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Emitting light toward on-demand directions is important for various optoelectronic applications, such as optical communication, displaying, and ranging. However, almost all existing directional emitters are assemblies of passive optical antennae and external light sources, which are usually bulky and fragile and show unendurable loss of light power. Here we theoretically propose and experimentally demonstrate a conceptual design of a directional emitter, by using a single surface-emitting laser source itself to achieve dynamically controlled beam steering. The laser is built on photonic crystals that operate near the band edges in the continuum. By shrinking laser sizes to tens-of-wavelength, the optical modes quantize in three-dimensional momentum space, and each of them directionally radiates toward the far-field. Further utilizing the luminescence spectrum shifting effect under current injection, we consecutively select a sequence of modes into lasing action and show the laser maintaining single-mode operation with line widths at a minimum of 1.8 MHz and an emitting power of â¼10 milliwatts, and we demonstrate fast beam steering across a range of 3.2° × 4° on a time scale of 500 ns. Our work proposes a method for on-chip active beam steering for the development of automotive, industrial, and robotic applications.
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Background: The metastasis of colorectal cancer (CRC) is one of the significant barriers impeding its treated consequence and bring about high mortality, less surgical resection rate and poor prognosis of CRC patients. PSAT1 is an enzyme involved in serine biosynthesis. The studies showed that PSAT1 plays the part of a crucial character in the regulation of tumor metastasis. And Epithelial-Mesenchymal Transition (EMT) is a process of cell reprogramming in which epithelialcells obtain mesenchymal phenotypes. It is a crucial course in promoting cell metastasis and the progression of malignant tumors. The relationship between PSAT1 and EMT in colorectal cancer, as well as the underlying molecular mechanisms, remains enigmatic and warrants thorough exploration. These findings suggest that PSAT1 may serve as a promising therapeutic target for mitigating colorectal cancer metastasis and holds the potential to emerge as a valuable prognostic biomarker in forthcoming research endeavors. Materials and Methods: Utilizing TCGA dataset in conjunction with clinical CRC specimens, our initial focus was directed towards an in-depth examination of PSAT1 expression within CRC, specifically exploring its potential correlation with the adverse prognostic outcomes experienced by patients. Furthermore, we conducted a comprehensive investigation into the regulatory influence exerted by PSAT1 on CRC through the utilization of siRNA knockdown techniques. In the realm of in vitro experimentation, we meticulously evaluated the impact of PSAT1 on various facets of CRC progression, including cell migration, invasion, proliferation, and colony formation. In order to elucidate the intricate effects in question, we adopted a multifaceted methodology that encompassed a range of assays and analyses. These included wound healing assays, transwell assays, utilization of the Cell Counting Kit-8 (CCK-8) assay, and colony formation assays. By employing this diverse array of investigative techniques, we were able to achieve a comprehensive comprehension of the multifaceted role that PSAT1 plays in the pathogenesis of colorectal cancer. This multifarious analysis greatly contributed to our in-depth understanding of the complex mechanisms at play in colorectal cancer pathogenesis. Using WB and PCR experiments, we found that PSAT1 has a role in regulating EMT development in CRC.In terms of mechanism, we found that PSAT1 affected EMT by Regulating Pl3K/AKT Signaling Pathway. Results: Our investigation revealed a noteworthy down-regulation of PSAT1 expression in CRC specimens. Importantly, this down-regulation exhibited a significant positive correlation with the unfavorable prognosis of patients afflicted with CRC. Functionally, our study showcased that the siRNA-mediated knockdown of PSAT1 markedly enhanced various key aspects of CRC pathogenesis in an in vitro setting. Specifically, this included a substantial promotion of CRC cell migration, invasion, proliferation, and colony formation. Moreover, the silencing of PSAT1 also demonstrated a substantial promotion of the EMT process. Intriguingly, our research unveiled a hitherto unexplored mechanism underlying the regulatory role of PSAT1 in CRC and EMT. We have established, for the first time, that PSAT1 exerts its influence by modulating the activation of the PI3K/AKT Signaling Pathway. This mechanistic insight provides a valuable contribution to the understanding of the molecular underpinnings of CRC progression and EMT induction mediated by PSAT1. Conclusions: In unison, our research findings shed light on the previously uncharted and significant role of the PSAT1/PI3K/AKT axis in the initiation of the EMT process in CRC. Furthermore, our discoveries introduce a novel biomarker with potential implications for the clinical diagnosis and treatment of CRC.
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Enfortumab vedotin (EV) is a novel treatment option for patients with advanced/metastatic urothelial carcinoma who have progressed after chemotherapy and immunotherapy. Two patients at two different New England tertiary cancer care centers were treated with EV while concurrently receiving hemodialysis (HD), where a complete response to EV in both patients was noted. The use of EV in patients requiring HD is extrapolated from the available pharmacokinetic and pharmacodynamic literature on monoclonal antibodies in patients requiring HD. There is a paucity of data for the use of antibody-drug conjugates like EV in patients needing dialysis.
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Anticorpos Monoclonais , Diálise Renal , Humanos , Masculino , Anticorpos Monoclonais/uso terapêutico , Idoso , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Pessoa de Meia-Idade , Feminino , Neoplasias Urológicas/tratamento farmacológico , Resultado do Tratamento , Imunoconjugados/uso terapêuticoRESUMO
Silenced protein tyrosine phosphatase receptor type R (PTPRR) participates in mitogen-activated protein kinase (MAPK) signaling cascades during the genesis and development of tumors. Rat sarcoma virus (Ras) genes are frequently mutated in lung adenocarcinoma, thereby resulting in hyperactivation of downstream MAPK signaling. However, the molecular mechanism manipulating the regulation and function of PTPRR in RAS-mutant lung adenocarcinoma is not known. Patient records collected from the Cancer Genome Atlas and Gene Expression Omnibus showed that silenced PTPRR was positively correlated with the prognosis. Exogenous expression of PTPRR suppressed the proliferation and migration of lung cancer cells. PTPRR expression and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibition acted synergistically to control ERK1/2 phosphorylation in RAS-driven lung cancer cells. Chromatin immunoprecipitation assay revealed that HDAC inhibition induced enriched histone acetylation in the promoter region of PTPRR and recovered PTPRR transcription. The combination of the HDAC inhibitor SAHA and SHP2 inhibitor SHP099 suppressed the progression of lung cancer markedly in vitro and in vivo. Therefore, we revealed the epigenetic silencing mechanism of PTPRR and demonstrated that combination therapy targeting HDAC and SHP2 might represent a novel strategy to treat RAS-mutant lung cancer.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Histonas/metabolismo , Acetilação , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Linhagem Celular Tumoral , Proteínas Tirosina Fosfatases Classe 7 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 7 Semelhantes a Receptores/metabolismoRESUMO
Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.
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Idiopathic pulmonary fibrosis (IPF) stands as a highly heterogeneous and deadly lung disease, yet the available treatment options remain limited. Combining myofibroblast inhibition with ROS modulation in damaged AECs offers a comprehensive strategy to halt IPF progression, but delivering drugs separately to these cell types is challenging. Inspired by the successful application of pulmonary surfactant (PS) replacement therapy in lung disease treatment, we have developed PS nano-biomimetic liposomes (PSBs) to utilize its natural transport pathway for targeting AECs while reducing lung tissue clearance. In this collaborative pulmonary drug delivery system, PSBs composed of DPPC/POPG/DPPG/CHO (20:9:5:4) were formulated for inhalation. These PSBs loaded with ROS-scavenger astaxanthin (AST) and anti-fibrosis drug pirfenidone (PFD) were aerosolized for precise quantification and mimicking patient inhalation. Through aerosol inhalation, the lipid membrane of PSBs gradually fused with natural PS, enabling AST delivery to AECs by hitchhiking with PS circulation. Simultaneously, PFD was released within the PS barrier, effectively penetrating lung tissue to exert therapeutic effects. In vivo results have shown that PSBs offer numerous therapeutic advantages in mice with IPF, particularly in terms of lung function recovery. This approach addresses the challenges of drug delivery to specific lung cells and offers potential benefits for IPF patients.
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Fibrose Pulmonar Idiopática , Surfactantes Pulmonares , Humanos , Camundongos , Animais , Surfactantes Pulmonares/uso terapêutico , Surfactantes Pulmonares/metabolismo , Surfactantes Pulmonares/farmacologia , Lipossomos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Biomimética , Aerossóis e Gotículas Respiratórios , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Piridonas/farmacologiaRESUMO
The KRT77 gene is a type II epithelial cell α-keratin gene family member that plays a crucial role in animal epidermal and coat formation. This study aimed to investigate the relationship between the KRT77 gene and the adaptability of Chinese cattle in varying environments by exploring the distribution of an exon insertion of the KRT77 gene in different cattle populations. Our analysis involved amplifying and sequencing DNA samples from 362 individuals from 24 cattle breeds in China. Our findings reveal a gradual increase in the frequency of insertion from the northwest to the southeast population. We conducted an association analysis between the genotypes and climate data, revealing a correlation between the insertion and local annual mean temperature, relative humidity, and temperature humidity index. The study highlights the significance of the newly identified KRT77 gene insertion as a variation associated with environmental adaptation in Chinese cattle.This insertion variation increased insights into the genetic mechanisms that drive adaptation in Chinese cattle, emphasizing the importance of the 30-bp insertion in the KRT77 gene. Our findings facilitate further research to improve cattle breeding strategies for adaptability to changing environments from the northwest to the southeast population. In conclusion, this study provides value.
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Genótipo , Humanos , Bovinos/genética , Animais , Éxons , ChinaRESUMO
Oral delivery of insulin could widely improve the quality of life of diabetic patients but still requires further exploration. Commonly utilized oral delivery vehicles hardly penetrate the intestinal mucus barrier, thus greatly hurdling their therapeutic efficacy. State-of-the-art technology shows that coating particles with neutral surface charge could reduce adsorption of mucins and improved the transport of particles within mucus. However, the synthesis of net-neutral particles (NNs) usually need complex purification and processing procedure. Herein, the NNs were conveniently constructed by simply adjusting the ratio of positive (chitosan) and negative (γ-glutamic acid) materials. To further achieve the optimal bioavailability of NNs, NNs formed materials were package in to wild chrysanthemum pollens, obtaining pH-triggered nanoparticles-extruding microcapsules (PNMs@insulin). At the small intestine pH value (â¼6.0), the amino groups of CS deprotonate gradually and trigger the swelling, followed by the rapid extrusion of NNs through nano-orifices on the pollens' surface. After oral administration of the microcapsules, plasma insulin levels were enhanced significantly with a high oral bioavailability of >40%, leading to a remarkable and longer-sustained blood glucose-reducing effect. Moreover, we discovered that the empty pollen shells could act as a potential saccharide-adsorbing agent, which helps to manage sugar intake. This oral strategy of insulin will provide a vast potential for daily and facile diabetes treatment.
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Quitosana , Nanopartículas , Humanos , Insulina , Portadores de Fármacos , Cápsulas , Qualidade de Vida , Administração Oral , Sistemas de Liberação de Medicamentos/métodosRESUMO
BACKGROUND: Chlorogenic acid (CHA) has been shown to have substantial biological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the pharmacological role of CHA in neuroblastoma has not yet been assessed. Neuroblastoma is a type of cancer that develops in undifferentiated sympathetic ganglion cells. This study aims to assess the antitumor activity of CHA against neuroblastoma and reveal its mechanism of action in cell differentiation. METHODS: Be(2)-M17 and SH-SY5Y neuroblastoma cells were used to confirm the differentiation phenotype. Subcutaneous and orthotopic xenograft mouse models were also used to evaluate the antitumor activity of CHA. Seahorse assays and metabolomic analyses were further performed to investigate the roles of CHA and its target ACAT1 in mitochondrial metabolism. RESULTS: CHA induced the differentiation of Be(2)-M17 and SH-SY5Y neuroblastoma cells in vivo and in vitro. The knockdown of mitochondrial ACAT1, which was inhibited by CHA, also resulted in differentiation characteristics in vivo and in vitro. A metabolomic analysis revealed that thiamine metabolism was involved in the differentiation of neuroblastoma cells. CONCLUSIONS: These results provide evidence that CHA shows good antitumor activity against neuroblastoma via the induction of differentiation, by which the ACAT1-TPK1-PDH pathway is involved. CHA is a potential drug candidate for neuroblastoma therapy.
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Green technological innovation has gained in importance in regional policy making towards gaining competitive advantage and sustainable development. This paper used the data envelopment analysis method to calculate regional green innovation efficiency in China, and empirically tested the effect of fiscal decentralization through Tobit model. The regression results show that the local governments with higher fiscal autonomy would prefer to strengthen environmental protection; thus, the regional green innovation efficiency was improved. After the guidance of relevant national development strategies, these effects became more apparent. Our research provided theoretical support and practical guidance for promoting regional led green innovation, improving environmental quality, achieving carbon neutrality, and promoting the high-quality and sustainable development.
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Conservação dos Recursos Naturais , Governo Local , Desenvolvimento Sustentável , China , Eficiência , Política , Desenvolvimento Econômico , Política AmbientalRESUMO
Microtubule-targeting agents are widely used as active anticancer drugs. However, drug resistance always emerges after their long-term use, especially in the case of paclitaxel, which is the cornerstone of all subtypes of breast cancer treatment. Hence, the development of novel agents to overcome this resistance is vital. This study reports on a novel, potent, and orally bioavailable tubulin inhibitor called S-72 and evaluated its preclinical efficacy in combating paclitaxel resistance in breast cancer and the molecular mechanisms behind it. We found that S-72 suppresses the proliferation, invasion and migration of paclitaxel-resistant breast cancer cells in vitro and displays desirable antitumor activities against xenografts in vivo. As a characterized tubulin inhibitor, S-72 typically inhibits tubulin polymerization and further triggers mitosis-phase cell cycle arrest and cell apoptosis, in addition to suppressing STAT3 signaling. Further studies showed that STING signaling is involved in paclitaxel resistance, and S-72 blocks STING activation in paclitaxel-resistant breast cancer cells. This effect further restores multipolar spindle formation and causes deadly chromosomal instability in cells. Our study offers a promising novel microtubule-destabilizing agent for paclitaxel-resistant breast cancer treatment as well as a potential strategy that can be used to improve paclitaxel sensitivity.
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Although Polygonum orientale L. (PO) has a beneficial effect on treatment of myocardial ischemia (MI), its mechanism remains unclear. This study aimed to explore the pharmacological mechanism of PO against MI through MAPK signaling pathways. Firstly, the therapeutic effect of PO was evaluated for treatment of MI mice. Using Western blot and immunohistochemistry, the influence of PO on MAPK signaling pathways and cell apoptosis was investigated. Subsequently, one key pathway (ERK) of MAPK signaling pathways was screened out, on which PO posed the most obvious impact. Finally, an inhibitor of ERK1/2 was utilized to further verify the regulatory effect of PO on the MAPK/ERK signaling pathway. It was found that PO could reduce the elevation of the ST segment; injury of heart tissue; the activity of LDH, CK, NOS, cNOS and iNOS and the levels of NO, BNP, TNF-α and IL-6. It is notable that PO could significantly modulate the protein content of p-ERK/ERK in mice suffering from MI but hardly had an effect on p-JNK/JNK and p-p38/p38. Additionally, the expressions of bax, caspase3 and caspase9 were inhibited in heart tissue in the PO-treated group. To evaluate whether ERK1/2 inhibitor (PD98059) could block the effect of PO on treatment of MI, both PO and PD98059 were given to mice with MI. It was discovered that the inhibitor indeed could significantly reverse the regulatory effects of PO on the above indicators, indicating that PO could regulate p-ERK/ERK. This study provides experimental evidence that PO extenuates MI injury, cardiomyocyte apoptosis and inflammation by activating the MAPK/ERK signaling pathway.
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Doença da Artéria Coronariana , Traumatismos Cardíacos , Isquemia Miocárdica , Polygonum , Camundongos , Animais , Sistema de Sinalização das MAP Quinases , Polygonum/metabolismo , Transdução de Sinais , Isquemia Miocárdica/tratamento farmacológico , Coração , Apoptose , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells' hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment.
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Glicina Hidroximetiltransferase , Neoplasias Gástricas , Humanos , Carbono/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Glicina Hidroximetiltransferase/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transdução de Sinais , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Weining cattle is a precious species with high tolerance to cold, disease, and stress, and accounts for a large proportion of agricultural economic output in Guizhou, China. However, there are gaps in information about the intestinal flora of Weining cattle. In this study, high-throughput sequencing were employed to analyze the intestinal flora of Weining cattle (WN), Angus cattle (An), and diarrheal Angus cattle (DA), and explore the potential bacteria associated with diarrhea. We collected 18 fecal samples from Weining, Guizhou, including Weining cattle, Healthy Angus, and Diarrheal Angus. The results of intestinal microbiota analysis showed there were no significant differences in intestinal flora diversity and richness among groups (p > 0.05). The abundance of beneficial bacteria (Lachnospiraceae, Rikenellaceae, Coprostanoligenes, and Cyanobacteria) in Weining cattle were significantly higher than in Angus cattle (p < 0.05). The potential pathogens including Anaerosporobacter and Campylobacteria were enriched in the DA group. Furthermore, the abundance of Lachnospiraceae was very high in the WN group (p < 0.05), which might explain why Weining cattle are less prone to diarrhea. This is the first report on the intestinal flora of Weining cattle, furthering understanding of the relationship between intestinal flora and health.
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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.
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This study was to investigate the potential mechanism of triptolide-induced hepatotoxicity. We found a novel and variable role of p53/Nrf2 crosstalk in triptolide-induced hepatotoxic process. Low doses of triptolide led to adaptive stress response without obvious toxicity, while high levels of triptolide caused severe adversity. Correspondingly, at the lower levels of triptolide treatment, nuclear translocation of Nrf2 as well as its downstream efflux transporters multidrug resistance proteins and bile salt export pump expressions were significantly enhanced, so did p53 pathways that also increased; at a toxic concentration, total and nuclear accumulations of Nrf2 decreased, while p53 showed an obvious nuclear translocation. Further studies showed the cross-regulation between p53 and Nrf2 after different concentrations of triptolide treatment. Under mild stress conditions, Nrf2 induced p53 highly expression to maintain the pro-survival outcome, while p53 showed no obvious effect on Nrf2 expression and transcriptional activity. Under high stress conditions, the remaining Nrf2 as well as the largely induced p53 mutually inhibited each other, leading to a hepatotoxic result. Nrf2 and p53 could physically and dynamically interact. Low levels of triptolide enhanced the interaction between Nrf2 and p53. Reversely, p53/Nrf2 complex dissociated at high levels of triptolide treatment. Altogether, variable p53/Nrf2 crosstalk contributes to triptolide-induced self-protection and hepatotoxicity, modulation of which may be a potential strategy for triptolide-induced hepatotoxicity intervention.
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Doença Hepática Induzida por Substâncias e Drogas , Diterpenos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fenantrenos , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Supressora de Tumor p53/genética , Diterpenos/toxicidade , Fenantrenos/toxicidade , Compostos de Epóxi/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologiaRESUMO
Semiconductor laser arrays based on the third-order supersymmetric (SUSY) transformation are proposed to increase the mode discrimination between fundamental supermode and high-order supermodes. The distance between the edge waveguide of the main array and that of the superpartners is optimized. Then, the electric field distributions of different modes are also calculated, which show that, except for the fundamental supermode, the high-order supermodes penetrate deeper into the superpartner arrays, which accounts for the increased loss of high-order supermodes. The fabricated third-order SUSY laser array can emit light with a single-lobe far-field pattern under an injection current of 70â mA, which is a promising candidate for optical couplings between lasers and optical elements.
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Stimulator of interferon genes (STING) is a crucial adaptor protein that can regulate the innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. Due to the key role of STING in the innate immune system, the activation of STING pathway is expected to be an efficacious immunotherapeutic tactic to treat cancer. In this study, we performed a structure-activity relationship study of amidobenzimidazole monomer, led to a series of ABZI STING agonist derivatives with potent STING-activating effects. Among them, compound 72, as a representative compound, markedly activated the STING-TBK1-IRF3 signaling pathway and significantly increased the mRNA and protein levels of IFN-ß, CXCL10 and IL-6 in both WT THP-1 cells and human peripheral blood mononuclear cells (hPBMCs). In addition, it was confirmed that compound 72 was highly selective for human STING, specifically targeting human STING signaling and showing no activation of m-STING.
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Leucócitos Mononucleares , Transdução de Sinais , Humanos , Imunidade Inata , Interferons , Relação Estrutura-AtividadeRESUMO
As a novel branch of topology, non-Hermitian topological systems have been extensively studied in theory and experiments recently. Topological parity-time (PT)-symmetric semiconductor stripe laser arrays based on the Su-Schreiffer-Heeger model are proposed. The degree of non-Hermicity can be tuned by altering the length of the cavities, and PT symmetry can be realized by patterned electrode. Three laser arrays working in different non-Hermitian phases are analyzed and fabricated. With the increasing degree of non-Hermicity, the peaks of output intensities move from the edge to the bulk. The proposed semiconductor stripe laser array can function as an active, flexible, and feasible platform to investigate and explore non-Hermitian topology for further developments in this field.
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Weining cattle is a Chinese indigenous breed influenced by complex breeding and geographical background. The multi-ethnic breeding culture makes Weining cattle require more attention as livestock resources for its genetic diversity. Here, we used 10 Weining cattle (five newly sequenced and five downloaded) and downloaded another 48 genome data to understand the aspects of Weining cattle: genetic diversity, population structure, and cold-adapted performance. In the current study, a high level of genetic diversity was found in Weining cattle, and its breed comprised two potential ancestries, which were Bos taurus and Bos indicus. The positive selective sweep analysis in Weining cattle was analyzed using composite likelihood ratio (CLR) and nucleotide diversity (θπ), resulting in 203 overlapped genes. In addition, we studied the cold adaptation of Weining cattle by comparing with other Chinese cattle (Wannan and Wenshan cattle) by three methods (F ST, θπ-ratio, and XP-EHH). Of the top 1% gene list, UBE3D and ZNF668 were analyzed, and these genes may be associated with fat metabolism and blood pressure regulation in cold adaptation. Our findings have provided invaluable information for the development and conservation of cattle genetic resources, especially in southwest China.