bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic, protein-DNA interaction, and metabolomic studies of VosA, VelB, and WetA inAspergillus nidulansasexual spores
Authors: Wu Ming-Yueh , Mead Matthew E. , Lee Mi-Kyung , Neuhaus George F. , Adpressa Donovon A. , Martien Julia I. , Son Ye-Eun , Moon Heungyun , Amador-Noguez Daniel , Han Kap-Hoon , Rokas Antonis , Loesgen Sandra , Yu Jae-Hyuk , Park Hee-Soo 
Published: September 2020

AbstractIn filamentous fungi, asexual development involves morphological differentiation and metabolic changes leading to the formation of asexual spores. The process of asexual spore formation inAspergillusis precisely regulated by multiple transcription factors (TFs), including VosA, VelB, and WetA, and these three TFs are key regulators of the formation and maturation of asexual spores (conidia) inAspergillusincluding the model fungusAspergillus nidulans. To gain a mechanistic insight on the complex regulatory roles of these TFs in asexual spores, we conducted genome-wide studies on the expression, protein-DNA interactions, and primary and secondary metabolism employingA. nidulansconidia. RNA sequencing and chromatin immunoprecipitation-sequencing data have revealed that the three TFs directly or indirectly regulate the expression of genes associated with spore-wall formation/integrity, asexual development, and secondary metabolism. In addition, metabolomics analyses of wild-type and mutant conidia indicate that these three TFs regulate a diverse array of primary and secondary metabolism. In summary, WetA, VosA, and VelB play inter-dependent and distinct roles governing morphological development and primary/secondary metabolic remodeling inAspergillusconidia.ImportanceFilamentous fungi produce a vast number of asexual spores that act as reproductive and propagator cells. These spores affect humans, due to the infectious or allergenic nature of the propagule.Aspergillusspecies produce asexual spores called conidia and their formation involves morphological development and metabolic changes, and the associated regulatory systems are coordinated by spore-specific transcription factors. To understand the underlying global regulatory programs and cellular outcomes associated with conidia formation, functional genomic and metabolomic analyses were performed in the model fungusAspergillus nidulans. Our results show that the fungus specific WetA/VosA/VelB transcription factors govern the coordination of morphological and chemical developments during sporogenesis. The results of this study provide insights into the genetic regulatory networks about how morphological developments and metabolic changes are coordinated in fungi. The findings are relevant for otherAspergillusspecies such as the major human pathogenAspergillus fumigatusand the aflatoxin-producerAspergillus flavus.
Sequencing and analysis ofArabidopsis thalianaNOR2 reveal its distinct organization and tissue-specific expression of rRNA ribosomal variants
Authors: Sims Jason , Sestini Giovanni , Elgert Christiane , von Haeseler Arndt , Schlögelhofer Peter 
Published: September 2020

AbstractDespite vast differences between organisms, some characteristics of their genomes are conserved, such as the nucleolus organizing region (NOR). The NOR is constituted of multiple, highly repetitive rDNA genes, encoding the catalytic ribosomal core RNAs which are transcribed from 45S rDNA units. Their precise sequence information and organization remained uncharacterized.We used a combination of long- and short-read sequencing technologies to assemble contigs of theArabidopsisNOR2 rDNA domain providing a first map. We identified several expressed rRNA gene variants which are integrated into translating ribosomes in a tissue-specific manner. These findings support the concept of tissue specific ribosome subpopulations that differ in their rRNA composition and provide the higher order organization of NOR2.
Network and systems based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy
Authors: Lai Xin , Dreyer Florian S. , Cantone Martina , Eberhardt Martin , Gerer Kerstin F. , Jaitly Tanushree , Uebe Steffen , Lischer Christopher , Ekici Arif , Wittmann Jürgen , Jäck Hans-Martin , Schaft Niels , Dörrie Jan , Vera Julio 
Published: September 2020

AbstractDendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses.Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates with miR-15a and miR-16 as the top ones. The results of our analysis are incorporated in a database which constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (www.synmirapy.net/dc-optimization).
Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects
Authors: Solman Maja , Blokzijl-Franke Sasja , Piques Florian , Yan Chuan , Yang Qiqi , Strullu Marion , Kamel Sarah M. , Ak Pakize , Bakkers Jeroen , Langenau David M. , Cavé Hélène , den Hertog Jeroen 
Published: September 2020

AbstractGain-of-function mutations in the protein-tyrosine phosphatase SHP2 are the most frequently occurring mutations in sporadic juvenile myelomonocytic leukemia (JMML) and JMML-like myeloproliferative neoplasm (MPN) associated with Noonan syndrome (NS). Hematopoietic stem and progenitor cells (HSPCs) are the disease propagating cells of JMML. Here, we explored transcriptomes of HSPCs with Shp2 mutations derived from JMML patients and a novel NS zebrafish model. In addition to major NS traits, CRISPR/Cas9 knock-in Shp2D61Gmutant zebrafish recapitulated a JMML-like MPN phenotype, including myeloid lineage hyperproliferation,ex vivogrowth of myeloid colonies andin vivotransplantability of HSPCs. Single cell mRNA sequencing of HSPCs from Shp2D61Gzebrafish embryos and bulk sequencing of HSPCs from JMML patients revealed an overlapping inflammatory gene expression pattern. Strikingly, an anti-inflammatory agent rescued JMML-like MPN in Shp2D61Gzebrafish embryos. Our results indicate that a common inflammatory response was triggered in the HSPCs from sporadic JMML patients and syndromic NS zebrafish, which potentiated MPN and may represent a future target for JMML therapies.
Single-Cell RNAseq of Out-of-Thaw Mesenchymal Stromal Cells Shows Striking Tissue-of-Origin Differences and Inter-donor Cell-Cycle Variations
Authors: Medrano-Trochez Camila , Chatterjee Paramita , Pradhan Pallab , Ogle Molly E , Botchwey Edward A , Kurtzberg Joanne , Yeago Carolyn , Gibson Greg , Roy Krishnendu 
Published: September 2020

AbstractMesenchymal stromal cells (MSCs) from a variety of tissue sources are widely investigated in clinical trials, and the MSCs are often administered immediately after thawing the cryopreserved product. While previous reports have examined the transcriptome of freshly-cultured MSCs from some tissues, little is known about the single-cell transcriptomic profiles of out-of-thaw MSCs from different tissue sources. Such understanding could help determine which tissue origins and delivery methods are best suited for specific indications. Here, we characterized cryopreserved MSCs, immediately post-thaw, from bone marrow (BM) and cord tissue (CT), using single-cell RNA sequencing (scRNA-seq). We show that out-of-thaw BM-vs. CT-MSCs have significant differences in gene expression. Gene-set enrichment analyses implied divergent functional potential. In addition, we show that MSC-batches can vary significantly in cell cycle status, suggesting different proliferative vs. immunomodulatory potentials. Our results provide a comprehensive single-cell transcriptomic landscape of clinically and industrially relevant MSC products.HighlightsSingle cell gene expression comparison between Bone-marrow derived MSCs and Cord-tissue derived MSCsDonor effects and cell heterogeneity on tissue-specific MSC gene expressionSingle Cell Pooling Enhances Differential Expression Analysis for Bone marrow and Cord tissue MSC samplesGene ontology reveals tissue specific unique molecular function and pathways
Stress Assessment of Vestibular Endurance Training for Civil Aviation Flight Students Based on EEG
Authors: Hu Haixu , Fang Zhou , Qian Zhiyu , Yao Liuye , Tao Ling , Qin Bing 
Published: September 2020

AbstractObjectiveThe main goal of our study is to clarify the EEG characteristics of the stress response caused by vestibular endurance training under the real conditions.MethodsTen pilot trainees received a series of acute anti-vertigo training stimulations on the rotary ladder while recording electroencephalographic data (64 electrodes). Afterwards, the subject’s anti-vertigo ability was tested for the best performance after 1 month of training, and verifying whether it is relating to the EEG signals we collected before.Results(1) The absolute power ofαwaves in the C3 and C4 regions is same as the difference between 1 min before and 2 min after stimulation, and their activity is enhanced by stimulation. Otherwise, the activation of the C3 region after 5min of stimulation is still significant changed. (2) Discover a spearman rank correlation, theαwaves in the C3 and C4 the greater the power change, the better the performance of the subject in the proficient stage.ConclusionsC3 and C4 areas are specific brain regions of the stress response of anti-vertigo endurance training, and the absolute power of theαwave can be used as a parameter for identifying the degree of motion sickness (MS). The absolute power changes ofαwaves in the C3 and C4 areas are positively correlated with their anti-vertigo potential.SignificanceThe increasing of the absolute power ofαwave in the C3 and C4 is a manifestation of MS stress adaptability.
Keratin5-BMP4 mechanosignaling regulates reciprocal acetylation and methylation at H3K9 to define blastema cell remodeling during zebrafish heart regeneration
Authors: Wang Xuelong , Guo Huiping , Yu Feifei , Zheng Wei , Zhang Hui , Peng Ying , Wang Chenghui , Wei Gang , Yan Jizhou 
Published: September 2020

AbstractHeart regeneration after myocardial infarction remains challenging due to scar and ischemia-reperfusion injury. Here, we show that zebrafish blastema regeneration can effectively resalvage the wound myocardium and blood clot through cytoplasmic exocytosis and nuclear reorganization. The cell remodeling process are also visualized by spatiotemporal expression of three core blastema genes: alpha-SMA- which marks for fibrogenesis, Flk1for angiogenesis/hematopoiesis, Pax3a for remusculogensis, and by characteristic chromatin depositions of H3K9Ac/H3K9Me3. Genome-wide enhancer identification links the depositions of the two histone marks to the chromatin state and these three core blastema cell phenotypes. When the blastema subcellular fractions are introduced into the cultured zebrafish embryonic fibroblasts the altered transcription profile is comparable to the blastema transcription in terms of extracellular matrix structural constituent, vasculature development/angiogenesis, and cardiac muscle regeneration. From the subcellular fractions we identify 15 extracellular components and intermediate filaments, and show that introduction of human Krt5 and noggin peptides conversely regulate PAC2 cells F-actin reorganization, chromatin depositions of H3K9Ac/ H3K9Me3 and phosphorylation of Smad, which are accompanied by characteristic transcriptions ofbmp, bmp4, three core blastema genes as well as specific histone acetylation/methylation-related genes. Collectively, this study establishes a new Krt5-BMP4 mechanosignaling cascade that links extracellular molecules to chromatin modifications and regulates blastema cell remodeling, thus providing mechanistic insights into the mesoderm-derived blastema regeneration and underlining a therapy strategy for myocardial infarction.
DTFLOW: Inference and Visualization of Single-cell Pseudo-temporal Trajectories Using Diffusion Propagation
Authors: Wei Jiangyong , Zhou Tianshou , Zhang Xinan , Tian Tianhai 
Published: September 2020

ABSTRACTOne of the major challenges in single-cell data analysis is the determination of cellular developmental trajectories using single-cell data. Although substantial studies have been conducted in recent years, more effective methods are still strongly needed to infer the developmental processes accurately. In this work we devise a new method, named DTFLOW, for determining the pseudo-temporal trajectories with multiple branches. This method consists of two major steps: namely a new dimension reduction method (i.e. Bhattacharyya kernel feature decomposition (BKFD)) and a novel approach, named Reverse Searching on kNN Graph (RSKG), to identify the underlying multi-branching processes of cellular differentiations. In BKFD we first establish a stationary distribution for each cell to represent the transition of cellular developmental states based on the random walk with restart algorithm and then propose a new distance metric for calculating pseudo-times of single-cells by introducing the Bhattacharyya kernel matrix. The effectiveness of DTFLOW is rigorously examined by using four single-cell datasets. We compare the efficiency of the new method with two state-of-the-art methods. Simulation results suggest that our proposed method has superior accuracy and strong robustness properties for constructing pseudo-time trajectories. Availability: DTFLOW is implemented in Python and available athttps://github.com/statway/DTFLOW.
FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis
Authors: Bonnycastle Katherine , Kind Peter C. , Cousin Michael A. 
Published: September 2020

ABSTRACTSynaptic vesicle (SV) recycling defects are linked to neurodevelopmental disorders, including fragile X syndrome (FXS), which results from loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. Hyperexcitability of neuronal circuits is a key feature of FXS, therefore we investigated whether SV recycling was affected by the absence of FMRP during increased neuronal activity. We revealed that primary neuronal cultures from a Fmr1 knockout rat model display a specific defect in activity-dependent bulk endocytosis (ADBE). This defect resulted in an inability of Fmr1 knockout neurons to sustain SV recycling during high frequency stimulation. Using a molecular replacement strategy, we also revealed that a human FMRP mutant that cannot bind BK channels failed to correct ADBE dysfunction in knockout neurons, however this dysfunction was corrected by BK channel agonists. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of ADBE, suggesting intervention via this endocytosis mode may correct hyperexcitabiltiy observed in FXS.SUMMARYFragile X syndrome (FXS) is caused by loss of fragile X mental retardation protein (FMRP). Bonnycastle et al show that FMRP is specifically required for activity-dependent bulk endocytosis (ADBE), revealing 1) FMRP sustains neurotransmitter release and 2) intervention via ADBE may correct circuit hyperexcitabilty in FXS.
Vanilloids HamperCaenorhabditis elegansResponse to Noxious Heat
Authors: Nkambeu Bruno , Salem Jennifer Ben , Beaudry Francis 
Published: September 2020

AbstractEugenol, a known vanilloid, was frequently used in dentistry as a local analgesic in addition, antibacterial and neuroprotective effects were also reported. Eugenol, capsaicin and many vanilloids are interacting with the transient receptor potential vanilloid 1 (TRPV1) in mammals and are activated by noxious heat. The pharmacological manipulation of the TRPV1 has been shown to have therapeutic value.Caenorhabditis elegans(C. elegans) express TRPV orthologs (e.g. OCR-2, OSM-9) and it is a commonly used animal model system to study nociception as it displays a well-defined and reproducible nocifensive behavior. After exposure to vanilloid solutions,C. eleganswild type (N2) and mutants were placed on petri dishes divided in quadrants for heat stimulation. Thermal avoidance index was used to phenotype each testedC. elegansexperimental groups. The results showed that eugenol, vanillin and zingerone can hamper nocifensive response ofC. elegansto noxious heat (32°C – 35°C) following a sustained exposition. Also, the effect was reversed 6h post exposition. Furthermore, eugenol and vanillin did not target specifically the OCR-2 or OSM-9 but zingerone did specifically target the OCR-2 similarly to capsaicin. Further structural and physicochemical analyses were performed. Key parameters for quantitative structure-property relationships (QSPR), quantitative structure-activity relationships (QSAR) and frontier orbital analyses suggest similarities and dissimilarities amongst the tested vanilloids and capsaicin in accordance with the relative anti-nociceptive effects observed.
Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway
Authors: Prieto-Garcia Cristian , Hartmann Oliver , Reissland Michaela , Fischer Thomas , Maier Carina R. , Rosenfeldt Mathias , Schülein-Völk Christina , Klann Kevin , Kalb Reinhard , Dikic Ivan , Münch Christian , Diefenbacher Markus E. 
Published: September 2020

AbstractSquamous cell carcinomas (SCC) frequently have a limited response to or develop resistance to platinum-based chemotherapy, and have an exceptionally high tumor mutational burden. As a consequence, overall survival is limited and novel therapeutic strategies are urgently required, especially in light of a rising incidences. SCC tumors express ΔNp63, a potent regulator of the Fanconi Anemia (FA) DNA-damage response pathway during chemotherapy, thereby directly contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 affects the FA DNA repair pathway during cisplatin treatment in SCC, thereby influencing therapy outcome. In an ATR-dependent fashion, USP28 is phosphorylated and activated to positively regulate the DNA damage response. Inhibition of USP28 reduces recombinational repair via an ΔNp63-Fanconi Anemia pathway axis, and weakens the ability of tumor cells to accurately repair DNA. Our study presents a novel mechanism by which tumor cells, and in particular ΔNp63 expressing SCC, can be targeted to overcome chemotherapy resistance.SignificanceLimited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ΔNp63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-ΔNp63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.
Multistage feedback driven compartmental dynamics of hematopoiesis
Authors: Mon Père Nathaniel V. , Lenaerts Tom , Pacheco Jorge M. , Dingli David 
Published: September 2020

AbstractHuman hematopoiesis is surprisingly resilient to disruptions, providing suitable responses to severe bleeding, long lasting immune activation, and even bone marrow transplants. Still, many blood disorders exist which push the system past its natural plasticity, resulting in abnormalities in the circulating blood. While proper treatment of such diseases can benefit from understanding the underlying cell dynamics, these are non-trivial to predict due to the hematopoietic system’s hierarchical nature and complex feedback networks. To characterize the dynamics following different types of perturbations we investigate a model representing hematopoiesis as a sequence of compartments covering all maturation stages – from stem to mature cells – where feedback regulates cell production to ongoing necessities. We find that a stable response to perturbations requires the simultaneous adaptation of cell differentiation and self-renewal rates, and show that under conditions of continuous disruption – as found in chronic hemolytic states – compartment cell numbers evolve to novel stable states.
Predictive encoding of motion begins in the primate retina
Authors: Liu Belle , Hong Arthur , Rieke Fred , Manookin Michael B. 
Published: September 2020

ABSTRACTSurvival in the natural environment often relies on an animal’s ability to quickly and accurately predict the trajectories of moving objects. Motion prediction is primarily understood in the context of translational motion, but the environment contains other types of behaviorally salient motion, such as that produced by approaching or receding objects. However, the neural mechanisms that detect and predictively encode these motion types remain unclear. Here, we address these questions in the macaque monkey retina. We report that four of the parallel output pathways in the primate retina encode predictive information about the future trajectory of moving objects. Predictive encoding occurs both for translational motion and for higher-order motion patterns found in natural vision. Further, predictive encoding of these motion types is nearly optimal with transmitted information approaching the theoretical limit imposed by the stimulus itself. These findings argue that natural selection has emphasized encoding of information that is relevant for anticipating future properties of the environment.
FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model
Authors: Paquette Mathieu , Yan Ming , El-Houjeiri Leeanna , Biondini Marco , Ramírez-Reyes Josué M. J. , Pacis Alain , Jeong Hyeonju , Estall Jennifer L. , Siegel Peter M. , Pause Arnim 
Published: September 2020

AbstractNon-alcoholic steatohepatitis (NASH) represents a major economic burden and is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat this condition. Emerging data suggests an important role of autophagy in this condition, which serves to degrade intracellular lipid stores, reduce hepatocellular damage, and dampen inflammation. Autophagy is primarily regulated by the transcription factors TFEB and TFE3, which are negatively regulated by mTORC1. Given that FLCN is an mTORC1 activator via its GAP activity towards RagC/D, we generated a liver specific Flcn knockout mouse model to study its role in NASH progression. We demonstrate that loss of FLCN results in reduced triglyceride accumulation, fibrosis, and inflammation in mice exposed to a NASH-inducing diet. Hence, the GAP activity of FLCN could a promising target for small molecule drugs to treat NASH progression by specifically activating autophagy and lysosomal biogenesis while leaving mRNA translation machinery unperturbed. Collectively, these results show an unexpected role for FLCN in NASH progression and highlight new possibilities for treatment strategies through its role in hepatocyte homeostasis.