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Mineralocorticoid receptor antagonists (MRAs) for bilateral primary aldosteronism (PA) are the mainstay option recommended by guidelines, but poor compliance occurs due to numerous side effects. We aimed to examine whether catheter-based adrenal ablation could be an alternative treatment for bilateral PA.644 PA patients were included from a total of 6054 hypertensive patients. Adrenal CT scan and adrenal venous sampling (AVS) were both performed for PA subtype classification. Clinical and biochemical outcomes were assessed at 6 months after treatment according to the Primary Aldosteronism Surgical Outcome (PASO) criteria.93 patients with PA were recruited to be treated by adrenal ablation, including 25 bilateral PA and 68 unilateral PA according to AVS results. Office SBP and DBP significantly decreased from baseline levels, serum potassium levels increased and ARR significantly decreased (p < 0.01) in both the bilateral and unilateral groups. In the bilateral group, complete, partial and absent clinical success was achieved in 6 (24.0%), 11 (44.0%) and 8(32.0%) patients, respectively. In the unilateral group, complete, partial and absent clinical success was achieved in 12 (17.6%), 37 (54.4%), and 19 (27.9%) patients, respectively. The numbers of patients achieving complete, partial, and absent biochemical success were 15 (60.0%), 6 (24.0%), and 4 (16.0%), respectively, in the bilateral group versus 37 (54.4%), 9 (13.2%), and 22 (32.3%), respectively, in the unilateral group. In conclusion, we provide evidence for the beneficial outcomes of unilateral adrenal ablation for patients with bilateral PA. Our findings provide insight into an alternative option for patients with bilateral excess aldosterone.
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Background: Several studies have systematically assessed the efficacy and safety of progressive or recurrent glioblastoma multiforme (GBM). However, the discernible limitations of efficacy and the elevated costs of interventions instigate an investigation into the cost-effectiveness of these treatments. Objectives: This study aimed to evaluate cost-effectivenesses of 11 pharmacotherapeutic interventions for recurrent GBM from the perspective of healthcare payers in the United States (US) and China. Design: A model-based pharmacoeconomic evaluation. Methods: A partitioned survival model was employed to evaluate the cost-effectiveness of 11 distinct drug-based treatments. The clinical efficacy and safety data were obtained from a network meta-analysis, while the medical expenditure and health utility were primarily derived from published literature. One-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses (PSA) were performed to scrutinize the impact of potential uncertainties to ensure the robustness of the model. The primary endpoint was the incremental cost-effectiveness ratio. Results: Among the therapeutic interventions evaluated, lomustine emerged as the cheapest option, with costs amounting to $78,998 in the United States and $30,231 in China, respectively. Regorafenib displayed the highest quality-adjusted life years at 0.475 in the United States and 0.465 in China. The one-way sensitivity analyses underscored that drug price was a key factor influencing cost-effectiveness. Both scenario and PSA consistently demonstrated that, considering the willingness-to-pay thresholds, lomustine was a cost-effective treatment with probability of more than 94%. Conclusion: In comparison to the alternative antitumor agents, lomustine was likely to be a cost-effective option for relapsed GBM patients from the perspective of healthcare payers in both the United States and China.
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BACKGROUND: Osteoarthritis is a widely prevalent cause of pain and disability among older adults. It is an incurable condition, and most treatments are aimed at alleviating symptoms. AIM: This study aimed to investigate the impact of statins on osteoarthritis by using a two-sample Mendelian randomization approach, using genetic variants associated with statin use as instrumental variables. METHOD: Information on single nucleotide polymorphisms associated with statin medication was obtained from the FinnGen study, and data on osteoarthritis were sourced from the UK Biobank. The inverse variance weighted method was used as the primary analytical approach for the Mendelian randomization analysis. Sensitivity analyses were conducted to evaluate horizontal pleiotropy and heterogeneity. To examine the genetic relationship between statins and osteoarthritis, linkage disequilibrium score regression-based estimates were used. RESULTS: Mendelian randomization analysis indicated a positive effect of statin use on the treatment of osteoarthritis (odds ratio 0.951, 95% confidence interval 0.914-0.99, p < 0.05). This conclusion was supported by various Mendelian randomization methods. Sensitivity analyses revealed no significant directional pleiotropy or influential single nucleotide polymorphisms that could compromise the overall causal inference. Linkage disequilibrium score regression-based estimates suggested a modest genetic correlation between statin use and osteoarthritis (Rg = 0.098, Se = 0.034, p < 0.05), thus reinforcing the robustness of the Mendelian randomization analysis. CONCLUSION: Statins reduce the risk of osteoarthritis, aligning with the results of observational studies. Further research is essential to validate these results and explore the underlying mechanisms in detail.
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The 1-3 piezoelectric composite is the key component of the acoustic transducer, which is widely used in detection, due to the high energy conversion efficiency, cheap raw material, and low aging. To reveal the influence of epoxy mixture, used to connect the piezoelectric column, on the composite performance, a 1-3 piezoelectric composite model was built. The effects of mixture properties on the impedance curves, vibration mode, and deformation displacement of the composite were determined. Six 1-3 piezoelectric composites with different filling mixture properties, by changing the glass microspheres' mass ratio in the epoxy, were prepared and measured to validate the model. The results showed that with the increase in the proportion of the glass microsphere in the epoxy mixture, the vibration coupling of the piezoelectric composites was gradually eliminated. The acoustic impedance was reduced by 12%. The electromechanical coupling coefficient and effective electromechanical coupling coefficient were increased by 5.4% and 8.3%, respectively. The density and Young's modulus decrease in filling mixture can significantly improve piezoelectric composite performance.
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AIMS: Specific identification of a hydatidiform mole (HM) and subclassification of a complete hydatidiform mole (CHM) or partial hydatidiform mole (PHM) are critical. This study aimed to reappraise the diagnostic performance of ultrasonography and histology with a refined diagnosis. METHODS: This was a retrospective, multicentre cohort study of 821 patients with histologically suspected HM specimens. Refined diagnostic algorithms with p57 immunohistochemistry and short tandem repeat (STR) genotyping were performed and used as the true standard for assessing the diagnostic performance of the original ultrasonography and morphology methods. The diagnostic performance was calculated using accuracy, agreement rate, sensitivity and the positive predictive value (PPV) compared with refined diagnostic results. RESULTS: Of the 821 histologically suspected HM cases included, 788 (95.98%) were successfully reclassified into 448 CHMs, 213 PHMs and 127 non-molar (NM) abortuses. Ultrasonography showed an overall accuracy of 44.38%, with a sensitivity of 44.33% for CHM and 37.5% for PHM. The overall classification accuracy of the original morphological diagnosis was 65.97%. After exclusion of the initially untyped HMs, the overall agreement rate was 59.11% (κ=0.364, p<0.0001) between the original and refined diagnoses, with a sensitivity of 40.09% and PPV of 96.05% for diagnosing CHMs and a sensitivity of 84.98% and a PPV of 45.59% for diagnosing PHMs. The interinstitutional variability of morphology in diagnosing HMs was significant among the 15 centres (range, 8.33%-100.00%, p<0.0001). CONCLUSION: The current diagnosis of HM based solely on ultrasound or morphology remains problematic, and ancillary techniques, particularly p57 immunohistochemistry and DNA genotyping, should be integrated into routine practice as much as possible.
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Murine hepatitis virus (MHV) infection is one of the most prevalent types of mice infection in laboratory. MHV could cause death in mice and even interfere with the results in animal experiments. Herein, we developed two isothermal approaches based on the Multienzyme Isothermal Rapid Amplification (MIRA), for rapid detection of MHV in conserved M gene. We designed and screened several pairs of primers and probes and the isothermal fluorescence detector was applied for the exonuclease â ¢ reverse transcription MIRA (exo-RT-MIRA) assay. To further simplify the workflow, the portable fluorescence visualization instrument, also as a palm-sized handheld system, was used for the naked-eye exo-RT-MIRA assay. The amplification temperature and time were optimized. The assay could be processed well at 42 °C 20 min for the exo-RT-MIRA and the naked-eye exo-RT-MIRA assay. The limit of detection (LoD) of the exo-RT-MIRA assay was 43.4 copies/µL. The LoD of the naked-eye exo-RT-MIRA assay was 68.2 copies/µL. No nonspecific amplifications were observed in the two assays. A total of 107 specimens were examined by qPCR and two assays developed. The experimental results statistical analysis demonstrated that the exo-RT-MIRA assay with the qPCR yielded sufficient agreement with a kappa value of 1.000 (p < 0.0001). The results also exhibited a good agreement (kappa value, 0.961) (p < 0.0001) between the naked-eye exo-RT-MIRA assay and the qPCR assay. In our study, the exo-RT-MIRA assay and the naked-eye exo-RT-MIRA assay presented the possibility of new methods in MHV point-of-testing diagnosis.
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Límite de Detección , Técnicas de Diagnóstico Molecular , Virus de la Hepatitis Murina , Técnicas de Amplificación de Ácido Nucleico , Sensibilidad y Especificidad , Animales , Técnicas de Amplificación de Ácido Nucleico/métodos , Ratones , Virus de la Hepatitis Murina/genética , Virus de la Hepatitis Murina/aislamiento & purificación , Técnicas de Diagnóstico Molecular/métodos , Cartilla de ADN/genética , Temperatura , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Hepatitis Viral Animal/diagnóstico , Hepatitis Viral Animal/virología , Fluorescencia , ARN Viral/genéticaRESUMEN
Ginger polysaccharides (GP) promote growth and development in fish. However, the effects of GP on crucian carp remain unclear. The present study investigated the effects of GP on the growth performance, immunity, intestinal microbiota, and disease resistance in crucian carp. Four treatment groups were established with different concentrations of GP (0.1 %, 0.2 %, 0.4 %, and 0.8 %). GP was not added as the control group, and the feeding period lasted for 56 d, followed by a 96-h anti-infection treatment using Aeromonas hydrophila. The results showed that dietary GP significantly improved growth performance, especially in the 0.4 % GP group. Furthermore, GP administration notably increased serum lysozyme (LMZ) activity, digestive enzyme performance, and antioxidant capacity of crucian carp. Moreover, dietary inclusion of GP up-regulated the expression of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), interferon-γ (IFN-γ), and nuclear factor kappa-B (NF-κB) genes while down-regulating IL-10 and transforming growth factor-ß (TGF-ß) gene expressions, thus promoting liver health in crucian carp. Additionally, incorporating GP into the diet regulated both the diversity and composition of the intestinal microbiota in crucian carp, explicitly enhancing the relative abundance of beneficial bacteria, such as Fusobacteriota and Firmicutes. Therefore, GP reduces the mortality of crucian carp infected with A. hydrophila. In conclusion, this study provides novel insights into the application of dietary GP in cultured fish and evaluates the value of traditional Chinese medicinal polysaccharides against pathogenic bacteria.
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Aeromonas hydrophila , Antioxidantes , Carpas , Resistencia a la Enfermedad , Enfermedades de los Peces , Microbioma Gastrointestinal , Polisacáridos , Zingiber officinale , Animales , Aeromonas hydrophila/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Polisacáridos/farmacología , Polisacáridos/química , Resistencia a la Enfermedad/efectos de los fármacos , Antioxidantes/farmacología , Enfermedades de los Peces/microbiología , Enfermedades de los Peces/inmunología , Zingiber officinale/química , Carpas/crecimiento & desarrollo , Carpas/inmunología , Carpas/microbiología , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Suplementos Dietéticos , Alimentación AnimalRESUMEN
Background: Multiple sclerosis (MS) represents a multifaceted autoimmune ailment, prompting the development and widespread utilization of numerous therapeutic interventions. However, extant medications for MS have proven inadequate in mitigating relapses and halting disease progression. Innovative drug targets for preventing multiple sclerosis are still required. The objective of this study is to discover novel therapeutic targets for MS by integrating single-cell transcriptomics and Mendelian randomization analysis. Methods: The study integrated MS genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data for analysis and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and MS. Sequential analyses involving colocalization and Phenome-wide association studies (PheWAS) were conducted to validate the causal role of candidate genes. Results: Following stringent quality control preprocessing of scRNA-seq data, 1,123 expression changes across seven peripheral cell types were identified. Among the seven most prevalent cell types, 97 genes exhibiting at least one eQTL were discerned. Examination of MR associations between 28 proteins with available index pQTL signals and the risk of MS outcomes was conducted. Co-localization analyses and PheWAS indicated that FCRL3 may exert influence on MS. Conclusion: The integration of scRNA-seq and MR analysis facilitated the identification of potential therapeutic targets for MS. Notably, FCRL3, implicated in immune function, emerged as a significant drug target in the deCODE databases. This research underscores the importance of FCRL3 in MS therapy and advocates for further investigation and clinical trials targeting FCRL3.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Esclerosis Múltiple , Sitios de Carácter Cuantitativo , Análisis de la Célula Individual , Transcriptoma , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Predisposición Genética a la Enfermedad , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Polimorfismo de Nucleótido Simple , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Although various aspects of cisplatin resistance have been studied, the impact of genetic variations still needs to be explored. AIM: This study aimed to investigate the impact of cisplatin on meningiomas using a two-sample Mendelian randomization (MR) approach, employing genetic variants associated with cisplatin use as instrumental variables. METHOD: We conducted a two-sample MR analysis using genome-wide association study (GWAS) data. Instrumental variables were derived from single-nucleotide polymorphisms (SNPs) associated with meningioma to estimate the causal relationship with cisplatin resistance. Sensitivity analyses were performed to confirm the findings. RESULTS: Genetic predisposition to meningioma significantly increased the risk of cisplatin resistance (odds ratio (OR): 1.63; 95% confidence interval (CI) 1.44-1.85, P < 0.05). Sensitivity analyses supported the causal link. CONCLUSION: This MR study suggests that genetic predisposition to meningioma increases susceptibility to cisplatin resistance. Further research is needed to uncover the mechanisms behind these causal effects.
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A single-frequency distributed Bragg Reflector (DBR) fiber laser operating at 1091 nm was demonstrated by using a Yb:YAG crystal-derived silica fiber (YDSF). The YDSF was prepared via the molten core (MC) method, with a Yb2O3 doping concentration of 5.60 wt.% in the core, resulting in a gain coefficient of 1.45 dB/cm at 1091 nm. Employing 0.8 cm of the YDSF, we attained a single-frequency laser with a maximum output power of 145 mW and a slope efficiency of 31.8%. The laser exhibited an optical signal-to-noise ratio (OSNR) exceeding 71 dB, a linewidth of â¼34 kHz, and a stabilized relative intensity noise (RIN) at -132 dB/Hz for frequencies over 4.5 MHz. The fiber laser could serve as an outstanding seed source for high-power, narrow-linewidth fiber amplifiers operating at 1091 nm.
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CRISPR mutagenesis screens conducted with SpCas9 and other nucleases have identified certain cis-regulatory elements and genetic variants but at a limited resolution due to the absence of protospacer adjacent motif (PAM) sequences. Here, leveraging the broad targeting scope of the near-PAMless SpRY variant, we have demonstrated that saturated SpRY mutagenesis and base editing screens can faithfully identify functional regulatory elements and essential genetic variants for target gene expression at single-base resolution. We further extended this methodology to investigate a genome-wide association study (GWAS) locus at 10q22.1 associated with a red blood cell trait, where we identified potential enhancers regulating HK1 gene expression, despite not all of these enhancers exhibiting typical chromatin signatures. More importantly, our saturated base editing screens pinpoint multiple causal variants within this locus that would otherwise be missed by Bayesian statistical fine-mapping. Our approach is generally applicable to functional interrogation of all non-coding genomic elements while complementing other high-coverage CRISPR screens.
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Sistemas CRISPR-Cas , Estudio de Asociación del Genoma Completo , Humanos , Estudio de Asociación del Genoma Completo/métodos , Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Mutagénesis , Elementos de Facilitación Genéticos/genéticaRESUMEN
AIM: To investigate the relationship between thyroid function and weight regain in patients with obesity after metabolic surgery. METHODS: This retrospective study enrolled 162 patients who underwent metabolic surgery. Correlations between decreases in thyroid hormone levels and changes in weight, waist circumference (WC) and the Chinese visceral adiposity index (CVAI) were assessed. Binary logistic regression and receiver operating characteristic (ROC) curves were used to identify predictors and clinically useful cut-off values, respectively. RESULTS: The levels of thyroid-stimulating hormone (TSH) and free triiodothyronine (FT3) decreased markedly at 1 year after surgery, as did weight, body mass index (BMI), triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, WC and CVAI. Decreases in TSH and FT3 after metabolic surgery were associated with changes in weight, BMI and CVAI. Binary logistic regression and ROC curve analyses confirmed that decreases in TSH can predict good weight loss after metabolic surgery to some extent. Finally, binary logistic regression and ROC curve analyses confirmed that changes in TSH can predict weight regain after metabolic surgery. CONCLUSIONS: Changes in TSH and FT3 after metabolic surgery were correlated with changes in weight and CVAI. Changes in thyroid hormones can predict weight regain in patients with obesity who underwent metabolic surgery.
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Tirotropina , Triyodotironina , Aumento de Peso , Humanos , Masculino , Femenino , Aumento de Peso/fisiología , Estudios Retrospectivos , Persona de Mediana Edad , Tirotropina/sangre , Triyodotironina/sangre , Adulto , Índice de Masa Corporal , Obesidad/cirugía , Obesidad/sangre , Obesidad/complicaciones , Cirugía Bariátrica , Circunferencia de la Cintura , Hormonas Tiroideas/sangre , Pérdida de Peso/fisiología , Valor Predictivo de las Pruebas , Curva ROCRESUMEN
Acute myeloid leukemia (AML) with mixed-lineage leukemia (MLL) gene rearrangements (MLL-r) is an aggressive subtype of blood cancer with dismal prognosis, underscoring the urgent need for novel therapeutic strategies. E1A-binding protein (EP300) and CREB-binding protein (CREBBP) function as essential transcriptional coactivators and acetyltransferases, governing leukemogenesis through diverse mechanisms. Targeting EP300/CREBBP holds great promise for treating leukemia with some certain cytogenetic abnormalities. Here, we demonstrated that EP300 and CREBBP are core epigenetic regulators in the pathogenesis of MLL-r AML through assaying the transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Knocking-out EP300/CREBBP and inhibitor (A-485) treatment depressed the MLL-r cells proliferation, while the MLL wild-type cells remained uninfluenced. We found that the CDK4/RB/E2F axis was downregulated specifically in MLL-r AML cell after A-485 treatment by RNA-seq, western blot and cut-tag analyses. EP300/CREBBP inhibitor selectively exerted potent anti-leukemia activity through blocking the MLL-r-BET complex binding to H3K27Ac modification on critical genes loci, distinct from global histone acetylation. Collectively, our study identified EP300/CREBBP as a critical epigenetic driver of MLL-r leukemia and validated their therapeutic potential through targeting inhibition, offering a promising avenue for improving clinical outcomes in this aggressive leukemia.
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Spectral preprocessing techniques can, to a certain extent, eliminate irrelevant information, such as current noise and stray light from spectral data, thereby enhancing the performance of prediction models. However, current preprocessing techniques mostly attempt to find the best single preprocessing method or their combination, overlooking the complementary information among different preprocessing methods. These preprocessing techniques fail to maximize the utilization of useful information in spectral data and restrict the performance of prediction models. This study proposed a spectral ensemble preprocessing method based on the rapidly developing ensemble learning methods in recent years and the ridge regression (RR) model, named stacking preprocessing ridge regression (SPRR), to address the aforementioned issues. Different from conventional ensemble learning methods, the proposed SPRR method applied multiple different preprocessing techniques to the original spectral data, generating multiple preprocessed datasets. These datasets were then individually inputted into RR base models for training. Ultimately, RR still served as the meta-model, integrating the output results of each RR base model through stacking. This approach not only produced diversity in base models but also achieved higher accuracy and lower computational complexity by using a single type of base model. On the apple spectral dataset collected by our team, correlation analysis showed significant complementary information among the data produced by different preprocessing techniques. This provided robust theoretical support for the proposed SPRR method. By introducing the currently popular averaging ensemble preprocessing method in a comparative experiment, the results of applying the proposed SPRR method to six datasets (apple, meat, wheat, olive oil, tablet, and corn) demonstrated that compared to the single preprocessing method and averaging ensemble preprocessing method, SPRR yielded the best accuracy and reliability for all six datasets. Furthermore, under the same conditions of the training and test datasets, the proposed SPRR method demonstrated better performance than the four commonly used ensemble preprocessing methods.
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In higher plants, mature male gametophytes have distinct apertures. After pollination, pollen grains germinate, and a pollen tube grows from the aperture to deliver sperm cells to the embryo sac, completing fertilization. In rice, the pollen aperture has a single-pore structure with a collar-like annulus and a plug-like operculum. A crucial step in aperture development is the formation of aperture plasma membrane protrusion (APMP) at the distal polar region of the microspore during the late tetrad stage. Previous studies identified OsINP1 and OsDAF1 as essential regulators of APMP and pollen aperture formation in rice, but their precise molecular mechanisms remain unclear. We demonstrate that the Poaceae-specific OsSRF8 gene, encoding a STRUBBELIG-receptor family 8 protein, is essential for pollen aperture formation in Oryza sativa. Mutants lacking functional OsSRF8 exhibit defects in APMP and pollen aperture formation, like loss-of-function OsINP1 mutants. OsSRF8 is specifically expressed during early anther development and initially diffusely distributed in the microsporocytes. At the tetrad stage, OsSRF8 is recruited by OsINP1 to the pre-aperture region through direct protein-protein interaction, promoting APMP formation. The OsSRF8-OsINP1 complex then recruits OsDAF1 to the APMP site to co-regulate annulus formation. Our findings provide insights into the mechanisms controlling pollen aperture formation in cereal species.
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Regulación de la Expresión Génica de las Plantas , Oryza , Proteínas de Plantas , Polen , Oryza/genética , Oryza/metabolismo , Oryza/crecimiento & desarrollo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Polen/metabolismo , Polen/genética , Polen/crecimiento & desarrollo , Mutación , Polinización , Membrana Celular/metabolismo , Plantas Modificadas Genéticamente , Tubo Polínico/metabolismo , Tubo Polínico/crecimiento & desarrollo , Tubo Polínico/genéticaRESUMEN
Background: Prostate cancer (PCa) is one of the most common malignancies in men with a poor prognosis. It is therefore of great clinical importance to find reliable prognostic indicators for PCa. Many studies have revealed the pivotal role of protein lactylation in tumor development and progression. This research aims to analyze the effect of lactylation-related genes on PCa prognosis. Methods: By downloading mRNA-Seq data of TCGA PCa, we obtained the differential genes related to lactylation in PCa. Five machine learning algorithms were used to screen for lactylation-related key genes for PCa, then the five overlapping key genes were used to construct a survival prognostic model by lasso cox regression analysis. Furthermore, the relationships between the model and related pathways, tumor mutation and immune cell subpopulations, and drug sensitivity were explored. Moreover, two risk groups were established according to the risk score calculated by the five lactylation-related genes (LRGs). Subsequently, a nomogram scoring system was established to predict disease-free survival (DFS) of patients by combining clinicopathological features and lactylation-related risk scores. In addition, the mRNA expression levels of five genes were verified in PCa cell lines by qPCR. Results: We identified 5 key LRGs (ALDOA, DDX39A, H2AX, KIF2C, RACGAP1) and constructed the LRGs prognostic model. The AUC values for 1 -, 3 -, and 5-year DFS in the TCGA dataset were 0.762, 0.745, and 0.709, respectively. The risk score was found a better predictor of DFS than traditional clinicopathological features in PCa. A nomogram that combined the risk score with clinical variables accurately predicted the outcome of the patients. The PCa patients in the high-risk group have a higher proportion of regulatory T cells and M2 macrophage, a higher tumor mutation burden, and a worse prognosis than those in the low-risk group. The high-risk group had a lower IC50 for certain chemotherapeutic drugs, such as Docetaxel, and Paclitaxel than the low-risk group. Furthermore, five key LRGs were found to be highly expressed in castration-resistant PCa cells. Conclusion: The lactylation-related genes prognostic model can effectively predict the DFS and therapeutic responses in patients with PCa.
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BACKGROUND: Lamotrigine is a new antiepileptic drug with substantial interindividual variability in its pharmacokinetics and therapeutic responses. This study aimed to develop population pharmacokinetic (PPK) models of lamotrigine and its N2-glucuronide metabolites for model-informed individualized therapy. METHODS: A total of 353 plasma concentrations from Chinese patients with epilepsy receiving oral lamotrigine were used to develop a population PPK model using a nonlinear mixed effects modeling method. One- and two-compartment models were applied to the nonmetabolite and metabolite model, respectively. Forward addition and backward elimination were used to establish the final model. Model validation was performed using standard goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. Finally, simulations were performed to propose lamotrigine dosages in different situations to achieve trough concentrations within the reference interval (2.5-15 mg/L). RESULTS: For both final population PPK models, coadministration with valproic acid (VPA) or enzyme inducer, and body weight significantly affected lamotrigine clearance. The final models for lamotrigine clearance were and for nonmetabolite and metabolite models, respectively. The precision of the PPK parameters was acceptable, and the models exhibited good predictability. Monte Carlo simulations revealed that the lamotrigine dosage administered to patients combined with an enzyme inducer must be tripled that administered with VPA to reach the target trough concentration. CONCLUSIONS: Variability in the pharmacokinetics of lamotrigine is large. Coadministration of VPA or an enzyme inducer and body weight are the most important factors in lamotrigine clearance in Chinese patients with epilepsy. The developed population PPK models might support further optimization of lamotrigine dosing regimens.
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Recently, horizontal well L47-1CH in the Longdong area of the southwestern Ordos Basin made a significant breakthrough in bauxite natural gas exploration, changing the traditional geological understanding that bauxite could not form effective reservoirs. To further explore the exploration and development potential of bauxite natural gas reservoirs in the northeast of the Ordos Basin, it is urgent to carry out basic geological studies. This paper discusses the sedimentary environment, reservoir characteristics, and formation patterns of the bauxite gas reservoirs in the LX Block using trace elements, thin sections, X-ray diffraction, scanning electron microscopy, conventional physical properties, constant pressure mercury, etc. Then, the distribution pattern of bauxite was studied according to the restoration of the karst paleogeomorphology, and the formation model of bauxite was ultimately established. The results show that bauxite developed a clear triple-segment structure vertically, characterized by rich iron at the bottom, high aluminum at the middle, and low iron at the top. The mineral composition of the bauxite section mainly includes diaspore, iron minerals, titanium minerals, and birnessite. The types of pores mainly include intra- and intergranular dissolved pores, matrix-dissolved pores, intercrystalline pores, and microfractures. The porosity ranges from 1.51 to 9.90%, with a relatively good sorting and connectivity of the pore and throat. The bauxite was formed in a hot and humid climate, deposited in a shallow-water tidal flat and lagoon sedimentary environment with oxygen depleted, and experienced oscillatory regression during the deposition process. The thickness of bauxite is significantly controlled by karst paleogeomorphology, and it is mainly distributed at the negative terrain positions of karat pits and karst terraces. The above results can provide a geological basis for the exploration and development of bauxite in the Ordos Basin and similar basins worldwide.
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In recent years, saline-alkaline aquaculture development has become an important measure for China to expand its fishery development space to ensure food safety. Previous studies have verified that salinity and alkalinity positively influence the quality of Chinese mitten crabs (Eriocheir sinensis). However, the regulatory mechanism of E. sinensis endures saline-alkaline stress which remains obscure. This study investigated the metabolic changes in puberty-molting E. sinensis gills exposed to freshwater (FW), sodium chloride salinity of 5 ppt (SW), and carbonate alkalinity 10.00 mmol/L (AW) for 50 days using untargeted liquid chromatography-mass spectrometry metabolomics (LC-MS). A total of 5802 (positive-ion mode) and 6520 (negative-ion mode) peaks were extracted by LC-MS, respectively. A total of 188 (50 upregulated and 138 downregulated), 141 (94 upregulated and 47 downregulated), and 130 (87 upregulated and 43 downregulated) significantly regulated metabolites (SRMs) were observed in the FW-SW, FW-AW, and SW-AW treatments, respectively, wherein 42 generic SRMs were also found by Venn diagram analysis. Seven of the top 10 SRMs with the highest (variable importance in projection) VIP values were similarly identified in FW-SW and SW-AW. Integrated analysis of key metabolic pathways revealed glycerophospholipid, choline in cancer, phenylalanine, and butanoate metabolism. Overall, significant differences were observed in the metabolites and key metabolic pathways of E. sinensis gill exposed to salinity and alkalinity stress. These results will be helpful in understanding the environmental adaptability of aquatic crustaceans to saline-alkaline water.
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Braquiuros , Branquias , Metabolómica , Salinidad , Animales , Braquiuros/metabolismo , Braquiuros/efectos de los fármacos , Branquias/metabolismo , Branquias/efectos de los fármacos , Cromatografía Liquida , Espectrometría de Masas , Estrés Salino , Metaboloma , Estrés Fisiológico , Cromatografía Líquida con Espectrometría de MasasRESUMEN
The fusion of electrochromic technology with optical resonant cavities presents an intriguing innovation in the electrochromic field. However, this fusion is mainly achieved in liquid electrolyte-based or sol-gel electrolyte-based electrochromic devices, but not in all-solid-state electrochromic devices, which have broader industrial applications. Here, a new all-solid-state electrochromic device is demonstrated with a metal-dielectric-metal (MDM) resonant cavity, which can achieve strong thin-film interference effects through resonance, enabling the device to achieve unique structural colors that have rarely appeared in reported all-solid-state electrochromic devices, such as yellow green, purple, and light red. The color gamut of the device can be further expanded due to the adjustable optical constants of the electrochromic layer. What is more, this device exhibits remarkable cycling stability (maintaining 84% modulation capability after 7200 cycles), rapid switching time (coloration in 2.6 s and bleaching in 2.8 s), and excellent optical memory effect (only increasing by 13.8% after almost 36â¯000 s). In addition, this exquisite structural design has dual-responsive anti-counterfeiting effects based on voltage and angle, further demonstrating the powerful color modulation capability of this device.