bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome Sequencing and Transcriptome Analysis Reveal Recent Species-specific Gene Duplications in the Plastic Gilthead Sea Bream
Authors: Pérez-Sánchez Jaume , Naya-Català Fernando , Soriano Beatriz , Piazzon M. Carla , Hafez Ahmed , Gabaldón Toni , Llorens Carlos , Sitjà-Bobadilla Ariadna , Calduch-Giner Josep A.
Published: September 2019

Gilthead sea bream is an economically important fish species that is remarkably well-adapted to farming and changing environments. Understanding the genomic basis of this plasticity will serve to orientate domestication and selective breeding towards more robust and efficient fish. To address this goal, a draft genome assembly was reconstructed combining short- and long-read high-throughput sequencing with genetic linkage maps. The assembled unmasked genome spans 1.24 Gb of an expected 1.59 Gb genome size with 932 scaffolds (∼732 Mb) anchored to 24 chromosomes that are available as a karyotype browser at www.nutrigroup-iats.org/seabreambrowser. Homology-based functional annotation, supported by RNA-seq transcripts, identified 55,423 actively transcribed genes corresponding to 21,275 unique descriptions with more than 55% of duplicated genes. The mobilome accounts for the 75% of the full genome size and it is mostly constituted by introns (599 Mb), whereas the rest is represented by low complexity repeats, RNA retrotransposons, DNA transposons and non-coding RNAs. This mobilome also contains a large number of chimeric/composite genes (i. e. loci presenting fragments or exons mostly surrounded by LINEs and Tc1/mariner DNA transposons), whose analysis revealed an enrichment in immune-related functions and processes. Analysis of synteny and gene phylogenies uncovered a high rate of species-specific duplications, resulting from recent independent duplications rather than from genome polyploidization (2.024 duplications per gene; 0.385 excluding gene expansions). These species-specific duplications were enriched in gene families functionally related to genome transposition, immune response and sensory responses. Additionally, transcriptional analysis of liver, skeletal muscle, intestine, gills and spleen supported a high number of functionally specialized paralogs under tissue-exclusive regulation. Altogether, these findings suggest a role of recent large-scale gene duplications coupled to tissue expression diversification in the evolution of gilthead sea bream genome during its successful adaptation to a changing and pathogen-rich environment. This issue also underscores a role of evolutionary routes for rapid increase of the gene repertoire in teleost fish that are independent of polyploidization. Since gilthead sea bream has a well-recognized plasticity, the current study will advance our understanding of fish biology and how organisms of this taxon interact with the environment.
GpABC: a Julia package for approximate Bayesian computation with Gaussian process emulation
Authors: Tankhilevich Evgeny , Ish-Horowicz Jonathan , Hameed Tara , Roesch Elisabeth , Kleijn Istvan , Stumpf Michael PH , He Fei
Published: September 2019

Approximate Bayesian computation (ABC) is an important framework within which to infer the structure and parameters of a systems biology model. It is especially suitable for biological systems with stochastic and nonlinear dynamics, for which the likelihood functions are intractable. However, the associated computational cost often limits ABC to models that are relatively quick to simulate in practice. We here present a Julia package, GpABC, that implements parameter inference and model selection for deterministic or stochastic models using i) standard rejection ABC or ABC-SMC, or ii) ABC with Gaussian process emulation. The latter significantly reduces the computational cost.

URL: https://github.com/tanhevg/GpABC.jl
Epilepsy and neurobehavioral abnormalities in mice with aKCNB1pathogenic variant that alters conducting and non-conducting functions of KV2.1
Authors: Hawkins Nicole A. , Misra Sunita N. , Jurado Manuel , Vierra Nicholas C. , Nguyen Kimberly , Wren Lisa , George Alfred L. , Trimmer James S. , Kearney Jennifer A.
Published: September 2019

Developmental and epileptic encephalopathies (DEE) are a group of severe epilepsies that usually present with intractable seizures, developmental delay and are at a higher risk for premature mortality. Numerous genes have been identified as a monogenic cause of DEE, includingKCNB1. The voltage-gated potassium channel KV2.1, encoded byKCNB1, is primarily responsible for delayed rectifier potassium currents that are important regulators of excitability in electrically excitable cells, including neurons and cardiomyocytes. Thede novopathogenic variantKCNB1-p.G379R was identified in an infant with epileptic spasms, atonic, focal and tonic-clonic seizures that were refractory to treatment with standard antiepileptic drugs. Previous work demonstrated deficits in potassium conductance, but did not assess non-conducting functions. To determine if the G379R variant affected clustering at endoplasmic reticulum-plasma membrane junctions KV2.1-G379R was expressed in HEK293T cells. KV2.1-G379R expression did not induce formation of endoplasmic reticulum-plasma membrane junctions, and co-expression of KV2.1-G379R with KV2.1-WT lowered induction of these structures relative to KV2.1-WT alone, suggesting a dominant negative effect. To model this variantin vivo, we introducedKcnb1G379Rinto mice using CRISPR/Cas9 genome editing. We characterized neurological and neurobehavioral phenotypes ofKcnb1G379R/+(Kcnb1R/+) andKcnb1G379R/G379R(Kcnb1R/R) mice, and screened for cardiac abnormalities. Immunohistochemistry studies on brains fromKcnb1+/+(WT), Kcnb1R/+andKcnb1R/Rmice revealed genotype-dependent differences in the levels and subcellular localization of KV2.1, with reduced plasma membrane expression of the KV2.1-G379R protein, consistent within vitrodata.Kcnb1R/+andKcnb1R/Rmice displayed profound hyperactivity, repetitive behaviors, impulsivity and reduced anxiety. In addition, bothKcnb1R/+andKcnb1R/Rmice exhibited abnormal interictal EEG abnormalities, including isolated spike and slow waves. Spontaneous seizure events were observed inKcnb1R/Rmice during exposure to novel environments and/or handling, while bothKcnb1R/+andKcnb1R/Rmutants were more susceptible to induced seizures.Kcnb1R/+andKcnb1R/Rmice exhibited prolonged rate-corrected QT interval on surface ECG recording. Overall, theKcnb1G379Rmice recapitulate many features observed in individuals with DEE due to pathogenic variants inKCNB1. This new mouse model ofKCNB1associated DEE will be valuable for improving the understanding of the underlying pathophysiology and will provide a valuable tool for the development of therapies to treat this pharmacoresistant DEE.
Testing Finch’s hypothesis: the role of organismal modularity on the escape from actuarial senescence
Authors: Bernard Connor , Compagnoni Aldo , Salguero-Gómez Roberto
Published: September 2019

Until recently, senescence was assumed to be a universal phenomenon. Evolutionary theories of senescence predict that no organism may escape the physiological decline that results in an increase in mortality risk and/or decline in fertility with age. However, evidence both in animals and plants has emerged in the last decade defying such predictions. Researchers are currently seeking mechanistic explanations for the observed variation in ageing trajectories.

We argue that the historical view on the inevitability of senescence is due, in part, to the development of its classical theories, which targeted primarily unitary organisms. In unitary species, the integration of resources and functions is high, and adult size is determined. In contrast, the architecture of modular organisms is indeterminate and built upon repeated modules. The isolation of mortality risk in species like hydra (Hydra spp.) or creosote brush (Larrea tridentata) may explain their null or even negative senescence.

Caleb Finch hypothesised three decades ago that species with the ability to compartmentalise risk may escape senescence. Here, we first review the evidence on organisms that slow down or even avoid senescence in the context of their architecture, along a continuum of unitarity-modularity. Then, we use open-access databases to comparatively analyse various moments of senescence and link longevity to the degree of anatomic modularity. Our analysis compares 138 plants and 151 animals. Our comparative analysis reveals that plant species that are more modular do indeed tend to escape from senescence more often than those that are unitary. The role of modularity in animal senescence is less clear.

In light of novel support for Finch’s hypothesis across a large diversity of plant species, and with less conclusive findings in animals, we identify new research directions. We highlight opportunities related to age-dependent mortality factors. Other areas for further research include the role of modularity in relation to endocrine actions, and the costs of modular anatomies.

“The actinozooid is a living thing which knows no time of youthful vigour, no waxing to a period of adult life, no waxing to senility – it knows no age – it practically knows no natural death.”– Wood-Jones (1912)
Audio-visual combination of syllables involves time-sensitive dynamics following from fusion failure
Authors: Bouton Sophie , Delgado-Saa Jaime , Olasagasti Itsaso , Giraud Anne-Lise
Published: September 2019

In face-to-face communication, audio-visual (AV) stimuli can be fused, combined or perceived as mismatching. While the left superior temporal sulcus (STS) is admittedly the locus of AV integration, the process leading to combination is unknown. Analysing behaviour and time-/source-resolved human MEG data, we show that while fusion and combination both involve early detection of AV physical features discrepancy in the STS, combination is associated in with activity of AV asynchrony-sensitive regions (auditory and inferior frontal cortices). Based on dynamic causal modelling, and neural signal decoding, we further show that AV speech integration outcome primarily depends on whether the STS can quickly converge onto an existing multimodal syllable representation, and that combination results from subsequent temporal processing, presumably re-ordering, of discrepant AV stimuli.
Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution
Authors: Andirkó Alejandro , Boeckx Cedric
Published: September 2019

The availability of high-coverage genomes of our extinct relatives, the Neanderthals and Denisovans, and the emergence of large, tissue-specific databases of modern human genetic variation, offer the possibility of probing the evolutionary trajectory of heterogenous structures of great interest, such as the brain. Using the GTEx cis-eQTL dataset and an extended catalog ofHomo sapiens-specific alleles relative to Neanderthals and Denisovans, we generated a dataset of nearly fixed,Homo sapiens-derived alleles that affect the regulation of gene expression across 15 brain (and brain related) structures. The list of variants obtained reveals enrichments in regions of the modern human genome showing putative signals of positive selection relative to archaic humans, and bring out the highly derived status of the cerebellum. Additionally, we complement previous literature on the expression effects of ancestral alleles in theHomo sapiensbrain by pointing at a downregulation bias caused by linkage disequilibrium.
Heart Rate Variability with Photoplethysmography in 8 Million Individuals: Results and Scaling Relations with Age, Gender, and Time of Day
Authors: Natarajan Aravind , Pantelopoulos Alexandros , Emir-Farinas Hulya , Natarajan Pradeep
Published: September 2019

Heart rate variability, or the variation in the time interval between consecutive beats, is a non-invasive dynamic metric of the autonomic nervous system and an independent risk factor for cardiovascular death. Prior limitations of use include requirements for continuous electrocardiography and lack of reference standards. Consumer wrist-worn tracking devices using photoplethysmography now provide the unique potential of continuously measuring surrogates of sympathetic and parasympathetic activity through the analysis of interbeat intervals. Here we leverage wrist-worn trackers to present the largest, to our knowledge, analysis of heart rate variability in humans across the time, frequency, and graphical domains. We derive diurnal parasympathetic and sympathetic measures and provide scaling parameters by age, sex, and time of day. Poincare plots graphically summarize heart rate variability metrics and may detect common arrhythmias. Lastly, we observe a strong dose-dependent correlation between daily steps and optimal heart rate variability metrics. Our results provide the ability to interpret continuous heart rate variability for tens of millions of wrist-worn trackers already in use.
Estimating Northern Fur Seal Pup Production: A Case Study of Batch Mark Abundance Estimation
Authors: Johnson Devin S. , Towell Rod G. , Baker Jason D.
Published: September 2019

We describe a hierarchical N-mixture model for estimating northern fur seal pup production from batch mark-resight data. Our goal was to improve upon a traditional design-based estimation method used for over 50 years. To this end, we propose a hierarchical N-mixture model to account for differences in animal availability for resighting and observer detection probabilities. A Bayesian approach is used for inference with three separate methods proposed for necessary computations. First a straightforward posterior sample is drawn using MCMC. This was considered the gold standard for this analysis. However, we also consider an approximate model-based on Gaussian approximation of the Poisson and binomial distributions used in the exact hierarchical model. By using the Gaussian approximations, analytic integration can be used to marginalize over latent components. Inference can then be made by maximizing the posterior to find the mode. Following this we investigate both delta-method and parametric bootstrap approaches for calculating abundance and the associated standard errors with batch sampling data collected on northern fur seals in 2016. Each of the three newly proposed methods produced virtually identical estimates and standard errors. In addition, the parametric bootstrap approximation to a posterior sample was also virtually the same as the MCMC derived sample. There were a handful of small differences in the point estimates of abundance but these were not large enough to be especially notable. There were some noticeable differences in uncertainty estimates. The production estimate coefficients of variation ranged from 2.5–9.5% for the model-based estimates, but 0.0–12.5% for the design-based estimates. The design-based estimates of uncertainty were more volatile using the design-based method with some standard error estimates unreasonably small. Through a case study we have provided support for using Gaussian approximation inN-mixture type models when abundance is relatively large. These situations are typically challenging for fitting models using any sort of marginalization because there is no analytic solution for the exact models. However, when abundances are large using a Gaussian approximated model allows for analytic integration over latent abundance states which can greatly facilitate methodology such as maximum likelihood or posterior inference.
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

The 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

Clostridioides (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.

Importance

The 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

Quantitative 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

Somatic 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.
Genes for ash tree resistance to an insect pest identified via comparative genomics
Authors: Kelly Laura J. , Plumb William J. , Carey David W. , Mason Mary E. , Cooper Endymion D. , Crowther William , Whittemore Alan T. , Rossiter Stephen J. , Koch Jennifer L. , Buggs Richard J. A.
Published: September 2019

Genome-wide discovery of candidate genes for functional traits within a species typically involves the sequencing of large samples of phenotyped individuals1, or linkage analysis through multiple generations2. When a trait occurs repeatedly among phylogenetically independent lineages within a genus, a more efficient approach may be to identify genes via detection of amino acid residues shared by species possessing that trait3,4. Here, by taking this approach, we identify candidate loci in the genusFraxinus(ash trees) for resistance to the emerald ash borer beetle (EAB;Agrilus planipennis), a pest species that appears innocuous to otherwise healthy ash in its native East Asian range5but is highly destructive in North America6and poses a threat to ash trees in Europe7. Assembling whole genome sequences for 24 diploid species and subspecies of ash, and estimating resistance to EAB for 26 taxa from egg bioassays, we find 53 genes containing amino acid variants shared between two or more independentFraxinuslineages with EAB-resistant species, that are unlikely to be due to chance or undetected paralogy. Of these, seven genes have putative roles relating to the phenylpropanoid biosynthesis pathway and 17 are potentially connected to herbivore recognition, defence signalling or programmed cell death. We also find that possible loss-of-function mutations among our 53 candidate genes are more frequent in susceptible species, than in resistant ones. Patterns of polymorphism for the EAB-associated amino acid variants in ash trees representing different European populations suggest that selection may be able to enhance their resistance to EAB.
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 Paragraph

Mutations 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

The 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.
High speed multi-plane super-resolution structured illumination microscopy of living cells using an image-splitting prism
Authors: Descloux Adrien , Müller Marcel , Navikas Vytautas , Markwirth Andreas , Van den Eynde Robin , Lukes Tomas , Hübner Wolfgang , Lasser Theo , Radenovic Aleksandra , Dedecker Peter , Huser Thomas
Published: September 2019

Super-resolution structured illumination microscopy (SR-SIM) can be conducted at video-rate acquisition speeds when combined with high-speed spatial light modulators and sCMOS cameras, rendering it particularly suitable for live cell imaging. If, however, three-dimensional (3D) information is desired, the sequential acquisition of vertical image stacks employed by current setups significantly slows down the acquisition process. In this work we present a multi-plane approach to SR-SIM that overcomes this slowdown via the simultaneous acquisition of multiple object planes, employing a recently introduced multi-plane image splitting prism combined with high-speed SR-SIM illumination. This strategy requires only the introduction of a single optical element and the addition of a second camera to acquire a laterally super-resolved three-dimensional image stack. We demonstrate the performance of multi-plane SR-SIM by applying this instrument to the dynamics of live mitochondrial network.
DNetPRO: A network approach for low-dimensional signatures from high-throughput data
Authors: Curti Nico , Giampieri Enrico , Levi Giuseppe , Castellani Gastone , Remondini Daniel
Published: September 2019

The objective of many high-throughput “omics” studies is to obtain a relatively low-dimensional set of observables - signature - for sample classification purposes (diagnosis, prognosis, stratification). We propose DNetPRO, Discriminant Analysis with Network PROcessing, a supervised signature identification method based on a bottom-up combinatorial approach that exploits the discriminant power of all variable pairs. The algorithm is easily scalable allowing efficient computing even for high number of observables (104 − 105). We show applications on real high-throughput genomic datasets in which our method outperforms existing results, or compares to them but with a smaller number of selected variables. Moreover the linearity of DNetPRO allows a clearer interpretation of the obtained signatures in comparison to non linear classification models
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

Although 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

The 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

Diversity 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

The 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

Drug 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

microRNA (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 implementation

Python source code is available at https://github.com/Amitai88/miRmedon

Contact

alal@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

Microtubules 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

Large-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 significance

Through 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.
The bacterial microbiota of a parasitic plant and its host
Authors: Fitzpatrick Connor R. , Schneider Adam C.
Published: September 2019

How plant-associated microbiota are shaped by, and potentially contribute to the unique ecology and heterotrophic life history of parasitic plants is relatively unknown. Here, we investigate the leaf and root bacterial communities associated with the root holoparasite Orobanche hederae and its host plant Hedera spp. We sequenced the V4 region of the 16S rRNA gene from DNA extracted from leaf and root samples of naturally growing populations of Orobanche and infected and uninfected Hedera. Root bacteria inhabiting Orobanche were less diverse, had fewer co-associations, and displayed increased compositional similarity to leaf bacteria relative to Hedera. Overall, Orobanche bacteria exhibited significant congruency with Hedera root bacteria across sites, but not the surrounding soil. Infection had localized and systemic effects on Hedera bacteria, which included effects on the abundance of individual taxa and root network properties. Collectively, our results indicate that the parasitic plant microbiome is derived but distinct from host plant microbiota, exhibits increased homogenization between shoot and root tissues, and displays far fewer co-associations among individual bacterial members. Host plant infection is accompanied by modest changes of associated microbiota at both local and systemic scales compared with uninfected individuals. Our results provide insight into the assembly and function of plant microbiota.
MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse
Authors: Bonhoure Nicolas , Praz Viviane , Moir Robyn D. , Willemin Gilles , Mange François , Moret Catherine , Willis Ian M. , Hernandez Nouria
Published: September 2019

Maf1-/- mice are lean, obesity-resistant and metabolically inefficient. Their increased energy expenditure is thought to be driven by a futile RNA cycle that reprograms metabolism to meet an increased demand for nucleotides stemming from the deregulation of RNA polymerase (pol) III transcription. Metabolic changes consistent with this model have been reported in both fasted and refed mice, however the impact of the fasting-refeeding-cycle on pol III function has not been examined. Here we show that changes in pol III occupancy in the liver of fasted versus refed wild-type mice are largely confined to low and intermediate occupancy genes; high occupancy genes are unchanged. However, in Maf1-/- mice, pol III occupancy of the vast majority of active loci in liver and the levels of specific precursor tRNAs in this tissue and other organs are higher than wild-type in both fasted and refed conditions. Thus, MAF1 functions as a chronic repressor of active pol III loci and can modulate transcription under different conditions. Our findings support the futile RNA cycle hypothesis, elaborate the mechanism of pol III repression by MAF1 and demonstrate a modest effect of MAF1 on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins.