ABSTRACT
Elucidating the regulatory mechanisms of human brain evolution is essential to understanding human cognition and mental disorders. We generated multi-omics profiles and constructed a high-resolution map of 3D genome architecture of rhesus macaque during corticogenesis. By comparing the 3D genomes of human, macaque, and mouse brains, we identified many human-specific chromatin structure changes, including 499 topologically associating domains (TADs) and 1,266 chromatin loops. The human-specific loops are significantly enriched in enhancer-enhancer interactions, and the regulated genes show human-specific expression changes in the subplate, a transient zone of the developing brain critical for neural circuit formation and plasticity. Notably, many human-specific sequence changes are located in the human-specific TAD boundaries and loop anchors, which may generate new transcription factor binding sites and chromatin structures in human. Collectively, the presented data highlight the value of comparative 3D genome analyses in dissecting the regulatory mechanisms of brain development and evolution.
Subject(s)
Brain/embryology , Evolution, Molecular , Fetus/embryology , Genome , Organogenesis/genetics , Animals , Base Sequence , Chromatin/metabolism , DNA Transposable Elements/genetics , Enhancer Elements, Genetic/genetics , Gene Expression Regulation, Developmental , Humans , Macaca mulatta , Mice , Species Specificity , Synteny/genetics , Transcription Factors/metabolismABSTRACT
Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin accessibility and gene expression in the same single cell, applicable to different tissues. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define domains of regulatory chromatin (DORCs) that significantly overlap with super-enhancers. During lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for lineage commitment. We computationally infer chromatin potential as a quantitative measure of chromatin lineage-priming and use it to predict cell fate outcomes. SHARE-seq is an extensible platform to study regulatory circuitry across diverse cells in tissues.
Subject(s)
Chromatin/metabolism , Gene Expression Profiling , RNA/genetics , Single-Cell Analysis , Animals , Cell Differentiation/genetics , Cell Line , Cell Lineage/genetics , Enhancer Elements, Genetic/genetics , Female , Gene Expression Regulation , Histones/metabolism , Mice, Inbred C57BL , Protein Processing, Post-Translational , RNA/metabolismABSTRACT
Although solid-state lithium (Li)-metal batteries promise both high energy density and safety, existing solid ion conductors fail to satisfy the rigorous requirements of battery operations. Inorganic ion conductors allow fast ion transport, but their rigid and brittle nature prevents good interfacial contact with electrodes. Conversely, polymer ion conductors that are Li-metal-stable usually provide better interfacial compatibility and mechanical tolerance, but typically suffer from inferior ionic conductivity owing to the coupling of the ion transport with the motion of the polymer chains1-3. Here we report a general strategy for achieving high-performance solid polymer ion conductors by engineering of molecular channels. Through the coordination of copper ions (Cu2+) with one-dimensional cellulose nanofibrils, we show that the opening of molecular channels within the normally ion-insulating cellulose enables rapid transport of Li+ ions along the polymer chains. In addition to high Li+ conductivity (1.5 × 10-3 siemens per centimetre at room temperature along the molecular chain direction), the Cu2+-coordinated cellulose ion conductor also exhibits a high transference number (0.78, compared with 0.2-0.5 in other polymers2) and a wide window of electrochemical stability (0-4.5 volts) that can accommodate both the Li-metal anode and high-voltage cathodes. This one-dimensional ion conductor also allows ion percolation in thick LiFePO4 solid-state cathodes for application in batteries with a high energy density. Furthermore, we have verified the universality of this molecular-channel engineering approach with other polymers and cations, achieving similarly high conductivities, with implications that could go beyond safe, high-performance solid-state batteries.
ABSTRACT
The planetesimals in the solar system exhibit varying degrees of moderately volatile elements (MVEs) depletion compared to the protosolar composition. Revealing the relevant mechanisms is crucial for exploring early solar system evolution. Most volatile-depleted materials in the solar system exhibit enrichments in the heavier isotopes of MVEs, which have traditionally been attributed to the loss of volatiles through partial evaporation. Angrites are so far an exception as they are enriched in the lighter isotopes of K. This has been interpreted as reflecting condensation processes. Here, we present Rb isotopic data of angrites and find that they have lighter Rb isotopic compositions than Vesta, Mars, and the Moon. The δ87Rb value of the angrite parent body (APB) is estimated to range between -1.19 and -0.67. The extremely light Rb isotopic composition of the APB is likely a result of the kinetic recondensation of Rb after near-complete evaporation during the magma ocean stage. This finding provides further support for the partial recondensation model to explain the light Rb and K isotopic compositions of the APB. In addition, the APB, alongside other terrestrial planetary bodies (e.g., Earth, Mars, Moon, and Vesta), exhibit a strong correlation between their Rb and K isotopic compositions. This coupling of Rb and K isotopes is indicative of a volatility-driven isotopic fractionation rather than nucleosynthetic anomalies. The extremely light Rb-K isotopic signatures of the APB suggest that beyond evaporation, condensation plays an equally significant role in shaping the planetary-scale distributions of volatile elements.
ABSTRACT
BACKGROUND: Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA, PSMB8-AS1, has been implicated in the development of tumors. Nevertheless, the precise role of PSMB8-AS1 in cardiovascular diseases, particularly atherosclerosis, has not been thoroughly elucidated. Thus, the primary aim of this investigation is to assess the influence of PSMB8-AS1 on vascular inflammation and the initiation of atherosclerosis. METHODS: We generated PSMB8-AS1 knockin and Apoe (Apolipoprotein E) knockout mice (Apoe-/-PSMB8-AS1KI) and global Apoe and proteasome subunit-ß type-9 (Psmb9) double knockout mice (Apoe-/-Psmb9-/-). To explore the roles of PSMB8-AS1 and Psmb9 in atherosclerosis, we fed the mice with a Western diet for 12 weeks. RESULTS: Long noncoding RNA PSMB8-AS1 is significantly elevated in human atherosclerotic plaques. Strikingly, Apoe-/-PSMB8-AS1KI mice exhibited increased atherosclerosis development, plaque vulnerability, and vascular inflammation compared with Apoe-/- mice. Moreover, the levels of VCAM1 (vascular adhesion molecule 1) and ICAM1 (intracellular adhesion molecule 1) were significantly upregulated in atherosclerotic lesions and serum of Apoe-/-PSMB8-AS1KI mice. Consistently, in vitro gain- and loss-of-function studies demonstrated that PSMB8-AS1 induced monocyte/macrophage adhesion to endothelial cells and increased VCAM1 and ICAM1 levels in a PSMB9-dependent manner. Mechanistic studies revealed that PSMB8-AS1 induced PSMB9 transcription by recruiting the transcription factor NONO (non-POU domain-containing octamer-binding protein) and binding to the PSMB9 promoter. PSMB9 (proteasome subunit-ß type-9) elevated VCAM1 and ICAM1 expression via the upregulation of ZEB1 (zinc finger E-box-binding homeobox 1). Psmb9 deficiency decreased atherosclerotic lesion size, plaque vulnerability, and vascular inflammation in Apoe-/- mice in vivo. Importantly, endothelial overexpression of PSMB8-AS1-increased atherosclerosis and vascular inflammation were attenuated by Psmb9 knockout. CONCLUSIONS: PSMB8-AS1 promotes vascular inflammation and atherosclerosis via the NONO/PSMB9/ZEB1 axis. Our findings support the development of new long noncoding RNA-based strategies to counteract atherosclerotic cardiovascular disease.
Subject(s)
Atherosclerosis , Plaque, Atherosclerotic , RNA, Long Noncoding , Animals , Humans , Mice , Apolipoproteins E/genetics , Atherosclerosis/metabolism , Endothelial Cells/metabolism , Inflammation/genetics , Mice, Inbred C57BL , Mice, Knockout , Plaque, Atherosclerotic/pathology , Proteasome Endopeptidase Complex/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolismABSTRACT
The ongoing outbreak of viral pneumonia in China and across the world is associated with a new coronavirus, SARS-CoV-21. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection2. Although bats are probable reservoir hosts for SARS-CoV-2, the identity of any intermediate host that may have facilitated transfer to humans is unknown. Here we report the identification of SARS-CoV-2-related coronaviruses in Malayan pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity in the receptor-binding domain to SARS-CoV-2. The discovery of multiple lineages of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of new coronaviruses and should be removed from wet markets to prevent zoonotic transmission.
Subject(s)
Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Eutheria/virology , Evolution, Molecular , Genome, Viral/genetics , Sequence Homology, Nucleic Acid , Amino Acid Sequence , Animals , Betacoronavirus/chemistry , Betacoronavirus/classification , COVID-19 , China/epidemiology , Chiroptera/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Disease Reservoirs/virology , Genomics , Humans , Malaysia , Pandemics , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Recombination, Genetic , SARS-CoV-2 , Sequence Alignment , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Zoonoses/virologyABSTRACT
Lymphotoxin ß-receptor (LTßR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3-6. How LTßR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTßR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTßR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTßR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTßR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTßR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFß signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/ß-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTßR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.
Subject(s)
Lung/drug effects , Lung/physiology , Lymphotoxin beta Receptor/antagonists & inhibitors , Regeneration/drug effects , Signal Transduction/drug effects , Wnt Proteins/agonists , Adaptive Immunity , Aging/metabolism , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Animals , Apoptosis/drug effects , Emphysema/metabolism , Female , Humans , Immunity, Innate , Lung/metabolism , Lymphotoxin beta Receptor/metabolism , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Pulmonary Disease, Chronic Obstructive/metabolism , Smoke/adverse effects , Stem Cells/drug effects , Stem Cells/metabolism , Wnt Proteins/metabolism , beta Catenin/metabolismABSTRACT
A cattle pangenome representation was created based on the genome sequences of 898 cattle representing 57 breeds. The pangenome identified 83 Mb of sequence not found in the cattle reference genome, representing 3.1% novel sequence compared with the 2.71-Gb reference. A catalog of structural variants developed from this cattle population identified 3.3 million deletions, 0.12 million inversions, and 0.18 million duplications. Estimates of breed ancestry and hybridization between cattle breeds using insertion/deletions as markers were similar to those produced by single nucleotide polymorphism-based analysis. Hundreds of deletions were observed to have stratification based on subspecies and breed. For example, an insertion of a Bov-tA1 repeat element was identified in the first intron of the APPL2 gene and correlated with cattle breed geographic distribution. This insertion falls within a segment overlapping predicted enhancer and promoter regions of the gene, and could affect important traits such as immune response, olfactory functions, cell proliferation, and glucose metabolism in muscle. The results indicate that pangenomes are a valuable resource for studying diversity and evolutionary history, and help to delineate how domestication, trait-based breeding, and adaptive introgression have shaped the cattle genome.
ABSTRACT
MOTIVATION: Large Language Models (LLMs) have the potential to revolutionize the field of Natural Language Processing, excelling not only in text generation and reasoning tasks but also in their ability for zero/few-shot learning, swiftly adapting to new tasks with minimal fine-tuning. LLMs have also demonstrated great promise in biomedical and healthcare applications. However, when it comes to Named Entity Recognition (NER), particularly within the biomedical domain, LLMs fall short of the effectiveness exhibited by fine-tuned domain-specific models. One key reason is that NER is typically conceptualized as a sequence labeling task, whereas LLMs are optimized for text generation and reasoning tasks. RESULTS: We developed an instruction-based learning paradigm that transforms biomedical NER from a sequence labeling task into a generation task. This paradigm is end-to-end and streamlines the training and evaluation process by automatically repurposing pre-existing biomedical NER datasets. We further developed BioNER-LLaMA using the proposed paradigm with LLaMA-7B as the foundational LLM. We conducted extensive testing on BioNER-LLaMA across three widely recognized biomedical NER datasets, consisting of entities related to diseases, chemicals, and genes. The results revealed that BioNER-LLaMA consistently achieved higher F1-scores ranging from 5% to 30% compared to the few-shot learning capabilities of GPT-4 on datasets with different biomedical entities. We show that a general-domain LLM can match the performance of rigorously fine-tuned PubMedBERT models and PMC-LLaMA, biomedical-specific language model. Our findings underscore the potential of our proposed paradigm in developing general-domain LLMs that can rival SOTA performances in multi-task, multi-domain scenarios in biomedical and health applications. AVAILABILITY AND IMPLEMENTATION: Datasets and other resources are available at https://github.com/BIDS-Xu-Lab/BioNER-LLaMA.
Subject(s)
Camelids, New World , Deep Learning , Animals , Language , Natural Language ProcessingABSTRACT
The methylation of N6-methyladenosine (m6A) involves writers, erasers, and readers, acting synergistically in posttranscriptional regulation. These processes influence various biological processes, including plant floral transition. However, the specific role of m6A modifications in photoperiod sensitivity in cotton (Gossypium hirsutum) remains obscure. To elucidate this, in this study, we conducted transcriptome-wide m6A sequencing during critical flowering transition stages in the photoperiod-sensitive wild G. hirsutum var. yucatanense (yucatanense) and the photoperiod-insensitive cultivated cotton G. hirsutum acc. TM-1 (TM-1). Our results revealed significant variations in m6A methylation of 2 cotton varieties, with yucatanense exhibiting elevated m6A modification levels compared with TM-1 under long-day conditions. Notably, distinct m6A peaks between TM-1 and yucatanense correlated significantly with photoperiod sensitivity. Moreover, our study highlighted the role of the demethylase G. hirsutum ALKB homolog 5 (GhALKBH5) in modulating m6A modification levels. Silencing GhALKBH5 led to a decreased mRNA level of key photoperiodic flowering genes (GhADO3, GhAGL24, and GhFT1), resulting in delayed bud emergence and flowering. Reverse transcription quantitative PCR analyses confirmed that silencing GhADO3 and GhAGL24 significantly downregulated the expression of the floral integrator GhFT1. Collectively, our findings unveiled a transcriptional regulatory mechanism in which GhALKBH5-mediated m6A demethylation of crucial photoperiodic flowering transcripts modulated photoperiod sensitivity in cotton.
ABSTRACT
Radiotherapy (RT), administered to roughly half of all cancer patients, occupies a crucial role in the landscape of cancer treatment. However, expanding the clinical indications of RT remains challenging. Inspired by the radiation-induced bystander effect (RIBE), we used the mediators of RIBE to mimic RT. Specifically, we discovered that irradiated tumor cell-released microparticles (RT-MPs) mediated the RIBE and had immune activation effects. To further boost the immune activation effect of RT-MPs to achieve cancer remission, even in advanced stages, we engineered RT-MPs with different cytokine and chemokine combinations by modifying their production method. After comparing the therapeutic effect of the engineered RT-MPs in vitro and in vivo, we demonstrated that tIL-15/tCCL19-RT-MPs effectively activated antitumor immune responses, significantly prolonged the survival of mice with malignant pleural effusion (MPE), and even achieved complete cancer remission. When tIL-15/tCCL19-RT-MPs were combined with PD-1 monoclonal antibody (mAb), a cure rate of up to 60% was achieved. This combination therapy relied on the activation of CD8+ T cells and macrophages, resulting in the inhibition of tumor growth and the establishment of immunological memory against tumor cells. Hence, our research may provide an alternative and promising strategy for cancers that are not amenable to conventional RT.
Subject(s)
Cell-Derived Microparticles , Pleural Effusion, Malignant , Humans , Animals , Mice , CD8-Positive T-Lymphocytes , Combined Modality Therapy , Cytokines , Tumor Microenvironment , Cell Line, TumorABSTRACT
BACKGROUND: Plants differ more than threefold in seed oil contents (SOCs). Soybean (Glycine max), cotton (Gossypium hirsutum), rapeseed (Brassica napus), and sesame (Sesamum indicum) are four important oil crops with markedly different SOCs and fatty acid compositions. RESULTS: Compared to grain crops like maize and rice, expanded acyl-lipid metabolism genes and relatively higher expression levels of genes involved in seed oil synthesis (SOS) in the oil crops contributed to the oil accumulation in seeds. Here, we conducted comparative transcriptomics on oil crops with two different SOC materials. In common, DIHYDROLIPOAMIDE DEHYDROGENASE, STEAROYL-ACYL CARRIER PROTEIN DESATURASE, PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE, and oil-body protein genes were both differentially expressed between the high- and low-oil materials of each crop. By comparing functional components of SOS networks, we found that the strong correlations between genes in "glycolysis/gluconeogenesis" and "fatty acid synthesis" were conserved in both grain and oil crops, with PYRUVATE KINASE being the common factor affecting starch and lipid accumulation. Network alignment also found a conserved clique among oil crops affecting seed oil accumulation, which has been validated in Arabidopsis. Differently, secondary and protein metabolism affected oil synthesis to different degrees in different crops, and high SOC was due to less competition of the same precursors. The comparison of Arabidopsis mutants and wild type showed that CINNAMYL ALCOHOL DEHYDROGENASE 9, the conserved regulator we identified, was a factor resulting in different relative contents of lignins to oil in seeds. The interconnection of lipids and proteins was common but in different ways among crops, which partly led to differential oil production. CONCLUSIONS: This study goes beyond the observations made in studies of individual species to provide new insights into which genes and networks may be fundamental to seed oil accumulation from a multispecies perspective.
Subject(s)
Crops, Agricultural , Gene Expression Profiling , Gene Regulatory Networks , Plant Oils , Crops, Agricultural/genetics , Crops, Agricultural/metabolism , Plant Oils/metabolism , Gene Expression Profiling/methods , Transcriptome , Seeds/genetics , Seeds/metabolism , Gene Expression Regulation, PlantABSTRACT
This study aimed to identify characteristic proteins in infantile epileptic spasm syndrome (IESS) patients' plasma, offering insights into potential early diagnostic biomarkers and its underlying causes. Plasma samples were gathered from 60 patients with IESS and 40 healthy controls. Data-independent acquisition proteomic analysis was utilized to identify differentially expressed proteins (DEPs). These DEPs underwent functional annotation through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Gene set enrichment analysis (GSEA) was employed for both GO (GSEA-GO) and KEGG (GSEA-KEGG) analyses to examine the gene expression profiles. Receiver operating characteristic (ROC) curves assessed biomarkers' discriminatory capacity. A total of 124 DEPs were identified in IESS patients' plasma, mainly linked to pathways, encompassing chemokines, cytokines, and oxidative detoxification. GSEA-GO and GSEA-KEGG analyses indicated significant enrichment of genes associated with cell migration, focal adhesion, and phagosome pathways. ROC curve analysis demonstrated that the combination of PRSS1 and ACTB, PRSS3, ACTB, and PRSS1 alone exhibited AUC values exceeding 0.7. This study elucidated the significant contribution of cytokines, chemokines, oxidative detoxification, and phagosomes to the IESS pathogenesis. The combination of PRSS1 and ACTB holds promise as biomarkers for the early diagnosis of IESS.
ABSTRACT
Autophagy is a key process in eukaryotes to maintain cellular homeostasis by delivering cellular components to lysosomes/vacuoles for degradation and reuse of the resulting metabolites. Membrane rearrangements and trafficking events are mediated by the core machinery of autophagy-related (Atg) proteins, which carry out a variety of functions. How Atg9, a lipid scramblase and the only conserved transmembrane protein within this core Atg machinery, is trafficked during autophagy remained largely unclear. Here, we addressed this question in yeast Saccharomyces cerevisiae and found that retromer complex and dynamin Vps1 mutants alter Atg9 subcellular distribution and severely impair the autophagic flux by affecting two separate autophagy steps. We provide evidence that Vps1 interacts with Atg9 at Atg9 reservoirs. In the absence of Vps1, Atg9 fails to reach the sites of autophagosome formation, and this results in an autophagy defect. The function of Vps1 in autophagy requires its GTPase activity. Moreover, Vps1 point mutants associated with human diseases such as microcytic anemia and Charcot-Marie-Tooth are unable to sustain autophagy and affect Atg9 trafficking. Together, our data provide novel insights on the role of dynamins in Atg9 trafficking and suggest that a defect in this autophagy step could contribute to severe human pathologies.
Subject(s)
Autophagosomes , Saccharomyces cerevisiae Proteins , Humans , Autophagosomes/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Dynamins/metabolism , Vacuoles/metabolism , Autophagy , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Protein Transport , GTP-Binding Proteins/metabolism , Vesicular Transport Proteins/genetics , Vesicular Transport Proteins/metabolism , Membrane Proteins/metabolismABSTRACT
Trichomes, the outward projection of plant epidermal tissue, provide an effective defense against stress and insect pests. Although numerous genes have been identified to be involved in trichome development, the molecular mechanism for trichome cell fate determination is not well enunciated. Here, we reported GoSTR functions as a master repressor for stem trichome formation, which was isolated by map-based cloning based on a large F2 segregating population derived from a cross between TM-1 (pubescent stem) and J220 (smooth stem). Sequence alignment revealed a critical G-to-T point mutation in GoSTR's coding region that converted codon 2 from GCA (Alanine) to TCA (Serine). This mutation occurred between the majority of Gossypium hirsutum with pubescent stem (GG-haplotype) and G. barbadense with glabrous stem (TT-haplotype). Silencing of GoSTR in J220 and Hai7124 via virus-induced gene silencing resulted in the pubescent stems but no visible change in leaf trichomes, suggesting stem trichomes and leaf trichomes are genetically distinct. Yeast two-hybrid assay and luciferase complementation imaging assay showed GoSTR interacts with GoHD1 and GoHOX3, two key regulators of trichome development. Comparative transcriptomic analysis further indicated that many transcription factors such as GhMYB109, GhTTG1, and GhMYC1/GhDEL65 which function as positive regulators of trichomes were significantly upregulated in the stem from the GoSTR-silencing plant. Taken together, these results indicate that GoSTR functions as an essential negative modulator of stem trichomes and its transcripts will greatly repress trichome cell differentiation and growth. This study provided valuable insights for plant epidermal hair initiation and differentiation research.
Subject(s)
Gossypium , Trichomes , Gossypium/genetics , Trichomes/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Plant Epidermis/metabolism , Gene Expression Regulation, Plant/geneticsABSTRACT
Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.
Subject(s)
Apigenin , Epithelial-Mesenchymal Transition , Glucose , Histones , Retinal Pigment Epithelium , Epithelial-Mesenchymal Transition/drug effects , Retinal Pigment Epithelium/drug effects , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Animals , Apigenin/pharmacology , Acetylation/drug effects , Humans , Glucose/metabolism , Glucose/toxicity , Histones/metabolism , Cell Line , Mice , p300-CBP Transcription Factors/metabolism , p300-CBP Transcription Factors/antagonists & inhibitors , Mice, Inbred C57BL , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/pathology , Diabetic Retinopathy/drug therapy , E1A-Associated p300 Protein/metabolism , Male , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , CREB-Binding Protein/metabolism , CREB-Binding Protein/geneticsABSTRACT
Phosphorescence in carbon dots (CDs) from triplet exciton radiative recombination at room temperature has achieved significant advancement. Confinement and nanoconfinement, serving as valuable techniques, are commonly utilized to brighten triplet exciton in CDs, thereby enhancing their phosphorescence. However, a comprehensive and universally applicable physical description of confinement-enhanced phosphorescence is still lacking, despite efforts to understand its underlying nature. In this study, the dominance of entropy is revealed in triplet exciton emission from CDs through the establishment of a microscopic vibration state model. CDs with varying entropy levels are studied, indicating that in a low entropy system, the multi-energy triplet exciton emission in CDs exhibits enhanced brightness, accompanied by a corresponding increase in their lifetimes. The product of lifetime and intensity in CDs serves as a descriptor for their phosphorescence properties. Moreover, an entropy-dependent information variation system based on the CDs is demonstrated. Specifically, in a low-entropy system, information is retained, whereas the corresponding information is erased in a high-entropy system. This work elucidates the underlying physical nature of confinement-enhanced triplet exciton emission, offering a deeper understanding of achieving ultralong phosphorescence in the future.
ABSTRACT
The elucidation of genetic architecture and molecular regulatory networks underlying complex traits remains a significant challenge in life science, largely due to the substantial background effects that arise from epistasis and gene-environment interactions. The chromosome segment substitution line (CSSL) is an ideal material for genetic and molecular dissection of complex traits due to its near-isogenic properties; yet a comprehensive analysis, from the basic identification of substitution segments to advanced regulatory network, is still insufficient. Here, we developed two cotton CSSL populations on the Gossypium hirsutum background, representing wide adaptation and high lint yield, with introgression from G. barbadense, representing superior fibre quality. We sequenced 99 CSSLs that demonstrated significant differences from G. hirsutum in fibre, and characterized 836 dynamic fibre transcriptomes in three crucial developmental stages. We developed a workflow for precise resolution of chromosomal substitution segments; the genome sequencing revealed substitutions collectively representing 87.25% of the G. barbadense genome. Together, the genomic and transcriptomic survey identified 18 novel fibre-quality-related quantitative trait loci with high genetic contributions and the comprehensive landscape of fibre development regulation. Furthermore, analysis determined unique cis-expression patterns in CSSLs to be the driving force for fibre quality alteration; building upon this, the co-expression regulatory network revealed biological relationships among the noted pathways and accurately described the molecular interactions of GhHOX3, GhRDL1 and GhEXPA1 during fibre elongation, along with reliable predictions for their interactions with GhTBA8A5. Our study will enhance more strategic employment of CSSL in crop molecular biology and breeding programmes.
ABSTRACT
Breast cancer (BC) with average human epidermal growth factor receptor 2 (HER2) signals/cell ≥6 and HER2/chromosome enumeration probe 17 (CEP17) ratio <2 (in situ hybridization [ISH] group 3) is very rare, accounting for 0.4% to 3.0% of cases sent for the dual-probe ISH assay. Although such patients are currently eligible for treatment with HER2-targeted therapy, their characteristics and outcomes remain poorly understood. Sixty-two BCs with equivocal HER2 immunohistochemical score (2+) and reflex ISH group 3 results were identified across 4 institutions. Available clinicopathologic characteristics, MammaPrint and BluePrint molecular results, and follow-up information were retrospectively analyzed. Most BCs with HER2 equivocal immunohistochemical and ISH group 3 results were histologic grade 2 or 3 (100%), estrogen receptor (ER) positive (90.3%), with an average HER2 signals/cell of 7.3. Molecular profiles revealed that 80% (16/20) of tumors were luminal subtypes, and HER2 molecular subtype was identified in 10% of tumors (2/20). Twelve (19.4%) out of 62 patients developed local recurrence and/or distant metastasis with a median follow-up of 50 months. One (10%) of 10 patients achieved pathologic complete response after neoadjuvant chemotherapy. Forty-nine (79%) out of 62 patients completed anti-HER2 agents, and exploratory analysis showed no statistically significant difference in disease outcomes between patients who completed anti-HER2 treatment and those who did not. Univariate analysis revealed advanced clinical stage, and ER/progesterone receptor negativity was associated with unfavorable disease outcomes, and exploratory multivariate analysis demonstrated that clinical stage was the most significant factor associated with disease outcomes in the studied population. These findings increase our understanding of this rare, but clinically important HER2 category. Large-scale prospective randomized studies are needed to further evaluate the role of perioperative HER2-targeted therapy in this patient population.
ABSTRACT
MOTIVATION: Automated extraction of participants, intervention, comparison/control, and outcome (PICO) from the randomized controlled trial (RCT) abstracts is important for evidence synthesis. Previous studies have demonstrated the feasibility of applying natural language processing (NLP) for PICO extraction. However, the performance is not optimal due to the complexity of PICO information in RCT abstracts and the challenges involved in their annotation. RESULTS: We propose a two-step NLP pipeline to extract PICO elements from RCT abstracts: (i) sentence classification using a prompt-based learning model and (ii) PICO extraction using a named entity recognition (NER) model. First, the sentences in abstracts were categorized into four sections namely background, methods, results, and conclusions. Next, the NER model was applied to extract the PICO elements from the sentences within the title and methods sections that include >96% of PICO information. We evaluated our proposed NLP pipeline on three datasets, the EBM-NLPmoddataset, a randomly selected and reannotated dataset of 500 RCT abstracts from the EBM-NLP corpus, a dataset of 150 COVID-19 RCT abstracts, and a dataset of 150 Alzheimer's disease (AD) RCT abstracts. The end-to-end evaluation reveals that our proposed approach achieved an overall micro F1 score of 0.833 on the EBM-NLPmod dataset, 0.928 on the COVID-19 dataset, and 0.899 on the AD dataset when measured at the token-level and an overall micro F1 score of 0.712 on EBM-NLPmod dataset, 0.850 on the COVID-19 dataset, and 0.805 on the AD dataset when measured at the entity-level. AVAILABILITY: Our codes and datasets are publicly available at https://github.com/BIDS-Xu-Lab/section_specific_annotation_of_PICO. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.