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The noradrenaline transporter has a pivotal role in regulating neurotransmitter balance and is crucial for normal physiology and neurobiology1. Dysfunction of noradrenaline transporter has been implicated in numerous neuropsychiatric diseases, including depression and attention deficit hyperactivity disorder2. Here we report cryo-electron microscopy structures of noradrenaline transporter in apo and substrate-bound forms, and as complexes with six antidepressants. The structures reveal a noradrenaline transporter dimer interface that is mediated predominantly by cholesterol and lipid molecules. The substrate noradrenaline binds deep in the central binding pocket, and its amine group interacts with a conserved aspartate residue. Our structures also provide insight into antidepressant recognition and monoamine transporter selectivity. Together, these findings advance our understanding of noradrenaline transporter regulation and inhibition, and provide templates for designing improved antidepressants to treat neuropsychiatric disorders.
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Antidepressivos , Microscopia Crioeletrônica , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Norepinefrina , Multimerização Proteica , Humanos , Antidepressivos/química , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Apoproteínas/química , Apoproteínas/metabolismo , Apoproteínas/ultraestrutura , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Sítios de Ligação , Colesterol/metabolismo , Colesterol/química , Modelos Moleculares , Norepinefrina/metabolismo , Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/ultraestrutura , Ligação Proteica , Especificidade por SubstratoRESUMO
Cancer-associated fibroblasts (CAFs) are increasingly recognized as playing a crucial role in regulating cancer progression and metastasis. These cells can be activated by long non-coding RNAs (lncRNAs), promoting the malignant biological processes of tumor cells. Therefore, it is essential to understand the regulatory relationship between CAFs and lncRNAs in cancers. Here, we identified CAF-related lncRNAs at the pan-cancer level to systematically predict their potential regulatory functions. The identified lncRNAs were also validated using various external data at both tissue and cellular levels. This study has revealed that these CAF-related lncRNAs exhibit expression perturbations in cancers and are highly correlated with the infiltration of stromal cells, particularly fibroblasts and endothelial cells. By prioritizing a list of CAF-related lncRNAs, we can further distinguish patient subtypes that show survival and molecular differences. In addition, we have developed a web server, CAFLnc (https://46906u5t63.zicp.fun/CAFLnc/), to visualize our results. In conclusion, CAF-related lncRNAs hold great potential as a valuable resource for comprehending lncRNA functions and advancing the identification of biomarkers for cancer progression and therapeutic targets in cancer treatment.
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Fibroblastos Associados a Câncer , Carcinogênese , Regulação Neoplásica da Expressão Gênica , Neoplasias , RNA Longo não Codificante , RNA Longo não Codificante/genética , Humanos , Neoplasias/genética , Neoplasias/patologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinogênese/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão Gênica , Microambiente Tumoral/genéticaRESUMO
Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.
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Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Proteínas Supressoras de Tumor , Proteínas Serina-Treonina Quinases/metabolismo , Humanos , Proteínas Supressoras de Tumor/metabolismo , Células HEK293 , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Camundongos , Proteínas de Sinalização YAP/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Pre-harvest sprouting (PHS) is a significant threat to global food security due to its association with losses in both yield and quality. Among the genes involved in PHS resistance in wheat, PHS-3D (TaMyb10-D) plays a crucial role. Here, we characterized the sequence variations of TaMyb10 genes in 416 bread wheat and 302 Aegilops tauschii accessions. Within TaMyb10-A sequences, we identified a deletion ranging from 214 to 305 bp in the signal and amino acid coding region, present in 61.3% of the accessions. Similarly, 79.3% of the TaMyb10-B sequences within the third exon region exhibited a 19 bp deletion. Additionally, 40.8% of the accessions lacked the 2.4 Mb fragment (in/del mutations) on Chr3D, where TaMyb10-D/PHS-3D was located. Interestingly, the geographical distribution of accessions showed little correlation with the divergence of TaMyb10. TaMyb10-A-IIIDele, TaMyb10-B-IVDele, and TaMyb10-D-VDele genotypes were prevalent in wheat populations across continents. Despite their structural variations, the five distinct protein types exhibited comparable ability to bind the promoters of downstream genes in the flavonoid and ABA pathways, such as CHS, DFR, and NCED. Furthermore, the combination of TaMyb10 homologs was significantly associated with grain color and germination percentages. Accessions exclusively harboring TaMyb10-D displayed red seed color and reduced germination percentages, indicating the predominant role of TaMyb10-D compared to TaMyb10-A and TaMyb10-B. This comprehensive investigation enhances our understanding of the structural variations and functional divergence of TaMyb10, providing valuable insights and resources for improving PHS resistance in wheat.
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Proteínas de Plantas , Triticum , Triticum/genética , Triticum/fisiologia , Triticum/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Grão Comestível/genética , Grão Comestível/crescimento & desenvolvimento , Aegilops/genética , Germinação/genética , Variação Genética , Sementes/genética , Sementes/crescimento & desenvolvimento , Sementes/fisiologiaRESUMO
Unveiling the mechanism behind chirality propagation and dissymmetry amplification at the molecular level is of significance for the development of chiral systems with comprehensively outstanding chiroptical performances. Herein, we have presented a straightforward Cu-mediated Ullmann homocoupling approach to synthesize perylene diimide-entwined double π-helical nanoribbons encompassing dimer, trimer, and tetramer while producing homochiral or heterochiral linking of chiral centers. A significant dissymmetry amplification was achieved, with absorption dissymmetry factors (|gabs|) increasing from 0.009 to 0.017 and further to 0.019, and luminescence dissymmetry factors (|glum|) rising from 0.007 to 0.013 and eventually to 0.015 for homochiral double π-helical oligomers. The disparity of magnetic transition dipole moment (m) densities in homochiral and heterochiral tetramers by time-dependent density functional theory calculations confirmed that homochiral oligomerization can maximize the total m, which is favorable for achieving ever-increasing g factors. Notably, these double π-helices exhibited exceptional photoluminescence quantum yields (ΦPL) ranging from 83 to 95%. The circularly polarized luminescence brightness (BCPL) eventually reached a remarkable 575 M-1 cm-1 for the homochiral tetramer, which is among the highest values reported for chiral small molecules. This kind of linearly extended double π-helices offers a platform for a comprehensive understanding of the mechanism behind chirality propagation and dissymmetry amplification.
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Inspired by the brilliant photochemical and photophysical properties of organic molecules containing chalcogenide substitutions that could be potentially applied across various disciplines, in this work, the effects of the atomic electronegativity of chalcogens (O, S, and Se) on hydrogen bond interactions and excited state proton transfer (ESPT) are mainly focused. We present characteristic oxygen-hydroxybenzazole-substituted 2,5-bis(4,5-diphenyl-1H-imidazol-2-yl)benzene-1,4-diol (BDIBD) derivatives that contain intramolecular double hydrogen bonds. The main objective of this study was to explore in detail the influence of the change of chalcogen atomic electronegativity on dual hydrogen bond interaction and ESPT behavior. By comparing the structural changes and infrared (IR) vibrational spectra of BDIBD derivative (BDIBD-O, BDIBD-S and BDIBD-Se) fluorophores in S0 and S1 states, combined with the preliminary detection of hydrogen bond interaction via the core-valence bifurcation (CVB) index and predicted hydrogen bonding energy (EHB), we conclude that dual hydrogen bonds should be strengthened in the S1 state, which is favorable for the occurrence of ESPT reactions. The charge recombination behavior of hydrogen bonds, induced by photoexcitation, further illustrates this point. By constructing potential energy surfaces (PESs) based on restrictive optimization and by searching the transition state (TS) structure, we finally elucidate stepwise excited-state double proton transfer (ESDPT). Specifically, we confirm that a change in atomic electronegativity has a regulatory effect on the ESDPT behavior in BDIBD derivatives, that is, lower atomic electronegativity is more conducive to stepwise ESDPT.
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Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.
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Transportador 1 de Cassete de Ligação de ATP , Colesterol , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Camundongos Endogâmicos C57BL , Podócitos , Animais , Podócitos/metabolismo , Podócitos/patologia , Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Camundongos , Masculino , Diabetes Mellitus Experimental/metabolismo , Camundongos Knockout , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
Increasing evidences implicate vital role of neuronal damage in the development of hepatic encephalopathy (HE). Neurofilament light chain (NfL) is the main frame component of neurons and is closely related to axonal radial growth and neuronal structural stability. We hypothesized that NfL as a biomarker of axonal injury may contribute to early diagnosis of HE. This study recruited 101 patients with liver cirrhosis, 10 healthy individuals, and 7 patients with Parkinson's disease. Minimal hepatic encephalopathy (MHE) was diagnosed using psychometric hepatic encephalopathy score. Serum NfL levels were measured by the electrochemiluminescence immunoassay. Serum NfL levels in cirrhotic patients with MHE were significantly higher than cirrhotic patients without MHE, and increased accordingly with the aggravation of HE. Serum NfL levels were associated with psychometric hepatic encephalopathy score, Child-Pugh score, model for end-stage liver disease score, and days of hospitalization. Additionally, serum NfL was an independent predictor of MHE (odds ratio of 1.020 (95% CI 1.005-1.034); P = 0.007). The discriminative abilities of serum NfL were high for identifying MHE (AUC of 0.8134 (95% CI 0.7130-0.9219); P Ë 0.001) and OHE (AUC of 0.8852 (95% CI 0.8117-0.9587); P Ë 0.001). Elevated serum NfL levels correlated with the presence of MHE and associated with the severity of HE, are expected to be a biomarker in patients with cirrhosis. Our study suggested that neuronal damage may play a critical role in the development of HE.
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PURPOSE: To investigate the post-operative refractive stabilisation time and provide evidence for the optimal timing of a spectacle prescription in myopic post-cataract surgery patients. METHODS: A total of 116 consecutive myopic cataract patients were recruited from the Zhongshan Ophthalmic Center in this prospective study. Post-operative subjective refraction was assessed after 1 week and 1 month (4-6 weeks), with the interval for the new spectacle acquisition being recorded. Visual Function Index-14 (VF-14) questionnaires were used to assess the vision-related quality of life. RESULTS: There was no significant difference in spherical (p = 0.33), cylindrical (p = 0.65) or spherical equivalent refractions (p = 0.45) obtained 1 week and 1 month post-operatively, indicating that subjects achieved refractive stability within 1 week. In subgroups having differing age and axial lengths, there were also no significant differences between the 1 week and 1 month findings. The spherical equivalent refractive shift between 1 week and 1 month was significantly correlated with the post-operative prediction error (R = 0.35; p < 0.001). Only five (4.3%) out of 116 patients obtained new spectacles 1 week post-surgery. The VF-14 values improved from 85.77 ± 7.24 to 90.45 ± 5.39 after acquiring new spectacles (p < 0.01). CONCLUSIONS: The stabilisation of subjective refraction occurred within 1 week in myopic cataract patients. Shortening the interval before prescribing a new spectacle prescription is recommended for myopic patients following cataract surgery to improve their vision-related quality of life.
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Extração de Catarata , Catarata , Miopia , Humanos , Recém-Nascido , Estudos Prospectivos , Óculos , Qualidade de Vida , Refração Ocular , Miopia/cirurgiaRESUMO
This study establishes a calibrated SWAT (Soil and Water Assessment Tool) model for the Huntai Basin, driven by SSP126, SSP245, SSP585, and multi-model ensemble (MME) models in CMIP6 (Coupled Model Intercomparison Project-6), to investigate the effects of climate change on hydrological processes and pollution load in the Huntai Basin. The results show that the annual mean temperature and the annual precipitation will gradually increase. The nitrogen and phosphorus pollution loads in the basin exhibit a trend of decreasing-increasing-decreasing. The correlation between the nitrogen-phosphorus pollution load and the hydrological process strengthens with increasing radiative forcing. In the four scenarios, CO2 is a primary driving factor that contributes greatly to nitrogen and phosphorus pollution. The main differences are in the total driving factors, and SSP126 and SSP245 are less than those of other models. The total phosphorus and total nitrogen pollution in different climate models were higher than the average level during the benchmark period, except for ammonia nitrogen pollution, which was lower. The nitrogen and phosphorus pollution in SSP126 and SSP245 modes will reach the maximum in 2040s, and the pollution in other periods will be lower than that in SSP585 and MME scenarios. In the long run, the development state between SSP126 and SSP245 may be better appropriate for the Huntai Basin's future sustainable development. This paper analyzes the occurrence and influencing factors of nitrogen and phosphorus pollution under climate change to provide reference to the protection of water environment under changing environments.
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Mudança Climática , Endrin/análogos & derivados , Monitoramento Ambiental , Nitrogênio , Fósforo , ÁguaRESUMO
Numerous bodily processes deteriorate with age, chief among them being the loss of muscle mass and function. The condition referred to as aging myasthenia gravis impairs older persons' quality of life and is linked to a higher risk of several chronic illnesses. An increasing number of studies conducted in the last several years has demonstrated that moderate exercise can halt this process. Specifically, by promoting autophagy, aerobic exercise helps to postpone the onset of senile myasthenia gravis. In this work, we will explore how aerobic exercise modulates autophagy to prevent muscle aging and examine the most recent findings in this area of study. We discovered that exercise-induced autophagy can effectively balance protein degradation and relieve skeletal muscle atrophy by looking through pertinent literature. Aerobic exercise has a direct impact on autophagy, but it can also delay the onset of senile myasthenia gravis by enhancing blood flow, lowering inflammation, and boosting muscle oxidative capacity. In order to postpone the onset of senile myasthenia gravis, research on the mechanism of action of aerobic exercise in inducing autophagy will be discussed in detail in this study.
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The escalating use of pesticides on fruits and vegetables has raised concerns about potential health risks. Therefore, we developed a superhydrophilic resin/graphene oxide (SR/GO) with rich adsorption interactions using an eco-friendly synthetic approach. SR/GO demonstrated excellent hydrophilicity, ensuring optimal contact with aqueous sample matrices. The multiple adsorption interactions, including π-π conjugation, hydrogen bonding, and electrostatic adsorption, facilitated multi-pesticide residue co-extraction. The synthesized SR/GO was applied to a miniaturized centrifugation-accelerated pipette-tip extraction method, coupled with high-performance liquid chromatography. The optimized method exhibited low consumption (15.0 mg adsorbent), and high efficiency, with low detection limits (1.4-2.9 ng g-1) and high recoveries (75.3-113.0%). Water-compatible SR/GO, along with a miniaturized extraction process, showcases a potent analytical approach for pesticide residue analysis in fruits and vegetables. The significance of this method lies in its ability to ensure agricultural and food safety by using a low-cost and efficient multi-pesticide residue analytical strategy.
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Frutas , Verduras , Interações Hidrofóbicas e Hidrofílicas , Grafite/química , Resíduos de Praguicidas/química , Frutas/química , Verduras/química , Pyrus/química , Citrullus/química , Solanum lycopersicum/química , Malus/química , Cucurbita/química , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND: The detection of disease biomarkers in biological samples plays an important role in early diagnosis and treatment of carcinoid tumor. However, due to the complexity of biological samples and the extremely low concentration of disease biomarkers, sample pretreatment is still the bottleneck of achieving accurate quantitative determination. In this work, new hydrophilic molecularly imprinted resin-hexagonal boron nitride (HMIR-h-BN) composites were developed and used as a new solid phase extraction (SPE) adsorbent for selective detection of 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of carcinoid tumor, in urine. RESULTS: Twenty-two types of HMIR-h-BN were successfully synthesized through growing hydrophilic molecularly imprinted resin on surface of activated two-dimensional h-BN nanosheets, and preparation parameters affecting the adsorption performance of HMIR-h-BN were investigated and optimized through adsorption experiments. HMIR-h-BN #19 (the ratio of resorcinol to hexamethylenetetramine: 6:3; the dosage of h-BN: 300 mg; the dosage of dummy template: 0.12 mmol; the imprinting time: 4 h) has demonstrated to be the optimal material for efficient separation and extraction of 5-HIAA. Combined with HPLC-UV, the limit of detection and the limit of quantification of 5-HIAA in real urine samples were 9.4 ng mL-1 and 31.3 ng mL-1, respectively, the coefficient of determination (R2) was 0.9996 in the linear range of 0.1-300 µg mL-1 and the relative recoveries ranged from 86.9 % to 97.7 % with RSD ≤5.1 %. Moreover, after being processed by HMIR-h-BN-SPE, there are no interferences from other peaks at the peak position of 5-HIAA. SIGNIFICANCE: The HMIR-h-BN composite has been demonstrated to be capable of selective extraction of 5-HIAA from urine samples and have a significant purification effect. Based on the established HMIR-h-BN-SPE-HPLC-UV method, accurate quantitative determination of 5-HIAA in urine samples was achieved, which is expected to be applied in the early diagnostic of carcinoid tumor.
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Compostos de Boro , Tumor Carcinoide , Impressão Molecular , Humanos , Biomarcadores Tumorais , Ácido Hidroxi-Indolacético , Extração em Fase Sólida/métodos , Impressão Molecular/métodos , Cromatografia Líquida de Alta Pressão , AdsorçãoRESUMO
This study presents novel methodologies and materials for selectively and sensitively determining gibberellin traces in licorice to address food safety concerns. A novel hydrophilic imprinted resin-graphene oxide composite (HMIR-GO) was developed with fast mass transfer, high adsorption capacity, and exceptional aqueous recognition performance for gibberellin. Leveraging the advantages of molecular imprinting, hydrophilic resin synthesis, and rapid mass transfer characteristics of GO, HMIR-GO was employed as an adsorbent, showing resistance to matrix interference. Coupled with HPLC, a rapid and selective method for determining gibberellin was established. Under optimal conditions, the method exhibited a wide linear range (0.02-5.00 µg g-1, r = 0.9999), low detection limits (3.3 ng g-1), and satisfactory recoveries (92.0-98.4%), enabling the accurate and rapid detection of gibberellin in licorice. This study introduces a pioneering strategy for the selective extraction and determination of trace gibberellin levels, offering insights for similar applications in functional foods.
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Giberelinas , Glycyrrhiza , Grafite , Interações Hidrofóbicas e Hidrofílicas , Impressão Molecular , Grafite/química , Glycyrrhiza/química , Giberelinas/química , Giberelinas/análise , Giberelinas/isolamento & purificação , Adsorção , Extração em Fase Sólida/métodos , Extração em Fase Sólida/instrumentação , Cromatografia Líquida de Alta Pressão , Limite de DetecçãoRESUMO
Among minimally invasive surgical procedures, colorectal surgery is associated with a notably higher incidence of incisional hernia (IH), ranging from 1.7% to 24.3%. This complication poses a significant burden on the healthcare system annually, necessitating urgent attention from surgeons. In a study published in the World Journal of Gastrointestinal Surgery, Fan et al compared the incidence of IH among 1614 patients who underwent laparoscopic colorectal surgery with different extraction site locations and evaluated the risk factors associated with its occurrence. This editorial analyzes the current risk factors for IH after laparoscopic colorectal surgery, emphasizing the impact of obesity, surgical site infection, and the choice of incision location on its development. Furthermore, we summarize the currently available preventive measures for IH. Given the low surgical repair rate and high recurrence rate associated with IH, prevention deserves greater research and attention compared to treatment.
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This editorial discusses the article "Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis" published in the latest edition of the World Journal of Gastrointestinal Surgery. Immunotherapy has achieved outstanding success in tumor treatment. However, the presence of liver metastasis (LM) restrains the efficacy of immunotherapy in various tumors, including lung cancer, colorectal cancer, renal cell carcinoma, melanoma, and gastric cancer. A decrease in CD8+ T cells and nature killer cells, along with an increase in macrophages and regulatory T cells, was observed in the microenvironment of LM, leading to immunotherapy resistance. More studies are necessary to determine the best strategy for enhancing the effectiveness of immunotherapy in patients with LM.
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AIMS: To investigate the association of accelerometer-measured intensity-specific physical activity (PA) with all-cause and cause-specific mortality among individuals with cardiovascular disease (CVD). METHODS: In this prospective cohort study, 8,024 individuals with pre-existing CVD (mean age: 66.6 years, female: 34.1%) from the UK Biobank had their PA measured using wrist-worn accelerometers over a 7-day period in 2013-2015. All-cause, cancer, and CVD mortality was ascertained from death registries. Cox regression modelling and restricted cubic splines were used to assess the associations. Population-attributable fractions (PAFs) were used to estimate the proportion of preventable deaths if more PA were undertaken. RESULTS: During an average of 6.8 years of follow-up, 691 deaths (273 from cancer and 219 from CVD) were recorded. An inverse non-linear association was found between PA duration and all-cause mortality risk, irrespective of PA intensity. The hazard ratio (HR) of all-cause mortality plateaued at 1800 minutes/week for light-intensity PA (LPA), 320 minutes/week for moderate-intensity PA (MPA) and 15 minutes/week for vigorous-intensity PA (VPA). The highest quartile of PA associated lower risks for all-cause mortality, with HRs of 0.63 (95% confidence interval [CI]: 0.51-0.79), 0.42 (0.33-0.54) and 0.47 (0.37-0.60) for LPA, MPA, and VPA, respectively. Similar associations were observed for cancer and CVD mortality. Additionally, the highest PAF were noted for VPA, followed by MPA. CONCLUSION: We found an inverse non-linear association between all intensities of PA (LPA, MPA, VPA, and MVPA) and mortality risk in CVD patients using accelerometer-derived data, but with larger magnitude of the associations than that in previous studies based on self-reported PA.
This study investigated the associations of accelerometer-derived intensity-specific physical activity (PA) with the risks of all-cause and cause-specific mortality among individuals with cardiovascular disease (CVD). L-shaped dose-response relationships between the duration of PA and all-cause mortality were observed across all levels of PA intensities. The risk reduction for mortality exhibited a sharp decline from 0 to 1800 minutes/week of light-intensity PA, followed by reaching a plateau. Notably, the inflection points for moderate-intensity PA and vigorous-intensity PA were found at 320 and 15 minutes per week, respectively. The population-attributable fraction analysis indicated that a significant number of deaths could potentially be prevented if individuals with CVD engaged in more vigorous physical activities.
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Haematopoietic stem cells (HSCs) possess unique physiological adaptations to sustain blood cell production and cope with stress responses throughout life. To maintain these adaptations, HSCs rely on maintaining a tightly controlled protein translation rate. However, the mechanism of how HSCs regulate protein translation remains to be fully elucidated. In this study, we investigate the role of transfer RNA (tRNA) m1A58 'writer' proteins TRMT6 and TRMT61A in regulating HSCs function. Trmt6 deletion promoted HSC proliferation through aberrant activation of mTORC1 signaling. TRMT6-deficient HSCs exhibited an impaired self-renewal ability in competitive transplantation assay. Mechanistically, single cell RNA-seq analysis reveals that the mTORC1 signaling pathway is highly upregulated in HSC-enriched cell populations after Trmt6 deletion. m1A-tRNA-seq and Western blot analysis suggest that TRMT6 promotes methylation modification of specific tRNA and expression of TSC1, fine-tuning mTORC1 signaling levels. Furthermore, Pharmacological inhibition of the mTORC1 pathway rescued functional defect in TRMT6-deficient HSCs. To our knowledge, this study is the first to elucidate a mechanism by which TRMT6-TRMT61A complex-mediated tRNA-m1A58 modification regulates HSC homeostasis.
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Proliferação de Células , Células-Tronco Hematopoéticas , Alvo Mecanístico do Complexo 1 de Rapamicina , RNA de Transferência , Transdução de Sinais , Proteína 1 do Complexo Esclerose Tuberosa , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Animais , RNA de Transferência/metabolismo , RNA de Transferência/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Camundongos , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Autorrenovação Celular/genética , Camundongos Knockout , Metiltransferases/metabolismo , Metiltransferases/genética , Camundongos Endogâmicos C57BL , MetilaçãoRESUMO
Several COVID-19 vaccines have been approved for emergency use according to China's immunization programs. These vaccines has created hope for patients with epilepsy, because the vaccines can help to reduce their risk of becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to investigate the COVID-19 vaccine safety in patients with epilepsy. Here, we assessed the time of symptom control and the features of adverse events of seizure patients following their COVID-19 vaccinations. The results showed that adverse events of COVID-19 vaccinations for epilepsy patients included local pain at the injection site, dizziness and headache, epileptic attack, somnolence, limb weakness, limb pain, allergy, and fever. In addition, the average recovery time of the adverse events was approximately 42 h. More importantly, our study showed that it was relatively safe to vaccinate epilepsy patients who did not experience seizures for approximately 12 months prior to the immunization date.
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In this study, we investigated detailedly the contribution of catechol in tuning the formation and adhesive properties of coacervates. We have constructed a series of catechol-grafted Chitosan (Chitosan-C), and investigated their coacervation with gum arabic (GA) and the corresponding adhesion. We demonstrate that, increasing catechol grafting ratio from 0 %-44 % impacted the coacervation moderately, while enhanced the adhesion of the coacervate up to 438 % when the catechol faction was 37 %. Further increasing the grafting ratio to 55 % led to precipitated coacervates associated with a declined adhesion. Our findings identify the optimal grafting threshold for coacervation and adhesion, providing insights into the underlying mechanism of coacervate binding. Moreover, the catechol enhancement on adhesion of coacervates tolerates different substrates and diverse polyelectrolyte pairs. The revealed principles shall be helpful for designing adhesive coacervates and boosting their applications in various industrial and biomedical areas.