bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting Human Protein Function with Multi-task Deep Neural Networks
Authors: Fa Rui , Cozzetto Domenico , Wan Cen , Jones David T. 
Published: January 2018

AbstractMachine learning methods for protein function prediction are urgently needed, especially now that a substantial fraction of known sequences remains unannotated despite the extensive use of functional assignments based on sequence similarity. One major bottleneck supervised learning faces in protein function prediction is the structured, multi-label nature of the problem, because biological roles are represented by lists of terms from hierarchically organised controlled vocabularies such as the Gene Ontology. In this work, we build on recent developments in the area of deep learning and investigate the usefulness of multi-task deep neural networks (MTDNN), which consist of upstream shared layers upon which are stacked in parallel as many independent modules (additional hidden layers with their own output units) as the number of output GO terms (the tasks). MTDNN learns individual tasks partially using shared representations and partially from task-specific characteristics. When no close homologues with experimentally validated functions can be identified, MTDNN gives more accurate predictions than baseline methods based on annotation frequencies in public databases or homology transfers. More importantly, the results show that MTDNN binary classification accuracy is higher than alternative machine learning-based methods that do not exploit commonalities and differences among prediction tasks. Interestingly, compared with a single-task predictor, the performance improvement is not linearly correlated with the number of tasks in MTDNN, but medium size models provide more improvement in our case. One of advantages of MTDNN is that given a set of features, there is no requirement for MTDNN to have a bootstrap feature selection procedure as what traditional machine learning algorithms do. Overall, the results indicate that the proposed MTDNN algorithm improves the performance of protein function prediction. On the other hand, there is still large room for deep learning techniques to further enhance prediction ability.
Ontology-based validation and identification of regulatory phenotypes
Authors: Kulmanov Maxat , Schofield Paul N , Gkoutos Georgios V , Hoehndorf Robert 
Published: January 2018

AbstractMotivationFunction annotations of gene products, and phenotype annotations of genotypes, provide valuable information about molecular mechanisms that can be utilized by computational methods to identify functional and phenotypic relatedness, improve our understanding of disease and pathobiology, and lead to discovery of drug targets. Identifying functions and phenotypes commonly requires experiments which are time-consuming and expensive to carry out; creating the annotations additionally requires a curator to make an assertion based on reported evidence. Support to validate the mutual consistency of functional and phenotype annotations as well as a computational method to predict phenotypes from function annotations, would greatly improve the utility of function annotations.ResultsWe developed a novel ontology-based method to validate the mutual consistency of function and phenotype annotations. We apply our method to mouse and human annotations, and identify several inconsistencies that can be resolved to improve overall annotation quality. Our method can also be applied to the rule-based prediction of phenotypes from functions. We show that the predicted phenotypes can be utilized for identification of protein-protein interactions and gene-disease associations. Based on experimental functional annotations, we predict phenotypes for 1,986 genes in mouse and 7,301 genes in human for which no experimental phenotypes have yet been determined.Availabilityhttps://github.com/bio-ontology-research-group/phenogoconContactrobert.hoehndorf@kaust.edu.sa
Time- and cost-efficient high-throughput transcriptomics enabled by Bulk RNA Barcoding and sequencing
Authors: Alpern Daniel , Gardeux Vincent , Russeil Julie , Deplancke Bart 
Published: January 2018

ABSTRACTGenome-wide gene expression analyses by RNA sequencing (RNA-seq) have quickly become a standard in molecular biology because of the widespread availability of high throughput sequencing technologies. While powerful, RNA-seq still has several limitations, including the time and cost of library preparation, which makes it difficult to profile many samples simultaneously. To deal with these constraints, the single-cell transcriptomics field has implemented the early multiplexing principle, making the library preparation of hundreds of samples (cells) markedly more affordable. However, the current standard methods for bulk transcriptomics (such as TruSeq Stranded mRNA) remain expensive, and relatively little effort has been invested to develop cheaper, but equally robust methods. Here, we present a novel approach, Bulk RNA Barcoding and sequencing (BRB-seq), that combines the multiplexing-driven cost-effectiveness of a single-cell RNA-seq workflow with the performance of a bulk RNA-seq procedure. BRB-seq produces 3’ enriched cDNA libraries that exhibit similar gene expression quantification to TruSeq and that maintain this quality, also in terms of number of detected differentially expressed genes, even with low quality RNA samples. We show that BRB-seq is about 25 times less expensive than TruSeq, enabling the generation of ready to sequence libraries for up to 192 samples in a day with only 2 hours of hands-on time. We conclude that BRB-seq constitutes a powerful alternative to TruSeq as a standard bulk RNA-seq approach. Moreover, we anticipate that this novel method will eventually replace RT-qPCR-based gene expression screens given its capacity to generate genome-wide transcriptomic data at a cost that is comparable to profiling 4 genes using RT-qPCR.‘SoftwareWe developed a suite of open source tools (BRB-seqTools) to aid with processing BRB-seq data and generating count matrices that are used for further analyses. This suite can perform demultiplexing, generate count/UMI matrices and trim BRB-seq constructs and is freely available at http://github.com/DeplanckeLab/BRB-seqToolsHighlightsRapid (~2h hands on time) and low-cost approach to perform transcriptomics on hundreds of RNA samplesStrand specificity preservedPerformance: number of detected genes is equal to Illumina TruSeq Stranded mRNA at same sequencing depthHigh capacity: low cost allows increasing the number of biological replicatesProduces reliable data even with low quality RNA samples (down to RIN value = 2)Complete user-friendly sequencing data pre-processing and analysis pipeline allowing result acquisition in a day
Pathogenicity and selective constraint on variation near splice sites
Authors: Lord Jenny , Gallone Giuseppe , Short Patrick J. , McRae Jeremy F. , Ironfield Holly , Wynn Elizabeth H. , Gerety Sebastian S. , He Liu , Kerr Bronwyn , Johnson Diana S. , McCann Emma , Kinning Esther , Flinter Frances , Temple I. Karen , Clayton-Smith Jill , McEntagart Meriel , Lynch Sally Ann , Joss Shelagh , Douzgou Sofia , Dabir Tabib , Clowes Virginia , McConnell Vivienne P. M. , Lam Wayne , Wright Caroline F. , FitzPatrick David R. , Firth Helen V. , Barrett Jeffrey C. , Hurles Matthew E. ,   on behalf of the Deciphering Developmental Disorders study
Published: January 2018

AbstractMutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.
Convolutional neural network, personalised, closed-loop Brain-Computer Interfaces for multi-way control mode switching in real-time
Authors: Ortega Pablo , Colas Cédric , Faisal Aldo 
Published: January 2018

AbstractExoskeletons and robotic devices are for many motor disabled people the only way to interact with their envi-ronment. Our lab previously developed a gaze guided assistive robotic system for grasping. It is well known that the same natural task can require different interactions described by different dynamical systems that would require different robotic controllers and their selection by the user in a self paced way. Therefore, we investigated different ways to achieve transitions between multiple states, finding that eye blinks were the most reliable to transition from ‘off’ to ‘control’ modes (binary classification) compared to voice and electromyography. In this paper be expanded on this work by investigating brain signals as sources for control mode switching. We developed a Brain Computer Interface (BCI) that allows users to switch between four control modes in self paced way in real time. Since the system is devised to be used in domestic environments in a user friendly way, we selected non-invasive electroencephalographic (EEG) signals and convolutional neural networks (ConvNets), known by their capability to find the optimal features for a classification task, which we hypothesised would add flexibility to the system in terms of which mental activities the user could perform to control it. We tested our system using the Cybathlon BrainRunners computer game, which represents all the challenges inherent to real time control. Our preliminary results show that an efficient architecture (SmallNet) composed by a convolutional layer, a fully connected layer and a sigmoid classification layer, is able to classify 4 mental activities that the user chose to perform. For his preferred mental activities, we run and validated the system online and retrained the system using online collected EEG data. We achieved 47, 6% accuracy in online operation in the 4-way classification task. In particular we found that models trained with online collected data predicted better the behaviour of the system in real time suggesting, as a side note, that similar (ConvNets based) offline classifying methods present in literature might find a decay in performance when applied online. To the best of our knowledge this is the first time such an architecture is tested in an online operation task. While compared to our previous method relying on blinks with this one we reduced in less than half (1.6 times) the accuracy but increased by 2 the amount of states among which we can transit, bringing the opportunity for finer control of specific subtasks composing natural grasping in a self paced way.
Wavelet for binocular vision modeling
Authors: Gaudart Louis , Gaudart Jean 
Published: January 2018

AbstractIn the present study, binocular vision properties were modeled using a single elementary wavelet. Opponent responses (ON-OFF) appeared in the first stages of the neural coding in the retina. This property was assumed to build an adequate wavelet showing a positive part (On) and a negative part (OFF). We have examined the experimental orientation and position disparity given by Bishop. We assumed that the theoretical position disparity was given by a combination of two wavelets for a given orientation disparity β. A change in β implied a change in the magnitude of one of the wavelets and consequently a change in the wavelets combination. There was a close match between the theoretical and experimental position disparity curves according to the changes in orientation disparity.
Characterization of flagellar and toxin phase variation inClostridium difficileribotype 012 isolates
Authors: Anjuwon-Foster Brandon R. , Maldonado-Vazquez Natalia , Tamayo Rita 
Published: January 2018

AbstractClostridium difficilecauses diarrheal diseases mediated in part by the secreted toxins TcdA and TcdB.C. difficileproduces flagella that also contribute to motility and bacterial adherence to intestinal cells during infection. Flagellum and toxin gene expression are linked via the flagellar alternative sigma factor, SigD. Recently, we identified a “flagellar switch” upstream of the early flagellar biosynthesis operon that mediates phase variation of both flagellum and toxin production inC. difficilestrain R20291. However, we were unable to detect flagellar switch inversion inC. difficilestrain 630, a ribotype 012 strain commonly used in research labs, suggesting the strain is phase-locked. To determine whether a “phase locked” flagellar switch is limited to 630 or present more broadly in ribotype 012 strains, we assessed the frequency and phenotypic outcomes of flagellar switch inversion in multipleC. difficileribotype 012 isolates. The laboratory-adapted strain JIR8094, a derivative of strain 630, and six clinical and environmental isolates were all found to be phase OFF, non-motile, and attenuated for toxin production. We isolated low frequency motile derivatives of JIR8094 with partial recovery of motility and toxin production, and found that additional changes in JIR8094 impact these processes. The clinical and environmental isolates varied considerably in the frequency by which flagellar phase ON derivatives arose, and these derivatives showed fully restored motility and toxin production. Taken together, these results demonstrate heterogeneity in flagellar and toxin phase variation amongC. difficileribotype 012 strains, and perhaps other ribotypes, which could impact disease progression and diagnosis.ImportanceClostridium difficilecauses diarrheal disease resulting in significant morbidity and mortality in many countries.C. difficileproduces flagella that enhance bacterial motility, and secretes toxins that promote diarrheal disease symptoms. Previously, we found that production of flagella and toxins are co-regulated via a flippable DNA element termed the “flagellar switch”, which mediates the phase variable production of these factors.C. difficilecan exist as flagellated, motile, toxigenic bacteria (“flgON”) or aflagellate, non-motile, nontoxigenic bacteria (“flgOFF”) due in part to the flagellar switch orientation. Here we evaluate multiple isolates ofC. difficileribotype 012 strains and find them to be primarilyflgOFF. Some, but not all, of these isolates showed the ability to switch betweenflgON and OFF states. These findings suggest heterogeneity in the ability ofC. difficileribotype 012 strains to phase vary flagellum and toxin production, which may broadly apply to pathogenicC. difficile.
Inherited DNA Repair Defects in Colorectal Cancer
Authors: AlDubayan Saud H. , Giannakis Marios , Moore Nathanael D. , Han G. Celine , Reardon Brendan , Hamada Tsuyoshi , Jasmine Mu Xinmeng , Nishihara Reiko , Qian Zhirong , Liu Li , Yurgelun Matthew B. , Syngal Sapna , Garraway Levi A. , Ogino Shuji , Fuchs Charles S. , Van Allen Eliezer M. 
Published: January 2018

AbstractColorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC susceptibility genes explain CRC risk in under 10% of the cases. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals compared to 27728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1661 unselected CRC cases and 1456 early-onset CRC cases. Of 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC susceptibility genes while another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations inATMandPALB2were enriched in both the discovery (OR= 2.81; P= 0.035 and OR= 4.91; P= 0.024, respectively) and validation sets (OR= 2.97; Adjusted P= 0.0013 and OR= 3.42; Adjusted P= 0.034, forATMandPALB2respectively). Biallelic loss ofATMwas evident in all cases with matched tumor profiling. CRC cases also had higher rates of actionable mutations in the HR pathway that can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence forATMandPALB2as CRC risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as PARPi.
Intron-mediated enhancement boosts Rtn4 circRNA expression: A robust method for exploring circRNA function
Authors: Mo Dingding , Li Xinping , Cui Di , Vollmar Jeanne-Franca 
Published: January 2018

AbstractCircRNAs are expressed in many important biological processes. Studying their function requires an effective expression method. When we used intron-mediated enhancement (IME) to improve circRNA expression of mouse Rtn4 (Nogo, a key protein in Nogo-Rho pathways) circRNA as a test case, we achieved a 4-6-fold improvement compared to an existing method. We further developed this approach into a general circRNA expression vector pCircRNA-DMo. An unexpected feature of our approach is its ability to promote translation of circRNA into detectable amounts of proteins. Intriguingly, both monomer and multimer repeating peptides can be observed as a result of rolling circle translation of RTN4 circRNA. We also confirmed the presence of both peptide forms in human and mouse brains, highlighting the significance of circRNA translation in vivo. In summary, we demonstrate the significant advantage of IME in enhancing circRNA biogenesis and hence our vector offers a robust platform for exploring potential circRNA peptide-encoding functions.
Modeling the mutation and reversal of engineered underdominance gene drives
Authors: Edgington Matthew P. , Alphey Luke S. 
Published: January 2018

AbstractA range of gene drive systems have been proposed that are predicted to increase their frequency and that of associated desirable genetic material even if they confer a fitness cost on individuals carrying them. Engineered underdominance (UD) is such a system and, in one version, is based on the introduction of two independently segregating transgenic constructs each carrying a lethal gene, a suppressor for the lethal at the other locus and a desirable genetic “cargo”. Under this system individuals carrying at least one copy of each construct (or no copies of either) are viable whilst those that possess just one of the transgenic constructs are non-viable. Previous theoretical work has explored various properties of these systems, concluding that they should persist indefinitely in absence of resistance or mutation. Here we study a population genetics model of UD gene drive that relaxes past assumptions by allowing for loss-of-function mutations in each introduced gene. We demonstrate that mutations are likely to cause UD systems to break down, eventually resulting in the elimination of introduced transgenes. We then go on to investigate the potential of releasing “free suppressor” carrying individuals as a new method for reversing UD gene drives and compare this to the release of wild-types; the only previously proposed reversal strategy for UD. This reveals that while free suppressor carrying individuals may represent an inexpensive reversal strategy due to extremely small release requirements, they are not able to return a fully wild-type population as rapidly as the release of wild-types.
When and how managerial ties matter in international competitive strategy, export financial and strategic performance framework
Authors: Chung Henry F.L. , Kuo Tsuang 
Published: January 2018

PurposeThis study aims to present two new contingent frameworks that hypothesize the moderation role of managerial ties (MTs) in the international competitive strategy-export financial and strategic performance framework. The purposes of this study are to explore whether a common standardized or individual customized conceptualization consisting of MTs, international competitive strategy and performance can be used to achieve export financial and strategic performance; to offer contingent factors for the current international competitive strategy-export performance framework; and to generalize the roles of MTs in the developed vis-à-vis developing region.Design/methodology/approachThis study uses the experience of 114 exporting firms operating in the European Union region to test its theoretical frameworks. MTs include both business and political ties.FindingsBusiness and political ties have completely different moderation effects on the relation between international differentiation/low-cost strategy and export financial/strategic performance. Business ties have a positive influence on the international differentiation strategy-export strategic performance and international low-cost strategy-export financial performance dyads, but a negative effect in the international low-cost strategy-export strategic performance framework. In contrast, political ties are revealed to have a negative effect on the international differentiation/low-cost strategy-export financial performance framework.Originality/valueThis research advances extant international competitive strategy-export performance literature by revealing the bright and dark sides of business ties and the down side of political ties in the framework. Performance should be investigated in terms of financial and strategic performance. The moderation effect of business ties is more complex than that reported in the developing region; thus, a cross-regional generalization on these ties’ effects is more difficult to establish. In contrast, the dark side effect of political ties is consistent across developed and developing regions; a cross-regional generalization on these ties is more viable. Collectively, the results show that a standardized process for achieving both export financial and export strategic performances is not feasible, while a customized process for each export performance is needed.