bluuebunny/crossref_metadata_2025_split huggingface dataset:
APC-mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness
Authors: Kawasaki Yoshihiro , Hamaji Tomoko , Owada Koji , Hayashi Akiko , Wu Yuping , Nogi Taisaku , Okada Miwa , Sakai Shoko , Tokushige Naoko , Kouyama Yuta , Niida Atsushi , Mimori Koshi , Kuroda Toshihiko , Senda Takao , Ohsugi Miho , Fumoto Katsumi , Kikuchi Akira , Widlund Per O. , Kiyosue Kazuyuki , Yamashita Norio , Morita Masahiko , Yokota Hideo , Arjunan Satya N. V. , Chew Wei-Xiang , Takahashi Koichi , Legant Wesley R. , Chen Bi-Chang , Betzig Eric , Smits Ron , Fodde Riccardo , Oshima Hiroko , Oshima Masanobu , Taketo M. Mark , Akiyama Tetsu , Mimori-Kiyosue Yuko 
Published: September 2020

AbstractCertain copy number alterations (CNAs) are strongly associated with particular cancer types. However, the mechanisms that underlie selection of specific CNAs remain unknown. Here, we identified functional relationships between recurrent CNAs in colorectal cancers (CRCs) andadenomatous polyposis coli(APC) mutations. Quantitative phenotyping of mitotic spindles highlighted APC functions at centrosomes where APC positively regulated Aurora A kinase (AURKA). Upon APC inactivation, elevated β-catenin levels blocked AURKA activation, which caused chromosome instability and suppressed proliferation, resulting in the generation and selection of AURKA-activating CNAs. Arm-level amplification of chromosomes that contained AURKA and AURKA activator genes was observed inAPC-mutant CRCs, early stage mouse tumours, and cells in culture, which was concomitant with an increase in growth potential. Our findings demonstrate a mechanism that restores tumour cell fitness through compensatory chromosome alterations to overcome adverse effects of prior mutations, which may affect the course of cancer type-specific CNA formation.
Joint language production: an electrophysiological investigation of simulated lexical access on behalf of task partner
Authors: Kuhlen Anna K. , Abdel Rahman Rasha 
Published: September 2020

AbstractThis study investigates in a joint action setting a well-established effect in speech production, cumulative semantic interference, an increase in naming latencies when naming a series of semantically related pictures. In a joint action setting, two task partners take turns naming pictures. Previous work in this setting demonstrated that naming latencies increase not only with each semantically related picture speakers named themselves, but also with each picture named by the partner (Hoedemaker, Ernst, Meyer, & Belke, 2017; Kuhlen & Abdel Rahman, 2017). This suggests that speakers pursue lexical access on behalf of their partner. In two electrophysiological experiments (N=30 each) we investigated the neuro-cognitive signatures of such simulated lexical access. As expected, in both experiments speakers’ naming latency increased with successive naming instances within a given semantic category. Correspondingly, speakers’ EEG showed an increasing posterior positivity between 250-400ms, an ERP modulation typically associated with lexical access. However, unlike previous experiments, speakers were not influenced by their partner’s picture naming. Accordingly, we found no electrophysiological evidence of lexical access. To reconcile these findings we pooled behavioral data from five experiments (N=144). Within this large sample we find empirical evidence for partner-elicited interference. Furthermore, our data suggests that speakers may be less affected by their partner’s naming response in settings with remotely located task partners (as in present experiments). We conclude that speakers do not always represent their partner’s naming response and that our experimental setting may have limited the participants’ evaluation of the task as a joint action.
Genomic approach for conservation and the sustainable management of endangered species of the Amazon
Authors: Fazzi-Gomes Paola , Aguiar Jonas , Cabral Gleyce Fonseca , Marques Diego , Palheta Helber , Moreira Fabiano , Rodrigues Marilia , Cavalcante Renata , Souza Jorge , Silva Caio , Hamoy Igor , Santos Sidney 
Published: September 2020

AbstractA broad panel of potentially amplifiable microsatellite loci and a multiplex system were developed for the Amazonian symbol fish species Arapaima gigas, which is currently in high danger of extinction due to the disorderly fishing exploitation. Several factors have contributed to the increase of this threat, among which we highlight the lack of genetic information about the structure and taxonomic status of the species, as well as the lack of accurate tools for evaluation of the effectivity of current management programs. Based on Arapaima gigas’ whole genome, available at the NCBI database (ID: 12404), a total of 95,098 unique perfect microsatellites were identified, including their proposed primers. From this panel, a multiplex system containing 12 tetranucleotide microsatellite markers was validated. These tools are valuable for research in as many areas as bioinformatics, ecology, genetics, evolution and comparative studies, since they are able to provide more accurate information for fishing management, conservation of wild populations and genetic management of aquaculture.
Compartmentalization of mRNAs in the giant, unicellular green algaeAcetabularia acetabulum
Authors: Andresen Ina J. , Orr Russell J. S. , Shalchian-Tabrizi Kamran , Bråte Jon 
Published: September 2020

AbstractAcetabularia acetabulumis a single-celled green alga previously used as a model species for studying the role of the nucleus in cell development and morphogenesis. The highly elongated cell, which stretches several centimeters, harbors a single nucleus located in the basal end. AlthoughA. acetabulumhistorically has been an important model in cell biology, almost nothing is known about its gene content, or how gene products are distributed in the cell. To study the composition and distribution of mRNAs inA. acetabulum, we have used quantitative RNA-seq to sequence the mRNA content of four sections of adultA. acetabulumcells. We found that although mRNAs are present throughout the cell, there are large pools of distinct mRNAs localized to the different subcellular sections. Conversely, we also find that gene transcripts related to intracellular transport are evenly distributed throughout the cell. This distribution hints at post-transcriptional regulation and selective transport of mRNAs as mechanisms to achieve mRNA localization inA. acetabulum.
Unexpected redundancy of Gpr56 and Gpr97 during hematopoietic cell development and differentiation
Authors: Maglitto A. , Mariani S.A. , de Pater E. , Rodriguez-Seoane C. , Vink C.S. , Piao X. , Lukke M.-L. , Dzierzak E. 
Published: September 2020

AbstractIntegrated molecular signals regulate cell fate during embryonic hematopoietic stem cell (HSC) generation. The G-protein coupled receptor 56 (Gpr56) is the most highly-upregulated receptor gene in cells that take on hematopoietic fate and it is expressed by adult bone marrow HSCs. Although Gpr56 is required for hematopoietic stem/progenitor cell (HS/PC) generation in zebrafish embryos, its function in mammalian hematopoiesis remains unclear. Here we examine the role of Gpr56 in HS/PC development in Gpr56 conditional knockout (cKO) mouse embryos and Gpr knockout (KO) embryonic stem cell (ESC) hematopoietic differentiation cultures. Our results show a myeloid bias of Gpr56 cKO fetal liver HSCs and an increased definitive myeloid progenitor cell frequency in Gpr56KO ESC differentiation cultures. Surprisingly, we find that mouse Gpr97 rescues Gpr56 morphant zebrafish hematopoietic generation, and that Gpr97 expression is upregulated in mouse Gpr56 deletion models. When both Gpr56 and Gpr97 are deleted in ESCs, no/few HS/PCs are generated upon ESC differentiation. Together, our results reveal novel and redundant functions for these two G-protein coupled receptors in normal mammalian hematopoietic cell development and differentiation.
Optic Atrophy-associated TMEM126A is an assembly factor for the ND4-module of Mitochondrial Complex I
Authors: Formosa Luke E. , Reljic Boris , Sharpe Alice J. , Muellner-Wong Linden , Stroud David A. , Ryan Michael T. 
Published: September 2020

AbstractMitochondrial disease is a debilitating condition with a diverse genetic aetiology. Here, we report that TMEM126A, a protein that is mutated in patients with autosomal recessive optic atrophy, participates directly in the assembly of mitochondrial complex I. Using a combination of genome editing, interaction studies and quantitative proteomics, we find that loss of TMEM126A results in an isolated complex I deficiency and that TMEM126A interacts with a number of complex I subunits and assembly factors. Pulse-labelling interaction studies reveal that TMEM126A associates with the newly synthesised mtDNA-encoded ND4 subunit of complex I. Our findings indicate that TMEM126A is involved in the assembly of the ND4 distal membrane module of complex I. Importantly, we clarify that the function of TMEM126A is distinct from its paralogue TMEM126B, which acts in assembly of the ND2-module of complex I, helping to explain the differences in disease aetiology observed between these two genes.
Eicosanoid content in fetal calf serum accounts for reproducibility challenges in cell culture
Authors: Niederstaetter Laura , Neuditschko Benjamin , Brunmair Julia , Janker Lukas , Bileck Andrea , Del Favero Giorgia , Gerner Christopher 
Published: September 2020

AbstractReproducibility issues regardingin vitrocell culture experiments are related to genetic fluctuations and batch-wise variations of biological materials such as fetal calf serum (FCS). Genome sequencing may control the former, while the latter may remain unrecognized. Using a U937 macrophage model for cell differentiation and inflammation, we investigated whether the formation of effector molecules was dependent on the FCS batch used for cultivation. High resolution mass spectrometry was used to identify FCS constituents and to explore their effects on cultured cells evaluating secreted cytokines, eicosanoids and other inflammatory mediators. Remarkably, the FCS eicosanoid composition showed more batch-dependent variations than the protein composition. Efficient uptake of fatty acids from medium by U937 macrophages and inflammation-induced release thereof was evidenced using C13-labelled arachidonic acid, highlighting rapid lipid metabolism. For functional testing, FCS batch-dependent nanomolar concentration differences of two selected eicosanoids, 5-HETE and 15-HETE, were balanced out by spiking in. Culturing U937 cells at these defined conditions indeed resulted in significant proteome alterations indicating HETE-induced PPARγ activation, independently corroborated by HETE-induced formation of peroxisomes observed by high-resolution microscopy. In conclusion, the present data demonstrate that FCS-contained eicosanoids, subject to substantial batch-wise variation, may modulate cellular effector functions in cell culture experiments.
Remarkable recent changes in genetic diversity of the avirulence geneAvrStb6in global populations of the wheat pathogenZymoseptoria tritici
Authors: Stephens Christopher , Ölmez Fatih , Blyth Hannah , McDonald Megan , Bansal Anuradha , Turgay Emine Burcu , Hahn Florian , Saintenac Cyrille , Nekrasov Vladimir , Solomon Peter , Milgate Andrew , Fraaije Bart , Rudd Jason , Kanyuka Kostya 
Published: September 2020

SUMMARYSeptoria tritici blotch (STB), caused by the fungusZymoseptoria tritici, is one of the most economically important diseases of wheat. Recently, both factors of a gene-for-gene interaction betweenZ. triticiand wheat, the wheat receptor-like kinase Stb6 and theZ. triticisecreted effector protein AvrStb6, have been identified. Previous analyses revealed a high diversity ofAvrStb6alleles present in historicZ. triticiisolate collections, with up to ~ 18% of analysed isolates possessing the avirulence isoform of AvrStb6 identical to that originally identified in the reference isolate IPO323. WithStb6present in many commercial wheat cultivars globally, we aimed to assess potential changes inAvrStb6genetic diversity and the incidence of alleles allowing evasion ofStb6-mediated resistance in more recentZ. triticipopulations. Here we show, using targeted re-sequencing ofAvrStb6,that this gene is universally present in field isolates sampled from major wheat-growing regions of the world between 2013–2017. However, in contrast to the data from studies of historic isolates, our study revealed a complete absence of the originally described avirulence isoform of AvrStb6 amongst modernZ. triticiisolates. Moreover, a remarkably small number of alleles, each encoding AvrStb6 protein isoforms conditioning virulence onStb6-containing wheat, were found to predominate among modernZ. triticiisolates. A single virulence isoform of AvrStb6 was found to be particularly abundant throughout the global population. These findings indicate that, despite the ability ofZ. triticito sexually reproduce on resistant hosts,AvrStb6avirulence alleles tend to be eliminated in subsequent populations.
The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity
Authors: Bolouri Hamid , Speake Cate , Skibinski David , Long S. Alice , Hocking Anne M. , Campbell Daniel J. , Hamerman Jessica A. , Malhotra Uma , Buckner Jane H. ,   the BRI COVID-19 Research Team
Published: September 2020

AbstractDespite a rapidly growing body of literature on COVID-19, our understanding of the immune correlates of disease severity, course and outcome remains poor. Using mass cytometry, we assessed the immune landscape in longitudinal whole blood specimens from 59 patients presenting with acute COVID-19, and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls. We found that the immune landscape in COVID-19 forms three dominant clusters, which correlate with disease severity. Longitudinal analysis identified a pattern of productive innate and adaptive immune responses in individuals who have a moderate disease course, whereas those with severe disease have features suggestive of a protracted and dysregulated immune response. Further, we identified coordinate immune alterations accompanying clinical improvement and decline that were also seen in patients who received IL-6 pathway blockade. The hospitalized COVID-19 negative cohort allowed us to identify immune alterations that were shared between severe COVID-19 and other critically ill patients. Collectively, our findings indicate that selection of immune interventions should be based in part on disease presentation and early disease trajectory due to the profound differences in the immune response in those with mild to moderate disease and those with the most severe disease.
Scribblemutation disrupts convergent extension and apical constriction during mammalian neural tube closure
Authors: Lesko Alyssa C. , Keller Raymond , Chen Ping , Sutherland Ann 
Published: September 2020

AbstractMorphogenesis of the vertebrate neural tube occurs by elongation and bending of the neural plate, tissue shape changes that are driven at the cellular level by polarized cell intercalation and cell shape changes, notably apical constriction and cell wedging. Coordinated cell intercalation, apical constriction, and wedging undoubtedly require complex underlying cytoskeletal dynamics and remodeling of adhesions. Mutations of the gene encoding Scribble result in neural tube defects in mice, however the cellular and molecular mechanisms by which Scrib regulates neural cell behavior remain unknown. Analysis of Scribble mutants revealed defects in neural tissue shape changes, and live cell imaging of mouse embryos showed that the Scrib mutation results in defects in polarized cell intercalation, particularly in rosette resolution, and failure of both cell apical constriction and cell wedging.Scribmutant embryos displayed aberrant expression of the junctional proteins ZO-1, Par3, Par6, E- and N-cadherins, and the cytoskeletal proteins actin and myosin. These findings show that Scribble has a central role in organizing the molecular complexes regulating the morphomechanical neural cell behaviors underlying vertebrate neurulation, and they advance our understanding of the molecular mechanisms involved in mammalian neural tube closure.HighlightsPolarized cell intercalation is lost inScribmutant embryosScribmutation has specific effects on rosette formation and resolutionScribmutation disrupts apical constriction and cell shape changes necessary for neural tube closureAdherens and tight junction composition is altered in the neural epithelial cells ofScribmutants
A dual-reporter system for investigating and optimizing protein translation and folding inE. coli
Authors: Zutz Ariane , Nielsen Louise Hamborg , Pedersen Lasse Ebdrup , Kassem Maher M. , Papaleo Elena , Koza Anna , Herrgård Markus J. , Teilum Kaare , Lindorff-Larsen Kresten , Nielsen Alex Toftgaard 
Published: September 2020

AbstractStrategies for investigating and optimising the expression and folding of proteins for biotechnological and pharmaceutical purposes are in high demand. Here, we describe a dual-reporter biosensor system that simultaneously assessesin vivoprotein translation and protein folding, thereby enabling rapid screening of mutant libraries. We have validated the dual-reporter system on five different proteins and find an excellent correlation between reporter intensity signals and the levels of protein expression and solubility of the proteins. We further demonstrate the applicability of the dual-reporter system as a screening assay for deep mutational scanning experiments. The system enables high throughput selection of protein variants with high expression levels and altered protein stability. Next generation sequencing analysis of the resulting libraries of protein variants show a good correlation between computationally predicted and experimentally determined protein stabilities. We furthermore show that the mutational experimental data obtained using this system may be useful for protein structure calculations.
The P2X7 receptor localizes to the mitochondria, modulates mitochondrial energy metabolism and enhances physical performance
Authors: Sarti Alba Clara , Vultaggio-Poma Valentina , Falzoni Simonetta , Missiroli Sonia , Giuliani Anna Lisa , Boldrini Paola , Bonora Massimo , Faita Francesco , Di Lascio Nicole , Kusmic Claudia , Solini Anna , Novello Salvatore , Morari Michele , Rossato Marco , Wieckowski Mariusz R. , Giorgi Carlotta , Pinton Paolo , Di Virgilio Francesco 
Published: September 2020

AbstractBasal expression of the P2X7 receptor (P2X7R) improves mitochondrial metabolism, ATP synthesis and overall fitness of immune and non-immune cells. We investigated P2X7R contribution to energy metabolism and subcellular localization in fibroblasts (mouse embryo fibroblasts and HEK293 human fibroblasts), mouse microglia (primary brain microglia and the N13 microglia cell line), and heart tissue. The P2X7R localizes to mitochondria, and its lack a) decreases basal respiratory rate, ATP-coupled respiration, maximal uncoupled respiration, resting mitochondrial potential, mitochondrial matrix Ca2+level, b) modifies expression pattern of oxidative phosphorylation (OxPhos) enzymes, and c) severely affects cardiac performance. Hearts fromP2rx7-deleted versus WT mice are larger, heart mitochondria smaller, and stroke volume (SV), ejection fraction (EF), fractional shortening (FS) and cardiac output (CO), are significantly decreased. Accordingly, physical fitness of P2X7R-null mice is severely reduced. Thus, the P2X7R is a key modulator of mitochondrial energy metabolism and a determinant of physical fitness.
Genetic models suggest single and multiple origins of dihydrofolate reductase mutations inPlasmodium vivax
Authors: Shaukat Ayaz , Ali Qasim , Raud Lucy , Wahab Abdul , Khan Taj Ali , Rashid Imran , Rashid Muhammad , Hussain Mubashir , Saleem Mushtaq A. , Sargison Neil D. , Chaudhry Umer 
Published: September 2020

AbstractPyrimethamine was first introduced for the treatment of malaria in Asia and Africa during the early 1980s, replacing chloroquine, and has become the first line of drugs in many countries. In recent years, development of pyrimethamine resistance inPlasmodium vivaxhas become a barrier to effective malaria control strategies. Here, we describe the use of meta-barcoded deep amplicon sequencing technology to assess the evolutionary origin of pyrimethamine resistance by analysing the flanking region of dihydrofolate reductase (dhfr) locus. The genetic modelling suggests that 58R and 173L single mutants and 58R/117N double mutants are present on a single lineage; suggesting a single origin of these mutations. The triple mutants (57L/58R/117N, 58R/61M/117N and 58R/117N/173L) share the lineage of 58R/117N, suggesting a common origin. In contrast, the 117N mutant is present on two separate lineages suggesting that there are multiple origins of this mutation. We characterised the allele frequency of theP. vivax dhfrlocus. Our results support the view that the single mutation of 117N and double mutations of 58R/117N arise commonly, whereas the single mutation of 173L and triple mutations of 57L/58R/117N, 58R/61M/117N and 58R/117N/173L are less common. Our work will help to inform mitigation strategies for pyrimethamine resistance inP. vivax.
Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1
Authors: Robert Vincent , Therreau Ludivine , Huang Arthur J.Y. , Boehringer Roman , Polygalov Denis , McHugh Thomas , Chevaleyre Vivien , Piskorowski Rebecca A. 
Published: September 2020

AbstractThe hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. We found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). We found that parvalbumin-expressing basket cells as responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulates CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.
USP28 and SPINT2 mediate cell cycle arrest after whole genome doubling
Authors: Seget-Trzensiok Katarzyna , Bernhard Sara Vanessa , Kuffer Christian , Krastev Dragomir B , Theis Mirko , Keuper Kristina , Boekenkamp Jan-Eric , Kschischo Maik , Buchholz Frank , Storchova Zuzana 
Published: September 2020

AbstractTetraploidy is frequent in cancer and whole genome doubling shapes the evolution of cancer genomes, thereby driving the transformation, metastasis and drug resistance. Yet, human cells usually arrest when they become tetraploid due to p53 activation that leads to CDKN1A expression, cell cycle arrest, senescence or apoptosis. To uncover the barriers that block proliferation of tetraploids, we performed an RNAi mediated genome-wide screen in a human cancer cell line. We identified 140 genes whose depletion improved survival of tetraploids and characterized in depth two of them: SPINT2 and USP28. We show that SPINT2 is a general regulator of CDKN1A, regulating its transcription via histone acetylation. By mass spectrometry and immunoprecipitation, we show that USP28 interacts with NuMA1 and affects centrosome clustering. Moreover, tetraploid cells accumulate DNA damage and loss of USP28 reduces checkpoint activation. Our results indicate three aspects that contribute to survival of tetraploid cells: i) increased mitogenic signaling and reduced expression of cell cycle inhibitors, ii) the ability to establish functional bipolar spindle, and iii) reduced DNA damage signaling.