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BACKGROUND: The ectoparasite Psoroptes ovis var. cuniculi causes substantial economic losses to the global rabbit industry. Currently, microscopy for identifying Psoroptes mite in skin scrapings, as the "diagnosis gold standard," remains a challenge owing to its poor sensitivity in detecting low-level and/or early stage mite infestations. Additionally, Psoroptes infestations rapidly trigger cutaneous inflammation, thus the mites might produce some molecules to deal with the harmful effects of inflammation for their long-time survival on the host skin, but these molecules are still mostly unknown. METHODS: To seek a sensitive diagnostic method and illuminate the new antiinflammatory molecules, we characterized a novel cystatin of P. ovis var. cuniculi (PsoCys) using bioinformatics and molecular biology methods. RESULTS: The results showed that PsoCys comprised the classical features of the type II cystatin superfamily including an N-terminal glycine residue, a central QXVXG motif, and a C-terminal LW motif. In mixed stages of mites, the transcription level of PsoCys was significantly higher in "fed" mites than in "starved" mites (P < 0.001), and among the different life-cycle stages of "fed" mites, the expression of PsoCys was higher in adult males than in larva, nymph, and adult females (P < 0.001). The established indirect ELISA based on recombinant PsoCys (rPsoCys-iELISA) presented 95.4% sensitivity and 95.7% specificity. The area under the receiver operating characteristic curve (AUC) for this method was 0.991, indicating its excellent diagnostic performance. Moreover, rPsoCys-iELISA had advantages over microscopy for detecting low-level and/or early stage mite infestations (90% versus 40% in artificial infestation cases at 3 weeks post-infestation; 61.9% versus 22.6% in clinical cases). In addition, rPsoCys could inhibit the activity of papain and cathepsin B in vitro, and significantly suppressed mRNA levels of toll-like receptors (TLR 1, 2, 4, and 6) and downstream molecules (NF-κB, p38, MyD88, IL-10, and IFN-γ) in LPS-stimulated rabbit PBMCs, indicating its anti-inflammatory property. CONCLUSIONS: Our findings indicated that PsoCys was a novel type II cystatin of Psoroptes mites, and it served as a potential serological diagnostic antigen for detecting low-level and/or early stage mite infestations, as well as a novel anti-inflammatory molecule of Psoroptes mites.
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Cistatinas , Leucocitos Mononucleares , Infestaciones por Ácaros , Psoroptidae , Animales , Conejos , Psoroptidae/inmunología , Cistatinas/genética , Cistatinas/inmunología , Infestaciones por Ácaros/veterinaria , Infestaciones por Ácaros/diagnóstico , Infestaciones por Ácaros/inmunología , Leucocitos Mononucleares/inmunología , Pruebas Serológicas/métodos , Pruebas Serológicas/veterinaria , Antiinflamatorios , FemeninoRESUMEN
The species-rich cosmopolitan genus Rhododendron offers a good system for exploring the genomic mechanisms underlying adaptation to diverse habitats. Here, we report high-quality chromosomal-level genome assemblies of nine species, representing all five subgenera, different altitudinal distributions, and all flower color types of this genus. Further comprehensive genomic analyses indicate diverse adaptive strategies employed by Rhododendron, particularly adaptation to alpine and subalpine habitats by expansion/contraction of gene families involved in pathogen defense and oxidative phosphorylation, genomic convergent evolution, and gene copy-number variation. The convergent adaptation to high altitudes is further shown by population genomic analysis of R. nivale from the Himalaya-Hengduan Mountains. Moreover, we identify the genes involved in the biosynthesis of anthocyanins and carotenoids, which play a crucial role in shaping flower color diversity and environmental adaptation. Our study is significant for comprehending plant adaptive evolution and the uneven distribution of species diversity across different geographical regions.
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Adaptación Fisiológica , Genoma de Planta , Rhododendron , Rhododendron/genética , Adaptación Fisiológica/genética , Filogenia , Evolución Molecular , Genómica/métodos , Flores/genética , Variaciones en el Número de Copia de ADN/genética , Carotenoides/metabolismo , Antocianinas/biosíntesis , Antocianinas/metabolismo , Antocianinas/genética , Especificidad de la EspecieRESUMEN
Finding novel energetic materials with good comprehensive performance has always been challenging because of the low efficiency in conventional trial and error experimental procedure. In this paper, we established a deep learning model with high prediction accuracy using embedded features in Directed Message Passing Neural Networks. The model combined with high-throughput screening was shown to facilitate rapid discovery of fused [5,5] biheterocyclic energetic materials with high energy and excellent thermal stability. Density Functional Theory (DFT) calculations proved that the performances of the targeting molecules are consistent with the predicted results from the deep learning model. Furthermore, 6,7-trinitro-3H-pyrrolo[1,2-b][1,2,4]triazo-5-amine with both good detonation properties and thermal stability was screened out, whose crystal structure and intermolecular interactions were also analyzed.
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High mountains harbor a considerable proportion of biodiversity, but we know little about how diverse plants adapt to the harsh environment. Here we finished a high-quality genome assembly for Dasiphora fruticosa, an ecologically important plant distributed in the Qinghai-Tibetan Plateau and lowland of the Northern Hemisphere, and resequenced 592 natural individuals to address how this horticulture plant adapts to highland. Demographic analysis revealed D. fruticosa underwent a bottleneck after Naynayxungla Glaciation. Selective sweep analysis of two pairs of lowland and highland populations identified 63 shared genes related to cell wall organization or biogenesis, cellular component organization, and dwarfism, suggesting parallel adaptation to highland habitats. Most importantly, we found that stronger purging of estimated genetic load due to inbreeding in highland populations apparently contributed to their adaptation to the highest mountain. Our results revealed how plants could tolerate the extreme plateau, which could provide potential insights for species conservation and crop breeding.
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Genoma de Planta , Selección Genética , Adaptación Fisiológica/genética , AltitudRESUMEN
All-hydrogel supercapacitors are emerging as promising power sources for next-generation wearable electronics due to their intrinsic mechanical flexibility, eco-friendliness, and enhanced safety. However, the insufficient interfacial adhesion between the electrode and electrolyte and the frozen hydrogel matrices at subzero temperatures largely limit the practical applications of all-hydrogel supercapacitors. Here, an all-hydrogel supercapacitor is reported with robust interfacial contact and anti-freezing property, fabricated by in situ polymerizing hydrogel electrolyte onto hydrogel electrodes. The robust interfacial adhesion is developed by the synergistic effect of a tough hydrogel matrix and topological entanglements. Meanwhile, the incorporation of zinc chloride (ZnCl2) in the hydrogel electrolyte prevents the freezing of water solvents and endows the all-hydrogel supercapacitor with mechanical flexibility and fatigue resistance across a wide temperature range of 20 °C to -60 °C. Such all-hydrogel supercapacitor demonstrates satisfactory low-temperature electrochemical performance, delivering a high energy density of 11 mWh cm-2 and excellent cycling stability with a capacitance retention of 90% over 10000 cycles at -40 °C. Notably, the fabricated all-hydrogel supercapacitor can endure dynamic deformations and operate well under 2000 tension cycles even at -40 °C, without experiencing delamination and electrochemical failure. This work offers a promising strategy for flexible energy storage devices with low-temperature adaptability.
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Solid-state zinc-ion capacitors are emerging as promising candidates for large-scale energy storage owing to improved safety, mechanical and thermal stability and easy-to-direct stacking. Hydrogel electrolytes are appealing solid-state electrolytes because of eco-friendliness, high conductivity and intrinsic flexibility. However, the electrolyte/electrode interfacial contact and anti-freezing properties of current hydrogel electrolytes are still challenging for practical applications of zinc-ion capacitors. Here, we report a class of hydrogel electrolytes that couple high interfacial adhesion and anti-freezing performance. The synergy of tough hydrogel matrix and chemical anchorage enables a well-adhered interface between hydrogel electrolyte and electrode. Meanwhile, the cooperative solvation of ZnCl2 and LiCl hybrid salts renders the hydrogel electrolyte high ionic conductivity and mechanical elasticity simultaneously at low temperatures. More significantly, the Zn||carbon nanotubes hybrid capacitor based on this hydrogel electrolyte exhibits low-temperature capacitive performance, delivering high-energy density of 39 Wh kg-1 at -60 °C with capacity retention of 98.7% over 10,000 cycles. With the benefits of the well-adhered electrolyte/electrode interface and the anti-freezing hydrogel electrolyte, the Zn/Li hybrid capacitor is able to accommodate dynamic deformations and function well under 1000 tension cycles even at -60 °C. This work provides a powerful strategy for enabling stable operation of low-temperature zinc-ion capacitors.
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Reconstructing a robust species phylogeny and disentangling the evolutionary and biogeographic history of the gymnosperm genus Ephedra, which has a large genome and rich polyploids, remain a big challenge. Here we reconstructed a transcriptome-based phylogeny of 19 diploid Ephedra species, and explored evolutionary reticulations in this genus represented by 50 diploid and polyploid species, using four low-copy nuclear and nine plastid genes. The diploid species phylogeny indicates that the Mediterranean species diverged first, and the remaining species split into three clades, including the American species (Clade A), E. rhytidosperma, and all other Asian species (Clade B). The single-gene trees placed E. rhytidosperma sister to Clade A, Clade B, or Clades A + B in similar proportions, suggesting that radiation and gene flow likely occurred in the early evolution of Ephedra. In addition, reticulate evolution occurred not only among the deep nodes, but also in the recently evolved South American species, which further caused difficulty in phylogenetic reconstruction. Moreover, we found that allopolyploid speciation was pervasive in Ephedra. Our study also suggests that Ephedra very likely originated in the Tethys coast during the late Cretaceous, and the South American Ephedra species have a single origin by dispersal from Mexico or North America.
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Ephedra , Filogenia , Ephedra/genética , Diploidia , PlastidiosRESUMEN
Demonstrating the process of transregional biogeography and mechanisms underlying evolutionary radiations is crucial to understanding biological evolution. Here, we use Hydrangeeae (Hydrangeaceae), a tribe with a unique disjunct distribution and complex trait variations, using a solid phylogenetic framework, to investigate how geographical and climatic factors interact with functional traits to trigger plant evolutionary radiations. We constructed the first highly supported and dated phylogenetic framework using 79 protein-coding genes obtained from 81 plastomes, representing 63 species and all major clades, and found that most extant species originated from asynchronous diversification of two lineages undergoing repeated expansion and retraction, at middle and high latitudes of the Northern Hemisphere between East Asia and North America, during the Eocene to Pleistocene (driven by geologic and climatic dynamics). In accordance with these drivers, interactions of flora between central-eastern China and Japan occurred frequently after the Late Tertiary. We found that resource limitation and range fragmentation probably accelerated the diversification of Hydrangeeae, which supports the resource-use hypothesis. Our study sheds light on the evolutionary radiation and assembly of flora within East Asia, and the East Asian-North American disjunction, through integration of phylogenomic and biogeographic data with functional trait and ecological data.
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Hydrangeaceae , Filogenia , Evolución Biológica , Asia Oriental , América del Norte , FilogeografíaRESUMEN
The continuous decline of traditional fossil energy has cast the shadow of an energy crisis on human society. Hydrogen generated from renewable energy sources is considered as a promising energy carrier, which can effectively promote the energy transformation of traditional high-carbon fossil energy to low-carbon clean energy. Hydrogen storage technology plays a key role in realizing the application of hydrogen energy and liquid organic hydrogen carrier technology, with many advantages such as storing hydrogen efficiently and reversibly. High-performance and low-cost catalysts are the key to the large-scale application of liquid organic hydrogen carrier technology. In the past few decades, the catalyst field of organic liquid hydrogen carriers has continued to develop and has achieved some breakthroughs. In this review, we summarized recent significant progress in this field and discussed the optimization strategies of catalyst performance, including the properties of support and active metals, metal-support interaction and the combination and proportion of multi-metals. Moreover, the catalytic mechanism and future development direction were also discussed.
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Diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs) bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a global reduction in the transcriptional repressive mark H3K27me3 accompanied by an increase in the transcriptional activation mark H3K27ac. We postulated that H3K27M mutations, in addition to altering H3K27 modifications, reprogram the master chromatin remodeling switch/sucrose nonfermentable (SWI/SNF) complex. The SWI/SNF complex can exist in two main forms termed BAF and PBAF that play central roles in neurodevelopment and cancer. Moreover, BAF antagonizes PRC2, the main enzyme catalyzing H3K27me3. We demonstrate that H3K27M gliomas show increased protein levels of the SWI/SNF complex ATPase subunits SMARCA4 and SMARCA2, and the PBAF component PBRM1. Additionally, knockdown of mutant H3K27M lowered SMARCA4 protein levels. The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells. AU-15330 lowered chromatin accessibility measured by ATAC-Seq at nonpromoter regions and reduced global H3K27ac levels. Integrated analysis of gene expression, proteomics, and chromatin accessibility in AU-15330-treated cells demonstrated reduction in the levels of FOXO1, a key member of the forkhead family of transcription factors. Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M up-regulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors.
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Neoplasias Encefálicas , Glioma Pontino Intrínseco Difuso , Glioma , Humanos , Niño , Histonas/genética , Adenosina Trifosfatasas/metabolismo , Lisina/genética , Cromatina , Glioma/genética , Neoplasias Encefálicas/genética , Mutación , ADN Helicasas/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Alzheimer's disease (AD) is a common cognitive disorder. Recently, many computer-aided diagnostic techniques have been used for AD prediction utilizing deep learning technology, among which graph neural networks have received increasing attention owing to their ability to model sample relationships on large population graphs. Most of the existing graph-based methods predict diseases according to a single model, which makes it difficult to select an appropriate node embedding algorithm for a certain classification task. Moreover, integrating data from different patterns into a unified model to improve the quality of disease diagnosis remains a challenge. Hence, in this study, we aimed to develop a multi-model fusion framework for AD prediction. A spectral graph attention model was used to aggregate intra- and inter-cluster node embeddings of normal and diseased populations, whereafter, a bilinear aggregation model was applied as an auxiliary model to enhance the abnormality degree in different categories of populations, and finally, an adaptive fusion module was designed to dynamically fuse the results of both models and enhance AD prediction. Compared to other comparison methods, the model proposed in this study provides the best results.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Algoritmos , Redes Neurales de la ComputaciónRESUMEN
The genus Rhododendron (Ericaceae), with more than 1000 species highly diverse in flower color, is providing distinct ornamental values and a model system for flower color studies. Here, we investigated the divergence between two parental species with different flower color widely used for azalea breeding. Gapless genome assembly was generated for the yellow-flowered azalea, Rhododendron molle. Comparative genomics found recent proliferation of long terminal repeat retrotransposons (LTR-RTs), especially Gypsy, has resulted in a 125 Mb (19%) genome size increase in species-specific regions, and a significant amount of dispersed gene duplicates (13 402) and pseudogenes (17 437). Metabolomic assessment revealed that yellow flower coloration is attributed to the dynamic changes of carotenoids/flavonols biosynthesis and chlorophyll degradation. Time-ordered gene co-expression networks (TO-GCNs) and the comparison confirmed the metabolome and uncovered the specific gene regulatory changes underpinning the distinct flower pigmentation. B3 and ERF TFs were found dominating the gene regulation of carotenoids/flavonols characterized pigmentation in R. molle, while WRKY, ERF, WD40, C2H2, and NAC TFs collectively regulated the anthocyanins characterized pigmentation in the red-flowered R simsii. This study employed a multi-omics strategy in disentangling the complex divergence between two important azaleas and provided references for further functional genetics and molecular breeding.
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Tumor-associated macrophages (TAM) and cancer-associated fibroblasts (CAF) and their precursor mesenchymal stromal cells (MSC) are often detected together in tumors, but how they cooperate is not well understood. Here, we show that TAM and CAF are the most abundant nonmalignant cells and are present together in untreated human neuroblastoma (NB) tumors that are also poorly infiltrated with T and natural killer (NK) cells. We then show that MSC and CAF-MSC harvested from NB tumors protected human monocytes (MN) from spontaneous apoptosis in an interleukin (IL)-6 dependent mechanism. The interactions of MN and MSC with NB cells resulted in a significant induction or increase in the expression of several pro-tumorigenic cytokines/chemokines (TGF-ß1, MCP-1, IL-6, IL-8, and IL-4) but not of anti-tumorigenic cytokines (TNF-α, IL-12) by MN or MSC, while also inducing cytokine expression in quiescent NB cells. We then identified a TGF-ß1/IL-6 pathway where TGF-ß1 stimulated the expression of IL-6 in NB cells and MSC, promoting TAM survival. Evidence for the contribution of TAM and MSC to the activation of this pathway was then provided in xenotransplanted NB tumors and patients with primary tumors by demonstrating a direct correlation between the presence of CAF and p-SMAD2 and p-STAT3. The data highlight a new mechanism of interaction between TAM and CAF supporting their pro-tumorigenic function in cancer.
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Fibroblastos , Interleucina-6 , Macrófagos , Neuroblastoma , Factor de Crecimiento Transformador beta1 , Humanos , Neuroblastoma/inmunología , Fibroblastos/inmunología , Macrófagos/inmunología , AnimalesRESUMEN
Few incidents of ancient allopolyploidization (polyploidization by hybridization or merging diverged genomes) were previously revealed, although there is significant evidence for the accumulation of whole genome duplications (WGD) in plants. Here, we focused on Ericales, one of the largest and most diverse angiosperm orders with significant ornamental and economic value. Through integrating 24 high-quality whole genome data selected from ~ 200 Superasterids genomes/species and an algorithm of topology-based gene-tree reconciliation, we explored the evolutionary history of in Ericales with ancient complex. We unraveled the allopolyploid origin of Ericales and detected extensive lineage-specific gene loss following the polyploidization. Our study provided a new hypothesis regarding the origin of Ericales and revealed an instructive perspective of gene loss as a pervasive source of genetic variation and adaptive phenotypic diversity in Ericales.
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Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cyclerelated genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WTexpressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.
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Ependimoma , Histonas , Animales , Niño , Ependimoma/genética , Epigénesis Genética , Epigenómica , Histonas/genética , Humanos , Redes y Vías Metabólicas , RatonesRESUMEN
Neocaridina denticulate sinensis is a small freshwater economic shrimp, as well as excellent laboratory model for their short life cycle and easy availability. However, the response of N. denticulate sinensis to pervasive copper pollution in aquatic environments has not been deeply investigated yet. Herein, we preformed Illumina sequencing technology to mine the alterations of cephalothorax transcriptome under 2.5 µmol/L of Cu2+ after 48 h. 122,512 unigenes were assembled and 219 unigenes were identified as significantly differentially expressed genes (DEGs) between control and Cu2+ treatment groups. Functional enrichment analysis revealed that DEGs were mostly associated with immune responses and molting, such as endocytosis, Fc gamma R-mediated phagocytosis and chitin metabolic process. Seven genes were chosen for qPCR verification, and the results showed that the transcriptome sequencing data were consistent with the qPCR results. This is the first report of transcriptome information about N. denticulate sinensis. These results provided a direction for the future research of resistance to Cu2+ in this shrimp, and simultaneously enriched gene information of N. denticulate sinensis.
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Cobre/toxicidad , Decápodos/genética , Regulación de la Expresión Génica/efectos de los fármacos , Mariscos , Contaminantes Químicos del Agua/toxicidad , Animales , Quitina/metabolismo , Decápodos/efectos de los fármacos , Decápodos/inmunología , Endocitosis/efectos de los fármacos , Endocitosis/genética , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Anotación de Secuencia Molecular , Muda/efectos de los fármacos , Muda/genética , Fagocitosis/efectos de los fármacos , Fagocitosis/genética , RNA-Seq , Transcriptoma/efectos de los fármacosRESUMEN
Azaleas (Ericaceae) comprise one of the most diverse ornamental plants, renowned for their cultural and economic importance. We present a chromosome-scale genome assembly for Rhododendron simsii, the primary ancestor of azalea cultivars. Genome analyses unveil the remnants of an ancient whole-genome duplication preceding the radiation of most Ericaceae, likely contributing to the genomic architecture of flowering time. Small-scale gene duplications contribute to the expansion of gene families involved in azalea pigment biosynthesis. We reconstruct entire metabolic pathways for anthocyanins and carotenoids and their potential regulatory networks by detailed analysis of time-ordered gene co-expression networks. MYB, bHLH, and WD40 transcription factors may collectively regulate anthocyanin accumulation in R. simsii, particularly at the initial stages of flower coloration, and with WRKY transcription factors controlling progressive flower coloring at later stages. This work provides a cornerstone for understanding the underlying genetics governing flower timing and coloration and could accelerate selective breeding in azalea.
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Cromosomas de las Plantas/genética , Genoma de Planta , Proteínas de Plantas/genética , Rhododendron/genética , Antocianinas/biosíntesis , Vías Biosintéticas , Carotenoides/metabolismo , Cromosomas de las Plantas/metabolismo , Flores/genética , Flores/crecimiento & desarrollo , Flores/metabolismo , Regulación de la Expresión Génica de las Plantas , Familia de Multigenes , Proteínas de Plantas/metabolismo , Rhododendron/crecimiento & desarrollo , Rhododendron/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.
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Neoplasias del Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/genética , Epigenómica/métodos , Histonas/genética , Mutación , Animales , Neoplasias del Tronco Encefálico/metabolismo , Línea Celular Tumoral , Glioma Pontino Intrínseco Difuso/metabolismo , Regulación Neoplásica de la Expresión Génica , Glucólisis , Histonas/metabolismo , Humanos , Lisina/genética , Lisina/metabolismo , Metilación , Ratones Endogámicos NOD , Ratones Noqueados , Ratones Desnudos , Ratones SCID , Trasplante HeterólogoAsunto(s)
Neoplasias del Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/genética , Ependimoma/genética , Proteínas Oncogénicas/genética , Biopsia , Neoplasias del Tronco Encefálico/diagnóstico por imagen , Neoplasias del Tronco Encefálico/patología , Preescolar , Metilación de ADN , Diagnóstico Diferencial , Glioma Pontino Intrínseco Difuso/diagnóstico por imagen , Glioma Pontino Intrínseco Difuso/patología , Ependimoma/patología , Humanos , Inmunohistoquímica , Neoplasias Infratentoriales/genética , Neoplasias Infratentoriales/patología , Imagen por Resonancia Magnética , Masculino , Técnicas de Diagnóstico Molecular , Patología Molecular , RNA-Seq , Secuenciación del ExomaRESUMEN
CRISPR/Cas9 technology is an efficient genome editing tool for producing genetically modified animals. Carotenoids color the world around us and their accumulation in animals could be used to culture colorful new verities in animal breeding. ß, ß-carotene 9', 10'-oxygenase (BCO2) is an important enzyme during ß-carotene metabolism. In this research, one full-length cDNA sequence encoding BCO2 (named EcBCO2) were obtained from Exopalaemon carinicauda. The genomic structure analysis showed that EcBCO2 gene was composed of 9 exons and 8 introns. Then, the CRISPR/Cas9-mediated deletion of EcBCO2 gene was generated by co-microinjection of Cas9 mRNA and EcBCO2 sgRNA into one-cell stage embryos of E. carinicauda. Subsequently, the phenotype of EcBCO2-KO prawns was compared with that of wild-type prawns, which showed that EcBCO2-KO resulted in the color change in the hepatopancreas of prawns. In addition, the EcBCO2-KO prawns had a higher survival rate than wild-type prawns when the prawns were challenged with Vibrio parahaemolyticus or Aeromonas hydrophila. These results indicate that BCO2 gene could be used as a candidate gene in molecular marker-assistant breeding of prawns.