bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining Gene Ontology with Deep Neural Networks to Enhance the Clustering of Single Cell RNA-Seq Data
Authors: Peng Jiajie , Wang Xiaoyu , Shang Xuequn
Published: October 2018

Background

Single cell RNA sequencing (scRNA-seq) is applied to assay the individual transcriptomes of large numbers of cells. The gene expression at single-cell level provides an opportunity for better understanding of cell function and new discoveries in biomedical areas. To ensure that the single-cell based gene expression data are interpreted appropriately, it is crucial to develop new computational methods.

Results

In this article, we try to construct the structure of neural networks based on the prior knowledge of Gene Ontology (GO). By integrating GO with both unsupervised and supervised models, two novel methods are proposed, named GOAE (Gene Ontology AutoEncoder) and GONN (Gene Ontology Neural Network) respectively, for clustering of scRNA-seq data.

Conclusions

The evaluation results show that the proposed models outperform some state-of-the-art approaches. Furthermore, incorporating with GO, we provide an opportunity to interpret the underlying biological mechanism behind the neural network-based model.
FT/FD-GRF5 repression loop directs growth to increase soybean yield
Authors: Xu Kun , Zhang Xiao-Mei , Yu Guolong , Lu Mingyang , Liu Chunyan , Chen Haifeng , Zhu Jinlong , Chen Fulu , Cheng Zhiyuan , Huang Penghui , Zhou Xinan , Chen Qingshan , Feng Xianzhong , Miao Yuchen , Liu Liangyu , Searle Iain , Fu Yong-Fu
Published: October 2018

Major advances in crop yield are eternally needed to cope with population growth. To balance vegetative and reproductive growth plays an important role in agricultural yield. To extend vegetative phase can increase crop yield, however, this strategy risks loss of yield in the field as crops may not mature in time before winter come. Here, we identified a repression feedback loop between GmFTL/GmFDL and GmGRF5-1 (Glycine-max-Flowering-Locus-T/Glycine-max-FDL and Glycine-max-GROWTH-REGULATING-FACTOR5-1), which functions as a pivotal regulator in balancing vegetative and reproductive phases in soybean. GmFTL/GmFDL and GmGRF5-1 directly repress gene expression each other. Additionally, GmGRF5-1 enhances vegetative growth by directly enhancing expression of photosynthesis- and auxin synthesis-related genes. To modulate the loop, such as fine-tuning GmFTL expression to trade-off vegetative and reproductive growth, increases substantially soybean yield in the field. Our findings not only uncover the mechanism balancing vegetative and reproductive growth, but open a new window to improve crop yield.
A Novel Denitrification Regulator, Adr, Mediates Denitrification Under Aerobic Conditions inSinorhizobium meliloti
Authors: Slape Coreen M. , Patankar Arati V. , GonzáLez Juan E.
Published: October 2018

Sinorhizobium melilotiis a soil dwelling bacteria capable of forming a symbiotic relationship with several legume hosts. Once symbiosis is established,S. melilotifixes atmospheric nitrogen into nitrogenated compounds, thus carrying out an important step in the nitrogen cycle.S. melilotiis also capable of the reverse process, denitrification, the reduction of nitrate and nitrite to nitrogen gas. In this study we have identified a novel regulator of denitrification inS. meliloti, Adr, which affects the expression of the denitrification genes in aerobically grown cultures. Analysis of the Adr sequence reveals a LuxR-like quorum sensing regulator, however, it does not respond to the known quorum sensing signals produced byS. meliloti. Additionally, we show that FixJ, the major regulator of denitrification and microaerobic respiration inS. meliloti, is active under our growth conditions. Comparison of the FixJ microarray to our Adr microarray shows a significant overlap between the two regulons. We also show that while Adr is not necessary for symbiotic nitrogen fixation, a functional copy of this regulator confers a competitive advantage toS. melilotiduring host invasion. Our findings suggest that Adr is a new type of denitrification regulator and that it acts at the same regulatory level as FixJ.

Importance

Rhizobia contribute to the nitrogen cycle by fixing atmospheric nitrogen to nitrogenated compounds and by denitrification, the reduction nitrate and nitrite to nitrogen gas. Denitrification enhances the survival ofSinorhizobium melilotiin the various environments it may encounter, such as free-living conditions in the rhizosphere, during invasion of the plant host, and after a symbiotic relationship has been established. Oxygen concentration is the typical signal for denitrification gene expression. Recent studies of low oxygen cultures ofS. melilotihave outlined the regulation structure for denitrification. In this study, we examine the regulation of denitrification in aerobically grownS. meliloticultures. Understanding howS. melilotiresponds to various oxygen concentrations will result in a more complete picture of denitrification regulation in this agriculturally important organism and the impact of denitrification on the soil microbiome as a whole.
Metatranscriptomics and nitrogen fixation from the rhizoplane of maize plantlets inoculated with a group of PGPRs
Authors: Gómez-Godínez Lorena Jacqueline , Ormeño-Orrillo Ernesto , Martínez-Romero Esperanza
Published: October 2018

The free-living soil bacteria that are beneficial for the growth of plants are known as plant growth-promoting rhizobacteria (PGPR). In this work, a multi-species of PGPR bacteria inoculant was designed, which included nitrogen-fixing strains such as Rhizobium phaseoli, Sinorhizobium americanum and Azospirillum brasilense, as well as other plant growth promoting bacteria such as Bacillus subtillis and Methylobacterium extorquens. The multi-species community exerted a beneficial effect on plant seedlings when it was inoculated, greater than the effect observed when inoculating each bacteria individually. Acetylene reduction of maize roots was recorded with the multi-species inoculant, which suggests that nitrogen fixation occurred under these conditions. To analyze the contributions of the different nitrogen-fixing bacteria that were inoculated, a metatranscriptomic analysis was performed. The differential expression analysis revealed that the predominantly nif transcripts of Azospirillum are overexpressed, suggesting that it was responsible for nitrogen fixation in maize. Overall, we analyzed the interaction of a synthetic community, suggesting it as an option, for future formulations of biofertilizers.

IMPORTANCE

While nodulation processes and nitrogen fixation by rhizobia have been well studied, little is known about the interaction between rhizobia and non-leguminous plants such as maize, which is used as a model for this study. Nitrogen fixation in cereals is a long searched goal. Instead of single species inoculants, multi-species inoculation may be more efficient to promote plant growth and fix nitrogen. Metatrascriptomes allowed us to recognize the bacteria responsible for nitrogen fixation in plant rootlets. The study of the function of certain genes may help to understand how microorganisms interact with the root plant, as well as allow a better use of microorganisms for the generation of novel biofertilizers using microbial consortia.
A statistical simulator scDesign for rational scRNA-seq experimental design
Authors: Li Wei Vivian , Li Jingyi Jessica
Published: October 2018

Motivation

Single-cell RNA-sequencing (scRNA-seq) has revolutionized biological sciences by revealing genome-wide gene expression levels within individual cells. However, a critical challenge faced by researchers is how to optimize the choices of sequencing platforms, sequencing depths, and cell numbers in designing scRNA-seq experiments, so as to balance the exploration of the depth and breadth of transcriptome information.

Results

Here we present a flexible and robust simulator, scDesign, the first statistical framework for researchers to quantitatively assess practical scRNA-seq experimental design in the context of differential gene expression analysis. In addition to experimental design, scDesign also assists computational method development by generating high-quality synthetic scRNA-seq datasets under customized experimental settings. In an evaluation based on 17 cell types and six different protocols, scDesign outperformed four state-of-the-art scRNA-seq simulation methods and led to rational experimental design. In addition, scDesign demonstrates reproducibility across biological replicates and independent studies. We also discuss the performance of multiple differential expression and dimension reduction methods based on the protocol-dependent scRNA-seq data generated by scDesign. scDesign is expected to be an effective bioinformatic tool that assists rational scRNA-seq experiment design based on specific research goals and compares various scRNA-seq computational methods.

Availability

We have implemented our method in the R package scDesign, which is freely available at https://github.com/Vivianstats/scDesign.

Contact

jli@stat.ucla.edu
Genetics and evidence for balancing selection of a sex-linked colour polymorphism in a songbird
Authors: Kim Kang-Wook , Jackson Benjamin C. , Zhang Hanyuan , Toews David P. L. , Taylor Scott A. , Greig Emma I. , Lovette Irby J. , Liu Mengning M. , Davison Angus , Griffith Simon C. , Zeng Kai , Burke Terry
Published: October 2018

Colour polymorphisms play a key role in sexual selection and speciation, yet the mechanisms that generate and maintain them are not fully understood. Here, we use genomic and transcriptomic tools to identify the precise genetic architecture and evolutionary history of a sex-linked colour polymorphism in the Gouldian finchErythrura gouldiaethat is also accompanied by remarkable differences in behaviour and physiology. We find that differences in colour are associated with an ~72-kbp region of the Z chromosome in a putative regulatory region forfollistatin, an antagonist of theTGF-βsuperfamily genes. The region is highly differentiated between morphs, unlike the rest of the genome, yet we find no evidence that an inversion is involved in maintaining the distinct haplotypes. Coalescent simulations confirm that there is elevated nucleotide diversity and an excess of intermediate frequency alleles at this locus. We conclude that this pleiotropic colour polymorphism is most probably maintained by balancing selection.
IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization
Authors: Kang Kyuho , Park Sung Ho , Kang Keunsoo , Ivashkiv Lionel B.
Published: October 2018

Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genesviaenhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
Reporter Ion Data Analysis Reduction (R.I.D.A.R) for isobaric proteomics quantification studies
Authors: Jenkins Conor , Norris Alexis L. , O’Neill Maura , Das Sudipto , Andresson Thorkell , Orsburn Ben
Published: October 2018

Isobaric labeling-based relative quantification techniques such as iTRAQ and TMT were introduced 15 years ago and are now nearly ubiquitous in shotgun proteomics labs around the world. The methods for data processing in these experiments has changed little since inception, with peptide database searching of all MS/MS spectra occurring concurrent or asynchronous to the quantification of the reporter fragment regions. In this study we present an alternative method for data processing whereby the reporter ion region of all MS/MS spectra are first examined and spectra that are not quantitatively interesting to the end user are discarded. The remaining MS/MS spectra that are retained can then be more rapidly searched for computationally expensive database alterations such as post-translational modifications and single amino acid variations in more practical time. We have termed this method Reporter Ion Data Analysis Reduction (RIDAR). To demonstrate the application of RIDAR, we reprocess a recent CPTAC 2 study containing approximately 7.8 million MS/MS spectra. Post RIDAR processing we can search this public dataset versus a human canonical FASTA database and a compiled proteogenomic database of over 875,000 known cancer mutations in a single day on a standard desktop computer, a time reduction of 85% compared to the conventional workflow. With the rapidly increasing size and density of shotgun proteomics data files, RIDAR facilitates rapid analysis of large proteomics datasets for researchers without access to high performance computational resources.

Abstract Graphic
Single-cell virus sequencing of influenza infections that trigger innate immunity
Authors: Russell Alistair B. , Kowalsky Jacob R. , Bloom Jesse D.
Published: October 2018

The outcome of viral infection is extremely heterogeneous, with infected cells only sometimes activating innate immunity. Here we develop a new approach to assess how the genetic variation inherent in viral populations contributes to this heterogeneity. We do this by determining both the transcriptome and full-length sequences of all viral genes in single influenza-infected cells. Most cells are infected by virions with defects such as amino-acid mutations, internal deletions, or failure to express a gene. We identify instances of each type of defect that increase the likelihood that a cell activates an innate-immune response. However, immune activation remains stochastic in cells infected by virions with these defects, and sometimes occurs even when a cell is infected by a virion that expresses unmutated copies of all genes. Our work shows that viral genetic variation substantially contributes to but does not fully explain the heterogeneity in single influenza-infected cells.
GrgA as a potential target of selective antichlamydials
Authors: Zhang Huirong , Vellappan Sangeevan , Tang M. Matt , Bao Xiaofeng , Fan Huizhou
Published: October 2018

Chlamydiais a common pathogen that can causes serious complications in the reproductive system and eyes. Lack of vaccine and other effective prophylactic measures coupled with the largely asymptomatic nature and unrare clinical treatment failure calls for development of new antichlamydials, particularly selective antichlamydials without adverse effects on humans and the beneficial microbiota. We previously reported that benzal-N-acylhydrazones (BAH) can inhibit chlamydiae without detectable adverse effects on host cells and beneficial lactobacilli that dominate the human vaginal microbiota among reproductive-age women. However, the antichlamydial mechanism of BAH is not known. Whereas 4 single nucleotide polymorphisms (i.e., SNP1-4) were identified in a rareChlamydiavariant with a low level of BAH resistance, termed MCR, previous studies failed to establish a causal effect of any particular SNP(s). In the present work, we performed recombination to segregate the four SNPs. Susceptibility tests indicate that the R51G GrgA allele is both necessary and sufficient for the low level of BAH resistance. Thus, theChlamydia-specific transcription factor GrgA either is a direct target of BAH or regulates BAH susceptibility. We further confirm an extremely low rate of BAH resistance inChlamydia. Our findings warrant exploration of GrgA as a therapeutic and prophylactic target for chlamydial infections.
The best of both worlds: A new lipid complex has micelle and bicelle-like properties
Authors: Rieth Monica D.
Published: October 2018

Bicelles have been demonstrated to be a valuable tool for studying membrane protein interactions and structure in vitro. They are distinguished by a distinct lipid bilayer that mimics the plasma membrane of cells making it more native-like than its detergent micelle counter-part. Bicelles are typically comprised of a long-chain phospholipid such as dimyristoylphosphatidylcholine (DMPC) and a short-chain phospholipid such as dihexanoylphosphatidylcholine (DHPC). When mixed together in solution DMPC-DHPC bicelles assume a discoidal structure comprised of a heterogeneous arrangement where the short-chain lipids gather around the rim of the disk and the long-chain lipids form the flat, planar, bilayer region. In this study, the nonionic surfactant, C8E5, was used to prepare mixtures with DMPC to determine if it adopts properties similar to bicelles with a q ≥ 0.5. At q ≥ 0.5, DMPC-DHPC bicelles are bilayered and DMPC is sequestered from the detergent micelle-like DHPC. Mixtures of DMPC and C8E5 were prepared at various q values, a parameter used to describe the mole ratio of DMPC to DHPC in the preparation of bicelles. Employing biophysical methods like dynamic light scattering, 31P-NMR and analytical ultracentrifugation, properties of these lipid-detergent complexes are described. Interestingly they adopted a spherical-shaped micellar structure morphology and did not assume a discoidal shape typical of bicelles at q ≥ 0.5. However, they appear to retain bilayer-like properties that may prove beneficial for in vitro biophysical studies of membrane proteins.
Histone acetyltransferase inhibition rescues differentiation of emerin-deficient myogenic progenitors
Authors: Bossone Katherine A. , Ellis Joseph A. , Holaska James M.
Published: October 2018

Introduction

Emery-Dreifuss Muscular Dystrophy (EDMD) is a disease characterized by skeletal muscle wasting, major tendon contractures, and cardiac conduction defects. Mutations in the gene encoding emerin cause EDMD1. Our previous studies suggested emerin activation of Histone Deacetylase 3 (HDAC3) to reduce Histone 4-Lysine 5 (H4K5) acetylation (ac) is important for myogenic differentiation.

Methods

Pharmacological inhibitors (Nu9056, L002) of histone acetyltransferases targeting acetylated H4K5 were used to test if increased acetylated H4K5 was responsible for the impaired differentiation seen in emerin deficient myogenic progenitors.

Results

Nu9056 and L002 rescued impaired differentiation in emerin deficiency. SRT1720, which inhibits the NAD+-dependent deacetylase Sirtuin 1 (SIRT1), failed to rescue myotube formation.

Discussion

We conclude emerin regulation of HDAC3 activity to affect H4K5 acetylation dynamics is important for myogenic differentiation. Targeting H4K5ac dynamics represents a new strategy for ameliorating the skeletal muscle wasting seen in EDMD1.
Cell-type-specific resolution epigenetics without the need for cell sorting or single-cell biology
Authors: Rahmani Elior , Schweiger Regev , Rhead Brooke , Criswell Lindsey A. , Barcellos Lisa F. , Eskin Eleazar , Rosset Saharon , Sankararaman Sriram , Halperin Eran
Published: October 2018

High costs and technical limitations of cell sorting and single-cell techniques currently restrict the collection of large-scale, cell-type-specific DNA methylation data. This, in turn, impedes our ability to tackle key biological questions that pertain to variation within a population, such as identification of disease-associated genes at a cell-type-specific resolution. Here, we show mathematically and empirically that cell-type-specific methylation levels of an individual can be learned from its tissue-level bulk data, conceptually emulating the case where the individual has been profiled with a single-cell resolution and then signals were aggregated in each cell population separately. Provided with this unprecedented way to perform powerful large-scale epigenetic studies with cell-type-specific resolution, we revisit previous studies with tissue-level bulk methylation and reveal novel associations with leukocyte composition in blood and with rheumatoid arthritis. For the latter, we further show consistency with validation data collected from sorted leukocyte sub-types. Corresponding software is available from: https://github.com/cozygene/TCA.
The biodiversity benefit of native forest over Grain-for-Green plantations
Authors: Wang Xiaoyang , Hua Fangyuan , Wang Lin , Wilcove David S. , Yu Douglas W
Published: October 2018

Aim

China’s Grain-for-Green Program (GFGP) is the largest reforestation program in the world and has been operating since 1999. The GFGP has promoted the establishment of tree plantations over the preservation of diverse native forest. In a previous study (Hua et al. 2016, Nat Comms 7:12717), we showed that native forest supports higher species richnesses of birds and bees than do GFGP plantations. We also showed that ‘mixed-plantation’ GFGP plantations, which are mostly made up of two to five neighboring monoculture stands of different tree species, planted in checkboard fashion, support a level of bird (but not bee) species richness that is higher than any of the individual GFGP monocultures, although still below that of native forest. To better protect terrestrial biodiversity, which is an important objective of China’s land-sustainability spending, we recommended that the GFGP should firstly prioritize native forest conservation and regeneration and secondly promote checkerboard planting arrangements over monocultures. Here, we use metabarcoding of arthropod biodiversity to test the generality of these results and policy recommendations.

Location

Sichuan, China

Methods

We used COI-amplicon sequencing (‘metabarcoding’) of bulk samples of arthropods that were collected with pan traps in native forest, cropland, mixed plantations, and monocultures.

Results

Native forest supports the highest overall levels of arthropod species richness and diversity, followed by cropland and mixed plantations, followed by bamboo monoculture, followed by the other monocultures. Also, the arthropod community in mixed plantations shares more species with native forest than do any of the monocultures. Together, these results show a biodiversity value of mixed plantations for arthropods that is higher than that previously indicated by bees alone.

Main conclusion

These results strengthen our original policy recommendations of (1) promoting the conservation and expansion of native forest and (2) promoting mixed-plantation arrangements. The value of this added metabarcoding-based analysis is that these policy prescriptions are now also based on a dataset that includes over 500 species-resolution taxa, ranging across the Arthropoda.
Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology
Authors: Suliman Reut , Title Ben , Cohen Yahel , Tal Maayan , Tal Nitzan , Gudmundsdottir Bjorg , Gudmundsson Kristbjorn O. , Keller Jonathan R , Huang Guo-Jen , Yarom Yosef , Shifman Sagiv
Published: October 2018

Genes implicated in autism spectrum disorder (ASD) are enriched with chromatin regulators, but the mechanisms leading to the abnormal behavior and cognition are still unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior. We generated conditional knockout mice with brain-specific mutation in Pogz, a heterochromatin regulator recurrently mutated in ASD and other neurodevelopmental disorders, and demonstrated that these mice display phenotypes that resemble the human condition. Pogz deficiency led to smaller brain, growth impairment, motor learning deficits, and increased social interactions that mimic the human overly friendly phenotype. At the molecular level, reporter assay indicated that POGZ functions as a negative regulator of transcription through its interaction with HP1 proteins. In accordance, we found a significant upregulation of gene expression, most notably in the cerebellum. Furthermore, Pogz deficiency was associated with a significant reduction in the firing frequency of simple and complex spikes in cerebellar Purkinje cells with no changes in their intrinsic properties. Overall, our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and to motor and social abnormalities in ASD.
Condensin II inactivation in interphase does not affect chromatin folding or gene expression
Authors: Abdennur Nezar , Schwarzer Wibke , Pekowska Aleksandra , Shaltiel Indra Alon , Huber Wolfgang , Haering Christian H , Mirny Leonid , Spitz François
Published: October 2018

Condensin complexes have been proposed to play a prominent role in interphase chromatin organization and control of gene expression. Here, we report that the deletion of the central condensin II kleisin subunit Ncaph2 in differentiated mouse hepatocytes does not lead to significant changes in chromosome organization or in gene expression. Both observations challenge current views that implicate condensin in interphase chromosomal domain formation and in enhancer-promoter interactions. Instead, we suggest that the previously reported effects of condensin perturbation may result from their structural role during mitosis, which might indirectly impact the re-establishment of interphase chromosomal architecture after cell division.
Single cell analyses of the effects of Amyloid-beta42 and Interleukin-4 on neural stem/progenitor cell plasticity in adult zebrafish brain
Authors: Cosacak Mehmet Ilyas , Bhattarai Prabesh , Zhang Yixin , Kizil Caghan
Published: October 2018

Neural stem cells (NSCs) constitute the reservoir for new cells and might be harnessed for stem cell-based regenerative therapies. Zebrafish has remarkable ability to regenerate its brain by inducing NSC plasticity upon Alzheimer’s pathology. We recently identified that NSCs enhance their proliferation and neurogenic outcome in an Amyloid-beta42-based (Aβ42) experimental Alzheimer’s disease model in zebrafish brain and Interleukin-4 (IL4) is a critical molecule for inducing NSC proliferation in AD conditions. However, the mechanisms by which Aβ42 and IL4 affect NSCs remained unknown. Using single cell transcriptomics, we determined distinct subtypes of NSCs and neurons in adult zebrafish brain, identified differentially expressed genes after Aβ42 and IL4 treatments, analyzed the gene ontology and pathways that are affected by Aβ42 and IL4, and investigated how cell-cell communication is altered through secreted molecules and their receptors. Our results constitute the most extensive resource in the Alzheimer’s disease model of adult zebrafish brain, are likely to provide unique insights into how Aβ42/IL4 affects NSC plasticity and yield in novel drug targets for mobilizing neural stem cells for endogenous neuro-regeneration.
Inferring Population Genetics Parameters of Evolving Viruses Using Time-series Data
Authors: Zinger Tal , Pennings Pleuni S. , Stern Adi
Published: October 2018

1

With the advent of deep sequencing techniques, it is now possible to track the evolution of viruses with ever-increasing detail. Here we present FITS (Flexible Inference from Time-Series) – a computational framework that allows inference of either the fitness of a mutation, the mutation rate or the population size from genomic time-series sequencing data. FITS was designed first and foremost for analysis of either short-term Evolve & Resequence (E&R) experiments, or for rapidly recombining populations of viruses. We thoroughly explore the performance of FITS on noisy simulated data, and highlight its ability to infer meaningful information even in those circumstances. In particular FITS is able to categorize a mutation as Advantageous, Neutral or Deleterious. We next apply FITS to empirical data from an E&R experiment on poliovirus where parameters were determined experimentally and demonstrate extremely high accuracy in inference. We highlight the ease of use of FITS for step-wise or iterative inference of mutation rates, population size, and fitness values for each mutation sequenced, when deep sequencing data is available at multiple time-points.

Availability

FITS is written in C++ and is available both with a highly user friendly graphical user interface but also as a command line program that allows parallel high throughput analyses. Source code, binaries (Windows and Mac) and complementary scripts, are available from GitHub at https://github.com/SternLabTAU/FITS.

Contact

sternadi@tau.ac.il
Experimental manipulation ofHeliconiuswarning patterns reduces harassment of previously mated females
Authors: Merrill Richard M. , Neggazi Sara , Morrison Colin R. , Crisp Rachel , McMillan W. Owen
Published: October 2018

Why warning patterns are so diverse is an enduring evolutionary problem. Because predators learn to associate particular patterns with unpleasant experiences, an individual’s risk of predation should decrease as the local density of its warning pattern increases.Heliconiusbutterflies, however, are known for their diversity of warning patterns, and the establishment of entirely new phenotypes is difficult to explain under strict frequency-dependent selection. One possibility is that during periods of relaxed selection, drift may allow new variants to rise above a threshold density until mimicry selection takes over. We propose an alternative hypothesis where novel pattern phenotypes arise due to a conflict of interests between the sexes. It is well established that maleHeliconiususe warning patterns as a mating cue. This will likely be beneficial to males as it will increase the efficiency of finding mates. However, already mated females may suffer fitness costs if these cues lead to harassment by males during oviposition or foraging. When constraints imposed by predation are locally relaxed, this could lead to rapid divergence in pattern phenotypes through chase-away sexual selection. To begin to test this hypothesis, we experimentally manipulated the warning patterns of matedHeliconius erato demaphoonfemales and recorded their interactions with conspecific males, and the effect of male presence on laying rate. As predicted, males interacted less with mated females whose red forewing band was blacked-out, as compared to control females whose warning pattern remained intact. We also show that females lay less eggs in the presence of males, but we were unable to detect a significant interaction between warning pattern treatment and the presence of males on female fecundity. Our results suggest that male attraction to conspecific warning patterns, may impose a previously unrecognized cost onHeliconiusfemales.
Structure of transcribing RNA polymerase II-nucleosome complex
Authors: Farnung Lucas , Vos Seychelle M. , Cramer Patrick
Published: October 2018

Transcription of eukaryotic protein-coding genes requires passage of RNA polymerase II (Pol II) through chromatin. Pol II passage is impaired by nucleosomes and requires elongation factors that help Pol II to efficiently overcome the nucleosomal barrier1-4. How the Pol II machinery transcribes through a nucleosome remains unclear because structural studies have been limited to Pol II elongation complexes formed on DNA templates lacking nucleosomes5. Here we report the cryo-electron microscopy (cryo-EM) structure of transcribing Pol II from the yeastSaccharomyces cerevisiaeengaged with a downstream nucleosome core particle (NCP) at an overall resolution of 4.4 Å with resolutions ranging from 4-6 Å in Pol II and 6-8 Å in the NCP. Pol II and the NCP adopt a defined orientation that could not be predicted from modelling. Pol II contacts DNA of the incoming NCP on both sides of the nucleosomal dyad with its domains ‘clamp head’ and ‘lobe’. Comparison of the Pol II-NCP structure to known structures of Pol II complexes reveals that the elongation factors TFIIS, DSIF, NELF, PAF1 complex, and SPT6 can be accommodated on the Pol II surface in the presence of the oriented nucleosome. Further structural comparisons show that the chromatin remodelling enzyme Chd1, which is also required for efficient Pol II passage6,7, could bind the oriented nucleosome with its motor domain. The DNA-binding region of Chd1 must however be released from DNA when Pol II approaches the nucleosome, and based on published data8,9this is predicted to stimulate Chd1 activity and to facilitate Pol II passage. Our results provide a starting point for a mechanistic analysis of chromatin transcription.
Phase separation of YAP reorganizes genome topology for long-term, YAP target gene expression
Authors: Cai Danfeng , Feliciano Daniel , Dong Peng , Flores Eduardo , Gruebele Martin , Porat-Shliom Natalie , Sukenik Shahar , Liu Zhe , Lippincott-Schwartz Jennifer
Published: October 2018

Yes-associated Protein (YAP) is a transcriptional co-activator that regulates cell proliferation and survival by binding to a selective set of enhancers for potent target gene activation, but how YAP coordinates these transcriptional responses is unknown. Here, we demonstrate that YAP forms liquid-like condensates in the nucleus in response to macromolecular crowding. Formed within seconds of hyperosmotic stress, YAP condensates compartmentalized YAP’s DNA binding cofactor TEAD1 along with other YAP-related transcription co-activators, including TAZ, and subsequently induced transcription of YAP-specific proliferation genes. Super-resolution imaging using Assay for Transposase Accessible Chromatin with photoactivated localization microscopy (ATAC-PALM) revealed that YAP nuclear condensates were areas enriched in accessible chromatin domains organized as super-enhancers. Initially devoid of RNA Polymerase II (Pol II), the accessible chromatin domains later acquired Pol II, producing newly transcribed RNA. Removal of YAP’s intrinsically-disordered transcription activation domain (TAD) prevented YAP condensate formation and diminished downstream YAP signaling. Thus, dynamic changes in genome organization and gene activation during YAP reprogramming is mediated by liquid-liquid phase separation.
Isolating syntax in natural language: MEG evidence for an early contribution of left posterior temporal cortex
Authors: Flick Graham , Pylkkänena Liina
Published: October 2018

Syntax is the engine that allows us to create an infinitude of linguistic expressions, and the construction of syntactic structures, such as noun phrases and verb phrases, is considered a fundamental component of language processing. Nevertheless, insights concerning the neurobiological basis of syntax have remained elusive, in part because it is difficult to isolate syntax from semantic composition. Consequently, many studies of syntax have relied on meaningless artificial stimuli, such as jabberwocky expressions or artificial grammars. However, while pure manipulations of syntax are challenging to design, natural language grammars do have a sparse set of constructions presenting this possibility. Here we examined one such case, English post-nominal adjectives (mountain TALL enough for a strenuous hike), which were contrasted with semantically parallel but structurally simpler noun-adjective sequences in an MEG experiment. We observed a sharp activity increase in the left posterior temporal lobe (PTL) when syntactic composition was more straightforward, approximately 200 ms after adjective onset. The semantic fit between the noun and adjective was also varied, but this affected anterior temporal cortex, consistent with prior work. These findings offer a unique demonstration of the relevance of posterior temporal cortex for syntactic processing in natural language. We also present connectivity evidence that the syntax-related PTL responses were relayed to ipsilateral inferior frontal and anterior temporal regions. The combined results draw an initial picture of the rapid spatio-temporal dynamics of the syntactic and semantic composition network in sentence processing.
A multifaceted approach for analyzing complex phenotypic data in rodent models of autism
Authors: Das Ishita , Estevez Marcel A. , Sarkar Anjali A. , Banerjee-Basu Sharmila
Published: October 2018

AutDB features a modular framework that aims at collating multifactorial risk factors associated with autism spectrum disorder (ASD). The animal model (AM) module of AutDB was first developed for mouse models of genes and CNVs associated with ASD (Kumar et al., 2011). Subsequently, environmentally induced rodent models were introduced to capture the full spectrum of risk-factors associated with ASD, along with idiopathic models represented by inbred strains. Using the data systematically annotated in AutDB, we depict the intricate trends in the research findings based on rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from 911 genetic, 269 induced and 17 inbred rodent models of ASD extracted from 787 publications. As expected, many of these include animal model equivalents of the ‘core’ phenotypes associated with ASD, as well as several comorbid features of ASD including anxiety, seizures and motor-control deficits. Uniquely, AutDB curates rescue models where various treatment strategies were used in rodent ASD models to alleviate ASD-relevant phenotypes. We further examine ASD models based on 52 genes and 2 CNV loci to identify 24 pharmaceutical agents that were used in 2 or more paradigms for testing their efficacy. As a case study, we analyze various Shank3 mouse models providing a high-resolution view of thein vivorole of this high-confidence ASD gene. Together, this resource provides a snapshot of genetic and induced models of ASD within a shared annotation platform to examine the complex meshing of diverse ASD-associated risk-factors.
Converging roles of glutamate receptors in domestication and prosociality
Authors: O’Rourke Thomas , Boeckx Cedric
Published: October 2018

The present paper highlights the prevalence of signals of positive selection on genes coding for glutamate receptors—most notably kainate and metabotropic receptors—in domesticated animals and anatomically modern humans. Relying on their expression in the central nervous system and phenotypes associated with mutations in these genes, we claim that regulatory changes in kainate and metabotropic receptor genes have led to alterations in limbic function and Hypothalamic-Pituitary-Adrenal axis regulation, with potential implications for the emergence of unique social behaviors and communicative abilities in (self-)domesticated species.
Magnetophospenes in humans exposed to ELF MF up to 50 mT, a threshold study
Authors: Legros A , Modolo J , Corbacio M , Goulet D , Plante M , Souques M , Deschamps F , Ostiguy G , Lambrozo J , Thomas AW
Published: October 2018

Although magnetophosphene perception is the most reliable reported effect on acute human neurophysiological responses to extremely low frequency (ELF) magnetic field (MF) exposure, current knowledge is based on small sample size, non-replicated experiments. In this study, we established MF levels triggering magnetophosphenes at 20, 50, 60 and 100 Hz in humans. Magnetophosphene perception and EEG were collected in 55 magnetic flux density conditions randomly delivered in each frequency group (2 experiments, total n=145). Results indicate that threshold values 1) need to be reported as a function of dB/dt instead of flux density, and 2) are frequency-dependent (higher sensitivity to lower frequencies). No clear trend was found in EEG data.
Illumina-based sequencing framework for accurate detection and mapping of influenza virus defective interfering particle-associated RNAs
Authors: Alnaji Fadi G. , Holmes Jessica R. , Rendon Gloria , Vera J. Cristobal , Fields Chris , Martin Brigitte E. , Brooke Christopher B.
Published: October 2018

The mechanisms and consequences of defective interfering particle (DIP) formation during influenza virus infection remain poorly understood. The development of next generation sequencing (NGS) technologies has made it possible to identify large numbers of DIP-associated sequences, providing a powerful tool to better understand their biological relevance. However, NGS approaches pose numerous technical challenges including the precise identification and mapping of deletion junctions in the presence of frequent mutation and base-calling errors, and the potential for numerous experimental and computational artifacts. Here we detail an Illumina-based sequencing framework and bioinformatics pipeline capable of generating highly accurate and reproducible profiles of DIP-associated junction sequences. We use a combination of simulated and experimental control datasets to optimize pipeline performance and demonstrate the absence of significant artifacts. Finally, we use this optimized pipeline to generate a high-resolution profile of DIP-associated junctions produced during influenza virus infection and demonstrate how this data can provide insight into mechanisms of DIP formation. This work highlights the specific challenges associated with NGS-based detection of DIP-associated sequences, and details the computational and experimental controls required for such studies.
Bodily sensations in social scenarios: Where in the body?
Authors: Novembre Giovanni , Zanon Marco , Morrison India , Ambron Elisabetta
Published: October 2018

Bodily states are fundamental to emotions′ emergence and are believed to constitute the first step in the chain of events that culminate in emotional awareness. Recent works have given fresh support to this view by showing that distinct topographical maps can be derived to describe how basic and more complex emotions are represented in the body. However, it is still unclear whether these bodily maps can also extend to emotions experienced specifically within social interactions and how these representations relate to basic emotions. To address this issue, we used the emBODY tool to obtain high-resolution bodily maps that represent the body activation and deactivation experienced by healthy participants in social scenarios depicting establishment or loss of social bonds. We show that clear patterns of activation/deactivation across the body emerge depending on the valence and on the characteristics of the single social scenarios, but also a common activation of head, chest and limbs across scenarios. Furthermore, we showed that maps related to complex social scenarios are strongly correlated with bodily states experienced in basic emotions, suggesting that the patterns of body activation/deactivation found for social scenarios might represent a combination of different basic emotions these experiences elicit. Our data tackle conscious emotional experiences and show for the first time how ′painful′ social events are felt on the body, providing findings that complement verbal reports and neuroimaging data on social rejection. Furthermore, they show that bodily feelings related to complex social scenarios, despite referring to unified independent emotional states, are also related to bodily correlates of basic emotions.
The mouse HP1 proteins are essential for preventing liver tumorigenesis
Authors: Saksouk Nehmé , Hajdari Shefqet , Pratlong Marine , Barrachina Célia , Graber Céline , Zavoriti Aliki , Sarrazin Amélie , Pirot Nelly , Noël Jean-Yohan , Khellaf Lakhdar , Fabbrizio Eric , Julien Eric , Cammas Florence M.
Published: October 2018

Chromatin organization is essential for appropriate interpretation of the genetic information. Here, we demonstrated that the chromatin associated proteins HP1 are dispensable for cell survival but are essential within hepatocytes to prevent liver tumor development. Molecular characterization of pre-malignant HP1-Triple KO livers revealed that HP1 are essential for the maintenance of the structural organization of heterochromatin but surprisingly, not for several well known heterochromatin functions such as the maintenance of the genome stability nor the regulation of major satellite repeat expression within liver. We further show that some specific retrotransposons, mainly of the ERV family, get reactivated in HP1-TKO livers correlating, in some cases, with the activation of the adjacent genes. We present evidence that this reactivation of ERV relies on the HP1-dependent ability of the corepressor TRIM28 to regulate KRAB-ZFP repressive activity. Intriguingly, we found that in contrast to the observation in young animals, the HP1-dependent maintenance of ERV silencing becomes independent of TRIM28 in old animals. Finally, we showed that HP1 are also essential directly or indirectly for the regulation of single genes with most of them having well characterized functions in liver homeostasis such as regulation of the redox and endoplasmic reticulum equilibrium, lipid metabolism and steroid biosynthesis.

Altogether, our findings indicate that HP1 proteins, through the modulation of multiple chromatin-associated events both within the heterochromatic and euchromatic compartments, act as guardians of liver homeostasis to prevent tumor development.
A comparison of automated lesion segmentation approaches for chronic stroke T1-weighted MRI data
Authors: Ito Kaori L. , Kim Hosung , Liew Sook-Lei
Published: October 2018

Accurate stroke lesion segmentation is a critical step in the neuroimaging processing pipeline to assess the relationship between post-stroke brain structure, function, and behavior. While many multimodal segmentation algorithms have been developed for acute stroke neuroimaging, few are effective with only a single T1-weighted (T1w) anatomical MRI. This is a critical gap because most stroke rehabilitation research relies on a single T1w MRI for defining the lesion. Although several attempts to automate the segmentation of chronic lesions on single-channel T1w MRI have been made, these approaches have not been systematically evaluated on a large dataset. Here, we performed an exhaustive review of the literature and identified one semi- and three fully automated approaches for segmentation of chronic stroke lesions using T1w MRI within the last ten years: Clusterize, Automated Lesion Identification, Gaussian naïve Bayes lesion detection, and LINDA. We evaluated each method on a large T1w stroke dataset (N=181) using visual and quantitative methods. LINDA was the most computationally expensive approach, but performed best across the three main evaluation metrics (median values: Dice Coefficient=0.50, Hausdorff’s Distance=36.34 mm, and Average Symmetric Surface Distance = 4.97 mm), whereas the Gaussian Bayes method had the highest recall/least false negatives (median=0.80). Segmentation accuracy in all automated methods were influenced by size (small: worst) and stroke territory (brainstem, cerebellum: worst) of the lesion. To facilitate reproducible science, we have made our analysis files publicly available online at https://github.com/npnl/elsa. We hope these findings are informative to future development of T1w lesion segmentation algorithms.