bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying Representative Network Motifs for Inferring Higher-order Structure of Biological Networks
Authors: Tao Wang , Wang Yadong , Peng Jiajie , Jin Chen 
Published: September 2018

AbstractNetwork motifs are recurring significant patterns of inter-connections, which are recognized as fundamental units to study the higher-order organizations of networks. However, the principle of selecting representative network motifs for local motif based clustering remains largely unexplored. We present a scalable algorithm called FSM for network motif discovery. FSM accelerates the motif discovery process by effectively reducing the number of times to do subgraph isomorphism labeling. Multiple heuristic optimizations for subgraph enumeration and subgraph classification are also adopted in FSM to further improve its performance. Experimental results show that FSM is more efficient than the compared models on computational efficiency and memory usage. Furthermore, our experiments indicate that large and frequent network motifs may be more appropriate to be selected as the representative network motifs for discovering higher-order organizational structures in biological networks than small or low-frequency network motifs.
Genome-wide association studies in Samoans give insight into the genetic architecture of fasting serum lipid levels
Authors: Carlson Jenna C. , Weeks Daniel E. , Hawley Nicola L. , Sun Guangyun , Cheng Hong , Naseri Take , Reupena Muagututi‘a Sefuiva , Deka Ranjan , McGarvey Stephen T. , Minster Ryan L. 
Published: September 2018

AbstractThe current understanding of the genetic architecture of lipids has largely come from genome-wide association studies. To date, few studies have examined the genetic architecture of lipids in Polynesians, and none have in Samoans, whose unique population history, including many population bottlenecks, may provide insight into the biological foundations of variation in lipid levels. Here we performed a genome-wide association study of four fasting serum lipid levels: total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) in a sample of 2,849 Samoans, with validation genotyping for associations in a replication cohort comprising 1,798 Samoans and American Samoans. We identified multiple genome-wide significant associations (P < 5 × 10−8) previously seen in other populations – APOA1 with TG, CETP with HDL, and APOE with TC and LDL – and several suggestive associations (P < 1 × 10−5), including an association of variants downstream of MGAT1 and RAB21 with HDL. However, we observed different association signals for variants near APOE than what has been previously reported in non-Polynesian populations. The association with several known lipid loci combined with the newly-identified associations with variants near MGAT1 and RAB21 suggest that while some of the genetic architecture of lipids is shared between Samoans and other populations, part of the genetic architecture may be Polynesian-specific.
No cell is an island: circulating T cell:monocyte complexes are markers of immune perturbations
Authors: Burel Julie G. , Pomaznoy Mikhail , Lindestam Arlehamn Cecilia S. , Weiskopf Daniela , da Silva Antunes Ricardo , Jung Yunmin , Babor Mariana , Schulten Veronique , Seumois Grégory , Greenbaum Jason A. , Premawansa Sunil , Premawansa Gayani , Wijewickrama Ananda , Vidanagama Dhammika , Gunasena Bandu , Tippalagama Rashmi , deSilva Aruna D. , Gilman Robert H. , Saito Mayuko , Taplitz Randy , Ley Klaus , Vijayanand Pandurangan , Sette Alessandro , Peters Bjoern 
Published: September 2018

AbstractOur results highlight for the first time that a significant proportion of cell doublets in flow cytometry, previously believed to be the result of technical artefacts and thus ignored in data acquisition and analysis, are the result of true biological interaction between immune cells. In particular, we show that cell:cell doublets pairing a T cell and a monocyte can be directly isolated from human blood, and high resolution microscopy shows polarized distribution of LFA1/ICAM1 in many doublets, suggesting in vivo formation. Intriguingly, T cell:monocyte complex frequency and phenotype fluctuate with the onset of immune perturbations such as infection or immunization, reflecting expected polarization of immune responses. Overall these data suggest that cell doublets reflecting T cell-monocyte in vivo immune interactions can be detected in human blood and that the common approach in flow cytometry to avoid studying cell:cell complexes should be revisited.
Transcriptomic analyses reveal groups of co-expressed, syntenic lncRNAs in four species of the genus Caenorhabditis
Authors: Pegueroles Cinta , Iraola-Guzmán Susana , Chorostecki Uciel P. , Ksiezopolska Ewa , Saus Ester , Gabaldón Toni 
Published: September 2018

AbstractLong non-coding RNAs (lncRNAs) are a heterogeneous class of genes that do not code for proteins. Since lncRNAs (or a fraction thereof) are expected to be functional, many efforts have been dedicated to catalog lncRNAs in numerous organisms, but our knowledge of lncRNAs in non vertebrate species remains very limited. Here, we annotated lncRNAs using transcriptomic data from the same larval stage of four Caenorhabditis species. The number of annotated lncRNAs in self-fertile nematodes was lower than in out-crossing species. We used a combination of approaches to identify putatively homologous lncRNAs: synteny, sequence conservation, and structural conservation. We classified a total of 1,532 out of 7,635 genes from the four species into families of lncRNAs with conserved synteny and expression at the larval stage, suggesting that a large fraction of the predicted lncRNAs may be species specific. Despite both sequence and local secondary structure seem to be poorly conserved, sequences within families frequently shared BLASTn hits and short sequence motifs, which were more likely to be unpaired in the predicted structures. We provide the first multi-species catalog of lncRNAs in nematodes and identify groups of lncRNAs with conserved synteny and expression, that share exposed motifs.
Chromatin-loop extrusion and chromatin unknotting
Authors: Racko Dusan , Benedetti Fabrizio , Goundaroulis Dimos , Stasiak Andrzej 
Published: September 2018

ABSTRACTIt has been a puzzle how decondensed interphase chromosomes remain essentially unknotted. The natural expectation is that in the presence of type II DNA topoisomerases that permit passages of double-stranded DNA regions through each other, all chromosomes should reach the state of topological equilibrium. The topological equilibrium in highly crowded interphase chromosomes forming chromosome territories would result in formation of highly knotted chromatin fibres. However, Chromosome Conformation Capture (3C) methods revealed that the decay of contacts with the genomic distance in interphase chromosomes is practically the same as in the crumpled globule state that is formed when long polymers condense without formation of any knots. To remove knots from highly crowded chromatin, one would need an active process that should not only provide the energy to move the system from the state of topological equilibrium but also guide topoisomerase-mediated passages in such a way that knots would be efficiently unknotted instead of making the knots even more complex. We show here that the process of chromatin-loop extrusion is ideally suited to actively unknot chromatin fibres in interphase chromosomes.SIGNIFICANCE STATEMENTSimilar to earphone cables crammed into a pocket, long and crowded chromatin fibres that form chromosomes in living cells have the natural tendency to get knotted. This is exacerbated by the action of DNA topoisomerases that transiently cut some chromatin fibres and let other to pass through. Yet, the knotting frequency of chromatin fibres is very low and it has been a puzzle how this is achieved. Recently a novel active mechanism known as chromatin loop extrusion has been proposed to be involved in shaping chromosomes by forming sequential arrays of ca 1 Mb large chromatin loops. Using numerical simulations, we show here that chromatin loop extrusion is ideally suited to remove knots from chromatin fibres.
A Low-Cost Biological Agglutination Assay for Medical Diagnostic Applications
Authors: Kylilis Nicolas , Riangrungroj Pinpunya , Lai Hung-En , Salema Valencio , Fernández Luis Ángel , Stan Guy-Bart V , Freemont Paul S , Polizzi Karen M 
Published: September 2018

ABSTRACTAffordable, easy-to-use diagnostic tests that can be readily deployed for point-of-care (POC) testing are key in addressing challenges in the diagnosis of medical conditions and for improving global health in general. Ideally, POC diagnostic tests should be highly selective for the biomarker, user-friendly, have a flexible design architecture and a low cost of production. Here we developed a novel agglutination assay based on wholeE. colicells surface-displaying nanobodies which bind selectively to a target protein analyte. As a proof-of-concept, we show the feasibility of this design as a new diagnostic platform by the detection of a model analyte at nanomolar concentrations. Moreover, we show that the design architecture is flexible by building assays optimized to detect a range of model analyte concentrations supported using straight-forward design rules and a mathematical model. Finally, we re-engineerE. colicells for the detection of a medically relevant biomarker by the display of two different antibodies against the human fibrinogen and demonstrate a detection limit as low as 10 pM in diluted human plasma. Overall, we demonstrate that our agglutination technology fulfills the requirement of POC testing by combining low-cost nanobody production, customizable detection range and low detection limits. This technology has the potential to produce affordable diagnostics for both field-testing in the developing world, emergency or disaster relief sites as well as routine medical testing and personalized medicine.
Accounting for individual-specific variation in habitat-selection studies: Efficient estimation of mixed-effects models using Bayesian or frequentist computation
Authors: Muff Stefanie , Signer Johannes , Fieberg John 
Published: September 2018

Abstract1. Popular frameworks for studying habitat selection include resource-selection functions (RSFs) and step-selection functions (SSFs) estimated using logistic and conditional logistic regression, respectively. Both frameworks compare environmental covariates associated with locations animals visit with environmental covariates at a set of locations assumed available to the animal. Conceptually, random coefficients could be used to accommodate inter-individual heterogeneity with either approach, but straightforward and efficient one-step procedures for fitting SSFs with random coefficients are currently lacking.2. We take advantage of the fact that the conditional logistic regression model (i. e., the SSF) is likelihood-equivalent to a Poisson model with stratum-specific intercepts. By interpreting the intercepts as a random effect with a large (fixed) variance, inference becomes feasible with standard Bayesian techniques, but also with frequentist methods that allow one to fix the variance of a random effect. We compare this approach to other commonly applied alternatives, including random intercept-only models, and to a two-step algorithm for fitting mixed-effects models.3. We also reinforce the need to weight available points when fitting RSFs, since models fit using “infinitely weighted logistic regression” have been shown to be equivalent to an inhomogeneous Poisson process (IPP). We generalize this result to “infinitely weighted Poisson regression”, which converges to the same underlying IPP distribution.4. Using data from Eurasian otters (Lutra lutra) and mountain goats (Oreamnos americanus), we illustrate that our models lead to valid and feasible inference. In addition, we conduct a simulation study to demonstrate the importance of including random slopes when estimating individual- and population-level habitat-selection parameters.5. By providing coded examples using integrated nested Laplace approximations (INLA) and Template Model Builder (TMB) for Bayesian and frequentist analysis via the R packagesR-INLAandglmmTMB, we hope to make efficient estimation of RSFs and SSFs with random effects accessible to anyone in the field. SSFs with individual-specific coefficients are particularly attractive since they can provide insights into movement and habitat-selection processes at fine-spatial and temporal scales, but these models had previously been very challenging to fit.
Molecular safeguarding of CRISPR gene drive experiments
Authors: Champer Jackson , Chung Joan , Lee Yoo Lim , Liu Chen , Yang Emily , Wen Zhaoxin , Clark Andrew G. , Messer Philipp W. 
Published: September 2018

ABSTRACTCRISPR-based gene drives have sparked both enthusiasm and deep concerns due to their potential for genetically altering entire species. This raises the question about our ability to prevent the unintended spread of such drives from the laboratory into a natural population. Here, we experimentally demonstrate the suitability of synthetic target sites and split drives as flexible safeguarding strategies for gene drive experiments.
FGF1 PromotesXenopus laevisLens Regeneration
Authors: Moore Lisa , Perry Kimberly J. , Sun Cindy , Henry Jonathan J. 
Published: September 2018

AbstractBackgroundThe frogXenopus laevishas notable regenerative capabilities, including that of the lens. The neural retina provides the factors that trigger lens regeneration from the cornea, but the identity of these factors is largely unknown. In contrast to the cornea, fibroblast growth factors FGF1, 8, and 9 are highly expressed within the retina, and are potential candidates for those factors. The purpose of this study is to determine whether specific FGF proteins can induce lens formation, and if perturbation of FGFR signaling inhibits lens regeneration.MethodsA novel cornea epithelial culture method was developed to investigate the sufficiency of FGFs in lens regeneration. Additionally, transgenic larvae expressing dominant negative FGFR1 were used to investigate the necessity of FGFR signaling in lens regeneration.ResultsTreatment of cultured corneas with FGF1 induced lens regeneration in a dose-dependent manner, whereas treatment with FGF2, FGF8, or FGF9 did not result in significant lens regeneration. Inhibition of FGFR signaling decreased the lens regeneration rate forin vitroeye cultures.ConclusionThe culture techniques developed here, and elsewhere, have provided reliable methods for examining the necessity of various factors that may be involved in lens regeneration. Based on the results demonstrated in this study, we found that FGF1 signaling and FGFR activation are key factors for lens regeneration inXenopus.
Three-dimensional tissue stiffness mapping in the mouse embryo supports durotaxis during early limb bud morphogenesis
Authors: Zhu Min , Tao Hirotaka , Samani Mohammad , Luo Mengxi , Wang Xian , Hopyan Sevan , Sun Yu 
Published: September 2018

ABSTRACTNumerous biophysical hypotheses invoke tissue stiffness as a key parameter for shaping tissue during development and for influencing cell behaviours during disease progression. However, currently available methods are insufficient to test hypotheses that concern the physical properties of bulk tissues. Here we introduce, validate and apply a new 3D magnetic device that generates a uniform magnetic field gradient within a space that is sufficient to accommodate a vertebrate, organ-stage embryo under live conditions. The device allows for rapid, nontoxic measurement of the spatial variation of absolute elastic modulus and viscosity deep within mesenchymal tissues and within epithelia. By applying the device to map the spatiotemporal variation of viscoelastic properties within the early mouse limb bud, we identified an anteriorly biased mesodermal stiffness gradient along which cells move collectively to shape the early bud. Tissue stiffness corresponds to the nascent expression domain of fibronectin that isWnt5a-dependent. The findings challenge the notion thatWnt5aregulates cell movements by chemotaxis, and raises the possibility thatWnt5amodifies the tissue microenvironment to promote durotaxisin vivo. Importantly, the ability to precisely measure tissue stiffness in 3D has the potential to instigate and refine mechanisms of development and disease progression.
cellHarmony: Cell-level matching and holistic comparison of single-cell transcriptomes
Authors: DePasquale Erica AK , Dexheimer Phillip , Schnell Daniel , Ferchen Kyle , Hay Stuart , Valiente-Alandí Íñigo , Blaxall Burns C. , Grimes H. Leighton , Salomonis Nathan 
Published: September 2018

ABSTRACTTo understand the molecular pathogenesis of human disease, precision analyses to define molecular alterations within (and between) disease-associated cell populations are desperately needed. Single-cell genomics represents an ideal platform to enable the identification and comparison of normal and diseased transcriptional cell states. We note that disease-associated perturbations usually retain cellular-identity programs (core genes), providing an appropriate reference for secondary comparison analyses. Thus, we created cellHarmony, an integrated solution for the unsupervised analysis and classification of cell types from diverse scRNA-Seq datasets. cellHarmony is an automated and easy-to-use tool that efficiently matches single-cell transcriptomes using a community clustering and alignment strategy. Utilizing core genes and community clustering to reveal disease and cell-state systems-level insights overcomes bias toward donor and disease effects that can be imposed by joint-alignment approaches. Moreover, cellHarmony directly compares cell frequencies and gene expression in a cell-type-specific manner, then produces a holistic representation of these differences across potentially dozens of cell populations and impacted regulatory networks. Using this approach, we identify gene regulatory programs that are selectively impacted in distinct hematopoietic and heart cell populations that suggest novel disease mechanisms and drug targets. Thus, this approach holds tremendous promise in revealing the molecular and cellular origins of complex diseases.
A V0-ATPase-dependent apical trafficking pathway maintains the polarity of the intestinal absorptive membrane
Authors: Bidaud-Meynard Aurélien , Nicolle Ophélie , Heck Markus , Michaux Grégoire 
Published: September 2018

AbstractIntestine function relies on the strong polarity of intestinal epithelial cells and the array of microvilli forming a brush border at their luminal pole. Combining genetic RNAi screen and in vivo super-resolution imaging in the C. elegans intestine, we uncovered that the V0 sector of the V-ATPase (V0-ATPase) controls a late apical trafficking step, involving RAB-11 endosomes and the SNARE SNAP-29, necessary to maintain the polarized localization of both apical polarity modules and brush border proteins. We show that the V0-ATPase pathway also genetically interacts with glycosphingolipids in enterocyte polarity maintenance. Finally, we demonstrate that depletion of the V0-ATPase fully recapitulates the severe structural, polarity and trafficking defects observed in enterocytes from patients with Microvillus inclusion disease (MVID) and used this new in vivo MVID model to follow the dynamics of microvillus inclusions. Hence, we describe a new function for the V0-ATPase in apical trafficking and epithelial polarity maintenance and the promising use of C. elegans intestine as an in vivo model to better understand the molecular mechanisms of rare genetic enteropathies.Summary statementV0-ATPase controls a late apical trafficking step involved in the maintenance of the apical absorptive intestinal membrane and its depletion phenocopies the trafficking and structural defects of MVID in C. elegans.
The atypical thiol-disulfide exchange protein α-DsbA2 fromWolbachia pipientisis a homotrimeric disulfide isomerase
Authors: Walden Patricia M. , Lakshmanane Premkumar , Halili Maria , Heras Begoña , King Gordon J. , Whitten Andrew E. , Martin Jennifer L. 
Published: September 2018

AbstractDiSulfide Bond (DSB) oxidative folding enzymes are master regulators of virulence localized to the periplasm of many Gram-negative bacteria. The archetypal DSB machinery fromEscherichia coliK12 has a dithiol oxidizing redox relay pair (DsbA/B), a disulfide isomerizing redox relay pair (DsbC/D) and specialist reducing enzymes DsbE and DsbG that also interact with DsbD. By contrast the Gram-negative bacteriumWolbachia pipientisencodes just three DSB enzymes. Two of these α-DsbA1 and α-DsbB form a redox relay pair analogous toE. coliDsbA/B. The third enzyme α-DsbA2 incorporates a DsbA-like sequence but does not interact with α-DsbB. In comparison with other DsbA enzymes, α-DsbA2 has ∼50 extra N-terminal residues. The crystal structure of α-DsbA2ΔN, the N-terminally truncated form in which these residues are removed confirms the DsbA-like nature of this domain. However, α-DsbA2 does not have DsbA-like activity: it is structurally and functionally different as a consequence of its N-terminal residues. First, α-DsbA2 is a powerful disulfide isomerase and a poor dithiol oxidase –ieits role is to shuffle rather than introduce disulfide bonds. Moreover, small-angle X-ray scattering of α-DsbA2 reveals a homotrimeric arrangement. Our results allow us to draw conclusions about the factors required for functionally equivalent enzymatic activity across structurally diverse protein architectures.
Epigenomic Profiling and Single-Nucleus-RNA-Seq Reveal Cis-Regulatory Elements in Human Retina, Macula and RPE and Non-Coding Genetic Variation
Authors: Cherry Timothy J. , Yang Marty G. , Harmin David A. , Tao Peter , Timms Andrew E. , Bauwens Miriam , Allikmets Rando , Jones Evan M. , Chen Rui , Baere Elfride De , Greenberg Michael E. 
Published: September 2018

ABSTRACTCis-regulatory elements (CREs) orchestrate the dynamic and diverse transcriptional programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. However, the cellular complexity of the human brain has largely precluded the identification of functional regulatory variation within the human CNS. We took advantage of the retina, a well-characterized region of the CNS with reduced cellular heterogeneity, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive resource of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines the regulatory elements with the potential to contribute to mendelian and complex disorders of human vision.