bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scribble controls social behaviors through the regulation of the ERK/Mnk1 pathway
Authors: Moreau Maïté M. , Pietropaolo Susanna , Ezan Jérôme , Robert Benjamin J.A. , Miraux Sylvain , Maître Marlène , Cho Yoon , Crusio Wim E. , Montcouquiol Mireille , Sans Nathalie 
Published: September 2020

AbstractSocial behavior is a basic domain affected in several neurodevelopmental disorders. Indeed, deficits in social interest, interactions and recognition represent core symptoms of Autism Spectrum Disorder but are also found associated with a heterogeneous set of neuropsychiatric and rare disorders. TheSCRIBgene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of open neural tube defect, found at high frequencies in autistic patients, as other congenital anomalies, while the deletions/mutations of the 8q24.3 region encompassingSCRIBgenes is associated with multisyndromic and rare disorders. Nonetheless, the potential link betweenSCRIBand ASD-relevant social phenotypes has not been investigated yet. Hence, we performed an extensive behavioral characterization of thecircletailline that carries a mutated version ofScrib. Scribcrc/+mice displayed reduced social interest, lack of preference for social novelty and social reward, and reduced social habituation while other behavioral domains were unaltered. Social deficits were associated with reduced hippocampal volume, upregulation of ERK phosphorylation in specific hippocampal regions, together with increased c-Fos activity in the same brain areas. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a specific link between polarity genes, social behaviors and hippocampal functionality, thus suggesting a role forSCRIBin the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway, in underlying the social deficits induced bySCRIBmutation, thus supporting its relevance as a therapeutic target.
Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions
Authors: Kim Lynn-Jee , Chalmers Timothy J. , Madawala Romanthi , Smith Greg C. , Li Catherine , Das Abhirup , Keung Poon Eric Wing , Wang Jun , Tucker Simon P. , Sinclair David A. , Quek Lake-Ee , Wu Lindsay E. 
Published: September 2020

ABSTRACTOral administration of nicotinamide mononucleotide (NMN) is a prominent strategy to elevate nicotinamide adenine dinucleotide (NAD+) levels to treat age-related pathologies, where it is assumed to be directly incorporated into the NAD+metabolome through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which can modify the NAD+metabolome through enzyme activities that are not present in mammals. Here, we show that orally delivered NMN can undergo direct deamidation and incorporation in mammalian tissue via thede novopathway, and that this deamidation is reduced in animals treated with antibiotics to ablate the gut microbiome. Further, we show that antibiotics treatment increases the overall availability of NAD+metabolites in the gut epithelium, with one possibility that the gut microbiome could be in competition with the host for dietary NAD+precursors. Together, these data highlight previously undescribed interactions between orally delivered NMN and the gut microbiome.
IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease
Authors: Wang Wei , Pottorf Tana S , Wang Henry H , Dong Ruochen , Kavanaugh Matthew A. , Cornelius Joseph T. , Apte Udayan , Pritchard Michele T , Sharma Madhulika , Tran Pamela V 
Published: September 2020

AbstractPolycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) genes in adult mouse models of ADPKD attenuates severity of PKD and PLD. Here we examine the role of deletion of IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knock-out mice. Perinatal deletion of Thm1 results in disorganized and expanded biliary regions, biliary fibrosis, shortened primary cilia on CK19+ biliary epithelial cells, and reduced Notch signaling. In contrast, perinatal deletion of Pkd2 causes PLD, with multiple CK19+ biliary epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knock-out mice increased hepatomegaly and liver necrosis, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 in adult mice, alone and together with Pkd2, did not cause a biliary phenotype nor affect Pkd2-mutant PLD, respectively. However, similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2-mutant cyst-lining cholangiocytes. Taken together, Thm1 is required for biliary tract development, likely by enabling Notch signaling, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not affect hepatic cystogenesis, suggesting divergent regulation of signaling and cystogenic processes in the liver by IFT-B and –A. Notably, increased Notch signaling in cyst-lining cholangiocytes may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target.
Diversity and dynamics of fungi during spontaneous fermentations and association with unique aroma profiles in wine
Authors: Liu Di , Legras Jean-Luc , Zhang Pangzhen , Chen Deli , Howell Kate 
Published: September 2020

AbstractMicrobial activity is an integral part of an agricultural ecosystem and influences the quality of agricultural commodities. Microbial ecology influences grapevine health and crop production, conversion of sugar to ethanol during fermentation, thus wine aroma and flavour. There are regionally differentiated microbial patterns in grapevines and must but how microbial patterns contribute to wine regional distinctiveness (terroir) at small scale (<100 km) is not well defined. Here we characterise fungal communities, yeast populations, andSaccharomyces cerevisiaepopulations during spontaneous fermentation using metagenomics and population genetics to investigate microbial distribution and fungal contributions to the resultant wine. We found differentiation of fungi, yeasts, andS. cerevisiaebetween geographic origins (estate/vineyard), with influences from the grape variety. Growth and dominance ofS. cerevisiaeduring fermentation reshaped the fungal community and showed geographic structure at the strain level. Associations between fungal microbiota diversity and wine chemicals suggest thatS. cerevisiaeplays a primary role in determining wine aroma profiles at a sub-regional scale. The geographic distribution at scales of less than 12 km supports that differential microbial communities, including the dominant fermentative yeastS. cerevisiaecan be distinct in a local setting. These findings provide further evidence for microbial contributions to wineterroir, and perspectives for sustainable agricultural practices to maintain microbial diversity and optimise fermentation function to craft beverage quality.
Spatial analysis of ligand-receptor interaction in skin cancer at genome-wide and single-cell resolution
Authors: Tran M , Yoon S , Teoh M , Andersen S , Lam PY , Purdue P , Raghubar A , Hanson SJ , Devitt K , Jones K , Walters S , Tuong ZK , Kulasinghe A , Monkman J , Soyer HP , Frazer I , Nguyen Q 
Published: September 2020

AbstractThe ability to study cancer-immune cell communication across the whole tumor section without tissue dissociation is needed for cancer immunotherapies, to understand molecular mechanisms and to discover potential druggable targets. In this work, we developed a powerful experimental and analytical toolbox to enable genome-wide scale discovery and targeted validation of cellular communication. We assessed the utilities of five sequencing and imaging technologies to study cancer tissue, including single-cell RNA sequencing and Spatial Transcriptomic (measuring over >20,000 genes), RNA In Situ Hybridization (multiplex 4-12 genes), digital droplet PCR, and Opal multiplex protein staining (4-9 proteins). To spatially integrate multimodal data, we developed a computational method called STRISH that can automatically scan across the whole tissue section for local expression of gene and/or protein markers to recapitulate an interaction landscape across the whole tissue. We evaluated the unique ability of this toolbox to discover and validate cell-cell interactionin situthrough in-depth analysis of two types of cancer, basal cell carcinoma and squamous cell carcinoma, which account for over 70% of cancer cases. We expect that the approach described here will be widely applied to discover and validate ligand receptor interaction in different types of solid cancer tumors.
R2DT: computational framework for template-based RNA secondary structure visualisation across non-coding RNA types
Authors: Sweeney Blake A. , Hoksza David , Nawrocki Eric P. , Ribas Carlos Eduardo , Madeira Fábio , Cannone Jamie J. , Gutell Robin , Maddala Aparna , Meade Caeden , Williams Loren Dean , Petrov Anton S. , Chan Patricia P. , Lowe Todd M. , Finn Robert D. , Petrov Anton I. 
Published: September 2020

AbstractNon-coding RNAs (ncRNA) are essential for all life, and the functions of many ncRNAs depend on their secondary (2D) and tertiary (3D) structure. Despite proliferation of 2D visualisation software, there is a lack of methods for automatically generating 2D representations in consistent, reproducible, and recognisable layouts, making them difficult to construct, compare and analyse. Here we present R2DT, a comprehensive method for visualising a wide range of RNA structures in standardised layouts. R2DT is based on a library of 3,632 templates representing the majority of known structured RNAs, from small RNAs to the large subunit ribosomal RNA. R2DT has been applied to ncRNA sequences from the RNAcentral database and produced >13 million diagrams, creating the world’s largest RNA 2D structure dataset. The software is freely available athttps://github.com/rnacentral/R2DTand a web server is found athttps://rnacentral.org/r2dt.
Repression by hdac3 and dax1 mediates lineage restriction of embryonic stem cells
Authors: Olivieri Daniel , Papasaikas Panagiotis , Lukonin Ilya , Rittirsch Melanie , Hess Daniel , Smallwood Sébastien A. , Stadler Michael B. , Betschinger Joerg 
Published: September 2020

ABSTRACTMouse embryonic stem cells (mESCs) give rise to embryonic but not extraembryonic endoderm fates. Here, we identify the mechanism of this lineage barrier and report that the histone deacetylase Hdac3 and the corepressor Dax1 cooperatively restrict transdifferentiation of mESCs by silencing an enhancer of the extraembryonic endoderm-specifying transcription factor (TF) Gata6. This restriction is opposed by the pluripotency TFs Nr5a2 and Esrrb, which promote cell type conversion. Perturbation of the barrier extends mESC potency, and allows formation of 3D spheroids that mimic the spatial segregation of embryonic epiblast and extraembryonic endoderm in early embryos. Overall, this study shows that transcriptional repressors stabilize pluripotency by biasing the equilibrium between embryonic and extraembryonic lineages that is hardwired into the mESC TF network.
Peripheral microtubules ensure asymmetric furrow positioning in neural stem cells
Authors: Thomas Alexandre , Gallaud Emmanuel , Pascal Aude , Serre Laurence , Arnal Isabelle , Richard-Parpaillon Laurent , Savoian Matthew Scott , Giet Régis 
Published: September 2020

AbstractNeuroblast (NB) cell division is characterized by a basal positioning of the cleavage furrow resulting in a large difference in size between the future daughter cells. In animal cells, furrow placement and assembly is governed by centralspindlin, a highly conserved complex that accumulates at the equatorial cell cortex of the future cleavage site and at the spindle midzone. In contrast to model systems studied so far, these two centralspindlin populations are spatially and temporally separated in NBs. A cortical leading pool is located at the basal cleavage furrow site and a second pool accumulates at the midzone before travelling to the site of the basal cleavage furrow during cytokinesis completion. By manipulating microtubule (MT) dynamics, we show that the cortical centralspindlin population requires peripheral astral microtubules and the Chromosome Passenger Complex (CPC) for efficient recruitment. Loss of this pool does not prevent cytokinesis but enhances centralspindlin levels at the midzone leading to furrow repositioning towards the equator and decreased size asymmetry between daughter cells. Together these data reveal that the asymmetrical furrow placement characteristic of NBs results from a competition between spatially and functionally separate centralspindlin pools in which the cortical pool is dominant and requires peripheral astral microtubules.
Engineered expression of the invertebrate-specific scorpion toxin AaHIT reduces adult longevity and female fecundity in the diamondback mothPlutella xylostella
Authors: Harvey-Samuel T.D. , Xu X. , Lovett E. , Dafa’alla T. , Walker A. , Norman V.C. , Carter R. , Teal J. , Akilan L. , Leftwich P.T. , Alphey L. 
Published: September 2020

AbstractBACKGROUNDPrevious Genetic Pest Management (GPM) systems in diamondback moth (DBM) have relied on expressing lethal proteins (‘effectors’) that are ‘cell-autonomous’ i.e. do not leave the cell they are expressed in. To increase the flexibility of future GPM systems in DBM, we aimed to assess the use of a non cell-autonomous, invertebrate-specific, neurotoxic effector – the scorpion toxin AaHIT. This AaHIT effector was designed to be secreted by expressing cells, potentially leading to effects on distant cells, specifically neuromuscular junctions.RESULTSExpression of AaHIT caused a ‘shaking/quivering’ phenotype which could be repressed by provision of an antidote (tetracycline); a phenotype consistent with the AaHIT mode-of-action. This effect was more pronounced when AaHIT expression was driven by theHr5/ie1promoter (82.44% of males, 65.14% of females) rather thanOp/ie2 (57.35% of males, 48.39% of females). Contrary to expectations, the shaking phenotype and observed fitness costs were limited to adults where they caused severe reductions in mean longevity (–81%) and median female fecundity (–93%). qPCR of AaHIT expression patterns and analysis ofpiggyBac-mediated transgene insertion sites suggest that restriction of observed effects to the adult stages may be due to influence of local genomic environment on the tetO-AaHIT transgene.CONCLUSIONWe have demonstrated the feasibility of using non cell-autonomous effectors within a GPM context for the first time in the Lepidoptera, one of the most economically damaging orders of insects. These findings provide a framework for extending this system to other pest Lepidoptera and to other secreted effectors.
The evolution of thermal performance in native and invasive populations of Mimulus guttatus
Authors: Querns Aleah , Wooliver Rachel , Vallejo-Marín Mario , Sheth Seema Nayan 
Published: September 2020

Abstract1. The rise of globalization has spread organisms beyond their natural range, allowing further opportunity for species to adapt to novel environments and potentially become invaders. Yet, the role of climatic niche evolution in promoting the success of invasive species remains poorly understood. Here, we use thermal performance curves (TPCs) to test hypotheses about thermal adaptation during the invasion process. First, if novel temperature regimes impose strong selection in the introduced range, invasive populations may evolve distinct TPCs relative to native populations. Second, invasive species may not exhibit specialist-generalist tradeoffs and instead may be “masters-of-all” with high maximum performance and broad TPCs. Third, with sufficient time, standing genetic variation, and temperature-mediated selection, TPCs of native and invasive populations may show parallel evolution in response to thermal gradients.2. To test these hypotheses, we built TPCs for 18 native (United States) and 13 invasive (United Kingdom) populations of the yellow monkeyflower, Mimulus guttatus. We grew clones of multiple genotypes per population across six temperature regimes in growth chambers.3. Invasive populations have not evolved different thermal optima or performance breadths, providing evidence for evolutionary stasis of thermal performance between the native and invasive ranges after over 200 years post-introduction. Further, both native and invasive populations experienced similar specialist-generalist tradeoffs whereby broad TPCS come at the cost of lower peak performance. Inconsistent with the idea that the degree of thermal specialization varies across spatial or temperature gradients, native and invasive populations did not exhibit adaptive clines in thermal performance breadth with latitude or temperature seasonality. However, thermal optimum increased with mean annual temperature in the native range, indicating some adaptive differentiation among native populations4.Synthesis: These findings suggest that thermal niches were static during the invasion process, and that general-purpose genotypes, rather than rapid evolution in the introduced range, may promote invasion.
Go Get Data (GGD): simple, reproducible access to scientific data
Authors: Cormier Michael J. , Belyeu Jonathan R. , Pedersen Brent S. , Brown Joseph , Koster Johannes , Quinlan Aaron R. 
Published: September 2020

AbstractGenomics research is complicated by the inherent difficulty of collecting, transforming, and integrating the numerous datasets and annotations germane to one’s research. Furthermore, these data exist in disparate sources, and are stored in numerous, often abused formats from multiple genome builds. Since these complexities waste time, inhibit reproducibility, and curtail research creativity, we developed Go Get Data (GGD;https://gogetdata.github.io/) as a fast, reproducible approach to installing standardized data recipes.
Clinicopathologic Correlates and Natural History of Atypical Chronic Myeloid Leukemia
Authors: Montalban-Bravo Guillermo , Kanagal-Shamanna Rashmi , Sasaki Koji , Masarova Lucia , Naqvi Kiran , Jabbour Elias , DiNardo Courtney , Takahashi Koichi , Konopleva Marina , Pemmaraju Naveen , Kadia Tapan , Ravandi Farhad , Daver Naval , Borthakur Gautam , Estrov Zeev , Khoury Joseph D. , Loghavi Sanam , Soltysiak Kelly A. , Pierce Sherry , Bueso-Ramos Carlos , Patel Keyur , Verstovsek Srdan , Kantarjian Hagop , Bose Prithviraj , Garcia-Manero Guillermo 
Published: September 2020

ABSTRACTThere is limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). We evaluated the clinicopathological features, outcomes, and responses to therapy of 65 patients with aCML. Median age was 67 years (range 46-89). The most frequently mutated genes includedASXL1(83%),SRSF2(68%), andSETBP1(58%). Mutations inSETBP1, SRSF2, TET2, andGATA2tended to appear within dominant clones, with frequentSRSF2andSETBP1codominance, while other RAS pathway mutations were more likely to appear as minor clones. Acquisition of new, previously undetectable mutations at transformation was observed in 63% of evaluable patients, the most common involving signaling pathway mutations. Hypomethylating agents were associated with the highest response rates and duration. With a median overall survival of 25 months (95% CI 20-30), intensive chemotherapy was associated with worse OS than other treatment modalities, and allogeneic stem cell transplantation was the only therapy associated with improved outcomes (HR 0.044, 95% CI 0.035-0.593, p=0.007). Age, platelet count, BM blast percentage, and serum LDH levels were independent predictors of survival and were integrated in a multivariable model which allowed to predict 1-year and 3-year survival.
Stability of Human Serum Amyloid A Fibrils
Authors: Wang Wenhua , Hansmann Ulrich H. E. 
Published: September 2020

ABSTRACTIn systemic amyloidosis, Serum amyloid A (SAA) fibril deposits cause widespread damages to tissues and organs that eventually may lead to death. A therapeutically intervention therefore has either to dissolve these fibrils or inhibit their formation. However, only recently has the human SAA fibril structure be resolved at a resolution that is sufficient for development of drug candidates. Here, we use molecular dynamic simulations to probe the factors that modulate the stability of this fibril model. Our simulations suggest that fibril formation starts with the stacking of two misfolded monomers into metastable dimers, with the stacking depending on the N-terminal amyloidogenic regions of different chains forming anchors. The resulting dimers pack in a second step into a two-fold two-layer tetramer that is stable enough to nucleate fibril formation. The stability of the initial dimers is enhanced under acidic conditions by a strong salt bridge and side-chain hydrogen bond network in the C-terminal cavity (residues 23 - 51) but not affected by the presence of the disordered C-terminal tail.Table of Content Graphics
Multiscale analysis of single and double maternal-zygotic Myh9 and Myh10 mutants during mouse preimplantation development
Authors: Schliffka Markus Frederik , Tortorelli Anna-Francesca , Özgüç Özge , de Plater Ludmilla , Polzer Oliver , Pelzer Diane , Maître Jean-Léon 
Published: September 2020

AbstractDuring the first days of mammalian development, the embryo forms the blastocyst, the structure responsible for implanting the mammalian embryo. Consisting of an epithelium enveloping the pluripotent inner cell mass and a fluid-filled lumen, the blastocyst results from a series of cleavages divisions, morphogenetic movements and lineage specification. Recent studies identified the essential role of actomyosin contractility in driving the morphogenesis, fate specification and cytokinesis leading to the formation of the blastocyst. However, the preimplantation development of contractility mutants has not been characterized. Here, we generated single and double maternal-zygotic mutants of non-muscle myosin-II heavy chains (NMHC) to characterize them using multiscale imaging. We find that Myh9 (NMHC II-A) is the major NMHC during preimplantation development as its maternal-zygotic loss causes failed cytokinesis, increased duration of the cell cycle, weaker embryo compaction and reduced differentiation, whereas Myh10 (NMHC II-B) maternal-zygotic loss is much less severe. Double maternal-zygotic mutants for Myh9 and Myh10 show a much stronger phenotype, failing most attempts of cytokinesis. We find that morphogenesis and fate specification are affected but nevertheless carry on in a timely fashion, regardless of the impact of the mutations on cell number. Strikingly, even when all cell divisions fail, the resulting single-celled embryo can initiate trophectoderm differentiation and lumen formation by accumulating fluid in increasingly large vacuoles. Therefore, contractility mutants reveal that fluid accumulation is a cell-autonomous process and that the preimplantation program carries on independently of successful cell division.