bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling longitudinal imaging biomarkers with parametric Bayesian multi-task learning
Authors: Aksman Leon M. , Scelsi Marzia A. , Marquand Andre F. , Alexander Daniel C. , Ourselin Sebastien , Altmann Andre ,   for ADNI
Published: April 2019

AbstractLongitudinal imaging biomarkers are invaluable for understanding the course of neurodegeneration, promising the ability to track disease progression and to detect disease earlier than cross-sectional biomarkers. To properly realize their potential, biomarker trajectory models must be robust to both under-sampling and measurement errors and should be able to integrate multi-modal information to improve trajectory inference and prediction. Here we present a parametric Bayesian multi-task learning based approach to modeling univariate trajectories across subjects that addresses these criteria.Our approach learns multiple subjects’ trajectories within a single model that allows for different types of information sharing, i.e.coupling, across subjects. It optimizes a combination of uncoupled, fully coupled and kernel coupled models. Kernel-based coupling allows linking subjects’ trajectories based on one or more biomarker measures. We demonstrate this using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, where we model longitudinal trajectories of MRI-derived cortical volumes in neurodegeneration, with coupling based on APOE genotype, cerebrospinal fluid (CSF) and amyloid PET-based biomarkers. In addition to detecting established disease effects, we detect disease related changes within the insula that have not received much attention within the literature.Due to its sensitivity in detecting disease effects, its competitive predictive performance and its ability to learn the optimal parameter covariance from data rather than choosing a specific set of random and fixed effects a priori, we propose that our model can be used in place of or in addition to linear mixed effects models when modeling biomarker trajectories. A software implementation of the method is publicly available.
Catching the big picture of the Mediterranean Sea biodiversity with an end-to-end model of climate and fishing impacts
Authors: Moullec Fabien , Velez Laure , Verley Philippe , Barrier Nicolas , Ulses Caroline , Carbonara Pierluigi , Esteban Antonio , Follesa Cristina , Gristina Michele , Jadaud Angélique , Ligas Alessandro , López Díaz Eduardo , Maiorano Porzia , Peristeraki Panagiota , Spedicato Maria Teresa , Thasitis Ioannis , Valls Maria , Guilhaumon François , Shin Yunne-Jai 
Published: April 2019

AbstractThe Mediterranean Sea is among the main hotspots of marine biodiversity in the world. Under combined pressures of fishing activities and climate change it has also become a hotspot of global change, with increased concern about the worsening status of marine exploited species. More integrated modelling approaches are needed to anticipate global change impacts in the Mediterranean Sea, in order to help decision makers prioritizing management actions and strategies, mitigating impacts and adapting to changes. Our challenge was to develop a holistic model of the marine biodiversity in the Mediterranean Sea with an explicit representation of the spatial multispecies dynamics of exploited resources under the combined influence of climate variability and fishing pressure. An individual-based ecosystem model OSMOSE (Object-oriented Simulator of Marine ecOSystEms), including 100 marine species (fish, cephalopods and crustaceans) and representing about 95 % of the total declared catches, has been implemented for the first time at a high spatial resolution (400 km2) and at a large spatial scale (whole Mediterranean basin). The coupling of OSMOSE to the NEMOMED 12 physical model, and to the Eco3M-S biogeochemical and low trophic level model has been achieved to build the OSMOSE-MED end-to-end model. We fitted OSMOSE-MED to observed and estimated data of biomass and commercial catches using a likelihood approach and an evolutionary optimization algorithm. The outputs of OSMOSE-MED were then verified against observed biomass and catches, and confronted to independent datasets (MEDITS data, diet compositions and trophic levels). Although some improvements are suggested for future developments, the model results at different hierarchical levels, from individuals up to the ecosystem scale, were consistent with current knowledge and observations on the structure, the functioning and the dynamics of the ecosystems in the Mediterranean Sea. All the modelling steps, from the comprehensive representation of key ecological processes and feedbacks, the careful parameterization of the model, the confrontation to observed data, and the positive outcome from the validation process, allowed to strengthen the degree of realism of OSMOSE-MED and its relevance as an impact model to explore the futures of marine biodiversity under scenarios of global change, and as a tool to support the implementation of ecosystem-based fisheries management in the Mediterranean Sea.
Breaking barriers: The effect of protected characteristics and their intersectionality on career transition in academics
Authors: Wanelik Klara M. , Griffin Joanne S. , Head Megan , Ingleby Fiona C. , Lewis Zenobia 
Published: April 2019

Lay summaryIn the past decade the scientific community has been trying to tackle the historical underrepresentation of women in science and the fact that gender can constitute a barrier to career success. However, other characteristics, such as being of an ethnic minority or coming from an under-privileged background, have received less attention. In this study we find that ethnicity and socioeconomic status impact detrimentally on career progression in early career scientists, despite the fact that gender is more likely to be reported as a barrier. Our data suggest we need to widen the discussion regarding diversity and equality in science to incorporate potential barriers to career success in addition to gender.AbstractThe academic disciplines of Science Technology Engineering and Mathematics (STEM) have long suffered from a lack of diversity. While in recent years there has been some progress in addressing the underrepresentation of women in STEM subjects, other protected characteristics have received less attention. In this study, we survey early career scientists in the fields of ecology, evolutionary biology, behaviour, and related disciplines. We (i) quantitatively examine the effect of protected characteristics and their intersectionality on career transition, and (ii) provide practical suggestions, based on the qualitative responses of those surveyed, for overcoming some of the barriers we identified. We found that socioeconomic background and ethnicity impacted negatively on the quantitative measures of career progression we examined. Respondents that were female, LGBT, and from a lower socioeconomic background were more likely to report having faced a barrier, and the most frequent barrier named was related to gender. Our results suggest that respondents may have felt more confident discussing the experiences they have had related to their gender, potentially because there is now widespread discourse on this subject. However, respondents were less likely to discuss barriers they have faced in relation to ethnicity and socioeconomic status, despite the fact that the data indicates these are more detrimental to career progression. This may reflect the fact that these characteristics have received less attention, and are therefore deemed more sensitive. We hope that this study will stimulate wider discussion, and help to inform strategies to address the underrepresentation of minority groups in STEM subjects.
First-principles prediction of the information processing capacity of a simple genetic circuit
Authors: Razo-Mejia Manuel , Marzen Sarah , Chure Griffin , Taubman Rachel , Morrison Muir , Phillips Rob 
Published: April 2019

AbstractGiven the stochastic nature of gene expression, genetically identical cells exposed to the same environmental inputs will produce different outputs. This heterogeneity has been hypothesized to have consequences for how cells are able to survive in changing environments. Recent work has explored the use of information theory as a framework to understand the accuracy with which cells can ascertain the state of their surroundings. Yet the predictive power of these approaches is limited and has not been rigorously tested using precision measurements. To that end, we generate a minimal model for a simple genetic circuit in which all parameter values for the model come from independently published data sets. We then predict the information processing capacity of the genetic circuit for a suite of biophysical parameters such as protein copy number and protein-DNA affinity. We compare these parameter-free predictions with an experimental determination of protein expression distributions and the resulting information processing capacity of E. coli cells. We find that our minimal model captures the scaling of the cell-to-cell variability in the data and the inferred information processing capacity of our simple genetic circuit up to a systematic deviation.
Activation of a zinc metallochaperone by the alarmone ZTP
Authors: Chandrangsu Pete , Huang Xiaojuan , Helmann John D. 
Published: April 2019

AbstractBacteria tightly regulate intracellular zinc levels to ensure sufficient zinc to support essential functions, while preventing toxicity. The bacterial response to zinc limitation includes the expression of putative zinc metallochaperones belonging to subfamily 1 of the COG0523 family of G3E GTPases. However, the client proteins and the metabolic processes served by these chaperones are unclear. Here, we demonstrate that theBacillus subtilisYciC zinc metallochaperone (here renamed ZagA forZTPactivatedGTPaseA) supportsde novofolate biosynthesis under conditions of zinc limitation through direct interaction with the zinc dependent GTP cyclohydrolase, FolE. Furthermore, we identify a role for the alarmone ZTP, a modified purine biosynthesis intermediate, in the response to zinc limitation. ZTP, a signal of 10-formyl-tetrahydrofolate deficiency (10f-THF) in bacteria, transiently accumulates as the Zn dependent GTP cyclohydrolase FolE begins to fail and stimulates the interaction between ZagA and FolE to sustain folate synthesis despite declining zinc availability.ImportanceMetallochaperones provide a mechanism for cells to regulate the delivery of metals to newly synthesized apoproteins. By selectively targeting specific proteins for metallation, cells can ensure that key pathways remain functional even as metals become limiting for growth. The COG0523 family of proteins contain a subgroup of candidate metallochaperones (the YciC subfamily) induced under conditions of zinc limitation. Although YciC family proteins have been suggested to be GTP-dependent metallochaperones, specific interactions with client proteins have not been demonstrated. Here, we show that theBacillus subtilisYciC (renamed ZagA) protein responds to ZTP as an activating ligand rather than GTP, and interacts specifically with a Zn-dependent enzyme critical for folate synthesis (FolE). Thus, under conditions of Zn limitation ZagA is synthesized, and as folate synthesis fails, it selectively delivers Zn to FolE to sustain folate synthesis.
SNPs associated withHHIPexpression have differential effects on lung function in males and females
Authors: Fawcett KA , Obeidat M , Melbourne CA , Shrine N , Guyatt AL , John C , Luan J , Richmond A , Moksnes MR , Granell R , Weiss S , Imboden M , May-Wilson S , Hysi P , Boutin TS , Portas L , Flexeder C , Harris SE , Wang CA , Lyytikäinen L , Palviainen T , Foong RE , Keidel D , Minelli C , Langenberg C , Bossé Y , van den Berge M , Sin D , Hao K , Campbell A , Porteous D , Padmanabhan S , Smith BH , Evans D , Ring S , Langhammer A , Hveem K , Willer C , Ewert R , Stubbe B , Pirastu N , Klaric L , Joshi PK , Patasova K , Massimo M , Polasek O , Starr JM , Rudan I , Rantanen T , Pietiläinen K , Kähönen M , Raitakari OT , Hall GL , Sly PD , Pennell CE , Kaprio J , Lehtimäki T , Vitart V , Deary IJ , Jarvis D , Wilson JF , Spector T , Probst-Hensch N , Wareham N , Völzke H , Henderson J , Strachan D , Brumpton BM , Hayward C , Hall IP , Tobin MD , Wain LV 
Published: April 2019

AbstractAdult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males and females. Here, we present the first genome-wide genotype-by-sex interaction study on four lung function traits in 303,612 participants from the UK Biobank. We detected five SNPs showing genome-wide significant (P<5 × 10−8) interactions with sex on lung function, as well as 21 suggestively significant interactions (P<1 × 10−6). The strongest sex interaction signal came from rs7697189 at 4:145436894 on forced expiratory volume in 1 second (FEV1) (P = 3.15 × 10−15), and was replicated (P = 0.016) in 75,696 individuals in the SpiroMeta consortium. Sex-stratified analyses demonstrated that the minor (C) allele of rs7697189 increased lung function to a greater extent in males than females (untransformed FEV1β = 0.028 [SE 0.0022] litres in males vs β = 0.009 [SE 0.0014] litres in females), and this effect was not accounted for by differential effects on height, smoking or age at puberty. This SNP resides upstream of the gene encoding hedgehog-interacting protein (HHIP) and has previously been reported for association with lung function andHHIPexpression in lung tissue. In our analyses, whileHHIPexpression in lung tissue was significantly different between the sexes with females having higher expression (most significant probeset P=6.90 × 10−6) after adjusting for age and smoking, rs7697189 did not demonstrate sex differential effects on expression. Establishing the mechanism by whichHHIPSNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases, such as chronic obstructive pulmonary disease (COPD), in both sexes.
Constitutive UPRERactivation sustains tumor cell differentiation
Authors: Doultsinos Dimitrios , McMahon Mari , Voutetakis Konstantinos , Obacz Joanna , Pineau Raphael , Le Reste Pierre-Jean , Obiedat Akram , Samal Juhi , Patterson John B. , Zheng Qingping , Samali Afshin , Pandit Abhay , Tirosh Boaz , Chatziioannou Aristotelis , Chevet Eric , Avril Tony 
Published: April 2019

AbstractEndoplasmic Reticulum (ER) proteostasis control and the Unfolded Protein Response (UPRER) have been shown to contribute to tumor development and aggressiveness. As such, the UPRERsensor IRE1α (referred to as IRE1 hereafter) is a major regulator of glioblastoma (GBM) development and is an appealing therapeutic target. To document IRE1 suitability as an antineoplastic pharmacological target, we investigated how this protein contributed to GBM cell reprogramming, a property involved in treatment resistance and disease recurrence. Probing the IRE1 activity molecular signature on transcriptome datasets of human tumors, showed that high IRE1 activity correlated with low expression of the main GBM stemness transcription factors SOX2, SALL2, POU3F2 and OLIG2. Henceforth, this phenotype was pharmacologically and genetically recapitulated in immortalized and primary GBM cell lines as well as in mouse models. We demonstrated that constitutive activation of the IRE1/XBP1/miR148a signaling axis repressed the expression of SOX2 and led to maintenance of a differentiation phenotype in GBM cells. Our results describe a novel role for IRE1 signaling in maintaining differentiated tumor cell state and highlight opportunities of informed IRE1 modulation utility in GBM therapy.
Quantitative characterization of random partitioning in the evolution of plasmid-encoded traits
Authors: Halleran Andrew D. , Flores-Bautista Emanuel , Murray Richard M. 
Published: April 2019

AbstractPlasmids are found across bacteria, archaea, and eukaryotes and play an important role in evolution. Plasmids exist at different copy numbers, the number of copies of the plasmid per cell, ranging from a single plasmid per cell to hundreds of plasmids per cell. This feature of a copy number greater than one can lead to a population of plasmids within a single cell that are not identical clones of one another, but rather have individual mutations that make a given plasmid unique. During cell division, this population of plasmids is partitioned into the two daughter cells, resulting in a random distribution of different plasmid variants in each daughter. In this study, we use stochastic simulations to investigate how random plasmid partitioning compares to a perfect partitioning model. Our simulation results demonstrate that random plasmid partitioning accelerates mutant allele fixation when the allele is beneficial and the selection is in an additive or recessive regime where increasing the copy number of the beneficial allele results in additional benefit for the host. This effect does not depend on the size of the benefit conferred or the mutation rate, but is magnified by increasing plasmid copy number.
Estimation of cell lineage trees by maximum-likelihood phylogenetics
Authors: Feng Jean , DeWitt William S , McKenna Aaron , Simon Noah , Willis Amy , Matsen Frederick A 
Published: April 2019

AbstractCRISPR technology has enabled large-scale cell lineage tracing for complex multicellular organisms by mutating synthetic genomic barcodes during organismal development. However, these sophisticated biological tools currently use ad-hoc and outmoded computational methods to reconstruct the cell lineage tree from the mutated barcodes. Because these methods are agnostic to the biological mechanism, they are unable to take full advantage of the data’s structure. We propose a statistical model for the mutation process and develop a procedure to estimate the tree topology, branch lengths, and mutation parameters by iteratively applying penalized maximum likelihood estimation. In contrast to existing techniques, our method estimates time along each branch, rather than number of mutation events, thus providing a detailed account of tissue-type differentiation. Via simulations, we demonstrate that our method is substantially more accurate than existing approaches. Our reconstructed trees also better recapitulate known aspects of zebrafish development and reproduce similar results across fish replicates.
A DNA barcode reference library of the French Polynesian shore fishes
Authors: Delrieu-Trottin Erwan , Williams Jeffrey T. , Pitassy Diane , Driskell Amy , Hubert Nicolas , Viviani Jérémie , Cribb Thomas H. , Espiau Benoit , Galzin René , Kulbicki Michel , de Loma Thierry Lison , Meyer Christopher , Mourier Johann , Mou-Tham Gérard , Parravicini Valeriano , Plantard Patrick , Sasal Pierre , Siu Gilles , Tolou Nathalie , Veuille Michel , Weigt Lee , Planes Serge 
Published: April 2019

AbstractThe emergence of DNA barcoding and metabarcoding opened new ways to study biological diversity, however, the completion of DNA barcode libraries is fundamental for such approaches to succeed. This dataset is a DNA barcode reference library (fragment of Cytochrome Oxydase I gene) for 2,190 specimens representing at least 540 species of shore fishes collected over 10 years at 154 sites across the four volcanic archipelagos of French Polynesia; the Austral, Gambier, Marquesas and Society Islands, a 5,000,000 km2area. At present, 65% of the known shore fish species of these archipelagoes possess a DNA barcode associated with preserved, photographed, tissue sampled and cataloged specimens, and extensive collection locality data. This dataset represents one of the most comprehensive DNA barcoding efforts for a vertebrate fauna to date. Considering the challenges associated with the conservation of coral reef fishes and the difficulties of accurately identifying species using morphological characters, this publicly available library is expected to be helpful for both authorities and academics in various fields.
Primary pterygium was not associated with corneal endothelial cell decrease in a rural Chinese population
Authors: Hu Yijun , Li Li , Qi Wei , Liu Zhenhao , Liu Yingpeng , Yuan Ling 
Published: April 2019

AbstractPurposeTo investigate the corneal endothelial cell density (ECD) in eyes with primary pterygium.MethodsWe first conducted a retrospective study to compare the ECD between 1670 eyes with primary pterygium and 4060 eyes without pterygium. Then we designed a prospective study to confirm the critical findings of the retrospective study in 95 patients with unilateral primary pterygium.ResultsIn the retrospective study, the mean preoperative ECD in eyes with primary ptergyium (2453±306 cells/mm2) was statistically significantly lower than those in eyes without pterygium (2529±313 cells/mm2, P<0.0001). However, the difference was minor (76 cells/mm2, 3.1%). In the prospective study, the mean ECD in eyes with unilateral primary pterygium (2480±263 cells/mm2) was not significantly different from those in the contralateral eyes (2527±277 cells/mm2, P=0.20). The hexagonality (P=0.10) or coefficient of variation of size (P=0.15) of corneal endothelial cells was not significantly different between eyes with pterygium and the contralateral eyes.ConclusionPrimary pterygium may not be associated with ECD decrease in our study cohort.
Suppression of transcytosis regulates zebrafish blood-brain barrier development
Authors: O’Brown Natasha M. , Megason Sean G. , Gu Chenghua 
Published: April 2019

AbstractAs an optically transparent model organism with an endothelial blood-brain barrier (BBB), zebrafish offer a powerful tool to study the vertebrate BBB. However, the precise developmental profile of functional zebrafish BBB acquisition and the subcellular and molecular mechanisms governing the zebrafish BBB remain poorly characterized. Here we find a spatiotemporal gradient of barrier acquisition. Moreover, we capture the dynamics of developmental BBB leakage using live imaging, revealing a combination of steady accumulation in the parenchyma and sporadic bursts of tracer leakage. Electron microscopy studies further reveal that this steady accumulation results from high levels of transcytosis that are eventually suppressed, sealing the BBB. Finally, we demonstrate a key mammalian BBB regulator Mfsd2a, which inhibits transcytosis, plays a conserved role in zebrafish. Mfsd2aa mutants display increased larval and adult BBB permeability due to increased transcytosis. Our findings indicate a conserved developmental program of barrier acquisition between zebrafish and mice.
Real-time integration of cell death mechanisms and proliferation kinetics at the single-cell and population-level using high-throughput live-cell imaging
Authors: Gelles Jesse D. , Mohammed Jarvier N. , Santos Luis C. , Legarda Diana , Ting Adrian T. , Chipuk Jerry E. 
Published: April 2019

SummaryQuantifying cytostatic and cytotoxic outcomes are integral components of characterizing perturbagens used as research tools and/or in drug discovery pipelines. Furthermore, data-rich acquisition coupled with robust methods for analysis is required to properly assess the function and impact of these perturbagens. Here, we present a detailed and versatile method for Single-cell and Population-level Analyses using Real-time Kinetic Labeling (SPARKL). SPARKL integrates high-content live-cell imaging with automated detection and analysis of fluorescent reporters of cell death. We outline several examples of zero-handling, non-disruptive protocols for detailing cell death mechanisms and proliferation profiles. Additionally, we suggest several methods for mathematically analyzing these data to best utilize the collected kinetic data. Compared to traditional methods of detection and analysis, SPARKL is more sensitive, accurate, and high-throughput while substantially eliminating sample processing and providing richer data.