bluuebunny/crossref_metadata_2025 huggingface dataset:
Paleochronic reversion in Psophocarpus: Dynamics II, rhizogeny on floral anatomic fields
Authors: Benya Edward G F
Published: January 2018

Paleochronic reversion is confirmed in Psophocarpus as a basic floral ground state. That state can expand to include dynamics T
(g,,h)
) of axial expansion (AE) as a permutation (T
X
) phase beginning as phyllotactic floral phylloid (T
Phyld
) and/or axial decompression (T
Axl
) manifest as linear elongation (T
Long
) and/or rotation (T
Rtn
) and/or latitudinal (TS
Lat
) expansion. Organ regions present a continuum as a vector space LT
Axl
of floral axial transformation. A generative phase of meristem activity (T
(Rz, SAM, Infl)
) can follow.
Experiments with 49 phylloid and/or phyllome paleochronically reverted flowers presented varying degrees of phyllotactic permutation involving development of a pericladial stalk (PCL) and/or inter-bracts stem (IBS) and/or activated pedicel (PdcL) and/or gynophore (Gnf), Cupule-like (Gnf)/Cupl-Lk) elongation. A meristem generative function included rhizogeny as root site generation (RSG) at the calyx (Cl), PCL, bracts (Bt), IBS, PdcL and/or Gnf/Cupl-Lk regions manifest as eigenvector functions as RSG whose density of generation was associated with permutation of the ground state. A continuum of pedicel to calyx regions constitutes a subset [PdcL,Cl] of a linear vector space [Bt,Crpl]=T
X
→ [PdcL,Crpl]=LT
Axl
whose extension is defined within the space: ∑ F PdcL + F Bt
(1,,z)
± S IBS
(1,,x)
+ F PCL
(1,,w)
+ F Cl + F Gyncm ± S Gnf ± S Cupl-Lk = L T
Axl
.
The vector space LT
Axl
transforms to a master vector field (F
[c,..,d]
) of generated Euclidian eigenvectors so that:
LT
Axl
→ F
[c,..,d]
A high-quality sequence ofRosa chinensisto elucidate genome structure and ornamental traits
Authors: Hibrand Saint-Oyant L. , Ruttink T. , Hamama L. , Kirov I. , Lakwani D. , Zhou N.-N. , Bourke P.M. , Daccord N. , Leus L. , Schulz D. , Van de Geest H. , Hesselink T. , Van Laere K. , Balzergue S. , Thouroude T. , Chastellier A. , Jeauffre J. , Voisine L. , Gaillard S. , Borm T.J.A. , Arens P. , Voorrips R.E. , Maliepaard C. , Neu E. , Linde M. , Le Paslier M.C. , Bérard A. , Bounon R. , Clotault J. , Choisne N. , Quesneville H. , Kawamura K. , Aubourg S. , Sakr S. , Smulders M.J.M. , Schijlen E. , Bucher E. , Debener T. , De Riek J. , Foucher F.
Published: January 2018

Rose is the world’s most important ornamental plant with economic, cultural and symbolic value. Roses are cultivated worldwide and sold as garden roses, cut flowers and potted plants. Rose has a complex genome with high heterozygosity and various ploidy levels. Our objectives were (i) to develop the first high-quality reference genome sequence for the genusRosaby sequencing a doubled haploid, combining long and short read sequencing, and anchoring to a high-density genetic map and (ii) to study the genome structure and the genetic basis of major ornamental traits.

We produced a haploid rose line fromR. chinensis‘Old Blush’ and generated the first rose genome sequence at the pseudo-molecule scale (512 Mbp with N50 of 3.4 Mb and L75 of 97). The sequence was validated using high-density diploid and tetraploid genetic maps. We delineated hallmark chromosomal features including the pericentromeric regions through annotation of TE families and positioned centromeric repeats using FISH. Genetic diversity was analysed by resequencing eightRosaspecies. Combining genetic and genomic approaches, we identified potential genetic regulators of key ornamental traits, including prickle density and number of flower petals. A roseAPETALA2homologue is proposed to be the major regulator of petals number in rose. This reference sequence is an important resource for studying polyploidisation, meiosis and developmental processes as we demonstrated for flower and prickle development. This reference sequence will also accelerate breeding through the development of molecular markers linked to traits, the identification of the genes underlying them and the exploitation of synteny acrossRosaceae.
EEG-based personal identification: comparison of different functional connectivity metrics
Authors: Fraschini Matteo , Didaci Luca , Marcialis Gian Luca
Published: January 2018

Growing interest is devoted to understanding how brain signals recorded from scalp electroencephalography (EEG) may represent unique fingerprints of individual neural activity. In this context, the present paper aims to investigate the impact of some of the most commonly used techniques to estimate functional connectivity on the ability to unveil personal distinctive patterns of inter-regional interactions. Different metrics, commonly used to estimate functional connectivity and derived centrality measures, were compared in terms of equal error rate. It is widely accepted that each metric carries specific information in respect to the underlying interactions network. Nevertheless, the reason why these metrics convey different subject specific information has not been investigated yet. Experimental results on two publicly available datasets suggest that different functional connectivity metrics define a peculiar subjective profile of connectivity and have different mechanisms to detect subject-specific patterns of inter-channel interactions. It is important to consider the effects that frequency content and spurious connectivity values may play in determining subject-specific characteristics.
FlowPot axenic plant growth system for microbiota research
Authors: Kremer James M. , Paasch Bradley C. , Rhodes David , Thireault Caitlin , Froehlich John E. , Schulze-Lefert Paul , Tiedje James M. , He Sheng Yang
Published: January 2018

The presence of resident microbiota on and inside plants is hypothesized to influence many phenotypic attributes of the host. Likewise, host factors and microbe-microbe interactions are believed to influence microbial community assembly. Rigorous testing of these hypotheses necessitates the ability to grow plants in the absence or presence of resident or defined microbiota. To enable such experiments, we developed the scalable and inexpensive FlowPot growth platform. FlowPots have a sterile peat substrate amenable to colonization by microbiota, and the platform supports growth of the model plant Arabidopsis thaliana in the absence or presence of soil-derived microbial communities. Mechanically, the FlowPot system is unique in that it allows for total-saturation of the sterile substrate by “flushing” with water and/or nutrient solution via an irrigation port. The irrigation port also facilitates passive drainage of the substrate, preventing root anoxia. Materials to construct an individual FlowPot total ∼$2. A simple experiment with 12 FlowPots requires ∼4.5 h of labor following peat and seed sterilization. Plants are grown on FlowPots within a standard tissue culture microbox after inoculation, thus the Flowpot system is modular and does not require a sterile growth chamber. Here, we provide a detailed assembly and microbiota inoculation protocol for the FlowPot system. Collectively, this standardized suite of tools and colonization protocols empowers the plant microbiome research community to conduct harmonized experiments to elucidate the rules microbial community assembly, the impact of microbiota on host phenotypes, and mechanisms by which host factors influence the structure and function of plant microbiota.
Imputation of posterior linkage probability relations reveals a significant influence of structural 3D constraints on linkage disequilibrium
Authors: Gerber Susanne , Fournier David , Hewel Charlotte , Horenko Illia
Published: January 2018

Genetic association studies have become increasingly important in unraveling the genetics of diseases or complex traits. Despite their value for modern genetics, conflicting conclusions often arise through the difficulty of confirming and replicating experimental results. We argue that this problem is largely based on the application of statistical relation measures that are not appropriate for genomic data analysis and demonstrate that the standard measures used for Genome-wide association studies or genomics linkage analysis bear a statistic bias. This may come from the violation of underlying assumptions (such as independence or stationarity) as well as from other conceptual limitations in the measures or relations, such as missing invariance with respect to coding or the inability to reflect latent factors. Attempts to introduce unbiased relation measures that avoid these limitations are usually computationally expensive and do not scale for large data sizes being typical for genomics applications.

To tackle these problems, we propose a straightforwardly computable relation measure called Linkage Probability (LP). This measure provides the posterior probability of a relation between two categorical data sets and considers potential biases from latent variables. We compare several aspects of popular relation measures through an illustrative example and human genomics data. We demonstrate that the application ofLPto the analysis of Single Nucleotide Polymorphisms (SNP) reveals latent 3D steric effects within 1D SNP data, that approximate to chromatin loops captured by high resolution Hi-C maps.
iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE
Authors: Oikonomidi Ioanna , Burbridge Emma , Cavadas Miguel , Sullivan Graeme , Clancy Danielle , Collis Blanka , Brezinova Jana , Humpolickova Jana , Hu Tianyi , Bileck Andrea , Gerner Christopher , Bolado Alfonso , von Kriegsheim Alex , Strisovsky Kvido , Martin Seamus J. , Adrain Colin
Published: January 2018

The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires ADAM17/TACE, which cleaves TNF from its transmembrane tether, releasing it for signalling. The trafficking of ADAM17/TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. Here we report a novel protein, that we name iTAP (iRhom tail-associatedprotein) that binds to iRhoms, enhancing the stability of iRhoms and TACE, preventing their degradation in lysosomes. iTAP-null primary human macrophages, or tissues from iTAP KO mice, are dramatically depleted in the levels of iRhom2 and active TACE, and are, consequently, profoundly impaired in TNF production. Our work illustrates iTAP as a physiological rheostat controlling TNF signalling and a novel target for the control of inflammation.
Binding during sequence learning does not alter cortical representations of individual actions
Authors: Beukema Patrick , Diedrichsen Jörn , Verstynen Timothy
Published: January 2018

As a movement sequence is learned, serially ordered actions get bound together into sets in order to reduce computational complexity during planning and execution. Here we examined how the binding of serial actions alters the cortical representations of individual movements. Across five weeks of practice, healthy human subjects learned either a complex 32-item sequence of finger movements (Trained group, N=9) or randomly ordered actions (Control group, N=9). After five weeks of training, responses during sequence production in the Trained group were correlated, consistent with being bound together under a common command. These behavioral changes, however, did not coincide with plasticity in the multivariate representations of individual finger movements, assessed using fMRI, at any level of the cortical motor hierarchy. This suggests that the representations of individual actions remain stable, even as the execution of those same actions become bound together in the context of producing a well learned sequence.
Visualizing BDNF cell-to-cell transfer reveals astrocytes are the primary recipient of neuronal BDNF
Authors: Stahlberg Markus A. , Kügler Sebastian , Dean Camin
Published: January 2018

Brain-derived neurotrophic factor (BDNF) is essential for neuronal growth, differentiation, and synaptic plasticity. Although the release and effects of BDNF have been well-studied separately, the transfer of BDNF between cells has not been investigated. Using a four-fluorophore imaging approach to identify both the cell of origin and target cells, we quantified the transfer of BDNF. Surprisingly, we found that astrocytes are the main recipient of neuronally expressed BDNF. We further found that astrocytes specifically take up mature (not pro) BDNF released by neurons. Over-expression of TrkB in neurons redirects released BDNF from astrocytes to neurons, indicating that TrkB levels determine neuronal versus astrocytic BDNF uptake. Increased neuronal activity further increased astrocytic (but not neuronal) uptake of neuronally expressed BDNF. Finally, we demonstrate that astrocytes are not simply a sink for excess BDNF, but that BDNF taken up by astrocytes mediates physiological effects on the astrocytic population by increasing astrocytic territory.
Crop domestication and pathogen virulence: Interactions of tomato andBotrytisgenetic diversity
Authors: Soltis Nicole E. , Atwell Susanna , Shi Gongjun , Fordyce Rachel , Gwinner Raoni , Gao Dihan , Shafi Aysha , Kliebenstein Daniel J.
Published: January 2018

Human selection during crop domestication alters numerous traits, including disease resistance. Studies of qualitative resistance to specialist pathogens typically find decreased resistance in domesticated crops in comparison to their wild relatives. However, less is known about how crop domestication affects quantitative interactions with generalist pathogens. To study how crop domestication impacts plant resistance to generalist pathogens, and correspondingly how this interacts with the pathogen’s genetics, we infected a collection of wild and domesticated tomato accessions with a genetically diverse population of the generalist pathogenBotrytis cinerea. We quantified variation in lesion size of 97B. cinereagenotypes (isolates) on 6 domesticatedSolanum lycopersicumand 6 wildS. pimpinellifoliumgenotypes. This showed that lesion size was significantly controlled by plant domestication, plant genetic variation, and the pathogen’s genotype. Overall, resistance was slightly elevated in the wild germplasm in comparison to domesticated tomato accessions. Genome-wide association (GWA) mapping inB. cinereaidentified a highly polygenic collection of genes. This suggests that breeding against this pathogen would need to utilize a diversity of isolates to capture all possible mechanisms. Critically, we identified a discrete subset ofB. cinereagenes where the allelic variation was linked to altered virulence against the wild versus domesticated tomato accessions. This indicates that this generalist pathogen already has the necessary allelic variation in place to handle the introgression of wild resistance mechanisms into the domesticated crop. Future studies are needed to assess how these observations extend to other domesticated crops and other generalist pathogens.
Efficient enrichment cloning of TAL effector genes fromXanthomonas
Authors: Tran Tuan Tu , Doucoure Hinda , Hutin Mathilde , Szurek Boris , Cunnac Sebastien , Koebnik Ralf
Published: January 2018

Many plant-pathogenic xanthomonads use a type III secretion system to translocate Transcription Activator-Like (TAL) effectors into eukaryotic host cells where they act as transcription factors. Target genes are induced upon binding of a TAL effector to double-stranded DNA in a sequence-specific manner. DNA binding is governed by a highly repetitive protein domain, which consists of an array of nearly identical repeats of ca. 102 base pairs. Many species and pathovars ofXanthomonas, including pathogens of rice, cereals, cassava, citrus and cotton, encode multiple TAL effectors in their genomes. Some of the TAL effectors have been shown to act as key pathogenicity factors, which induce the expression of susceptibility genes to the benefit of the pathogen. However, due to the repetitive character and the presence of multiple gene copies, high-throughput cloning of TAL effector genes remains a challenge. In order to isolate complete TAL effector gene repertoires, we developed an enrichment cloning strategy based on (i) genome-informed in silico optimization of restriction digestions, (ii) selective restriction digestion of genomic DNA, and (iii) size fractionation of DNA fragments. Our rapid, cheap and powerful method allows efficient cloning of TAL effector genes from xanthomonads, as demonstrated for two rice-pathogenic strains ofXanthomonas oryzaefrom Africa.
Lineage space and the propensity of bacterial cells to undergo growth transitions
Authors: Bandyopadhyay Arnab , Wang Huijing , Ray J. Christian J.
Published: January 2018

The molecular makeup of the offspring of a dividing cell gradually becomes phenotypically decorrelated from the parent cell by noise and regulatory mechanisms that amplify phenotypic heterogeneity. Such regulatory mechanisms form networks that contain thresholds between phenotypes. Populations of cells can be poised near the threshold so that a subset of the population probabilistically undergoes the phenotypic transition. We sought to characterize the diversity of bacterial populations around a growth-modulating threshold via analysis of the effect of non-genetic inheritance, similar to conditions that create antibiotictolerant persister cells and other examples of bet hedging. Using simulations and experimental lineage data inEscherichia coli, we present evidence that regulation of growth amplifies the dependence of growth arrest on cellular lineage, causing clusters of related cells undergo growth arrest in certain conditions. Our simulations predict that lineage correlations and the sensitivity of growth to changes in toxin levels coincide in a critical regime. Below the critical regime, the sizes of related growth arrested clusters are distributed exponentially, while in the critical regime clusters sizes are more likely to become large. Furthermore, phenotypic diversity can be nearly as high as possible near the critical regime, but for most parameter values it falls far below the theoretical limit. We conclude that lineage information is indispensable for understanding regulation of cellular growth.

Author Summary

One of the most important characteristics of a cell is whether it is growing. Actively growing cells can multiply exponentially. In the case of infections and cancer, growth causes problems for the host organism. On the other hand, cells that have stopped growing can allocate cellular resources toward different activities, such as bacteria surviving antibiotics and tissues in multicellular organisms performing their physiological roles. Observing small bacterial colonies in a microscope over time, we have found that cells closely related to each other often have similar growth state. We were curious if lineage dependence was an intrinsic property of growth regulation or if other factors were needed to explain this effect. We therefore built a computational model of a growing and dividing cellular colony with an encoded growth regulation network. We found that regulation of growth is sufficient for lineage dependence to emerge. We next asked if lineage dependence constrains how diverse the cellular population can become. We found that cellular diversity can reach a peak that is nearly as high as possible near the conditions that have the highest lineage dependence, but that most conditions do not permit such high diversity. We conclude that lineage is an important constraint and discuss how the growth arrest transition is in some ways like a phase transition from physics, and in some ways strikingly different, making it a unique phenomenon.
DREAM-Yara: An exact read mapper for very large databases with short update time
Authors: Dadi Temesgen Hailemariam , Siragusa Enrico , Piro Vitor C. , Andrusch Andreas , Seiler Enrico , Renard Bernhard Y. , Reinert Knut
Published: January 2018

Motivation

Mapping-based approaches have become limited in their application to very large sets of references since computing an FM-index for very large databases (e.g. > 10 GB) has become a bottleneck. This affects many analyses that need such index as an essential step for approximate matching of the NGS reads to reference databases. For instance, in typical metagenomics analysis, the size of the reference sequences has become prohibitive to compute a single full-text index on standard machines. Even on large memory machines, computing such index takes about one day of computing time. As a result, updates of indices are rarely performed. Hence, it is desirable to create an alternative way of indexing while preserving fast search times.

Results

To solve the index construction and update problem we propose the DREAM (Dynamic seaRchablE pArallel coMpressed index) framework and provide an implementation. The main contributions are the introduction of an approximate search distributor directories via a novel use of Bloom filters. We combine several Bloom filters to form an interleaved Bloom filter and use this new data structure to quickly exclude reads for parts of the databases where they cannot match. This allows us to keep the databases in several indices which can be easily rebuilt if parts are updated while maintaining a fast search time. The second main contribution is an implementation of DREAM-Yara a distributed version of a fully sensitive read mapper under the DREAM framework.

Contact

temesgen.dadi@fu-berlin.de

Availability

https://gitlab.com/pirovc/dream_yara/
Predicting Human Protein Function with Multi-task Deep Neural Networks
Authors: Fa Rui , Cozzetto Domenico , Wan Cen , Jones David T.
Published: January 2018

Machine 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

Motivation

Function 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.

Results

We 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.

Availability

https://github.com/bio-ontology-research-group/phenogocon

Contact

robert.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

Genome-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.

‘Software

We 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-seqTools

Highlights

Rapid (~2h hands on time) and low-cost approach to perform transcriptomics on hundreds of RNA samples

Strand specificity preserved

Performance: number of detected genes is equal to Illumina TruSeq Stranded mRNA at same sequencing depth

High capacity: low cost allows increasing the number of biological replicates

Produces 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

Mutations 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

Exoskeletons 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

In 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

Clostridium 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.

Importance

Clostridium 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

Colorectal 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

CircRNAs 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

A 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.
Using structural mimics for accessing and exploring structural landscapes of poorly soluble molecular solids
Authors: Perera Manomi D. , Sinha Abhijeet S. , Aakeröy Christer B.
Published: January 2018

The importance of using structural mimics for mapping out the structural landscape of a poorly soluble active pharmaceutical ingredient was investigated using erlotinib as an example. A mimic was synthesized by preserving the main molecular functionalities responsible for creating the most probable structural arrangements in the solid state. Calculated molecular electrostatic potentials on both erlotinib and the mimic showed very comparable values indicating that the latter would be able to form hydrogen bonds of similar probability and strength as those of erlotinib. In order to establish the binding preference in co-crystallization experiments, the mimic molecule was co-crystallized with US Food and Drug Administration approved dicarboxylic acids. The crystal structures of the mimic and of four co-crystals thereof were obtained. The mimic forms hydrogen bonds in a way that closely resembles those found in the crystal structure of erlotinib. The four co-crystals display self-consistent hydrogen-bond interactions. Thermal and solubility data for the co-crystals demonstrate that by making systematic and controllable changes to the solid forms of the mimic, it is also possible to alter the behaviour and properties of the new solid forms. The use of a suitable structural mimic can allow for a systematic structural examination of a compound that is otherwise not amenable to such investigations by facilitating the elucidation and mapping out of a closely related structural landscape.
Crystal structure refinements of tetragonal (OH,F)-rich spessartine and henritermierite garnets
Authors: Antao Sytle M. , Cruickshank Laura A.
Published: January 2018

Cubic garnet (space group Ia\overline 3 d) has the general formula X
3
Y
2
Z
3O12, where X, Y and Z are cation sites. In the tetragonal garnet (space group I41/acd), the corresponding cation sites are X1 and X2, Y, and Z1 and Z2. In both space groups only the Y site is the same. The crystal chemistry of a tetragonal (OH,F)-rich spessartine sample from Tongbei, near Yunxiao, Fujian Province, China, with composition
X
(Mn2.82Fe^{2+}_{0.14}Ca0.04)Σ3

Y
{Al1.95Fe^{3+}_{0.05}}Σ2

Z
[(SiO4)2.61(O4H4)0.28(F4)0.11]Σ3 (Sps94Alm5Grs1) was studied with single-crystal X-ray diffraction and space group I41/acd. The deviation of the unit-cell parameters from cubic symmetry is small [a = 11.64463 (1), c = 11.65481 (2) Å, c/a = 1.0009]. Point analyses and back-scattered electron images, obtained by electron-probe microanalysis, indicate a homogeneous composition. The Z2 site is fully occupied, but the Z1 site contains vacancies. The occupied Z1 and Z2 sites with Si atoms are surrounded by four O atoms, as in anhydrous cubic garnets. Pairs of split sites are O1 with F11 and O2 with O22. When the Z1 site is vacant, a larger [(O2H2)F2] tetrahedron is formed by two OH and two F anions in the O22 and F11 sites, respectively. This [(O2H2)F2] tetrahedron is similar to the O4H4 tetrahedron in hydrogarnets. These results indicate ^{X}{{\rm Mn}^ {2+}_{3}}\,^{Y}{\rm Al}_{2}^{Z}[({\rm SiO}_{4})_{2}({\rm O}_{2}{\rm H}_{2})_{0.5}({\rm F}_{2})_{0.5}]_{\Sigma3} as a possible end member, which is yet unknown. The H atom that is bonded to the O22 site is not located because of the small number of OH groups. In contrast, tetragonal henritermierite, ideally ^{X}{\rm Ca}_{3}\,^{Y}{\rm Mn}^{3+}_{2}\,^{Z}[({\rm SiO}_{4})_{2}({\rm O}_{4}{\rm H}_{4})_1]_{\Sigma3}, has a vacant Z2 site that contains the O4H4 tetrahedron. The H atom is bonded to an O3 atom [O3—H3 = 0.73 (2) Å]. Because of O2—Mn3+—O2 Jahn–Teller elongation of the Mn3+O6 octahedron, a weak hydrogen bond is formed to the under-bonded O2 atom. This causes a large deviation from cubic symmetry (c/a = 0.9534).
Crystal structure and quantum-chemical calculations of a trimethylaluminium–THF adduct
Authors: Brieger Lukas , Hermann Andreas , Unkelbach Christian , Strohmann Carsten
Published: January 2018

The title compound, trimethyl(tetrahydrofuran-κO)aluminium(III), [Al(CH3)3(C4H8O)], is an addition product of trimethylaluminium and tetrahydrofuran (THF). Instead of a dimeric structure, which is very common for these types of compounds, a monomeric molecular structure is observed. The C—Al—C angles in the molecule are very different from the C—Al—C angles found in dimeric molecular structures, leading to a different symmetry around the AlIII atom. The reasons for these differences are discussed.
3-Methyl-1-{(E)-[1-(4-methylpyridin-2-yl)ethylidene]amino}thiourea: crystal structure and Hirshfeld surface analysis
Authors: Lai Lee Chin , Rahman Che Nursarah Binti Che Abdul , Tahir M. Ibrahim M. , Ravoof Thahira B. S. A. , Jotani Mukesh M. , Tiekink Edward R. T.
Published: January 2018

The title disubstituted thiourea derivative, C10H14N4S, features an almost planar imine (E configuration, C3N) core flanked by thiourea (CN2S) and methylpyridyl (C5N) residues (each plane has a r.m.s. deviation of the respective fitted atoms of 0.0066 Å). The dihedral angles between the core and the thiourea and pyridyl residues are 20.25 (8) and 7.60 (9)°, respectively, indicating twists in the molecule; the dihedral angle between the outer planes is 13.62 (7)°. There is an anti-disposition of the amine-N—H atoms which allows for the formation of an intramolecular amine-N—H...N(imine) hydrogen bond that closes an S(5) loop. In the crystal, amine-N—H...N(pyridyl) hydrogen bonds lead to zigzag (glide symmetry) supramolecular chains along the c-axis direction. These are connected into a supramolecular layer propagating in the bc plane by thioamide-N—H...S(thione) hydrogen bonds via eight-membered thioamide {...HNCS}2 synthons.