bluuebunny/crossref_metadata_2025_split huggingface dataset:
RedOak: a reference-free and alignment-free structure for indexing a collection of similar genomes
Authors: Agret Clément , Chateau Annie , Droc Gaetan , Sarah Gautier , Ruiz Manuel , Mancheron Alban 
Published: December 2020

AbstractBackgroundAs the cost of DNA sequencing decreases, high-throughput sequencing technologies become increasingly accessible to many laboratories. Consequently, new issues emerge that require new algorithms, including tools for indexing and compressing hundred to thousands of complete genomes.ResultsThis paper presents RedOak, a reference-free and alignment-free software package that allows for the indexing of a large collection of similar genomes. RedOak can also be applied to reads from unassembled genomes, and it provides a nucleotide sequence query function. This software is based on ak-mer approach and has been developed to be heavily parallelized and distributed on several nodes of a cluster. The source code of our RedOak algorithm is available athttps://gite.lirmm.fr/doccy/RedOak.ConclusionsRedOak may be really useful for biologists and bioinformaticians expecting to extract information from large sequence datasets.
Honeybee gut microbiota modulates host behaviors and neurological processes
Authors: Zhang Zijing , Mu Xiaohuan , Cao Qina , Shi Yao , Hu Xiaosong , Zheng Hao 
Published: December 2020

AbstractHoneybee is a highly social insect with a reach behavioral repertoire and is a versatile model for neurobiological research. The honeybee gut microbiota is composed of a limited number of bacterial phylotypes that play an important role in host health. However, it remains unclear whether the microbiota can shape brain profiles and behaviors. Here, we revealed that the gut microbiota is requisite for the olfactory learning and memory ability of honeybees and alters the level of neurotransmitters in the brain. Transcriptomic and proteomic analysis showed distinctive gene expression and protein signatures for gnotobiotic bees associated with different gut bacteria. Specifically, genes related to olfactory functions and labor division are most upregulated. Moreover, differentially spliced genes in the brains of colonized bees largely overlapped with the datasets for human autism. The circulating metabolome profiles identified that different gut species regulated specific module of metabolites in the host hemolymph. Most altered metabolites are involved in the amino acid and glycerophospholipid metabolism pathways for the production of neuroactive compounds. Finally, antibiotic treatment disturbed the gut community and the nursing behavior of worker bees under field conditions. The brain transcripts and gut metabolism was also greatly interfered in treated bees. Collectively, we demonstrate that the gut microbiota regulates honeybee behaviors, brain gene transcription, and the circulating metabolism. Our findings highlight the contributions of honeybee gut microbes in the neurological processes with striking parallels to those found in other animals, thus providing a promising model to understand the host-microbe interactions via the gut-brain axis.
Dopamine D1 receptor-expressing neurons activity is essential for locomotor and sensitizing effects of a single injection of cocaine
Authors: Nakamura Yukari , Longueville Sophie , Nishi Akinori , Hervé Denis , Girault Jean-Antoine , Nakamura Yuki 
Published: December 2020

AbstractD1 dopamine receptors play an important role in the effects of cocaine. Here we investigated the role of neurons which express these receptors (D1-neurons) in the acute locomotor effects of cocaine and the locomotor sensitization observed after a second injection of this drug. We inhibited D1-neurons using double transgenic mice conditionally expressing the inhibitory Gi-coupleddesigner receptor exclusively activated by designer drugs(Gi-DREADD) in D1-neurons. Chemogenetic inhibition of D1-neurons by a low dose of clozapine (0.1 mg/kg) decreased the induction ofFosin striatal neurons. It diminished the basal locomotor activity and acute hyper-locomotion induced by cocaine (20 mg/kg). Clozapine 0.1 mg/kg had no effect by itself and did not alter cocaine effects in non-transgenic mice. Inhibition of D1-neurons during the first cocaine administration reduced the sensitization of the locomotor response in response to a second cocaine administration ten days later. At day 11, inhibition of D1-neurons by clozapine stimulation of Gi-DREADD, prevented the expression of the sensitized locomotor response, whereas at day 12, in the absence of clozapine and D1-neurons inhibition, all mice displayed a sensitized response to cocaine. These results show that chemogenetic inhibition of D1-neurons decreases spontaneous and cocaine-induced locomotor activity. It blunts the induction and prevents the expression of sensitization in a two-injection protocol of sensitization but does not alter established sensitization. Our study further supports the central role of D1-neurons in mediating the acute locomotor effects of cocaine and its sensitization.
Alternative promoter usage modulates miRNA-guided translation inhibition of a m6A reader in phosphate starvation
Authors: Reis Rodrigo Siqueira , Deforges Jules , Clúa Joaquín , Poirier Yves 
Published: December 2020

AbstractAlternative transcription start sites (TSSs) are widespread in eukaryotes. In plants, light, development and tissue regulate selective usage of several TSSs, producing transcripts with distinct 5′UTR as well as shorter protein isoforms with distinct subcellular localization or activity. However, the function of non-coding transcripts generated by alternative TSSs is still largely unknown. We show that phosphate availability regulates numerous alternative TSSs, including a non-coding alternative TSS (ALTECT4) associated withECT4, encoding a N6-methyladenosine (m6A) reader. We found thatECT4harbors a cleavage-resistant miR826b target site at its 3’UTR, also present inALTECT4. In the absence ofALTECT4, miR826b guides translation inhibition ofECT4. Phosphate deficiency triggers specific and robust expression ofALTECT4, counteracting miR826b inhibition of its targets, includingECT4. The role ofALTECT4as a miR826b antagonist shows that it acts incisto regulate translation of the m6A reader ECT4, and this function might be shared among other non-coding transcripts generated by alternative TSS.
Predicting speech from a cortical hierarchy of event-based timescales
Authors: Schmitt Lea-Maria , Erb Julia , Tune Sarah , Rysop Anna , Hartwigsen Gesa , Obleser Jonas 
Published: December 2020

AbstractHow can anticipatory neural processes structure the temporal unfolding of context in our natural environment? We here provide evidence for a neural coding scheme that sparsely updates contextual representations at the boundary of events and gives rise to a hierarchical, multi-layered organization of predictive language comprehension. Training artificial neural networks to predict the next word in a story at five stacked timescales and then using model-based functional MRI, we observe a sparse, event-based “surprisal hierarchy”. The hierarchy evolved along a temporo-parietal pathway, with model-based surprisal at longest timescales represented in inferior parietal regions. Along this hierarchy, surprisal at any given timescale gated bottom-up and top-down connectivity to neighbouring timescales. In contrast, surprisal derived from a continuously updated context influenced temporo-parietal activity only at short timescales. Representing context in the form of increasingly coarse events constitutes a network architecture for making predictions that is both computationally efficient and semantically rich.
Disablingde novoDNA methylation in embryonic stem cells allows an illegitimate fate trajectory
Authors: Kinoshita Masaki , Li Meng Amy , Barber Michael , Mansfield William , Dietmann Sabine , Smith Austin 
Published: December 2020

ABSTRACTGenome remethylation is essential for mammalian development but specific reasons are unclear. Here we examined embryonic stem (ES) cell fate in the absence ofde novoDNA methyltransferases. We observed that ES cells deficient for bothDnmt3aandDnmt3bare rapidly eliminated from chimaeras. On further investigation we found that in vivo and in vitro the formative pluripotency transition is derailed towards production of trophoblast. This aberrant trajectory is associated with failure to suppress activation ofAscl2. Ascl2encodes a bHLH transcription factor expressed in placenta. Misexpression ofAscl2in ES cells provokes transdifferentiation to trophoblast-like cells. Conversely,Ascl2deletion rescues formative transition ofDnmt3a/bmutants and improves contribution to chimaeric epiblast. Thus,de novoDNA methylation safeguards against ectopic activation ofAscl2. However,Dnmt3a/b-deficient cells remain defective in ongoing embryogenesis. We surmise that multiple developmental transitions may be secured by DNA methylation silencing potentially disruptive genes.SIGNIFICANCE STATEMENTMammalian DNA is widely modified by methylation of cytosine residues. This modification is added to DNA during early development. If methylation is prevented, the embryo dies by mid-gestation with multiple abnormalities. In this study we found that stem cells lacking the DNA methylation enzymes do not differentiate efficiently into cell types of the embryo and are diverted into producing placental cells. This switch in cell fate is driven by a transcription factor, Ascl2, which should only be produced in placenta. In the absence of DNA methylation, theAscl2gene is mis-expressed. Removing Ascl2 redirects embryonic fate but not full differentiation potential, suggesting that methylation acts at multiple developmental transitions to restrict activation of disruptive genes.
Linker histone H1.8 inhibits chromatin-binding of condensins and DNA topoisomerase II to tune chromosome length and individualization
Authors: Choppakatla Pavan , Dekker Bastiaan , Cutts Erin E. , Vannini Alessandro , Dekker Job , Funabiki Hironori 
Published: December 2020

SummaryDNA loop extrusion by condensins and decatenation by DNA topoisomerase II (topo II) are thought to drive mitotic chromosome compaction and individualization. Here, we reveal that the linker histone H1.8 antagonizes condensins and topo II to shape mitotic chromosome organization. In vitro chromatin reconstitution experiments demonstrate that H1.8 inhibits binding of condensins and topo II to nucleosome arrays. Accordingly, H1.8 depletion in Xenopus egg extracts increased condensins and topo II levels on mitotic chromatin. Chromosome morphology and Hi-C analyses suggest that H1.8 depletion makes chromosomes thinner and longer through shortening the average loop size and reducing the DNA amount in each layer of mitotic loops. Furthermore, excess loading of condensins and topo II to chromosomes by H1.8 depletion causes hyper-chromosome individualization and dispersion. We propose that condensins and topo II are essential for chromosome individualization, but their functions are tuned by the linker histone to keep chromosomes together until anaphase.
A global map of the impact of deletion of Post-Translational Modification sites in genetic diseases
Authors: Vellosillo Perceval , Minguez Pablo 
Published: December 2020

AbstractBackgroundThere are >200 protein post-translational modification (PTMs) types described in eukaryotes, having diverse species conservation levels, proteome coverage, number of high-throughput experiments and functional roles. From a clinical perspective, a number of diseases have been associated to deregulated PTM sites and missense rare variants are globally enriched in PTMs. We hypothesize that some genetic diseases may be caused by the deregulation of particular functions produced by the removal of a specific PTM type by genomic variants.ResultsWe collected >320,000 human PTMs of 59 types and cross them with >4M missense DNA variants annotated with pathogenic predictions and disease associations. We report >1.74M PTM-variant concurrences in >16,500 proteins that an enrichment analysis distributed in 217 pairwise significant associations between 18 PTM types and 150 genetic diseases. Around 23% of these associations are already described in the literature, 34% have partial evidences based on single variants, related diseases or regulatory evidences, and 43% are novel. Removal of acetylation presents the highest effect, still low studied PTM types like S-glutathionylation or S-nitrosylation show relevance. A network of PTM types and phenotypes associations is also discussed. Using pathogenicity predictions we identified potential PTM sites to produce particular diseases if genomic variants remove them.ConclusionsOur results show an important impact of PTM removal producing genetic diseases and phenotypes that is PTM type specific. We describe for the first time a general scenario of PTM types and genetic diseases direct associations, many of them novel, that provides new capacities to understand and diagnose these disorders.
A Distributed Circuit for Associating Environmental Context to Motor Choice in Retrosplenial Cortex
Authors: Franco Luis M. , Goard Michael J. 
Published: December 2020

ABSTRACTDuring navigation, animals often use recognition of familiar environmental contexts to guide motor action selection. The retrosplenial cortex (RSC) receives inputs from both visual cortex and subcortical regions required for spatial memory, and projects to motor planning regions. However, it is not known whether RSC is important for associating familiar environmental contexts with specific motor actions. Here, we test this possibility by developing a task in which trajectories are chosen based on the context. We find that mice exhibit differential pre-decision activity in RSC, and that optogenetic suppression of RSC activity impairs task performance. Individual RSC neurons encode a range of task variables, often multiplexed with distinct temporal profiles. However, the responses are spatiotemporally organized, with task variables represented along a posterior-to-anterior gradient along RSC during the behavioral performance, consistent with histological characterization. These results reveal an anatomically-organized retrosplenial cortical circuit for associating environmental contexts to appropriate motor outputs.
CTCF is a Barrier for Totipotent-like Reprogramming
Authors: Olbrich Teresa , Vega-Sendino Maria , Tillo Desiree , Wu Wei , Zolnerowich Nicholas , Tran Andy D. , Domingo Catherine N. , Franco Mariajose , Markiewicz-Potoczny Marta , Pegoraro Gianluca , FitzGerald Peter C. , Kruhlak Michael J. , Lazzerini-Denchi Eros , Nora Elphege P. , Nussenzweig Andre , Ruiz Sergio 
Published: December 2020

SUMMARYTotipotent cells have the ability of generating embryonic and extra-embryonic tissues1,2. Interestingly, a rare population of cells with totipotent-like potential was identified within ESC cultures3. These cells, known as 2 cell (2C)-like cells, arise from ESC and display similar features to those found in the totipotent 2 cell embryo2-4. However, the molecular determinants of 2C-like conversion have not been completely elucidated. Here, we show that CTCF is a barrier for 2C-like reprogramming. Indeed, forced conversion to a 2C-like state by DUX expression was associated with DNA damage at a subset of CTCF binding sites. Endogenous or DUX-induced 2C-like ESC showed decreased CTCF enrichment at known binding sites, suggesting that acquisition of a totipotent-like state is associated with a highly dynamic chromatin architecture. Accordingly, depletion of CTCF in ESC efficiently promoted spontaneous and asynchronous conversion to a totipotent-like state. This phenotypic reprogramming was reversible upon restoration of CTCF levels. Furthermore, we showed that transcriptional activation of the ZSCAN4 cluster was necessary for successful 2C-like reprogramming. In summary, we revealed the intimate relation between CTCF and totipotent-like reprogramming.
Voltage-clamp fluorometry analysis of structural rearrangements of ATP-gated channel P2X2 upon hyperpolarization
Authors: Andriani Rizki Tsari , Kubo Yoshihiro 
Published: December 2020

ABSTRACTThe gating of the ATP-activated channel P2X2 has been shown to be dependent not only on [ATP] but also on membrane voltage, despite the absence of a canonical voltage-sensor domain. We aimed to investigate the structural rearrangements of the rat P2X2 during ATP- and voltage-dependent gating by voltage-clamp fluorometry technique. We observed fast and linearly voltage-dependent fluorescence intensity (F) changes at Ala337 and Ile341 in the TM2 domain, which could be due to the electrochromic effect, reflecting the presence of a converged electric field here. We also observed slow and voltage-dependent F changes at Ala337, which reflect the structural rearrangements. Furthermore, we identified that the interaction between Ala337 in TM2 and Phe44 in TM1, located in close proximity in the ATP-bound open state, is critical for activation. Taken together, we propose that the voltage dependence of the interaction in the converged electric field underlies the voltage-dependent gating.
Discovery of synthetic lethal and tumor suppressive paralog pairs in the human genome
Authors: Parrish Phoebe C. R. , Thomas James D. , Kamlapurkar Shriya , Gabel Austin , Bradley Robert K. , Berger Alice H. 
Published: December 2020

AbstractCRISPR knockout screens have accelerated the discovery of important cancer genetic dependencies. However, traditional CRISPR-Cas9 screens are limited in their ability to assay the function of redundant or duplicated genes. Paralogs in multi-gene families constitute two-thirds of the protein-coding genome, so this blind spot is the rule, not the exception. To overcome the limitations of single gene CRISPR knockout screens, we developedpairedguide RNAs forParalog gENetic interaction mapping (pgPEN), a pooled CRISPR/Cas9 approach which targets over a thousand duplicated human paralogs in single knockout and double knockout configurations. We applied pgPEN to two cell lineages and discovered that over 10% of human paralogs exhibit synthetic lethality in at least one cellular context. We recovered known synthetic lethal paralogs such asMAP2K1/MAP2K2, important drug targets such asCDK4/CDK6, and numerous other synthetic lethal pairs such asCCNL1/CCNL2.In addition, we identified ten tumor suppressive paralog pairs whose compound loss promotes cell growth. These findings identify a large number of previously unidentified essential gene families and nominate new druggable targets for oncology drug discovery.HighlightsComprehensive genetic interaction mapping of 1,030 human duplicated paralogs using a dual targeting CRISPR/Cas9 approachDuplicated paralogs are highly enriched for genetic interactionsSynthetic lethal paralogs includeCCNL1/CCNL2, CDK4/CDK6, andGSK3A/GSK3BTumor suppressor paralog pairs includeCDKN2A/CDKN2BandFBXO25/FBXO32
In-depth characterization of denitrifier communities across different soil ecosystems in the tundra
Authors: Pessi Igor S. , Viitamäki Sirja , Virkkala Anna-Maria , Eronen-Rasimus Eeva , Delmont Tom O. , Marushchak Maija E. , Luoto Miska , Hultman Jenni 
Published: December 2020

AbstractBackgroundIn contrast to earlier assumptions, there is now mounting evidence for the role of tundra soils as important sources of the greenhouse gas nitrous oxide (N2O). However, the microorganisms involved in the cycling of N2O in this system remain largely uncharacterized. Since tundra soils are variable sources and sinks of N2O, we aimed at investigating differences in community structure across different soil ecosystems in the tundra.ResultsWe analysed 1.4 Tb of metagenomic data from soils in northern Finland covering a range of ecosystems from dry upland soils to water-logged fens and obtained 796 manually binned and curated metagenome-assembled genomes (MAGs). We then searched for MAGs harbouring genes involved in denitrification, an important process driving N2O emissions. Communities of potential denitrifiers were dominated by microorganisms with truncated denitrification pathways (i.e., lacking one or more denitrification genes) and differed across soil ecosystems. Upland soils showed a strong N2O sink potential and were dominated by members of the Alphaproteobacteria such as Bradyrhizobium and Reyranella. Fens, which had in general net-zero N2O fluxes, had a high abundance of poorly characterized taxa affiliated with the Chloroflexota lineage Ellin6529 and the Acidobacteriota subdivision Gp23.ConclusionsBy coupling an in-depth characterization of microbial communities with in situ measurements of N2O fluxes, our results suggest that the observed spatial patterns of N2O fluxes in the tundra are related to differences in the composition of denitrifier communities.
Oligomerization of the Human Adenosine A2AReceptor is Driven by the Intrinsically Disordered C-terminus
Authors: Nguyen Khanh D. Q. , Vigers Michael , Sefah Eric , Seppälä Susanna , Hoover Jennifer P. , Schonenbach Nicole S. , Mertz Blake , O’Malley Michelle A. , Han Songi 
Published: December 2020

ABSTRACTG protein-coupled receptors (GPCRs) have long been shown to exist as oligomers with functional properties distinct from those of the monomeric counterparts, but the driving factors of GPCR oligomerization remain relatively unexplored. In this study, we focus on the human adenosine A2Areceptor (A2AR), a model GPCR that forms oligomers bothin vitroandin vivo. Combining experimental and computational approaches, we discover that the intrinsically disordered C-terminus of A2AR drives the homo-oligomerization of the receptor. The formation of A2AR oligomers declines progressively and systematically with the shortening of the C-terminus. Multiple interaction sites and types are responsible for A2AR oligomerization, including disulfide linkages, hydrogen bonds, electrostatic interactions, and hydrophobic interactions. These interactions are enhanced by depletion interactions along the C-terminus, forming a tunable network of bonds that allow A2AR oligomers to adopt multiple interfaces. This study uncovers the disordered C-terminus as a prominent driving factor for the oligomerization of a GPCR, offering important guidance for structure-function studies of A2AR and other GPCRs.