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The shortage of resources such as lithium and cobalt has promoted the development of novel battery systems with low cost, abundance, high performance, and efficient environmental adaptability. Due to the abundance and low cost of sodium, sodium-ion battery chemistry has drawn worldwide attention in energy storage systems. It is widely considered that wide-temperature tolerance sodium-ion batteries (WT-SIBs) can be rapidly developed due to their unique electrochemical and chemical properties. However, WT-SIBs, especially for their electrode materials and electrolyte systems, still face various challenges in harsh-temperature conditions. In this review, we focus on the achievements, failure mechanisms, fundamental chemistry, and scientific challenges of WT-SIBs. The insights of their design principles, current research, and safety issues are presented. Moreover, the possible future research directions on the battery materials for WT-SIBs are deeply discussed. Progress toward a comprehensive understanding of the emerging chemistry for WT-SIBs comprehensively discussed in this review will accelerate the practical applications of wide-temperature tolerance rechargeable batteries.
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The pathogenesis of acute lung injury is not fully understood. Stimulator of interferon genes (STING) and ferroptosis have been implicated in various pathological and physiological processes, including acute lung injury (ALI). However, the relationship between STING and ferroptosis in lipopolysaccharide (LPS)-induced ALI is unclear. We found that LPS stimulation activated STING and ferroptosis. Furthermore, STING knockout and ferroptosis inhibitor alleviated lung inflammation and epithelial cell damage. Also, STING knockout reduced inflammation injury and ferroptosis. Notably, the ferroptosis inducer reversed the alleviation of inflammation caused by STING knockout. These results show that STING participates in the inflammation injury of ALI by regulating ferroptosis. Results also showed that p-STAT3 levels increased after STING knockout, suggesting that STING negatively regulates STAT3 activation. Besides, STAT3 inhibitor aggravated ferroptosis after STING knockout, indicating that STING regulates ferroptosis through STAT3 signaling. In conclusion, STING mediates LPS-induced ALI by regulating ferroptosis, indicating that STING and ferroptosis may be new targets for ALI treatment.
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Lesão Pulmonar Aguda , Ferroptose , Lipopolissacarídeos , Proteínas de Membrana , Fator de Transcrição STAT3 , Animais , Humanos , Masculino , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genéticaRESUMO
BACKGROUND: Twenty-five states have implemented insulin out-of-pocket (OOP) cost caps, but their effectiveness is uncertain. OBJECTIVE: To examine the effect of state insulin OOP caps on insulin use and OOP costs among commercially insured persons with diabetes. DESIGN: Pre-post study with control group. SETTING: Eight states implementing insulin OOP caps of $25 to $30, $50, or $100 in January 2021, and 17 control states. PARTICIPANTS: Commercially insured persons with diabetes and insulin users younger than 65 years. Subgroups of particular interest included members from states with insulin OOP caps of $25 to $30, enrollees with health savings accounts (HSAs) that require high insulin OOP payments, and lower-income members. MEASUREMENTS: Mean monthly 30-day insulin fills and OOP costs. RESULTS: State insulin caps were not associated with changes in insulin use in the overall population (relative change in fills per month, 1.8% [95% CI, -3.2% to 6.9%]). Insulin users in intervention states saw a 17.4% (CI, -23.9% to -10.9%) relative reduction in insulin OOP costs, largely driven by reductions among HSA enrollees; there was no difference in OOP costs among nonaccount plan members. More generous ($25 to $30) state insulin OOP caps were associated with insulin OOP cost reductions of 40.0% (CI, -62.5% to -17.6%), again primarily driven by a larger reduction in the subgroup with HSA plans. LIMITATIONS: Single national insurer; 9-month follow-up. CONCLUSION: Insulin OOP caps were associated with reduced insulin OOP costs but no overall increases in insulin use. A proposed national insulin cap of $35 for commercially insured persons might lead to meaningful insulin OOP savings but have a limited effect on insulin use. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention and National Institute of Diabetes and Digestive and Kidney Diseases.
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Diabetes Mellitus , Insulina , Humanos , Estados Unidos , Insulina/uso terapêutico , Grupos Controle , Diabetes Mellitus/tratamento farmacológico , Custo Compartilhado de Seguro , Gastos em SaúdeRESUMO
With more flexible active sites and intermetal interaction, dual-atom catalysts (DACs) have emerged as a new frontier in various electrocatalytic reactions. Constructing a typical p-d orbital hybridization between p-block and d-block metal atoms may bring new avenues for manipulating the electronic properties and thus boosting the electrocatalytic activities. Herein, we report a distinctive heteronuclear dual-metal atom catalyst with asymmetrical FeSn dual atom sites embedded on a two-dimensional C2N nanosheet (FeSn-C2N), which displays excellent oxygen reduction reaction (ORR) performance with a half-wave potential of 0.914 V in an alkaline electrolyte. Theoretical calculations further unveil the powerful p-d orbital hybridization between p-block stannum and d-block ferrum in FeSn dual atom sites, which triggers electron delocalization and lowers the energy barrier of *OH protonation, consequently enhancing the ORR activity. In addition, the FeSn-C2N-based Zn-air battery provides a high maximum power density (265.5 mW cm-2) and a high specific capacity (754.6 mA h g-1). Consequently, this work validates the immense potential of p-d orbital hybridization along dual-metal atom catalysts and provides new perception into the logical design of heteronuclear DACs.
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Antiangiogenic therapy targeting VEGF-A has become the standard of first-line therapy for non-small cell lung cancer (NSCLC). However, its clinical response rate is still less than 50%, and most patients eventually develop resistance, even when using combination therapy with chemotherapy. The major cause of resistance is the activation of complex bypass signals that induce angiogenesis and tumor progression. Therefore, exploring novel proangiogenic mechanisms and developing promising targets for combination therapy are crucial for improving the efficacy of antiangiogenic therapy. Immunoglobulin-like transcript (ILT) 4 is a classic immunosuppressive molecule that inhibits myeloid cell activation. Recent studies have shown that tumor cell-derived ILT4 drives tumor progression via the induction of malignant biologies and creation of an immunosuppressive microenvironment. However, whether and how ILT4 participates in NSCLC angiogenesis remain elusive. Herein, we found that enriched ILT4 in NSCLC is positively correlated with high microvessel density, advanced disease, and poor overall survival. Tumor cell-derived ILT4 induced angiogenesis both in vitro and in vivo and tumor progression and metastasis in vivo. Mechanistically, ILT4 was upregulated by its ligand angiopoietin-like protein 2 (ANGPTL2). Their interaction subsequently activated the ERK1/2 signaling pathway to increase the secretion of the proangiogenic factors VEGF-A and MMP-9, which are responsible for NSCLC angiogenesis. Our study explored a novel mechanism for ILT4-induced tumor progression and provided a potential target for antiangiogenic therapy in NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neovascularização Patológica , Receptores Imunológicos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Animais , Camundongos , Linhagem Celular Tumoral , Receptores Imunológicos/metabolismo , Feminino , Masculino , Glicoproteínas de Membrana/metabolismo , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Microambiente Tumoral , AngiogêneseRESUMO
BACKGROUND: 5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. METHODS: Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RTâqPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. RESULTS: The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. CONCLUSION: We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Fluoruracila , Imunoterapia , Humanos , Fluoruracila/uso terapêutico , Fluoruracila/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Prognóstico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Feminino , Masculino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/imunologia , Simulação de Acoplamento MolecularRESUMO
PURPOSE: To report a case of a five-month-old Chinese infant who died of interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency presenting with rapid and progressive Pseudomonas aeruginosa sepsis. METHODS: The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay. RESULTS: Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, IRAK-4 (NM_016123.3): c.942-1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity. CONCLUSIONS: Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.
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Quinases Associadas a Receptores de Interleucina-1 , Infecções por Pseudomonas , Pseudomonas aeruginosa , Sepse , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/deficiência , Pseudomonas aeruginosa/genética , Infecções por Pseudomonas/genética , Masculino , Lactente , Sepse/genética , Sepse/microbiologia , Doenças da Imunodeficiência Primária/genética , Mutação com Perda de Função , Heterozigoto , Sequenciamento do Exoma , Síndromes de Imunodeficiência/genéticaRESUMO
OBJECTIVE: To compare the risk of incident cardiovascular disease (CVD) events following sleeve gastrectomy (SG) and Roux en Y gastric bypass (RYGB). SUMMARY BACKGROUND DATA: Bariatric surgery is associated with reduced CVD risk but the differential effect of contemporary bariatric procedures is unclear. METHODS: We used insurance claims to conduct a retrospective cohort study of CVD outcomes for patients who underwent RYGB versus SG between 2010 and 2021. Patients were followed for up to 5 years for a primary composite major adverse cardiovascular event (MACE) outcome as well as individual outcomes including myocardial infarction, stroke, heart failure, and arrhythmia. We compared cumulative risks of CVD events using multivariable Cox proportional hazards modeling, in overall cohorts and in sub-cohorts of older adults and those with type 2 diabetes (T2D) or pre-existing CVD and elevated morbidity. RESULTS: Matched, weighted cohorts of 13,545 SG and RYGB patients were observed for an average of 2.5 years after surgery, with 26.2% not lost to follow-up by the end of 5 years. There was no difference in MACE risk between procedures (aHR 1.01 for RYGB vs. SG [95% CI 0.90, 1.12]) in the overall cohort or among the subgroup of older adults (aHR 0.97 for RYGB vs. SG [95% CI 0.85, 1.10]). Patients with T2D experienced lower risk of MACE following RYGB compared to SG (aHR 0.78 [95% CI 0.66, 0.92]), as did those with pre-existing CVD or elevated morbidity prior to surgery (aHR 0.81 [95% CI 0.70, 0.93]). CONCLUSIONS: These findings further support the preferential use of RYGB over SG for patients with T2D or who have pre-existing CVD. However, among other groups of patients, including older adults, we did not observe a relative benefit of RYGB during the time horizon in this study.
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Accurate analysis of microRNAs (miRNAs) at the single-cell level is extremely important for deeply understanding their multiple and intricate biological functions. Despite some advancements in analyzing single-cell miRNAs, challenges such as intracellular interferences and insufficient detection limits still remain. In this work, an ultrasensitive nanopore sensor for quantitative single-cell miRNA-155 detection is constructed based on ionic current rectification (ICR) coupled with enzyme-free catalytic hairpin assembly (CHA). Benefiting from the enzyme-free CHA amplification strategy, the detection limit of the nanopore sensor for miRNA-155 reaches 10 fM and the nanopore sensor is more adaptable to complex intracellular environments. With the nanopore sensor, the concentration of miRNA-155 in living single cells is quantified to realize the early diagnosis of triple-negative breast cancer (TNBC). Furthermore, the nanopore sensor can be applied in screening anticancer drugs by tracking the expression level of miRNA-155. This work provides an adaptive and universal method for quantitatively analyzing intracellular miRNAs, which will greatly improve our understanding of cell heterogeneity and provide a more reliable scientific basis for exploring major diseases at the single-cell level.
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MicroRNAs , Nanoporos , Análise de Célula Única , Neoplasias de Mama Triplo Negativas , MicroRNAs/análise , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Humanos , Feminino , Linhagem Celular Tumoral , Limite de DetecçãoRESUMO
Atherosclerosis (AS) is a common cause of coronary heart disease and stroke. The delivery of exogenous H2S and in situ production of O2 within atherosclerotic plaques can help suppress inflammatory cell infiltration and alleviate disease progression. However, the uncontrolled release of gas donors hinders achieving effective drug concentrations and causes toxic effects. Herein, diallyl trisulfide (DATS)-loaded metal-organic cage (MOC)-68-doped MnO2 nanoparticles are developed as a microenvironment-responsive nanodrug with the capacity for the in situ co-delivery of H2S and O2 to inflammatory cells within plaques. This nanomedicine exhibited excellent monodispersity and stability and protected DATS from degradation in the circulation. In vitro studies showed that the nanomedicine reduced macrophage polarization toward an inflammatory phenotype and inhibited the formation of foam cells, while suppressing the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin-1ß. In a mouse model of ApoE-/- genotype, the nanomedicine reduces the plaque burden, inflammatory infiltration, and hypoxic conditions within the plaques. Furthermore, the treatment process and therapeutic effects can be monitored by magnetic resonance image (MRI), in real time upon Mn2+ release from the acidic- and H2O2- microenvironment-responsive MnO2 nanoparticles. The DATS-loaded MOC-68-doped MnO2-based nanodrug holds great promise as a novel theranostic platform for AS.
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Reactive oxygen species (ROS)-dependent monotherapy usually demonstrates poor therapeutic outcomes, due to the accompanied activation of protective autophagy in tumor cells, which results in ROS tolerance and immune suppression. In this study, a bimetallic electro-sensitizer, Pt-Ir NPs is constructed, loaded with the autophagy inhibitor chloroquine (Pt-Ir-CQ NPs), to enhance the effectiveness of electrotherapy by inhibiting autophagy and activating anti-tumor immune responses. This novel electrotherapy platform demonstrates unique advantages, particularly in the treatment of hypoxic and immunosuppressive tumors. First, the electro-sensitizer catalyzes water molecules into ROS under electric field, achieving tumor ablation through electrotoxicity. Second, the incorporated CQ inhibits the protective autophagy induced by electrotherapy, restoring the sensitivity of tumor cells to ROS and thereby enhancing the anti-tumor effects of electrotherapy. Third, Pt-Ir-CQ NPs enhance the functionality of antigen-presenting cells and immunogenic cells through inhibiting autophagy, synergistically activating the anti-tumor immune responses along with the immunogenic cell death (ICD) effect induced by electrotherapy. This study provides a novel approach for the effective ablation and long-term inhibition of solid tumors through flexible modulation by an exogenous electric field.
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BACKGROUND: Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol. METHODS: The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a-/- and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers. RESULTS: We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells. CONCLUSIONS: We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.
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Propofol , Sepse , Camundongos , Humanos , Animais , Propofol/farmacologia , Propofol/uso terapêutico , Propofol/metabolismo , Receptor 4 Toll-Like/metabolismo , Modelos Animais de Doenças , Macrófagos/metabolismo , Sepse/complicações , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismoRESUMO
Chinese hamster ovary (CHO) cells require cysteine for growth and productivity in fed-batch cultures. In intensified processes, supplementation of cysteine at high concentrations is a challenge due to its limited solubility and instability in solution. Methionine can be converted to cysteine (CYS) but key enzymes, cystathionine beta-synthase (Cbs) and cystathionine gamma-lyase (Cth), are not active in CHO cells resulting in accumulation of an intermediate, homocysteine (HCY), in cell culture milieu. In this study, Cbs and Cth were overexpressed in CHO cells to confer cysteine prototrophy, i.e., the ability to grow in a cysteine free environment. These pools (CbCt) needed homocysteine and beta-mercaptoethanol (ßME) to grow in CYS-free medium. To increase intracellular homocysteine levels, Gnmt was overexpressed in CbCt pools. The resultant cell pools (GnCbCt), post adaptation in CYS-free medium with decreasing residual HCY and ßME levels, were able to proliferate in the HCY-free, ßME-free and CYS-free environment. Interestingly, CbCt pools were also able to be adapted to grow in HCY-free and CYS-free conditions, albeit at significantly higher doubling times than GnCbCt cells, but couldn't completely adapt to ßME-free conditions. Further, single cell clones derived from the GnCbCt cell pool had a wide range in expression levels of Cbs, Cth and Gnmt and, when cultivated in CYS-free fed-batch conditions, performed similarly to the wild type (WT) cell line cultivated in CYS supplemented fed-batch culture. Intracellular metabolomic analysis showed that HCY and glutathione (GSH) levels were lower in the CbCt pool in CYS-free conditions but were restored closer to WT levels in the GnCbCt cells cultivated in CYS-free conditions. Transcriptomic analysis showed that GnCbCt cells upregulated several genes encoding transporters as well as methionine catabolism and transsulfuration pathway enzymes that support these cells to biosynthesize cysteine effectively. Further, 'omics analysis suggested CbCt pool was under ferroptotic stress in CYS-free conditions, which, when inhibited, enhanced the growth and viability of these cells in CYS-free conditions.
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Cricetulus , Cisteína , Engenharia Metabólica , Células CHO , Animais , Cisteína/metabolismo , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Cricetinae , Homocisteína/metabolismo , Homocisteína/genéticaRESUMO
In this paper, two-dimensional Graphdiyne and Hexakis-[(trimethylsilyl)ethynyl]benzene nanosheets were prepared using the liquid-phase exfoliation method and were then successfully applied to 1.06â µm passively Q-Switched all-solid-state lasers. The Hexakis-[(trimethylsilyl)ethynyl]benzene was applied for the first time in passively Q-Switched all-solid-state lasers, as we know. For Graphdiyne, the Q-Switched pulse achieved a narrowest pulse width of 415â ns, a maximum repetition frequency of 244.2 kHz, a maximum pulse energy of 133.53 nJ, and peak power of 321.77â mW was obtained. While, the narrowest pulse width, maximum repetition frequency, maximum pulse energy, and peak power for Hexakis-[(trimethylsilyl)ethynyl]benzene are approximately 398.4â ns, 297.1 kHz, 89.61 nJ, and 220.39â mW respectively. The findings demonstrate the promising potential of both candidates as saturable absorbers for signal modulation in solid-state lasers.
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Due to the intrinsic polarized emission property, polarized emissive materials with anisotropic nanostructures are expected to be potential substitutes for polarizers. Herein, by the template-assisted strategy, well-aligned lead-free metal halide Cs3Cu2I5 nanowire (NW) arrays are fabricated by evaporating the precursor ink in the anodic aluminum oxide (AAO) for polarized emission. The Cs3Cu2I5/AAO composite film emits highly polarized light with a degree of polarization (DOP) of 0.50. Furthermore, by changing the molar ratio of CsI/CuI, the stability of Cs3Cu2I5 precursor inks is improved. Finally, an ultraviolet (UV) light-emitting diode (LED) is adopted to pump the composite film to achieve a blue LED device. The reported Cs3Cu2I5/AAO composite film with highly polarized light emissions will have great potential for polarized emission applications such as liquid crystal display backlights, waveguides, and lasers.
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BACKGROUND: Ethanol elicits a rapid stimulatory effect and a subsequent, prolonged sedative response, which are potential predictors of EtOH consumption by decreasing adenosine signaling; this phenomenon also reflects the obvious sex difference. cAMP-PKA signaling pathway modulation can influence the stimulatory and sedative effects induced by EtOH in mice. This study's objective is to clarify the role of phosphodiesterase (PDE) in mediating the observed sex differences in ethanol responsiveness between male and female animals. METHODS: EtOH was administered intraperitoneally (i.p.) for 7 days to identify the changes in PDE isoforms in response to EtOH treatment. Additionally, EtOH consumption and preference of male and female C57BL/6J mice were assessed using the drinking-in-the-dark (DID) and two-bottle choice (2BC) tests. Further, pharmacological inhibition of PDE7A heterozygote knockout mice was performed to investigate its effects on ethanol-induced stimulation and sedation in both male and female mice. Finally, Western blotting analysis was performed to evaluate the alterations in cAMP-PKA/Epac2 pathways. RESULTS: Ethanol administration resulted in an immediate upregulation in PDE7A expression in female mice, indicating a strong association between PDE7A and ethanol stimulation. Through the pharmacological inhibition of PDE7A KD mice, we have demonstrated, for the first time, that PDE7A selectively attenuates ethanol responsiveness and consumption exclusively in female mice may be associated with the cAMP-PKA/Epac2 pathway and downstream phosphorylation of CREB and ERK1/2. CONCLUSIONS: PDE7A inhibition or knockdown attenuates EtOH responsiveness and consumption exclusively in female mice associated the change of cAMP-PKA/Epac2 signaling pathways, thereby highlighting its potential as a novel therapeutic target for alcohol use disorder.
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Several organizations have published nutrition guidelines for cancer survivors during and after treatment. This review compared nutrition guidelines for cancer survivors published in the United States for the topics that are covered in the guidelines and evaluated the evidence that these guidelines are based upon. A team of researchers, patient stakeholders, and healthcare providers collectively identified 5 nutrition guidelines for cancer survivors in the United States: the 2022 American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors, the 2018 American Institute for Cancer Research Cancer Nutrition Guide, the 2022 National Cancer Institute Physician Data Query and Eating Hints, the 2024 National Comprehensive Cancer Network Guidelines for Cancer Survivors, and the 2020 American Society for Clinical Oncology Guidelines. The 5 guidelines cover a comprehensive list of nutrition topics but overall promote to follow those recommendations for cancer prevention. This review also evaluated the current evidence from meta-analyses on dietary patterns and intakes of foods and nutrients in relation to survival outcomes among cancer survivors. Although the evidence on dietary patterns is strong, the evidence on most dietary factors is still limited and the current research was primarily conducted among breast and colorectal cancer survivors. Although nutrition recommendations are available for cancer survivors, practical strategies need to be implemented to integrate nutrition into oncology care and help cancer survivors follow these recommendations. Further research is warranted to provide additional evidence on the role of nutrition in the health outcomes of cancer survivors and guide the development of evidence-based nutrition recommendations. The protocol is registered in PROSPERO: CRD42023429240.
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Sobreviventes de Câncer , Dieta , Política Nutricional , Humanos , Neoplasias/terapia , Oncologia/normas , Estado Nutricional , Estados UnidosRESUMO
Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.
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3',5'-AMP Cíclico Fosfodiesterases , Doença de Alzheimer , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Animais , Feminino , Masculino , Camundongos , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Hipocampo/metabolismoRESUMO
The nanomaterialization of traditional Chinese medicine (TCM) has aroused widespread interest among researchers. Sanguinarine (SAN) is a kind of TCM with good antibacterial properties, which has important applications in anti-infection of wounds. Additionally, the combination of photothermal therapy and chemotherapy can overcome bacterial resistance, further improving bactericidal and wound healing efficiency. In this paper, we prepared an antibacterial agent by loading SAN on the zwitterion-modified MXene quantum dot nanocarrier (SAN@AHEP@Ta4C3), realizing pH/NIR controlled drug release and photothermal/chemotherapy synergistic antibacterial and wound healing. The particle size of SAN@AHEP@Ta4C3 is about 120 nm, and it has a good water solubility and stability. In addition, it also has excellent photothermal conversion performance (η = 39.2%), which can effectively convert light energy into heat energy under near-infrared (NIR) laser irradiation, further promoting drug release and achieving bactericidal effects by synergistic chemotherapy and photothermal therapy. The in vitro and in vivo experiments show that SAN@AHEP@Ta4C3 exhibits an excellent antibacterial effect against Staphylococcus aureus and Escherichia coli, and it can effectively promote the wound healing of mice. Moreover, the SAN@AHEP@Ta4C3 also has good biocompatibility and has no side effects on normal tissue and organs. This work introduces a multifunctional antibacterial agent based on TCM and hot-spot material MXene, which will have considerable application prospects in biomedical fields.
Assuntos
Antibacterianos , Benzofenantridinas , Portadores de Fármacos , Escherichia coli , Isoquinolinas , Pontos Quânticos , Staphylococcus aureus , Cicatrização , Antibacterianos/farmacologia , Antibacterianos/química , Cicatrização/efeitos dos fármacos , Pontos Quânticos/química , Staphylococcus aureus/efeitos dos fármacos , Animais , Benzofenantridinas/química , Benzofenantridinas/farmacologia , Escherichia coli/efeitos dos fármacos , Camundongos , Portadores de Fármacos/química , Isoquinolinas/química , Isoquinolinas/farmacologia , Medicina Tradicional Chinesa , Terapia Fototérmica , Liberação Controlada de Fármacos , Testes de Sensibilidade MicrobianaRESUMO
Synergistic engineering of energy band alignment and interfacial electric field distribution is essential for photocatalyst design but is still challenging because of the limitation on refined regulation in the nanoscale. This study addresses the issue by employing surface modification and thermal-induced phase transformation in Bi2MoO6/BixOyIz hetero-nanofiber frameworks. The energy band alignment switches from a type-II interface to a Z-scheme contact with stronger redox potentials and inhibited electron traps, and the optimized built-in electric field distribution could be reached based on experimental and theoretical investigations. The engineered hetero-nanofibers exhibit outstanding visible-light-driven photocatalytic nitrogen reduction activity (605 µmol/g/h) and tetracycline hydrochloride removal rate (81.5% within 30 min), ranking them among the top-performing bismuth series materials. Furthermore, the photocatalysts show promise in activating advanced oxidants for efficient organic pollutant degradation. Moreover, the Bi2MoO6/Bi5O7I hetero-nanofibers possess good recycling stability owing to their three-dimensional network structure. This research offers valuable insights into heterojunction design for environmental remediation and industrial applications.