bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leveraging targeted sequencing for non-model species: a step-by-step guide to obtain a reduced SNP set and a pipeline to automate data processing in the Antarctic Midge, Belgica antarctica
Authors: Pavinato Vitor A. C. , Wijeratne Saranga , Spacht Drew , Denlinger David L. , Meulia Tea , Michel Andrew P. 
Published: September 2019

AbstractThe sequencing of whole or partial (e.g. reduced representation) genomes are commonly employed in molecular ecology and conservation genetics studies. However, due to sequencing costs, a trade-off between the number of samples and genome coverage can hinder research for non-model organisms. Furthermore, the processing of raw sequences requires familiarity with coding and bioinformatic tools that are not always available. Here, we present a guide for isolating a set of short, SNP-containing genomic regions for use with targeted amplicon sequencing protocols. We also present a python pipeline--PypeAmplicon-- that facilitates processing of reads to individual genotypes. We demonstrate the applicability of our method by generating an informative set of amplicons for genotyping of the Antarctic midge, Belgica antarctica, an endemic dipteran species of the Antarctic Peninsula. Our pipeline analyzed raw sequences produced by a combination of high-multiplexed PCR and next-generation sequencing. A total of 38 out of 47 (81%) amplicons designed by our panel were recovered, allowing successful genotyping of 42 out of 55 (76%) targeted SNPs. The sequencing of ∼150 bp around the targeted SNPs also uncovered 80 new SNPs, which complemented our analyses. By comparing overall patterns of genetic diversity and population structure of amplicon data with the low-coverage, whole-genome re-sequencing (lcWGR) data used to isolate the informative amplicons, we were able to demonstrate that amplicon sequencing produces information and results similar to that of lcWGR. Our methods will benefit other research programs where rapid development of population genetic data is needed but yet prevented due to high expense and a lack of bioinformatic experience.
Flexible cobamide metabolism in Clostridioides (Clostridium) difficile 630 Δerm
Authors: Shelton Amanda N. , Lyu Xun , Taga Michiko E. 
Published: September 2019

AbstractClostridioides (Clostridium) difficile is an opportunistic pathogen known for its ability to colonize the human gut under conditions of dysbiosis. Several aspects of its carbon and amino acid metabolism have been investigated, but its cobamide (vitamin B12 and related cofactors) metabolism remains largely unexplored. C. difficile has seven predicted cobamide-dependent metabolisms encoded in its genome in addition to a nearly complete cobamide biosynthesis pathway and a cobamide uptake system. To address the importance of cobamides to C. difficile, we studied C. difficile 630 Δerm and mutant derivatives under cobamide-dependent conditions in vitro. Our results show that C. difficile can use a surprisingly diverse array of cobamides for methionine and deoxyribonucleotide synthesis, and can use alternative metabolites or enzymes, respectively, to bypass these cobamide-dependent processes. C. difficile 630 Δerm produces the cobamide pseudocobalamin when provided the early precursor 5-aminolevulinc acid or the late intermediate cobinamide, and produces other cobamides if provided an alternative lower ligand. The ability of C. difficile 630 Δerm to take up cobamides and Cbi at micromolar or lower concentrations requires the transporter BtuFCD. Genomic analysis revealed genetic variations in in the btuFCD locus of different C. difficile strains, which may result in differences in the ability to take up cobamides and Cbi. These results together demonstrate that, like other aspects of its physiology, cobamide metabolism in C. difficile is versatile.ImportanceThe ability of the opportunistic pathogen Clostridioides difficile to cause disease is closely linked to its propensity to adapt to conditions created by dysbiosis of the human gut microbiota. The cobamide (vitamin B12) metabolism of C. difficile has been underexplored, though it has seven metabolic pathways that are predicted to require cobamide-dependent enzymes. Here, we show that C. difficile cobamide metabolism is versatile, as it can use a surprisingly wide variety of cobamides and has alternative functions that can bypass some of its cobamide requirements. Furthermore, C. difficile does not synthesize cobamides de novo, but produces them when given cobamide precursors. Better understanding of C. difficile cobamide metabolism may lead to new strategies to treat and prevent C. difficile-associated disease.
How flat can a horse be? Exploring 2D approximations of 3D crania in equids
Authors: Andrea Cardini , Chiappelli Marika 
Published: September 2019

ABSTRACTQuantitative analyses of morphological variation using geometric morphometrics are often performed on 2D photos of 3D structures. It is generally assumed that the error due to the flattening of the third dimension is negligible. However, despite hundreds of 2D studies, few have actually tested this assumption and none has done it on large animals, such as those typically classified as megafauna. We explore this issue in living equids, focusing on ventral cranial variation at both micro- and macro-evolutionary levels. By comparing 2D and 3D data, we found that size is well approximated, whereas shape is more strongly impacted by 2D inaccuracies, as it is especially evident in intra-specific analyses. The 2D approximation improves when shape differences are larger, as in macroevolution, but even at this level precise inter-individual similarity relationships are altered. Despite this, main patterns of sex, species and allometric variation in 2D were the same as in 3D, thus suggesting that 2D may be a source of ‘noise’ that does not mask the main signal in the data. However, the problem is complex and any generalization premature. Morphometricians should therefore test the appropriateness of 2D using preliminary investigations in relation to the specific study questions in their own samples. We discuss whether this might be feasible using a reduced landmark configuration and smaller samples, which would save time and money. In an exploratory analysis, we found that in equids results seem robust to sampling, but become less precise and, with fewer landmarks, may slightly overestimate 2D inaccuracies.
Whole genome sequencing of cell-free DNA yields genome-wide read distribution patterns to track tissue of origin in cancer patients
Authors: Liang Han , Li Fuqiang , Qiao Sitan , Zhou Xinlan , Xie Guoyun , Zhao Xin , Wu Kui 
Published: September 2019

AbstractSomatic mosaicism is widespread among tissues and could indicate distinct tissue origins of circulating cell-free DNA (cfDNA), DNA fragments released by lytic cells into the blood. By investigating the alignment patterns of whole genome sequencing reads with the genomic DNA of different tissues, we found that the read distributions formed type-specific patterns in some regions as a result of somatic mosaicism. We then utilized this information to construct a tissue-of-origin mapping model and evaluated its predictive performance on whole genome sequencing data from tissue and cfDNA samples. In total, 1,545 tissue samples associated with 13 cancer types were included, and identification of the tissue of origin achieved a specificity of 82% and a sensitivity of 80%. Furthermore, a total of 30 cfDNA samples from lung cancer and liver cancer patients and healthy controls were analyzed to predict their tissues of origin with a specificity of 87% and a sensitivity of 87%. Our results show that read distribution patterns from whole genome sequencing could be used to identify cfDNA tissues of origin with high accuracy, suggesting the potential application of our model to early cancer detection and diagnosis.
Mutation distribution density in tumors reconstructs human’s lost diversity
Authors: Heredia-Genestar José María , Marquès-Bonet Tomàs , Juan David , Navarro Arcadi 
Published: September 2019

Introductory ParagraphMutations do not accumulate uniformly across the genome. Human germline and tumor mutation density correlate poorly, and each is associated with different genomic features. Here, we analyze the genome-wide distribution of mutation densities in human and non-human Great Ape (NHGA) germlines as well as human tumors. Strikingly, non-human Great Ape germlines present higher correlation with tumors than the human germline does. This situation is mediated by a different distribution in the human germline of mutations at non-CpG sites, but not of CpG>T transitions. We propose that the impact of ancestral and historical human demographic events on human mutation density leads to this specific disruption in its expected genome-wide distribution. Tumors partially recover this distribution by the accumulation of pre-neoplastic-like somatic mutations. Our results highlight the potential utility of using Great Ape population data, rather than human controls, to establish the expected mutational background of healthy somatic cells.
Nuclear poly(A) tail size is regulated by Cnot1 during the serum response
Authors: Singhania Richa , Thorn Graeme J. , Williams Kathryn , Gandhi Raj D. , Daher Clara , Barthet-Barateig Adeline , Parker Hannah N. , Utami Wahyu , Al-Siraj Mustafa , Barrett David A. , Wattis Jonathan A.D. , de Moor Cornelia H. 
Published: September 2019

ABSTRACTThe poly(A) tail removal from mRNAs introduces a delay between mRNA synthesis and decay. We measured levels and poly(A) tail sizes of serum-induced mRNAs and used mathematical modelling to compare their deadenylation time with the delay in decay and found that they are indeed correlated. Discrepancies between our data and the polyadenylation models at later time points after the peak of induction led us to investigate the size of the poly(A) tails on newly made mRNA. Surprisingly, new serum-induced mRNAs synthesised late in induction had short poly(A) tails (around A25) in the nucleus. In addition, newly made constitutive mRNAs had medium sized poly(A) tails (around A50). To see if deadenylation was responsible for the new short poly(A) tails, we depleted Cnot1, a subunit of the CCR4/NOT deadenylase. Cnot1 depletion led to slower deadenylation of cytoplasmic mRNAs, as expected, but also decreased transcription and led to longer nuclear mRNA poly(A) tails. These observations implicate CCR4/NOT in regulating both the transcription and the nuclear poly(A) tail size of serum-induced mRNAs. Detection of some chromatin-associated mRNAs with long poly(A) tails suggested that nuclear deadenylation is an early event. Our data show that initial poly(A) tail size of mRNAs can be regulated and is not always 200-250 nucleotides, adding a novel layer to the control of gene expression.
Myt Transcription Factors prevent stress-response gene over-activation to enable postnatal pancreatic β cell proliferation and function
Authors: Hu Ruiying , Walker Emily , Xu Yanwen , Huang Chen , Weng Chen , Erickson Gillian E. , Golovin Anastasia , Yang Xiaodun , Brissova Marcella , Balamurugan Appakalai N. , Wright Christopher V. E. , Li Yan , Stein Roland , Gu Guoqiang 
Published: September 2019

SummaryAlthough stress response maintains cell function and survival under adverse conditions, over-activation of late-stage stress-gene effectors causes dysfunction and death. Here we show that the Myelin Transcription Factors (Myt 1, 2, and 3 TFs) prevent this over-activation. Co-inactivatingMyt TFsin mouse pancreatic progenitors compromised postnatal β-cell function, proliferation, and survival, preceded by upregulation of late-stage stress-response genesActivating Transcription Factors(e.g.,Atf4) andHeat Shock Proteins(Hsps). Myt1 binds the putative enhancers ofAtf4andHsps, whose over-expression in mouse β cells largely recapitulated theMytmutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in functional mouse and human β cells by metabolic stress but downregulated in those of type 2 diabetic islets that displayATF4andHSPover-activation. Lastly, humanMYTknockdown caused stress-gene over-activation and death in Endo-βH1 cells. These findings suggest that the Myt TFs restrict stress-response to physiologically tolerable levels in mice and human.
Characterizing the Network Architecture of Emotion Regulation Neurodevelopment
Authors: Guassi Moreira João F. , McLaughlin Katie A. , Silvers Jennifer A. 
Published: September 2019

AbstractThe ability to regulate emotions is key to goal attainment and wellbeing. Although much has been discovered about how the human brain develops to support the acquisition of emotion regulation, very little of this work has leveraged information encoded in whole-brain networks. Here we employed a network neuroscience framework to parse the neural underpinnings of emotion regulation skill acquisition while accounting for age in a sample of youth (N = 70, 34 female). Focusing on three key network metrics—network differentiation, modularity, and community structure differences between active regulation and a passive emotional baseline—we found that the control network, the default mode network, and limbic network were each related to emotion regulation ability while controlling for chronological age. Greater network differentiation in the control and limbic networks was related to better emotion regulation ability. With regards to network community structure, more communities and more crosstalk between modules (i.e., less modularity) in the control network were associated with better regulatory ability. By contrast, less crosstalk (i.e., more modularity) between modules in the default mode network was associated with better regulatory ability. Together, these findings highlight possible whole-brain connectome features that support the acquisition of emotion regulation in youth.
Diversity in CRISPR-based immunity protects susceptible genotypes by restricting phage spread and evolution
Authors: Common Jack , Walker-Sünderhauf David , van Houte Stineke , Westra Edze R 
Published: September 2019

AbstractDiversity in host resistance often associates with reduced pathogen spread. This may result from ecological and evolutionary processes, likely with feedback between them. Theory and experiments on bacteria-phage interactions have shown that genetic diversity of the bacterial adaptive immune system can limit phage evolution to overcome resistance. Using the CRISPR-Cas bacterial immune system and lytic phage, we engineered a host-pathogen system where each bacterial host genotype could be infected by only one phage genotype. With this model system, we explored how CRISPR diversity impacts the spread of phage when they can overcome a resistance allele, how immune diversity affects the evolution of the phage to increase its host range, and if there was feedback between these processes. We show that increasing CRISPR diversity benefits susceptible bacteria via a dilution effect, which limits the spread of the phage. We suggest that this ecological effect impacts the evolution of novel phage genotypes, which then feeds back into phage population dynamics.
Structural basis for two-way communication between dynein and microtubules
Authors: Nishida Noritaka , Komori Yuta , Takarada Osamu , Watanabe Atsushi , Tamura Satoko , Kubo Satoshi , Shimada Ichio , Kikkawa Masahide 
Published: September 2019

AbstractThe movements of cytoplasmic dynein on microtubule (MT) tracks is achieved by two-way communication between the microtubule-binding domain (MTBD) and the ATPase domain of dynein via an a-helical coiled-coil stalk, but the structural basis of this communication remains elusive. Here, we regulated MTBD either in high-affinity or low-affinity states by introducing a disulfide bond between the coiled-coils and analyzed the resulting structures by NMRand cryo-EM. In the MT-unbound state, the affinity changes of MTBD were achieved by sliding of the N-terminal α-helix by one half-turn, which suggests that structural changes propagate from the ATPase-domain to MTBD. In addition, cryo-EM analysis showed that MT binding induced further sliding of the N-terminal α-helix even without the disulfide bond, which suggests the MT-induced conformational changes propagate toward the ATPase domain. Based on differences in the MT-binding surface between the high- and low-affinity states, we propose a potential mechanism for the directional bias of dynein movement on MT tracks.
Drug-Target Interaction prediction using Multi-Graph Regularized Deep Matrix Factorization
Authors: Mongia Aanchal , Majumdar Angshul 
Published: September 2019

AbstractDrug discovery is an important field in the pharmaceutical industry with one of its crucial chemogenomic process being drug-target interaction prediction. This interaction determination is expensive and laborious, which brings the need for alternative computational approaches which could help reduce the search space for biological experiments. This paper proposes a novel framework for drug-target interaction (DTI) prediction: Multi-Graph Regularized Deep Matrix Factorization (MGRDMF). The proposed method, motivated by the success of deep learning, finds a low-rank solution which is structured by the proximities of drugs and targets (drug similarities and target similarities) using deep matrix factorization. Deep matrix factorization is capable of learning deep representations of drugs and targets for interaction prediction. It is an established fact that drug and target similarities incorporation preserves the local geometries of the data in original space and learns the data manifold better. However, there is no literature on which the type of similarity matrix (apart from the standard biological chemical structure similarity for drugs and genomic sequence similarity for targets) could best help in DTI prediction. Therefore, we attempt to take into account various types of similarities between drugs/targets as multiple graph Laplacian regularization terms which take into account the neighborhood information between drugs/targets. This is the first work which has leveraged multiple similarity/neighborhood information into the deep learning framework for drug-target interaction prediction. The cross-validation results on four benchmark data sets validate the efficacy of the proposed algorithm by outperforming shallow state-of-the-art computational methods on the grounds of AUPR and AUC.
miRmedon: confident detection of microRNA editing
Authors: Mordechai Amitai , Eran Alal 
Published: September 2019

SummarymicroRNA (miRNA), key regulators of gene expression, are prime targets for adenosine deaminase acting on RNA (ADAR) enzymes. Although ADAR-mediated A-to-I miRNA editing has been shown to be essential for orchestrating complex processes, including neurodevelopment and cancer progression, only a few human miRNA editing sites have been reported. Several computational approaches have been developed for the detection of miRNA editing in small RNAseq data, all based on the identification of systematic mismatches of ‘G’ at primary adenosine sites in known miRNA sequences. However, these methods have several limitations, including their ability to detect only one editing site per sequence (although editing of multiple sites per miRNA has been reproducibly validated), their focus on uniquely mapping reads (although 20% of human miRNA are transcribed from multiple loci), and their inability to detect editing in miRNA genes harboring genomic variants (although 73% of human miRNA loci include a reported SNP or indel). To overcome these limitations, we developed miRmedon, that leverages large scale human variation data, a combination of local and global alignments, and a comparison of the inferred editing and error distributions, for a confident detection of miRNA editing in small RNAseq data. We demonstrate its improved performance as compared to currently available methods and describe its advantages.Availability and implementationPython source code is available at https://github.com/Amitai88/miRmedonContactalal@bgu.ac.il
The inner junction complex of the cilia is an interaction hub that involves tubulin post-translational modifications
Authors: Khalifa Ahmad , Ichikawa Muneyoshi , Dai Daniel , Kubo Shintaroh , Black Corbin , Peri Katya , McAlear Thomas S. , Veyron Simon , Yang Shun Kai , Vargas Javier , Bechstedt Susanne , Trempe Jean-Francois , Bui Khanh Huy 
Published: September 2019

AbstractMicrotubules are cytoskeletal structures involved in structural support, microtubule-based transport and the organization of organelles in the cells. The building blocks of the microtubule, the α- and β-tubulin heterodimers, polymerize into protofilaments, that associate laterally to form the hollow microtubule. There exists a specific type of microtubule structures in the cilia, termed doublet microtubules, where high stability is required for ciliary beating and function. The doublet microtubule, consisting of a complete A-tubule and a partial B-tubule maintains its stability through unique interactions at its outer and inner junctions, where the A- and B-tubules meet.Using cryo-electron microscopy, we present the answer to the long-standing question regarding the identities, localizations and structures of the Chlamydomonas doublet microtubule inner junction proteins. Using a combination of sequence bioinformatics and mass spectrometry, we identified two new inner junction proteins, FAP276 and FAP106, and an inner junction associated protein FAP126. We show that inner junction proteins PACRG and FAP20, together with FAP52, previously unidentified FAP276, FAP106 and FAP126, form an interaction hub at the inner junction, which involves tubulin sites for post-translational modifications. We further compare the Chlamydomonas and Tetrahymena doublet microtubule structures to understand the common and species-specific features of the inner junction.
Controlled Self-Assembly of λ-DNA Networks with the Synergistic Effect of DC Electric Field
Authors: Gao M. , Hu J. , Wang Y. , Liu M. , Wang J. , Song Z. , Xu H. , Hu C. , Wang Z. 
Published: September 2019

AbstractLarge-scale and morphologically controlled self-assembled λ-DNA networks were successfully constructed by the synergistic effect of DC electric field. The effect of DNA concentration, direction and intensity of the electric field, even the modification of the mica surface using Mg2+ on the characteristics of the as-prepared DNA networks were investigated in detail by atomic force microscopy (AFM). It was found that the horizontal electric field was more advantageous to the formation of DNA networks with more regular structures. At the same concentration, the height of DNA network was not affected significantly by the intensity change of the horizontal electric field. The modification of Mg2+ on mica surface increased the aggregation of DNA molecules, which contributed to the morphological change of the DNA networks. Furthermore, DNA molecules were obviously stretched in both horizontal and vertical electric fields at low DNA concentrations.Statement of significanceThrough the synergistic effect of DC electric field, a series of large-scale and morphologically controlled self-assembled λ-DNA networks were successfully fabricated. We found that the horizontal electric field was more advantageous to the formation of DNA networks with more regular structures. At the same concentration of DNA solution, the height of DNA network was not affected significantly by the intensity change of the horizontal electric field. The modification of Mg2+ on mica surface increased the aggregation of DNA molecules, which contributed to the morphological change of the DNA networks. We suggest this study will promote the understanding on the preparation of controllable self-assembled λ-DNA networks and the application of DNA networks.