole genomes, which operates in a four-taxon context. Thus,DIPcan be applied to infer the directionality of IG when additional taxa are not available. We use simulations to show thatDIPcan polarize IG and identify potential sources of bias in the assignment of directionality, and we applyDIPto a well-described hominin IG event.
A Genome-Wide Association Study of Non-Photochemical Quenching in response to local seasonal climates in Arabidopsis thaliana
Authors: Rungrat Tepsuda , Almonte Andrew A. , Cheng Riyan , Gollan Peter J. , Stuart Tim , Aro Eva-Mari , Borevitz Justin O. , Pogson Barry , Wilson Pip B. 
Published: February 2019

AbstractField-grown plants have variable exposure to sunlight as a result of shifting cloud-cover, seasonal changes, canopy shading, and other environmental factors. As a result, they need to have developed a method for dissipating excess energy obtained from periodic excessive sunlight exposure. Non-photochemical quenching (NPQ) dissipates excess energy as heat, however the physical and molecular genetic mechanics of NPQ variation are not understood. In this study, we investigated the genetic loci involved in NPQ by first growing different Arabidopsis thaliana accessions in local and seasonal climate conditions, then measured their NPQ kinetics through development by chlorophyll fluorescence. We used genome-wide association studies (GWAS) to identify 15 significant quantitative trait loci (QTL) for a range of photosynthetic traits, including a QTL co-located with known NPQ gene PSBS (AT1G44575). We found there were large alternative regulatory segments between the PSBS promoter regions of the functional haplotypes and a significant difference in PsbS protein concentration. These findings parallel studies in rice showing recurrent regulatory evolution of this gene. The variation in the PSBS promoter and the changes underlying other QTLs could give insight to allow manipulations of NPQ in crops to improve their photosynthetic efficiency and yield.B.P. & J.B. conceived the project; B.P., J.B., P.W. and T.R. designed the research plan and analysis; P.W. supervised the experiments; T.R. performed most of the experiments and analysis; P.G., T.S., A.A. & E.A. designed and undertook experimental design, experiments and analysis for Figure 4; R.C. did the GWAS analysis; P.W., T.R. & A.A. wrote the article with contributions of all the authors.