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Regulatory T (Treg) cells require (interleukin-2) IL-2 for their homeostasis by affecting their proliferation, survival and activation. Here we investigated transcriptional and epigenetic changes after acute, periodic and persistent IL-2 receptor (IL-2R) signaling in mouse peripheral Treg cells in vivo using IL-2 or the long-acting IL-2-based biologic mouse IL-2-CD25. We show that initially IL-2R-dependent STAT5 transcription factor-dependent pathways enhanced gene activation, chromatin accessibility and metabolic reprogramming to support Treg cell proliferation. Unexpectedly, at peak proliferation, less accessible chromatin prevailed and was associated with Treg cell contraction. Restimulation of IL-2R signaling after contraction activated signature IL-2-dependent genes and others associated with effector Treg cells, whereas genes associated with signal transduction were downregulated to somewhat temper expansion. Thus, IL-2R-dependent Treg cell homeostasis depends in part on a shift from more accessible chromatin and expansion to less accessible chromatin and contraction. Mouse IL-2-CD25 supported greater expansion and a more extensive transcriptional state than IL-2 in Treg cells, consistent with greater efficacy to control autoimmunity.
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Montagem e Desmontagem da Cromatina , Interleucina-2 , Linfócitos T Reguladores , Animais , Cromatina/metabolismo , Interleucina-2/metabolismo , Camundongos , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Transdução de SinaisRESUMO
Programmed cell death (PCD) is a collective term for diverse processes causing an actively induced, tightly controlled cellular suicide. PCD has a multitude of functions in the development and health of multicellular organisms. In comparison to intensively studied forms of animal PCD such as apoptosis, our knowledge of the regulation of PCD in plants remains limited. Despite the importance of PCD in plant development and as a response to biotic and abiotic stresses, the complex molecular networks controlling different forms of plant PCD are only just beginning to emerge. With this review, we provide an update on the considerable progress that has been made over the last decade in our understanding of PCD as an inherent part of plant development. We highlight both functions of developmental PCD and central aspects of its molecular regulation.
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Apoptose , Desenvolvimento Vegetal , Senescência Celular , Células Vegetais/metabolismo , ReproduçãoRESUMO
The paradigmatic example of a topological phase of matter, the two-dimensional Chern insulator1-5, is characterized by a topological invariant consisting of a single integer, the scalar Chern number. Extending the Chern insulator phase from two to three dimensions requires generalization of the Chern number to a three-vector6,7, similar to the three-dimensional (3D) quantum Hall effect8-13. Such Chern vectors for 3D Chern insulators have never been explored experimentally. Here we use magnetically tunable 3D photonic crystals to achieve the experimental demonstration of Chern vectors and their topological surface states. We demonstrate Chern vector magnitudes of up to six, higher than all scalar Chern numbers previously realized in topological materials. The isofrequency contours formed by the topological surface states in the surface Brillouin zone form torus knots or links, whose characteristic integers are determined by the Chern vectors. We demonstrate a sample with surface states forming a (2, 2) torus link or Hopf link in the surface Brillouin zone, which is topologically distinct from the surface states of other 3D topological phases. These results establish the Chern vector as an intrinsic bulk topological invariant in 3D topological materials, with surface states possessing unique topological characteristics.
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Displays are basic building blocks of modern electronics1,2. Integrating displays into textiles offers exciting opportunities for smart electronic textiles-the ultimate goal of wearable technology, poised to change the way in which we interact with electronic devices3-6. Display textiles serve to bridge human-machine interactions7-9, offering, for instance, a real-time communication tool for individuals with voice or speech difficulties. Electronic textiles capable of communicating10, sensing11,12 and supplying electricity13,14 have been reported previously. However, textiles with functional, large-area displays have not yet been achieved, because it is challenging to obtain small illuminating units that are both durable and easy to assemble over a wide area. Here we report a 6-metre-long, 25-centimetre-wide display textile containing 5 × 105 electroluminescent units spaced approximately 800 micrometres apart. Weaving conductive weft and luminescent warp fibres forms micrometre-scale electroluminescent units at the weft-warp contact points. The brightness between electroluminescent units deviates by less than 8 per cent and remains stable even when the textile is bent, stretched or pressed. Our display textile is flexible and breathable and withstands repeated machine-washing, making it suitable for practical applications. We show that an integrated textile system consisting of display, keyboard and power supply can serve as a communication tool, demonstrating the system's potential within the 'internet of things' in various areas, including healthcare. Our approach unifies the fabrication and function of electronic devices with textiles, and we expect that woven-fibre materials will shape the next generation of electronics.
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Terminais de Computador , Eletrônica/instrumentação , Têxteis , Humanos , Maleabilidade , Dispositivos Eletrônicos VestíveisRESUMO
The inference of gene regulatory networks (GRNs) from gene expression profiles has been a key issue in systems biology, prompting many researchers to develop diverse computational methods. However, most of these methods do not reconstruct directed GRNs with regulatory types because of the lack of benchmark datasets or defects in the computational methods. Here, we collect benchmark datasets and propose a deep learning-based model, DeepFGRN, for reconstructing fine gene regulatory networks (FGRNs) with both regulation types and directions. In addition, the GRNs of real species are always large graphs with direction and high sparsity, which impede the advancement of GRN inference. Therefore, DeepFGRN builds a node bidirectional representation module to capture the directed graph embedding representation of the GRN. Specifically, the source and target generators are designed to learn the low-dimensional dense embedding of the source and target neighbors of a gene, respectively. An adversarial learning strategy is applied to iteratively learn the real neighbors of each gene. In addition, because the expression profiles of genes with regulatory associations are correlative, a correlation analysis module is designed. Specifically, this module not only fully extracts gene expression features, but also captures the correlation between regulators and target genes. Experimental results show that DeepFGRN has a competitive capability for both GRN and FGRN inference. Potential biomarkers and therapeutic drugs for breast cancer, liver cancer, lung cancer and coronavirus disease 2019 are identified based on the candidate FGRNs, providing a possible opportunity to advance our knowledge of disease treatments.
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Redes Reguladoras de Genes , Neoplasias Hepáticas , Humanos , Biologia de Sistemas/métodos , Transcriptoma , Algoritmos , Biologia Computacional/métodosRESUMO
Inferring gene regulatory network (GRN) is one of the important challenges in systems biology, and many outstanding computational methods have been proposed; however there remains some challenges especially in real datasets. In this study, we propose Directed Graph Convolutional neural network-based method for GRN inference (DGCGRN). To better understand and process the directed graph structure data of GRN, a directed graph convolutional neural network is conducted which retains the structural information of the directed graph while also making full use of neighbor node features. The local augmentation strategy is adopted in graph neural network to solve the problem of poor prediction accuracy caused by a large number of low-degree nodes in GRN. In addition, for real data such as E.coli, sequence features are obtained by extracting hidden features using Bi-GRU and calculating the statistical physicochemical characteristics of gene sequence. At the training stage, a dynamic update strategy is used to convert the obtained edge prediction scores into edge weights to guide the subsequent training process of the model. The results on synthetic benchmark datasets and real datasets show that the prediction performance of DGCGRN is significantly better than existing models. Furthermore, the case studies on bladder uroepithelial carcinoma and lung cancer cells also illustrate the performance of the proposed model.
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Biologia Computacional , Redes Reguladoras de Genes , Redes Neurais de Computação , Humanos , Biologia Computacional/métodos , Algoritmos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Escherichia coli/genéticaRESUMO
Confining photons in a finite volume is highly desirable in modern photonic devices, such as waveguides, lasers and cavities. Decades ago, this motivated the study and application of photonic crystals, which have a photonic bandgap that forbids light propagation in all directions1-3. Recently, inspired by the discoveries of topological insulators4,5, the confinement of photons with topological protection has been demonstrated in two-dimensional (2D) photonic structures known as photonic topological insulators6-8, with promising applications in topological lasers9,10 and robust optical delay lines11. However, a fully three-dimensional (3D) topological photonic bandgap has not been achieved. Here we experimentally demonstrate a 3D photonic topological insulator with an extremely wide (more than 25 per cent bandwidth) 3D topological bandgap. The composite material (metallic patterns on printed circuit boards) consists of split-ring resonators (classical electromagnetic artificial atoms) with strong magneto-electric coupling and behaves like a 'weak' topological insulator (that is, with an even number of surface Dirac cones), or a stack of 2D quantum spin Hall insulators. Using direct field measurements, we map out both the gapped bulk band structure and the Dirac-like dispersion of the photonic surface states, and demonstrate robust photonic propagation along a non-planar surface. Our work extends the family of 3D topological insulators from fermions to bosons and paves the way for applications in topological photonic cavities, circuits and lasers in 3D geometries.
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Keloid disorder is a tumour-like disease with invasive growth and a high recurrence rate. Genetic contribution is well expected due to the presence of autosomal dominant inheritance and various genetic mutations in keloid lesions. However, GWAS failed to reveal functional variants in exon regions but single nucleotide polymorphisms in the non-coding regions, suggesting the necessity of innovative genetic investigation. This study employed combined GWAS, RNA-sequence and Hi-C analyses to dissect keloid disorder genetic mechanisms using paired keloid tissues and normal skins. Differentially expressed genes, miRNAs and lncRNAs mined by RNA-sequence were identified to construct a network. From which, 8 significant pathways involved in keloid disorder pathogenesis were enriched and 6 of them were verified. Furthermore, topologically associated domains at susceptible loci were located via the Hi-C database and ten differentially expressed RNAs were identified. Among them, the functions of six molecules for cell proliferation, cell cycle and apoptosis were particularly examined and confirmed by overexpressing and knocking-down assays. This study firstly revealed unknown key biomarkers and pathways in keloid lesions using RNA-sequence and previously reported mutation loci, indicating a feasible approach to reveal the genetic contribution to keloid disorder and possibly to other diseases that are failed by GWAS analysis alone.
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Queloide , MicroRNAs , RNA Longo não Codificante , Estudo de Associação Genômica Ampla , Humanos , Queloide/genética , Queloide/patologia , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genéticaRESUMO
CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.
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MicroRNAs , Neoplasias , Linfócitos T CD8-Positivos , Humanos , Imunoterapia/métodos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/metabolismo , Infecção PersistenteRESUMO
Several observational studies have reported an association between obesity and primary liver cancer (PLC), while the causality behind this association and the comparison of the risk effects of different obesity indicators on PLC remain unclear. In this study, we performed two-sample Mendelian randomization (MR) analyses to assess the associations of genetically determined liver fat, visceral adipose tissue (VAT), and body mass index (BMI) with the risk of PLC. The summary statistics of exposures were obtained from two genome-wide association studies (GWASs) based on the UK Biobank (UKB) imaging cohort and the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. GWAS summary statistics for PLC were obtained from FinnGen consortium R7 release data, including 304 PLC cases and 218 488 controls. Inverse-variance weighted (IVW) was used as the primary analysis, and a series of sensitivity analyses were performed to further verify the robustness of these findings. IVW analysis highlighted a significant association of genetically determined liver fat (OR per SD increase: 7.14; 95% CI: 5.10-9.99; P = 2.35E-30) and VAT (OR per SD increase: 5.70; 95% CI: 1.32-24.72; P = .020) with PLC but not of BMI with PLC. The findings were further confirmed by a series of MR methods. No evidence of horizontal pleiotropy between these associations existed. Our study suggested that genetically determined liver fat and VAT rather than BMI were associated with an increased risk of PLC, which suggested that visceral fat distribution is more predictive of the clinical risk of PLC than common in vitro measures.
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Estudo de Associação Genômica Ampla , Neoplasias Hepáticas , Adulto , Humanos , Análise da Randomização Mendeliana , Obesidade/complicações , Obesidade/genética , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Icariin (ICA) inhibits inflammatory response in various diseases, but the mechanism underlying ICA treating airway inflammation in asthma needs further understood. We aimed to predict and validate the potential targets of ICA against asthma-associated airway inflammation using network pharmacology and experiments. METHODS: The ovalbumin-induced asthma-associated airway inflammation mice model was established. The effects of ICA were evaluated by behavioral, airway hyperresponsiveness, lung pathological changes, inflammatory cell and cytokines counts. Next, the corresponding targets of ICA were mined via the SEA, CTD, HERB, PharmMapper, Symmap database and the literature. Pubmed-Gene and GeneCards databases were used to screen asthma and airway inflammation-related targets. The overlapping targets were used to build an interaction network, analyze gene ontology and enrich pathways. Subsequently, flow cytometry, quantitative real-time PCR and western blotting were employed for validation. RESULTS: ICA alleviated the airway inflammation of asthma; 402 targets of ICA, 5136 targets of asthma and 4531 targets of airway inflammation were screened; 216 overlapping targets were matched and predicted ICA possesses the potential to modulate asthmatic airway inflammation by macrophage activation/polarization. Additionally, ICA decreased M1 but elevated M2. Potential targets that were disrupted by asthma inflammation were restored by ICA treatment. CONCLUSIONS: ICA alleviates airway inflammation in asthma by inhibiting the M1 polarization of alveolar macrophages, which is related to metabolic reprogramming. Jun, Jak2, Syk, Tnf, Aldh2, Aldh9a1, Nos1, Nos2 and Nos3 represent potential targets of therapeutic intervention. The present study enhances understanding of the anti-airway inflammation effects of ICA, especially in asthma.
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Asma , Modelos Animais de Doenças , Flavonoides , Ativação de Macrófagos , Macrófagos Alveolares , Farmacologia em Rede , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Camundongos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Citocinas/metabolismo , Ovalbumina , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , FemininoRESUMO
BACKGROUND: Patients with lung adenocarcinoma (LUAD) have a low response rate to immune checkpoint blockade. It is highly important to explore the tumor immune escape mechanism of LUAD patients and expand the population of patients who may benefit from immunotherapy. METHODS: Based on 954 bulk RNA-seq data of LUAD patients and 15 single-cell RNA-seq data, the relationships between tumor immune dysfunction and exclusion (TIDE) scores and survival prognosis in each patient were calculated and evaluated, and the immune escape mechanism affecting the independent prognosis of LUAD patients was identified. Functional enrichment analysis explored the antitumour immune response and biological behavior of tumor cells among different LUAD groups. Single-cell annotation and pseudotemporal analysis were used to explore the target molecules and immune escape mechanisms of LUAD. RESULTS: Myeloid-derived suppressor cells (MDSCs) and IRF8 were identified as risk and protective factors for the independent prognosis of LUAD patients, respectively. In the tumor microenvironment of patients with high infiltration of MDSCs, the antitumor immune response is significantly suppressed, while tumor cell division, proliferation, and distant metastasis are significantly enhanced. Single-cell RNA-seq analysis revealed that IRF8 is an important regulator of MDSC differentiation in LUAD myeloid cells. In addition, IRF8 may regulate the differentiation of MDSCs through the IL6-JAK-STAT3 signalling pathway. CONCLUSIONS: IRF8 deficiency impairs the normal development of LUAD myeloid cells and induces their differentiation into MDSCs, thereby accelerating the immune escape of LUAD cells. IRF8-targeted activation to inhibit the formation of MDSCs may be a new target for immunotherapy in LUAD.
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Adenocarcinoma de Pulmão , Fatores Reguladores de Interferon , Neoplasias Pulmonares , Células Supressoras Mieloides , Microambiente Tumoral , Humanos , Células Supressoras Mieloides/imunologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Fatores Reguladores de Interferon/metabolismo , Fatores Reguladores de Interferon/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Microambiente Tumoral/imunologia , Prognóstico , Feminino , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Masculino , Evasão Tumoral , Evasão da Resposta Imune , Análise de Célula Única , Diferenciação CelularRESUMO
Legume nodulation requires light perception by plant shoots and precise long-distance communication between shoot and root. Recent studies have revealed that TGACG-motif binding factors (GmSTFs) integrate light signals to promote root nodulation; however, the regulatory mechanisms underlying nodule formation in changing light conditions remain elusive. Here, we applied genetic engineering, metabolite measurement, and transcriptional analysis to study soybean (Glycine max) nodules. We clarify a fine-tuning mechanism in response to ultraviolet B (UV-B) irradiation and rhizobia infection, involving GmUVR8-dependent UV-B perception and GmSTF3/4-GmMYB12-GmCHS-mediated (iso)flavonoid biosynthesis for soybean nodule formation. GmUVR8 receptor-perceived UV-B signal triggered R2R3-MYB transcription factors GmMYB12-dependent flavonoid biosynthesis separately in shoot and root. In shoot, UV-B-triggered flavonoid biosynthesis relied on GmUVR8a, b, c receptor-dependent activation of GmMYB12L-GmCHS8 (chalcone synthase) module. In root, UV-B signaling distinctly promotes the accumulation of the isoflavones, daidzein, and its derivative coumestrol, via GmMYB12B2-GmCHS9 module, resulting in hypernodulation. The mobile transcription factors, GmSTF3/4, bind to cis-regulatory elements in the GmMYB12L, GmMYB12B2, and GmCHS9 promoters, to coordinate UV-B light perception in shoot and (iso)flavonoid biosynthesis in root. Our findings establish a novel shoot-to-root communication module involved in soybean nodulation and reveal an adaptive strategy employed by soybean roots in response to UV-B light.
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Glycine max , Transdução de Sinais , Glycine max/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regiões Promotoras Genéticas/genética , Comunicação , Nodulação/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV-1) inhibitors with improved drug resistance profiles and favorable drug-like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non-nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano-substituted benzyl moiety proved to be the most effective inhibitor against HIV-1 wild-type and mutant strains (EC50 = 0.0039-0.338 µM), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 µM). Preliminary structure-activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug-likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half-lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti-HIV-1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug-like profiles.
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Fármacos Anti-HIV , Desenho de Fármacos , HIV-1 , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa , Sulfonas , HIV-1/efeitos dos fármacos , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Estrutura-Atividade , Sulfonas/farmacologia , Sulfonas/síntese química , Sulfonas/química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismoRESUMO
The HIV capsid (CA) protein is a promising target for anti-AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well-documented CA inhibitor PF74 as our lead compound and designed a series of low-molecular-weight phenylalanine derivatives. Among them, compound 7t exhibited remarkable antiviral activity with a high selection index (EC50 = 0.040 µM, SI = 2815), surpassing that of PF74 (EC50 = 0.50 µM, SI = 258). Furthermore, when evaluated against the HIV-2 strain, 7t (EC50 = 0.13 µM) demonstrated approximately 14-fold higher potency than that of PF74 (EC50 = 1.76 µM). Insights obtained from surface plasmon resonance (SPR) revealed that 7t exhibited stronger target affinity to the CA hexamer and monomer in comparison to PF74. The potential interactions between 7t and the HIV-1 CA were further elucidated using molecular docking and molecular dynamics simulations, providing a plausible explanation for the enhanced target affinity with 7t over PF74. Moreover, the metabolic stability assay demonstrated that 7t (T1/2 = 77.0 min) significantly outperforms PF74 (T1/2 = 0.7 min) in human liver microsome, exhibiting an improvement factor of 110-fold. In conclusion, 7t emerges as a promising drug candidate warranting further investigation.
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Fármacos Anti-HIV , Soropositividade para HIV , Humanos , Capsídeo/metabolismo , Fenilalanina/farmacologia , Fenilalanina/metabolismo , Simulação de Acoplamento Molecular , Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/metabolismo , AntirretroviraisRESUMO
The primary cell wall is a fundamental plant constituent that is flexible but sufficiently rigid to support the plant cell shape. Although many studies have demonstrated that reactive oxygen species (ROS) serve as important signaling messengers to modify the cell wall structure and affect cellular growth, the regulatory mechanism underlying the spatial-temporal regulation of ROS activity for cell wall maintenance remains largely unclear. Here, we demonstrate the role of the Arabidopsis (Arabidopsis thaliana) multicopper oxidase-like protein skewed 5 (SKU5) and its homolog SKU5-similar 1 (SKS1) in root cell wall formation through modulating ROS homeostasis. Loss of SKU5 and SKS1 function resulted in aberrant division planes, protruding cell walls, ectopic deposition of iron, and reduced nicotinamide adeninedinucleotide phosphate (NADPH) oxidase-dependent ROS overproduction in the root epidermis-cortex and cortex-endodermis junctions. A decrease in ROS level or inhibition of NADPH oxidase activity rescued the cell wall defects of sku5 sks1 double mutants. SKU5 and SKS1 proteins were activated by iron treatment, and iron over-accumulated in the walls between the root epidermis and cortex cell layers of sku5 sks1. The glycosylphosphatidylinositol-anchored motif was crucial for membrane association and functionality of SKU5 and SKS1. Overall, our results identified SKU5 and SKS1 as regulators of ROS at the cell surface for regulation of cell wall structure and root cell growth.
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Proteínas de Arabidopsis , Arabidopsis , Parede Celular , Raízes de Plantas , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Parede Celular/metabolismo , Ferro/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Oxirredução , Oxirredutases/genética , Oxirredutases/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: This study compared the surgical conversion rate and overall survival (OS) between induction chemotherapy (iC) and induction immunochemotherapy (iIC) for patients with initially unresectable esophageal squamous cell carcinoma (iuESCC). METHODS: In this multicenter, retrospective cohort study, patients from four high-volume institutions with unresectable diseases were included. The primary endpoints were the conversion surgery rate and OS. A multivariate Cox regression analysis was used to identify the independent significant prognostic factors associated with OS. The stabilized inverse probability of treatment weighting was applied to confirm the survival comparison between the iIC and iC cohorts. RESULTS: A total of 309 patients (150 in the iIC cohort and 159 in the iC cohort) were included. A significantly higher conversion surgical rate was observed in the iIC cohort (iIC vs. iC: 127/150, 84.7% vs. 79/159, 49.7%, P < 0.001). The pathological complete response rates were 22.0% and 5.1% in the iIC and the iC cohorts, respectively (P = 0.001). A significant difference in the OS was observed between the iIC (not reached) and iC cohorts (median 95% CI 36.3 [range 27.2-45.5]). The stabilized inverse probability of treatment weighting yielded similar results. Regimen (iIC vs. iC, HR 0.215, 95% CI 0.102-0.454, P < 0.001) and operation (yes vs. no, HR 0.262, 95% CI 0.161-0.427, P < 0.001) were the significant prognostic factors for OS. CONCLUSIONS: Immunochemotherapy plus conversion surgery in the induction setting may be a better treatment option to achieve high pathological responses and improve OS in iuESCC patients.
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To overcome nitrogen deficiency, legume roots establish symbiotic interactions with nitrogen-fixing rhizobia that are fostered in specialized organs (nodules). Similar to other organs, nodule formation is determined by a local maximum of the phytohormone auxin at the primordium site. However, how auxin regulates nodule development remains poorly understood. Here, we found that in soybean, (Glycine max), dynamic auxin transport driven by PIN-FORMED (PIN) transporter GmPIN1 is involved in nodule primordium formation. GmPIN1 was specifically expressed in nodule primordium cells and GmPIN1 was polarly localized in these cells. Two nodulation regulators, (iso)flavonoids trigger expanded distribution of GmPIN1b to root cortical cells, and cytokinin rearranges GmPIN1b polarity. Gmpin1abc triple mutants generated with CRISPR-Cas9 showed the impaired establishment of auxin maxima in nodule meristems and aberrant divisions in the nodule primordium cells. Moreover, overexpression of GmPIN1 suppressed nodule primordium initiation. GmPIN9d, an ortholog of Arabidopsis thaliana PIN2, acts together with GmPIN1 later in nodule development to acropetally transport auxin in vascular bundles, fine-tuning the auxin supply for nodule enlargement. Our findings reveal how PIN-dependent auxin transport modulates different aspects of soybean nodule development and suggest that the establishment of auxin gradient is a prerequisite for the proper interaction between legumes and rhizobia.
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Glycine max/crescimento & desenvolvimento , Ácidos Indolacéticos/metabolismo , Proteínas de Plantas/genética , Nódulos Radiculares de Plantas/crescimento & desenvolvimento , Transporte Biológico , Proteínas de Plantas/metabolismo , Nódulos Radiculares de Plantas/metabolismo , Glycine max/genética , Glycine max/metabolismoRESUMO
Photonic Chern insulators are known for their topological chiral edge states (CESs), whose absolute existence is determined by the bulk band topology, but concrete dispersion can be engineered to exhibit various properties. For example, the previous theory suggested that the edge dispersion can wind many times around the Brillouin zone to slow down light, which can potentially overcome fundamental limitations in conventional slow-light devices: narrow bandwidth and keen sensitivity to fabrication imperfection. Here, we report the first experimental demonstration of this idea, achieved by coupling CESs with resonance-induced nearly flat bands. We show that the backscattering-immune hybridized CESs are significantly slowed down over a relatively broad bandwidth. Our work thus paves an avenue to broadband topological slow-light devices.
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Quantum Hall systems host chiral edge states extending along the one-dimensional boundary of any two-dimensional sample. In solid state materials, the edge states serve as perfectly robust transport channels that produce a quantized Hall conductance; due to their chirality, and the topological protection by the Chern number of the bulk band structure, they cannot be spatially localized by defects or disorder. Here, we show experimentally that the chiral edge states of a lossy quantum Hall system can be localized. In a gyromagnetic photonic crystal exhibiting the quantum Hall topological phase, an appropriately structured loss configuration imparts the edge states' complex energy spectrum with a feature known as point-gap winding. This intrinsically non-Hermitian topological invariant is distinct from the Chern number invariant of the bulk (which remains intact) and induces mode localization via the "non-Hermitian skin effect." The interplay of the two topological phenomena-the Chern number and point-gap winding-gives rise to a non-Hermitian generalization of the paradigmatic Chern-type bulk-boundary correspondence principle. Compared to previous realizations of the non-Hermitian skin effect, the skin modes in this system have superior robustness against local defects and disorders.