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Due to the disturbance of couplings, the anthropomorphic finger lacks sufficient stability and accuracy in joint motion control, which further affects the performance of complex grasping and operating for anthropomorphic hands. In order to obtain stable and accurate joint motion control effect, an anthropomorphic finger control strategy is proposed for an anthropomorphic finger driven by pneumatic artificial muscles (PAMs) in this paper. A nonlinear extended state observer (NESO) is presented to observe the disturbance of couplings for the anthropomorphic finger. An integral sliding mode controller (ISMC) is proposed to realize joint motion control and improve steady state performance. The convergences of the NESO and the ISMC are demonstrated by Lyapunov methods. Furthermore, experimental results illustrate the validity of the proposed control strategy.
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Heavy metal exposure is a known risk factor for hematologic disorders in children, yet the impact of co-exposure to multiple metals remains underexplored. This cross-sectional study investigates the relationship between urinary levels of 23 metals and haemoglobin (Hb) in 1460 Chinese preschoolers. The concentrations of the 23 urinary metals were quantified using an inductively coupled plasma mass spectrometer, while Hb levels were assessed through finger prick blood samples. To evaluate the co-exposure effects, we employed three approaches: Generalized linear regression model, joint effect models including Quantile g-Computation and Bayesian Kernel Machine Regression (BKMR). From the generalized linear regression and Quantile g-computation, urinary uranium, thallium, aluminium, iron and tungsten were correlated negatively with Hb, while urinary barium was correlated positively (all P < 0.05). Moreover, significant negative associations between metal mixtures exposure with Hb were identified in both Quantile g-computation [ß (95% CI): -0.083 (-0.132, -0.033), P = 0.0012] and BKMR [90th percentile vs. 50th percentile ß (95% CI): -0.238 (-0.368, -0.107), P < 0.001] with aluminium emerging as the primary contributor to this joint effect (weight in Quantile g-computation = 0.399, PIPs in BKMR = 0.896). These findings provide a potential explanation for environmental exposure to metals and Hb-related disease in preschoolers.
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Hemoglobinas , Humanos , Preescolar , Masculino , Femenino , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Estudios Transversales , China , Metales Pesados/orina , Metales Pesados/sangre , Metales/orina , Metales/sangre , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Pueblos del Este de AsiaRESUMEN
[This corrects the article DOI: 10.3897/mycokeys.100.109423.].
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The population of Caragana tibetica, situated on the edge of the typical grassland-to-desert transition in the Mu Us Sandy Land, plays a vital ecological role in maintaining stability within the regional fragile ecosystem. Despite the consistent growth of C. tibetica following animal grazing, the biological mechanisms underlying its compensatory growth in response to livestock consumption remain unclear. Analyzing 48 metabolomic profiles from C. tibetica, our study reveals that the grazing process induces significant changes in the metabolic pathways of C. tibetica branches. Differential metabolites show correlations with soluble protein content, catalase, peroxidase, superoxide dismutase, malondialdehyde, and proline levels. Moreover, machine learning models built on these differential metabolites accurately predict the intensity of C. tibetica grazing (with an accuracy of 83.3%). The content of various metabolites, indicative of plant stress responses, including Enterolactone, Narceine, and Folcepri, exhibits significant variations in response to varying grazing intensities (P<0.05). Our investigation reveals that elevated grazing intensity intensifies the stress response in C. tibetica, triggering heightened antioxidative defenses and stress-induced biochemical activities. Distinctive metabolites play a pivotal role in responding to stress, facilitating the plant's adaptation to environmental challenges and fostering regeneration.
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Persicaria capitata was a frequently used Hmong medicinal flora in China. In this study, one new phenolic compound, capitaone A (1) together with 20 known ones, were isolated from the whole herb of P. capitata. Among them, 7 components (4, 9-11, 15-16, 20-21) were discovered from P. capitata for the first time. Their chemical structures were elucidated on the basis of extensive NMR and MS spectrum. Furthermore, three compounds (15, 20, 21) displayed remarkable cytotoxic activities against two human cancer cell lines (A549 and HepG2).
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The Wiskott-Aldrich syndrome protein (WASp) regulates actin cytoskeletal dynamics and function of hematopoietic cells. Mutations in the WAS gene lead to two different syndromes; Wiskott-Aldrich syndrome (WAS) caused by loss-of-function mutations, and X-linked neutropenia (XLN) caused by gain-of-function mutations. We previously showed that WASp-deficient mice have a decreased number of regulatory T (Treg) cells in the thymus and the periphery. We here evaluated the impact of WASp mutations on Treg cells in the thymus of WAS and XLN mouse models. Using in vitro Treg differentiation assays, WAS CD4 single-positive thymocytes have decreased differentiation to Treg cells, despite normal early signaling upon IL-2 and TGF-ß stimulation. They failed to proliferate and express CD25 at high levels, leading to poor survival and a lower number of Foxp3+ Treg cells. Conversely, XLN CD4 single-positive thymocytes efficiently differentiate into Foxp3+ Treg cells following a high proliferative response to IL-2 and TGF-ß, associated with high CD25 expression when compared with WT cells. Altogether, these results show that specific mutations of WASp affect Treg cell development differently, demonstrating a critical role of WASp activity in supporting Treg cell development and expansion.
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Diferenciación Celular , Proliferación Celular , Linfocitos T Reguladores , Timo , Proteína del Síndrome de Wiskott-Aldrich , Animales , Linfocitos T Reguladores/inmunología , Diferenciación Celular/inmunología , Proteína del Síndrome de Wiskott-Aldrich/genética , Proteína del Síndrome de Wiskott-Aldrich/metabolismo , Ratones , Timo/inmunología , Timo/citología , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Interleucina-2/metabolismo , Interleucina-2/inmunología , Mutación , Factor de Crecimiento Transformador beta/metabolismo , Síndrome de Wiskott-Aldrich/inmunología , Síndrome de Wiskott-Aldrich/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/genética , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
The recently developed advanced electrolytes possess many crucial qualities, including robust stability, Li dendrite-free, and comparable interface compatibility, for the manufacturing of Li metal batteries with a high energy density. In this study, lithium bis(trifluoromethane)sulfonimide, acrylamide, and succinonitrile were first used to design a polymerizable monomer. Then, it went through in situ thermal polymerization to attain a new solid polymer electrolyte [named poly(PDES)]. The synthesized poly(PDES) electrolyte achieved higher ionic conductivity (â¼1.89 × 10-3 S cm-1), oxidation potential (â¼5.10 V versus Li+/Li), and a larger lithium-ion transfer number (â¼0.63). Moreover, poly(PDES) was nonflammable and could effectively inhibit the formation of Li dendrites. As a result, the assembled batteries using the poly(PDES) electrolyte for both Li||LiFePO4 and Li||LiNi0.8Co0.1Mn0.1O2 exhibited excellent interface compatibility and electrochemical performances. This poly(PDES) electrolyte has promising potential for broad application in lithium-metal batteries with elevated energy density and safety performance in the near future.
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Here, we present a gene regulation strategy enabling programmable control over eukaryotic translational initiation. By excising the natural poly-adenylation (poly-A) signal of target genes and replacing it with a synthetic control region harboring RNA-binding protein (RBP)-specific aptamers, cap-dependent translation is rendered exclusively dependent on synthetic translation initiation factors (STIFs) containing different RBPs engineered to conditionally associate with different eIF4F-binding proteins (eIFBPs). This modular design framework facilitates the engineering of various gene switches and intracellular sensors responding to many user-defined trigger signals of interest, demonstrating tightly controlled, rapid and reversible regulation of transgene expression in mammalian cells as well as compatibility with various clinically applicable delivery routes of in vivo gene therapy. Therapeutic efficacy was demonstrated in two animal models. To exemplify disease treatments that require on-demand drug secretion, we show that a custom-designed gene switch triggered by the FDA-approved drug grazoprevir can effectively control insulin expression and restore glucose homeostasis in diabetic mice. For diseases that require instantaneous sense-and-response treatment programs, we create highly specific sensors for various subcellularly (mis)localized protein markers (such as cancer-related fusion proteins) and show that translation-based protein sensors can be used either alone or in combination with other cell-state classification strategies to create therapeutic biocomputers driving self-sufficient elimination of tumor cells in mice. This design strategy demonstrates unprecedented flexibility for translational regulation and could form the basis for a novel class of programmable gene therapies in vivo.
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Diabetes Mellitus Experimental , Animales , Ratones , Factor 4F Eucariótico de Iniciación/metabolismo , Procesamiento Proteico-Postraduccional , Regulación de la Expresión Génica , Proteínas Portadoras/metabolismo , MamíferosRESUMEN
Pleosporales comprise a diverse group of fungi with a global distribution and significant ecological importance. A survey on Pleosporales (in Didymosphaeriaceae, Roussoellaceae and Nigrogranaceae) in Guizhou Province, China, was conducted. Specimens were identified, based on morphological characteristics and phylogenetic analyses using a dataset composed of ITS, LSU, SSU, tef1 and rpb2 loci. Maximum Likelihood (ML) and Bayesian analyses were performed. As a result, three new species (Neokalmusiakarka, Nigrogranaschinifolium and N.trachycarpus) have been discovered, along with two new records for China (Roussoellaneopustulans and R.doimaesalongensis) and a known species (Roussoellapseudohysterioides). Morphologically similar species and phylogenetically close taxa are compared and discussed. This study provides detailed information and descriptions of all newly-identified taxa.
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Error in Figure [...].
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During the research on rust fungi in medicinal plants of Guizhou Province, China, a total of 9 rust fungal species were introduced, including 3 new species (Hamaspora rubi-alceifolii, Nyssopsora altissima, and Phragmidium cymosum), as well as 6 known species (Melampsora laricis-populina, Melampsoridium carpini, Neophysopella ampelopsidis, Nyssopsora koelrezidis, P. rosae-roxburghii, P. tormentillae). Notably, N. ampelopsidis and P. tormentillae were discovered for the first time in China, while M. laricis-populina, Me. carpini, and Ny. koelreuteriae were first documented in Guizhou Province. Morphological observation and molecular phylogenetic analyses of these species with similar taxa were compared to confirm their taxonomic identities, and taxonomic descriptions, illustrations and host species of those rust fungi on medicinal plant are provided.
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For the first time, a global regression quantitative structure-toxicity/activity relationship (QSTR/QSAR) model was developed for the toxicity of a large data set including 1236 chemicals towards Vibrio fischeri, by using random forest (RF) regression algorithm. The optimal RF model with RF parameters of mtry = 3, ntree = 150 and nodesize = 5 was based on 13 molecular descriptors. It can achieve accurate prediction for the toxicity of 99.1% of 1236 chemicals, and yield coefficients of determination R2 of 0.893 for 930 log(Mw/IBC50) in the training set, 0.723 for 306 log(Mw/IBC50) in the test se, and 0.865 for 1236 toxicity log(Mw/IBC50) in the total set. The optimal RF global model proposed in this work is comparable to other published local QSTR models on small datasets of the toxicity to Vibrio fischeri.
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Aliivibrio fischeri , Relación Estructura-Actividad Cuantitativa , Bosques AleatoriosRESUMEN
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T-cell lymphoma type with distinct clinical, molecular and genetic features. Establishment of BIA-ALCL cell lines and patient-derived xenograft (PDX) models are essential experimental tools to investigate the molecular pathogenesis of the disease. We characterized a novel BIA-ALCL cell line and PDX model, named BIA-XR1, derived from a patient with textured breast implant who developed lymphoma. Next-generation sequencing revealed a STAT3 mutation, commonly detected in BIA-ALCL, and a unique KRAS mutation reported for the first time in this lymphoma type. Both JAK/STAT3 and RAS/MEK/ERK oncogenic pathways were activated in BIA-XR1, which are targetable with clinically available agents.
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ETHNOPHARMACOLOGY RELEVANCE: Sophora flavescens Aiton, was a crucial source of Traditional Chinese Medicine (TCM) that has benefited human health for hundreds of years. Alkaloids and flavonoids were the major bioactive constituents from S. flavescens, which had been widely used for liver disease treatment in China. However, the liver-protective components of flavonoids from S. flavescens and their mechanism of action were not clear. AIM OF THE STUDY: This work aimed to evaluate the in vitro hepatoprotective activities of 35 flavonoids from S. flavescens and screen active compounds. Furthermore, it was conducted to demonstrate the hepatoprotective effects of a new active compound (kurarinol A, 1) was isolated by authors and the ethyl acetate (EtOAc) extract form S. flavescens against carbon tetrachloride (CCl4)-induced hepatic injury in Kunming (KM) mice, meanwhile revealed the potential mechanism. MATERIALS AND METHODS: The 35 flavonoids from S. flavescens were co-incubated with HepG2 cells and treated with 0.35% CCl4 for 6 h cell viability was measured by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) assay. Then, in vivo animal experiments, the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the serum were analyzed, the degree of hepatic injury was examined using hematoxylin-eosin (H&E) staining, the mRNA expression of Superoxide Dismutase 2 (SOD2), Nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), Interleukin 6 (IL-6), Tumor Necrosis Factor-α (TNF-α), interleukin-1ß (IL-1ß), and the protein levels of nuclear factor-kappa B p65/p-p65 (NF-κB p65/p-p65), toll-like receptor 2 (TLR2), IL-1ß and cyclooxygenase-2 (COX2) in hepatic tissues were detected. RESULTS: The lavandulyl flavonoid (kurarinol A, 1) and the EtOAc extract from S. flavescens showed protective effects on CCl4-injured HepG2 cells, increasing cell viability from 24.5% to 61.3% and 91.8%, respectively. What's more, we found that treatment with kurarinol A (1) and the EtOAc extract lead to a significant reduction in hepatotoxicity in response to acute CCl4 exposure. Compared with the model group, experimental results exhibited kurarinol A (10 mg/kg, i.p.) and the EtOAc extract (300 mg/kg, i.p.) could decrease the levels of AST, ALT, ALP and tissue damage. Further mechanistic investigations revealed that up-regulated the mRNA expression of SOD2, Nrf2, OH-1 and down-regulated the IL-1ß in liver tissues, respectively. Additionally, Western blot analyses elucidated that inhibition of IL-1ß, TLR2, COX-2, NF-κB (p65/p-p65) via TLR2/NF-κB signaling pathway by kurarinol A and the EtOAc extract contribute to its hepatoprotective activity. CONCLUSION: These findings demonstrated that the novel compound (kurarinol A, 1) possessed notable hepatoprotective activity against CCl4. It was confirmed that kurarinol A had a certain effect on mice with liver damage induced by CCl4, and its mechanism could be include inhibiting inflammation and reducing of oxidative stress reaction by regulating expression of related genes and proteins. Thus, kurarinol A could as a novel active agent that contributes to the hepatoprotective activity of S. flavescens for the treatment of live injury.
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Enfermedad Hepática Inducida por Sustancias y Drogas , FN-kappa B , Ratones , Humanos , Animales , FN-kappa B/metabolismo , Sophora flavescens , Factor 2 Relacionado con NF-E2/metabolismo , Receptor Toll-Like 2/metabolismo , Hígado , Transducción de Señal , Estrés Oxidativo , Tetracloruro de Carbono/toxicidad , Flavonoides/farmacología , ARN Mensajero/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patologíaRESUMEN
OBJECTIVE: Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies. DESIGN: We performed 5'and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts. RESULTS: Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells' cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients. CONCLUSION: True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/metabolismo , Virus de la Hepatitis B/genética , Linfocitos T CD8-positivos , Ecosistema , ARN/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Dendritic cell (DC) vaccines for cancer therapy offer the possibility to let the patient's own immune system kill cancer cells. However, DC vaccines have shown less efficacy than expected due to failure to induce cancer cell killing and by activating T regulatory cells. METHODS: We tested if inhibition of signalling via WASp and Arp2/3 using the small molecule CK666 would enhance DC-mediated killing of tumour cells in vitro and in vivo. RESULTS: Using CK666 during the ex vivo phase of antigen processing of ovalbumin (OVA), murine and human DCs showed decreased phagosomal acidification, indicating activation of the cross-presentation pathway. When compared to untreated DCs, DCs treated with CK666 during uptake and processing of OVA-induced increased proliferation of OVA-specific CD8+ OT-I T cells in vitro and in vivo. Using the aggressive B16-mOVA melanoma tumour model, we show that mice injected with CK666-treated DCs and OVA-specific CD8+ OT-I T cells showed higher rejection of B16 melanoma cells when compared to mice receiving non-treated DCs. This resulted in the prolonged survival of tumour-bearing mice receiving CK666-treated DCs. Moreover, combining CK666-treated DCs with the checkpoint inhibitor anti-PD1 further prolonged survival. CONCLUSION: Our data suggest that the small molecule inhibitor CK666 is a good candidate to enhance DC cross-presentation for cancer therapy.
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Reactividad Cruzada , Vacunas , Ratones , Animales , Humanos , Linfocitos T CD8-positivos , Células Dendríticas , Presentación de Antígeno , Ovalbúmina/metabolismo , Vacunas/metabolismo , Ratones Endogámicos C57BLRESUMEN
ETHNOPHARMACOLOGY RELEVANCE: Sophora flavescens is a frequently used traditional Chinese medicine (TCM) for the treatment of skin disorders, diarrhea, vaginal itching and inflammatory diseases. In particular, the root of S. flavescens combination with other herbs mainly treat eczema ailment in the clinical applications. However, a holistic network pharmacology approach to understanding the mechanism by which alkaloids in S. flavescens treat eczema has not been pursued. AIM OF THE STUDY: To examine the network pharmacological potential effect of S. flavescens on eczema, we studied the alkaloids, performed protein targets prediction and investigated interacting signal pathways. Furthermore, animal experiment was carried out to evaluate its efficacy and real-time quantitative polymerase chain reactions (RT-qPCR) analysis was explored the mechanism of action. MATERIALS AND METHODS: The detail information on alkaloids from S. flavescens were obtained from a handful of public databases on the basis of oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18). Then, correlations between compounds and protein targets were linked using the STRING database, and targets associated with eczema were gathered by the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis. Particularly, matrine, the crucial alkaloid from S. flavescens, was estimated using a 2,4-dinitrochlorobenzene (DNCB)-induced eczema Kunming (KM) mice model, administered (50 mg/kg and 10 mg/kg) to mice for 22 days. On the last day, the activities of serum tumor necrosis factor α (TNF-α), interleukin-4 (IL-4) and histopathologic examinations were determined. For further to elucidate the mechanisms, the mRNA levels of TNF-α, STAT3, TP53, AKT1, IL-6, JUN and EGFR in dorsal skin tissues were also tested. RESULTS: Network analysis collected and identified 35 alkaloids from S. flavescens. Among them, in total 10 dominating alkaloids, including matrine, oxymatrine, sophoridine, sophocarpine, oxysophocarpine, allomatrine, sophoramine, anagyrine, cytisine and N-methylcytisine. And 71 related targets were provided of alkaloids for the treatment of eczema from S. flavescens. Furthermore, matrine dose-dependently (50 or 10 mg/kg, 22 days, apply to dorsal skin) remarkable decreased the serum levels of TNF-α and IL-4, and significantly alleviated the skin lesions. The effects of 50 mg/kg of matrine were almost identical to those of 200 mg/kg of the positive drug dexamethasone (DXM). The further RT-qPCR analyses could reveal that matrine down-regulate TNF-α, STAT3 and TP53 at transcriptional level in dorsal skin tissues. CONCLUSION: Pharmacological network analysis can utilize to illuminate the pharmacodynamic substances and the potential molecular mechanism of S. flavescens for treating eczema. Matrine, as the crucial alkaloid from S. flavescens, could be a promising drug candidate for the treatment of eczema ailment.
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Alcaloides , Eccema , Sophora , Humanos , Ratones , Animales , Interleucina-4 , Factor de Necrosis Tumoral alfa , Farmacología en Red , Quinolizinas/farmacología , Quinolizinas/uso terapéutico , Alcaloides/farmacología , Alcaloides/uso terapéutico , Alcaloides/análisisRESUMEN
Introduction: The biosynthesis of the secondary cell wall (SCW) is orchestrated by an intricate hierarchical transcriptional regulatory network. This network is initiated by first-layer master switches, SCW-NAC transcription factors, which in turn activate the second-layer master switches MYBs. These switches play a crucial role in regulating xylem specification and differentiation during SCW formation. However, the roles of most MYBs in woody plants are yet to be fully understood. Methods: In this study, we identified and isolated the R2R3-MYB transcription factor, PtoMYB031, from Populus tomentosa. We explored its expression, mainly in xylem tissues, and its role as a transcriptional repressor in the nucleus. We used overexpression and RNA interference techniques in poplar, along with Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays, to analyze the regulatory effects of PtoMYB031. Results: Overexpression of PtoMYB031 in poplar significantly reduced lignin, cellulose, and hemicellulose content, and inhibited vascular development in stems, resulting in decreased SCW thickness in xylem tissues. Gene expression analysis showed that structural genes involved in SCW biosynthesis were downregulated in PtoMYB031-OE lines. Conversely, RNA interference of PtoMYB031 increased these compounds. Additionally, PtoMYB031 was found to recruit the repressor PtoZAT11, forming a transcriptional inhibition complex. Discussion: Our findings provide new insights into how PtoMYB031, through its interaction with PtoZAT11, forms a complex that can suppress the expression of key regulatory genes, PtoWND1A and PtoWND2B, in SCW biosynthesis. This study enhances our understanding of the transcriptional regulation involved in SCW formation in poplar, highlighting the significant role of PtoMYB031.
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Papillary thyroid carcinoma (PTC) is heterogeneous and its molecular characteristics remain elusive. We integrated transcriptomic sequencing, genomic analysis and clinicopathologic information from 582 tissue samples of 216 PTC and 75 benign thyroid nodule (BTN) patients. We discovered four subtypes of PTC including Immune-enriched Subtype, BRAF-enriched Subtype, Stromal Subtype and CNV-enriched Subtype. Molecular subtypes were validated in an external cohort of 497 PTC cases from the TCGA. Tumors in the Immune-enriched Subtype showed higher immune infiltration and overexpression of immune checkpoints, whilst BRAF-enriched Subtype showed a higher tendency for extrathyroidal extension and more advanced TNM stage. Key oncogenes including LRRK2, SLC34A2, MUC1, FOXQ1 and KRT19 were overexpressed and enriched in oncogenic MAPK and PI3K/AKT signaling pathways in BRAF-enriched subtype. Further analysis of BRAF-enriched Subtype identified three subclasses with different degrees of malignancies. We also uncovered the molecular link of the initiation and progression from BTN to subtypes of PTC using trajectory analysis. Moreover, a 20-gene expression signature was generated for differential diagnosis of PTC from BTN patients. Together, our work identified previously unreported molecular subtypes of PTC, offering opportunities to stratify patients into optimal treatment plans based on molecular subtyping.