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BACKGROUND: Elaeocarpus spp. stem blight, caused by Pseudocryphonectria elaeocarpicola, is a destructive disease, which will significantly reduce the productivity and longevity of Elaeocarpus spp. plants, especially in the Guangdong Province of China. However, few information is available for P. elaeocarpicola. To unravel the potential adaptation mechanism of stem adaptation, the whole genome of P. elaeocarpicola was sequenced by using the DNBSEQ and PacBio platforms. RESULTS: P. elaeocarpicola harbors 44.49 Mb genome with 10,894 predicted coding genes. Genome analysis revealed that the P. elaeocarpicola genome encodes a plethora of pathogenicity-related genes. Analysis of carbohydrate-active enzymes (CAZymes) revealed a rich variety of enzymes participated in plant cell wall degradation, which could effectively degrade cellulose, hemicellulose and xyloglucans in the plant cell wall and promote the invasion of the host plant. There are 213 CAZyme families found in P. elaeocarpicola, among which glycoside hydrolase (GH) family has the largest number, far exceeding other tested fungi by 53%. Besides, P. elaeocarpicola has twice as many genes encoding chitin and cellulose degradation as Cryphonectria parasitica, which belong to the same family. The predicted typical secreted proteins of P. elaeocarpicola are numerous and functional, including many known virulence effector factors, indicating that P. elaeocarpicola has great potential to secrete virulence effectors to promote pathogenicity on host plants. AntiSMASH revealed that the genome encoded 61 secondary metabolic gene clusters including 86 secondary metabolic core genes which was much higher than C. parasitica (49). Among them, two gene cluster of P. elaeocarpicola, cluster12 and cluster52 showed 100% similarity with the mycotoxins synthesis clusters from Aspergillus steynii and Alternaria alternata, respectively. In addition, we annotated cytochrome P450 related enzymes, transporters, and transcription factors in P. elaeocarpicola, which are important virulence determinants of pathogenic fungi. CONCLUSIONS: Taken together, our study represents the first genome assembly for P. elaeocarpicola and reveals the key virulence factors in the pathogenic process of P. elaeocarpicola, which will promote our understanding of its pathogenic mechanism. The acquired knowledge lays a foundation for further exploration of molecular interactions with the host and provide target for management strategies in future research.
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Ascomicetos , Genoma Fúngico , Enfermedades de las Plantas , Ascomicetos/genética , Ascomicetos/patogenicidad , Enfermedades de las Plantas/microbiología , Corteza de la Planta/microbiología , Filogenia , Adaptación Fisiológica/genética , Secuenciación Completa del GenomaRESUMEN
Rust disease is a common plant disease that can cause wilting, slow growth of plant leaves, and even affect the growth and development of plants. Orchardgrass (Dactylis glomerata L.) is native to temperate regions of Europe, which has been introduced as a superior forage grass in temperate regions worldwide. Orchardgrass has rich genetic diversity and is widely distributed in the world, which may contain rust resistance genes not found in other crops. Therefore, we collected a total of 333 orchardgrass accessions from different regions around the world. Through a genome-wide association study (GWAS) analysis conducted in four different environments, 91 genes that overlap or are adjacent to significant single nucleotide polymorphisms (SNPs) were identified as potential rust disease resistance genes. Combining transcriptome data from susceptible (PI292589) and resistant (PI251814) accessions, the GWAS candidate gene DG5C04160.1 encoding glutathione S-transferase (GST) was found to be important for orchardgrass rust (Puccinia graminis) resistance. Interestingly, by comparing the number of GST gene family members in seven species, it was found that orchardgrass has the most GST gene family members, containing 119 GST genes. Among them, 23 GST genes showed significant differential expression after inoculation with the rust pathogen in resistant and susceptible accessions; 82% of the genes still showed significantly increased expression 14 days after inoculation in resistant accessions, while the expression level significantly decreased in susceptible accessions. These results indicate that GST genes play an important role in orchardgrass resistance to rust (P. graminis) stress by encoding GST to reduce its oxidative stress response.
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Dactylis , Resistencia a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades de las Plantas , Puccinia , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Resistencia a la Enfermedad/genética , Puccinia/genética , Puccinia/fisiología , Dactylis/genética , Dactylis/microbiología , Perfilación de la Expresión Génica , Polimorfismo de Nucleótido Simple/genética , Glutatión Transferasa/genética , Genes de Plantas/genética , Transcriptoma , Basidiomycota/fisiología , Basidiomycota/genéticaRESUMEN
BACKGROUND: The yeast Komagataella phaffii is widely used for manufacturing recombinant proteins, but secreted titers of recombinant proteins could be improved by genetic engineering. In this study, we hypothesized that cellular resources could be redirected from production of endogenous proteins to production of recombinant proteins by deleting unneeded endogenous proteins. In non-model microorganisms such as K. phaffii, however, genetic engineering is limited by lack gene annotation and knowledge of gene essentiality. RESULTS: We identified a set of endogenous secreted proteins in K. phaffii by mass spectrometry and signal peptide prediction. Our efforts to disrupt these genes were hindered by limited annotation of essential genes. To predict essential genes, therefore, we designed, transformed, and sequenced a pooled library of guide RNAs for CRISPR-Cas9-mediated knockout of all endogenous secreted proteins. We then used predicted gene essentiality to guide iterative disruptions of up to 11 non-essential genes. Engineered strains exhibited a ~20× increase in the production of human serum albumin and a twofold increase in the production of a monoclonal antibody. CONCLUSIONS: We demonstrated that disruption of as few as six genes can increase production of recombinant proteins. Further reduction of the endogenous proteome of K. phaffii may further improve strain performance. The pooled library of secretome-targeted guides for CRISPR-Cas9 and knowledge of gene essentiality reported here will facilitate future efforts to engineer K. phaffii for production of other recombinant proteins and enzymes.
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Sistemas CRISPR-Cas , Proteínas Recombinantes , Saccharomycetales , Saccharomycetales/genética , Saccharomycetales/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/metabolismo , Humanos , Técnicas de Inactivación de Genes/métodos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteoma/metabolismo , Anticuerpos Monoclonales/biosíntesis , Albúmina Sérica Humana/genética , Albúmina Sérica Humana/metabolismoRESUMEN
KEY MESSAGE: Analyze the evolutionary pattern of DNAJ protein genes in the Panicoideae, including pearl millet, to identify and characterize the biological function of PgDNAJ genes in pearl millet. Global warming has become a major factor threatening food security and human development. It is urgent to analyze the heat-tolerant mechanism of plants and cultivate crops that are adapted to high temperature conditions. The Panicoideae are the second largest subfamily of the Poaceae, widely distributed in warm temperate and tropical regions. Many of these species have been reported to have strong adaptability to high temperature stress, such as pearl millet, foxtail millet and sorghum. The evolutionary differences in DNAJ protein genes among 12 Panicoideae species and 10 other species were identified and analyzed. Among them, 79% of Panicoideae DNAJ protein genes were associated with retrotransposon insertion. Analysis of the DNAJ protein pan-gene family in six pearl millet accessions revealed that the non-core genes contained significantly more TEs than the core genes. By identifying and analyzing the distribution and types of TEs near the DNAJ protein genes, it was found that the insertion of Copia and Gypsy retrotransposons provided the source of expansion for the DNAJ protein genes in the Panicoideae. Based on the analysis of the evolutionary pattern of DNAJ protein genes in Panicoideae, the PgDNAJ was obtained from pearl millet through identification. PgDNAJ reduces the accumulation of reactive oxygen species caused by high temperature by activating ascorbate peroxidase (APX), thereby improving the heat resistance of plants. In summary, these data provide new ideas for mining potential heat-tolerant genes in Panicoideae, and help to improve the heat tolerance of other crops.
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Pennisetum , Proteínas de Plantas , Pennisetum/genética , Pennisetum/fisiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia , Proteínas del Choque Térmico HSP40/genética , Regulación de la Expresión Génica de las Plantas , Retroelementos/genética , Poaceae/genética , Evolución Molecular , Genes de PlantasRESUMEN
Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.
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Subunidad p19 de la Interleucina-23 , Fosfatidilinositol 3-Quinasas , Receptor de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Linfocitos T Citotóxicos , Neoplasias de la Mama Triple Negativas , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/inmunología , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Línea Celular Tumoral , Femenino , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Subunidad p19 de la Interleucina-23/metabolismo , Animales , Ratones , Anticuerpos Monoclonales/farmacologíaRESUMEN
Objective: Paradoxical embolism from right-to-left shunting is a common cause of cryptogenic stroke in the young. Circulatory ischemia of the cochlea is closely connected with severe-to-profound sudden sensorineural hearing loss. This study aimed to explore the role of paradoxical embolism in severe-to-profound sudden sensorineural hearing loss in juveniles and young adults. Methods: From August 2021 to September 2022, consecutive outpatients under 35 years of age with severe-to-profound sudden hearing loss were included in the study. Routine auditory electrophysiological testing and contrast transcranial Doppler ultrasonography (c-TCD) were conducted, and the results were retrospectively analyzed. Results: Seven patients (age: 19.4 ± 6.5 years) were enrolled, including 5 juveniles and 2 young adults. Three patients had severe deafness, and 4 patients had profound deafness. Right-to-left shunting was detected in all patients through c-TCD. Patent foramen ovale was found in 2 patients while pulmonary arteriovenous fistula was found in 1 patient through contrast transthoracic echocardiography or cardiac catheterization. No patients had precipitating factors for sudden sensorineural hearing loss, and none had abnormalities on head magnetic resonance imaging. Six patients underwent whole-exome sequencing, and no known deafness gene variant was detected. After standard treatment for 1 month, 2, 3, and 2 patients had complete, slight, and no hearing recovery, respectively. Conclusions: Paradoxical embolism is a possible cause of severe-to-profound sudden sensorineural hearing loss in juveniles and young adults. In young patients, c-TCD is an effective screening tool to detect right-to-left shunting, while contrast transthoracic echocardiography is a complementary examination to c-TCD.
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The resolution of traffic congestion and personal safety issues holds paramount importance for human's life. The ability of an autonomous driving system to navigate complex road conditions is crucial. Deep learning has greatly facilitated machine vision perception in autonomous driving. Aiming at the problem of small target detection in traditional YOLOv5s, this paper proposes an optimized target detection algorithm. The C3 module on the algorithm's backbone is upgraded to the CBAMC3 module, introducing a novel GELU activation function and EfficiCIoU loss function, which accelerate convergence on position loss lbox, confidence loss lobj, and classification loss lcls, enhance image learning capabilities and address the issue of inaccurate detection of small targets by improving the algorithm. Testing with a vehicle-mounted camera on a predefined route effectively identifies road vehicles and analyzes depth position information. The avoidance model, combined with Pure Pursuit and MPC control algorithms, exhibits more stable variations in vehicle speed, front-wheel steering angle, lateral acceleration, etc., compared to the non-optimized version. The robustness of the driving system's visual avoidance functionality is enhanced, further ameliorating congestion issues and ensuring personal safety.
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Alternative splicing (AS) is an important post-transcriptional mechanism for adaptation of fish to environmental stress. Here, we performed a genome-wide investigation to AS dynamics in greater amberjack (Seriola dumerili), an economical marine teleost, in response to hypo- (10 ppt) and hyper-salinity (40 ppt) stresses. Totally, 2267-2611 differentially spliced events were identified in gills and kidney upon the exposure to undesired salinity regimes. In gills, genes involved in energy metabolism, stimulus response and epithelial cell differentiation were differentially spliced in response to salinity variation, while sodium ion transport and cellular amide metabolism were enhanced in kidney to combat the adverse impacts of salinity changes. Most of these differentially spliced genes were not differentially expressed, and AS was found to regulate different biological processes from differential gene expression, indicative of the functionally nonredundant role of AS in modulating salinity acclimation in greater amberjack. Together, our study highlights the important contribution of post-transcriptional mechanisms to the adaptation of fish to ambient salinity fluctuations and provides theoretical guidance for the conservation of marine fishery resources against increasingly environmental challenges.
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Aclimatación , Empalme Alternativo , Salinidad , Animales , Aclimatación/genética , Branquias/metabolismo , Peces/genética , Peces/fisiologíaRESUMEN
Photosynthesis of H2O2 from earth-abundant O2 and H2O molecules offers an eco-friendly route for solar-to-chemical conversion. The persistent challenge is to tune the photo-/thermo- dynamics of a photocatalyst toward efficient electron-hole separation while maintaining an effective driving force for charge transfer. Such a case is achieved here by way of a synergetic strategy of sub-band-assisted Z-Scheme for effective H2O2 photosynthesis via direct O2 reduction and H2O oxidation without a sacrificial agent. The optimized SnS2/g-C3N4 heterojunction shows a high reactivity of 623.0 µmol g-1 h-1 for H2O2 production under visible-light irradiation (λ > 400 nm) in pure water, ≈6 times higher than pristine g-C3N4 (100.5 µmol g-1 h-1). Photodynamic characterizations and theoretical calculations reveal that the enhanced photoactivity is due to a markedly promoted lifetime of trapped active electrons (204.9 ps in the sub-band and >2.0 ns in a shallow band) and highly improved O2 activation, as a result of the formation of a suitable sub-band and catalytic sites along with a low Gibbs-free energy for charge transfer. Moreover, the Z-Scheme heterojunction creates and sustains a large driving force for O2 and H2O conversion to high value-added H2O2.
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A copper-catalyzed [3+2] annulation reaction of exocyclic enamines/enol ethers with 1,4-benzoquinone esters has been developed, providing facile access to N,O-spiroketals and spiroketals under mild conditions with broad substrate scope (26 examples, 71-94 % yields). Gram scale synthesis and chemical transformations demonstrated that this method is potentially useful in the synthesis of natural products and drugs containing a N,O- spiroketal moiety. The chiral N,O-spiroketal could be obtained with 98 % ee after recrystallization, when a chiral SaBOX ligand was employed.
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This paper introduces a pixelwise calibration method designed for a structured light system utilizing a camera attached with a telecentric lens. In the calibration process, a white flat surface and a flat surface with circle dots serve as the calibration targets. After deriving the properties of the pinhole projector through a conventional camera calibration method using circle dots and determining the camera's attributes via 3D feature points estimation through iterative optimizations, the white surface calibration target was positioned at various poses and reconstructed with initial camera and projector calibration data. Each 3D reconstruction was fitted with a virtual ideal plane that was further used to create the pixelwise phase-to-coordinate mapping. To optimize the calibration accuracy, various angled poses of the calibration target are employed to refine the initial results. Experimental findings show that the proposed approach offers high calibration accuracy for a structured light system using a telecentric lens.
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Chiral spiro-polycyclic oxindoles are valuable heterocyclic ring systems that are widely distributed in natural alkaloids and biologically active compounds. Herein, we reported an asymmetric tandem Michael addition/interrupted Nef reaction of nitromethane with oxindole-derived alkenes catalyzed by a chiral 2-aminobenzimidazole bifunctional organocatalyst. A series of novel enantiomerically enriched spiro-polycyclic oxindole derivatives bearing an oxime group were synthesized in moderate to excellent isolated yields (up to 99%) with an excellent level of enantioselectivities (up to 99% ee). Furthermore, the antiproliferation activity of the resulting oxindoles derivatives were evaluated, and compound 2d demonstrated promising anticancer properties against HCT116 (IC50 = 14.08 µM) and HT29 (IC50 = 15.46 µM) cell lines.
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Nonalcoholic fatty liver disease (NAFLD) is closely related to metabolic syndrome (MetS). Bone morphogenetic protein 9 (BMP9) is an essential factor in glucose, lipid and energy metabolism. This study aims to investigate whether BMP9 can serve as a serological marker for the severity of NAFLD or MetS. Blood samples, clinical data and FibroTouch test were collected from consecutively recruited 263 individuals in Shanghai East hospital. All the participants were divided into three groups: the healthy controls, nonalcoholic fatty liver (NAFL) group and nonalcoholic steatohepatitis (NASH) at-risk group according to the results of FibroTouch test and liver function. Serum BMP9 levels were measured by enzyme-linked immunosorbent assay. Serum BMP9 levels were positively correlated with transaminase, triglyceride, fasting plasma glucose, glycated hemoglobin (HbA1c) and uric acid while it showed a downward trend as the increasing number of MetS components. Furthermore, it differentiated NASH at-risk (58.13 ± 2.82 ng/L) from the other groups: healthy control (70.32 ± 3.70 ng/L) and NAFL (64.34 ± 4.76 ng/L) (p < 0.0001). Controlled attenuation parameter of liver fat and liver stiffness measurement were negatively correlated with BMP9 levels, while high-density lipoprotein levels were positively correlated. The risk of developing NAFLD increased along with elevated serum BMP9 and BMI, and a significantly higher risk was observed in men compared to women. BMP9 should be considered a protective factor for the onset and development of NAFLD, as well as a promising biomarker for the severity of the NAFLD and MetS.
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Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Femenino , Humanos , Masculino , Biomarcadores , China , Factor 2 de Diferenciación de Crecimiento/metabolismo , Hígado , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
OBJECTIVES: To characterize the complex interplay between multiple clinical conditions in a time-to-event analysis framework using data from multiple hospitals, we developed two novel one-shot distributed algorithms for competing risk models (ODACoR). By applying our algorithms to the EHR data from eight national children's hospitals, we quantified the impacts of a wide range of risk factors on the risk of post-acute sequelae of SARS-COV-2 (PASC) among children and adolescents. MATERIALS AND METHODS: Our ODACoR algorithms are effectively executed due to their devised simplicity and communication efficiency. We evaluated our algorithms via extensive simulation studies as applications to quantification of the impacts of risk factors for PASC among children and adolescents using data from eight children's hospitals including the Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, Children's Hospital of Colorado covering over 6.5 million pediatric patients. The accuracy of the estimation was assessed by comparing the results from our ODACoR algorithms with the estimators derived from the meta-analysis and the pooled data. RESULTS: The meta-analysis estimator showed a high relative bias (â¼40%) when the clinical condition is relatively rare (â¼0.5%), whereas ODACoR algorithms exhibited a substantially lower relative bias (â¼0.2%). The estimated effects from our ODACoR algorithms were identical on par with the estimates from the pooled data, suggesting the high reliability of our federated learning algorithms. In contrast, the meta-analysis estimate failed to identify risk factors such as age, gender, chronic conditions history, and obesity, compared to the pooled data. DISCUSSION: Our proposed ODACoR algorithms are communication-efficient, highly accurate, and suitable to characterize the complex interplay between multiple clinical conditions. CONCLUSION: Our study demonstrates that our ODACoR algorithms are communication-efficient and can be widely applicable for analyzing multiple clinical conditions in a time-to-event analysis framework.
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Algoritmos , Hospitales , Adolescente , Niño , Humanos , Reproducibilidad de los Resultados , Simulación por Computador , Factores de RiesgoRESUMEN
Synovial angiogenesis is a key player in the development of rheumatoid arthritis (RA), and anti-angiogenic therapy is considered a promising approach for treating RA. CPD-002 has demonstrated efficacy in suppressing tumor angiogenesis as a VEGFR2 inhibitor, but its specific impacts on RA synovial angiogenesis and possible anti-RA effects need further study. We examined the influences of CPD-002 on the migration and invasion of human umbilical vein endothelial cells (HUVECs) and its impacts on HUVECs' tube formation and vessel sprouting ex vivo. The therapeutic potential of CPD-002 in adjuvant-induced arthritis (AIA) rats and its suppression of synovial angiogenesis were examined. The involvement of the VEGFR2/PI3K/AKT pathway was assessed both in HUVECs and AIA rat synovium. Here, CPD-002 inhibited the migration and invasion of VEGF-stimulated HUVECs, decreased their chemotactic response to RA fibroblast-like synoviocyte-released chemoattractants, and exhibited anti-angiogenic effects in vitro and ex vivo. CPD-002's targeting of VEGFR2 was confirmed with molecular docking and cellular thermal shift assays, supported by the abolishment of CPD-002's effects upon using VEGFR2 siRNA. CPD-002 relieved paw swelling, arthritis index, joint damage, and synovial angiogenesis, indicating its anti-arthritic and anti-angiogenic effects in AIA rats. Moreover, the anti-inflammatory effects in vivo and in vitro of CPD-002 contributed to its anti-angiogenic effects. Mechanistically, CPD-002 hindered the activation of VEGFR2/PI3K/AKT pathway in VEGF-induced HUVECs and AIA rat synovium, as evidenced by reduced p-VEGFR2, p-PI3K, and p-AKT protein levels alongside elevated PTEN protein levels. Totally, CPD-002 showed anti-rheumatoid effects via attenuating angiogenesis through the inhibition of the VEGFR2/PI3K/AKT pathway.
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Artritis Reumatoide , Proteínas Proto-Oncogénicas c-akt , Ratas , Humanos , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Angiogénesis , Simulación del Acoplamiento Molecular , Movimiento Celular , Transducción de Señal , Artritis Reumatoide/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Proliferación CelularRESUMEN
The efficacy of STING (stimulator of interferon genes) agonists is due to various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours, and a complex balance between tumour control and progression. Here we report a universal STING mimic (uniSTING) based on a polymeric architecture. UniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNPs) results in potent antitumour efficacy across established and advanced metastatic tumour models, including triple-negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2'3'-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the proinflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen-specific CD8+ T-cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitize dendritic cells via exosome-containing miRNAs that reduced the immunosuppressive Wnt2b, and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibits tumour growth and prolongs animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
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Proteínas de la Membrana , Transducción de Señal , Animales , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Transducción de Señal/efectos de los fármacos , Ratones , Línea Celular Tumoral , Factor 3 Regulador del Interferón/metabolismo , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/metabolismo , Femenino , ARN Mensajero/genética , ARN Mensajero/metabolismo , FN-kappa B/metabolismo , Ratones Endogámicos C57BL , LiposomasRESUMEN
Cardiac regeneration requires coordinated participation of multiple cell types whereby their communications result in transient activation of proregenerative cell states. Although the molecular characteristics and lineage origins of these activated cell states and their contribution to cardiac regeneration have been studied, the extracellular signaling and the intrinsic genetic program underlying the activation of the transient functional cell states remain largely unexplored. In this study, we delineated the chromatin landscapes of the noncardiomyocytes (nonCMs) of the regenerating heart at the single-cell level and inferred the cis-regulatory architectures and trans-acting factors that control cell type-specific gene expression programs. Moreover, further motif analysis and cell-specific genetic manipulations suggest that the macrophage-derived inflammatory signal tumor necrosis factor-α, acting via its downstream transcription factor complex activator protein-1, functions cooperatively with discrete transcription regulators to activate respective nonCM cell types critical for cardiac regeneration. Thus, our study defines the regulatory architectures and intercellular communication principles in zebrafish heart regeneration.
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Cromatina , Pez Cebra , Animales , Cromatina/genética , Pez Cebra/genética , Regulación del Desarrollo de la Expresión Génica , Corazón/fisiología , Regeneración/genéticaRESUMEN
Implant-associated infections are significant impediments to successful surgical outcomes, often resulting from persistent bacterial contamination. It has been hypothesized that bacteria can transfer electrons to semiconductors with comparable potential to the biological redox potential (BRP). Building on this concept, we developed an antibiotic-free bactericidal system, Co3O4/TiO2-Ti, capable of achieving real-time and sustainable bactericidal effects. Our study demonstrated that Co3O4/TiO2-Ti, possessing an appropriately set valence band, initiated charge transfer, reactive oxygen species (ROS) production, and membrane damage in adherent Staphylococcus aureus (S. aureus). Notably, in vivo experiments illustrated the remarkable antibacterial activity of Co3O4/TiO2-Ti, while promoting soft-tissue reconstruction and demonstrating excellent cytocompatibility. Transcriptomic analysis further revealed a down-regulation of aerobic respiration-associated genes and an up-regulation of ROS-associated genes in S. aureus in the presence of Co3O4/TiO2-Ti compared to Ti. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene set enrichment analysis (GSEA) identified alterations in respiratory metabolism, oxidative phosphorylation, and the synthesis of amino acid in S. aureus cultured on Co3O4/TiO2-Ti. Furthermore, when combined with near-infrared (NIR) irradiation and photothermal therapy (PTT), Co3O4/TiO2-Ti eliminated 95.71% of floating and adherent S. aureus in vitro. The findings suggest that this antibiotic-free strategy holds substantial promise in enhancing implant sterilization capabilities, thereby contributing to the prevention and treatment of bacterial infections through bandgap engineering of implants and NIR irradiation.
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Cobalto , Óxidos , Terapia Fototérmica , Staphylococcus aureus , Especies Reactivas de Oxígeno , Electrones , Antibacterianos/farmacología , Titanio/químicaRESUMEN
Bryophytes, known as poikilohydric plants, possess vegetative desiccation-tolerant (DT) ability to withstand water deficit stress. Consequently, they offer valuable genetic resources for enhancing resistance to water scarcity stress. In this research, we examined the physiological, phytohormonal, and transcriptomic changes in DT mosses Calohypnum plumiforme from two populations, with and without desiccation treatment. Comparative analysis revealed population differentiation at physiological, gene sequence, and expression levels. Under desiccation stress, the activities of superoxide dismutase (SOD) and peroxidase (POD) showed significant increases, along with elevation of soluble sugars and proteins, consistent with the transcriptome changes. Notable activation of the bypass pathway of JA biosynthesis suggested their roles in compensating for JA accumulation. Furthermore, our analysis revealed significant correlations among phytohormones and DEGs in their respective signaling pathway, indicating potential complex interplays of hormones in C plumiforme. Protein phosphatase 2C (PP2C) in the abscisic acid signaling pathway emerged as the pivotal hub in the phytohormone crosstalk regulation network. Overall, this study was one of the first comprehensive transcriptome analyses of moss C. plumiforme under slow desiccation rates, expanding our knowledge of bryophyte transcriptomes and shedding light on the gene regulatory network involved in response to desiccation, as well as the evolutionary processes of local adaptation across moss populations.