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BACKGROUND: Parkinson's disease (PD) is linked with metabolic risk factors including body mass index (BMI), fasting blood glucose (FBG), cholesterol levels, and triglycerides (TG). The extent to which these factors affect motor symptoms, depression, and sleep problems in PD, as well as their role in determining the success of deep brain stimulation (DBS) therapy, is yet to be fully understood. METHODS: This study delved into the effects of metabolic risk factors like BMI, FBG, cholesterol, and TG on the outcomes of DBS in treating PD-related depression and sleep disturbances, across both mouse models and human subjects. RESULTS: DBS showcased noticeable betterment in depression and sleep perturbations in both PD-afflicted mice and patients. High-sugar-high-fat diet aggravates MPTP-induced depression and sleep disorders in mice. PD-afflicted individuals presenting with depressive and sleep disorders demonstrated elevated metrics of BMI, FBG, blood cholesterol, and TG. Remarkably, these metrics bore considerable adverse influences on the efficiency of DBS in ameliorating depression and sleep issues, yet spared motor symptoms. The favorable impacts of DBS persisted for approximately 6 years, post which a significant decline was noted. Importantly, our translational evidence from both murine controls and patient cohorts indicated that antihyperglycemic and antihyperlipidemic therapies bolstered the efficacy of DBS in mitigating PD-related depression and sleep disturbances, without impinging upon motor functions in patients. CONCLUSION: In summary, this research emphasizes that DBS is a powerful treatment option for depression and sleep issues in PD, with its success influenced by metabolic risk factors. It further suggests that incorporating treatments for high blood sugar and cholesterol can enhance the efficacy of DBS in treating depression and sleep disturbances in PD, without impacting motor symptoms, highlighting the importance of metabolic risk management in PD patients receiving DBS.

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Utilizing Diesel Oxidation Catalysts (DOC) to partially oxidize NO to NO2 is a crucial step in controlling NOx emissions from diesel engines. However, enhancing both catalytic activity and hydrothermal stability remains a significant challenge. Benefiting from abundant asymmetric oxygen vacancies and increased Mn4+ content, MnRE0.5Zr0.5 exhibits superior NO oxidation performance (T63 = 337 °C) and hydrothermal aging resistance (T52 = 340 °C) compared to the undoped sample (T53 = 365 °C). XPS, Raman, TPR, and XAS are employed to verify the elevation of oxygen vacancy concentration and Mn valence state modulation due to Zr introduction. Furthermore, compared to MnRE (1.36 eV), the formation energy of oxygen vacancies in MnRE0.5Zr0.5 is significantly reduced (0.17 eV). This work elucidates the dual regulatory role of Zr in the Mn-RE-Zr ternary system, providing theoretical support and guidance for the design of catalysts for atmospheric pollutant purification and industrial catalysis.

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Non-alcoholic fatty liver disease (NAFLD), a metabolic-associated fatty liver disease, has become the most common chronic liver disease worldwide. Recently, the discovery of cuproptosis, a newly identified mode of cell death, further highlighted the importance of copper in maintaining metabolic homeostasis. An increasing number of studies have confirmed that liver copper metabolism is closely related to the pathogenesis of NAFLD. However, the relationship between NAFLD and copper metabolism, especially cuproptosis, remains unclear. In this review, we aim to summarize the current understanding of copper metabolism and its dysregulation, particularly the role of copper metabolism dysregulation in the pathogenesis of NAFLD. More importantly, this review emphasizes potential gene-targeted therapeutic strategies, challenges and the future of cuproptosis-related genes in the treatment of NAFLD. This review aims to provide innovative therapeutic strategies for NAFLD.

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Down syndrome (DS), caused by an additional chromosome 21, has a high risk of congenital heart defects (CHD), one of the primary causes of mortality in DS newborns. To elucidate the pathogenetic mechanisms underlying this condition, we explored the role of RNA m6A methylation, regulated by METTL3, in DS cardiac development and its impact on the expression of SH3BGR, a gene located at Down syndrome congenital heart disease (DS-CHD) minimal region. We analyzed DS fetal cardiac tissues to assess RNA m6A methylation levels and identify potential contributors. RNA sequencing was performed to detect differentially expressed genes in the same tissues. To further understand METTL3's function in heart development, we inactivated Mettl3 in the developing mouse heart to mimic the significantly reduced METTL3 observed in DS cardiac development. Additionally, human cardiomyocyte AC16 cells were used to investigate the molecular mechanism by which METTL3 regulates SH3BGR expression. Apoptosis was analyzed to evaluate METTL3's effect on heart development through SH3BGR regulation. Reduced m6A modification and decreased METTL3 expression were observed in human DS fetal hearts, along with a significant increase of SH3BGR expression. METTL3, through m6A modification, was found to regulate SH3BGR expression, by influencing mRNA stability. METTL3-deficient mouse embryos exhibited heart malformation with increased apoptosis, emphasizing its role in heart development. In DS hearts, METTL3 downregulation and SH3BGR upregulation, potentially orchestrated by abnormal m6A modification, contribute to gene dysregulation and apoptosis. This study reveals novel insights into DS cardiac pathology, highlighting the intricate role of METTL3 in DS congenital heart defects and presenting the m6A modification of SH3BGR as a potential therapeutic target.

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Sepsis is a prevalent critical illness observed in emergency intensive care unit (ICU), characterized by life-threatening organ dysfunction caused by infection-induced inflammatory immune disorders in the body. The suppression of immune function plays a crucial role in the development and progression of sepsis. Traditional Chinese medicine theory of "acute deficiency syndrome" in sepsis shares similarities with the concept of "immunosuppression". According to this theory, ginseng is frequently utilized in clinical treatment of sepsis due to its ability to invigorate vitality and strengthen the body, playing a crucial role in tonifying deficiency and improving the overall health of patients. This paper provides a detailed discussion of the pathophysiological mechanisms of sepsis immune dysfunction and its correlation with "acute deficiency syndrome" in traditional Chinese medicine. It summarizes the current state of modern pharmacological research on ginseng's impact on the body's immune function, discusses relevant research progress and shortcomings regarding ginseng's therapeutic effects on immunosuppression in sepsis, and proposes future research directions.

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Panax , Sepsis , Humanos , Sepsis/tratamiento farmacológico , Sepsis/inmunología , Medicina Tradicional China/métodos , Medicamentos Herbarios Chinos/uso terapéutico

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Controlling the random lasing action from disordered media is important to obtain customizable lasers with unprecedented properties. In this paper, systematic investigations of random scattering based on GaAs/AlGaAs axial heterostructure nanowire (NW) arrays are presented. By manipulating the diameter and density of GaAs/AlGaAs axial heterostructure NWs during growth, different types of random lasers (Anderson localized and delocalized random lasers) have been successfully realized. The threshold, Q factor, and spatial coherence of these two types of lasers are experimentally discussed and analyzed. Finally, a proof-of-concept demonstration of speckle-free imaging based on the NW lasers has been conducted. This research enables the tunability of random lasers with exceptional performance and lays the foundation for achieving random lasing control.

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Implementing novel technologies, including the "well factory" model and zipper fracturing techniques, has become prevalent in shale gas development. During completion operations such as lowering casing and multistage fracturing, the casing is subjected to many complex loads, reducing its strength and increasing the risk of casing deformation. By establishing a casing wear model and conducting multistage cyclic loading experiments and numerical simulations, we analyzed the change rule of casing anticollapse strength under complex loads, developed a calculation method for casing comprehensive anticollapse ability under complex loads, and applied the method to an illustrative calculation. The study shows that the wear effect during completion has a negligible impact on the strength of the casing. The casing anticollapse strength exhibits a linear decline in correlation with the number of cycles. The zipper fracturing operation resulted in a nonuniform distribution of geo-stress around the well, and the casing anticollapse strength demonstrated a nearly linear decline in correlation with the nonuniformity of geo-stress. In the presence of both internal and external effects, the casing anticollapse strength exhibited a decline exceeding 15%, thereby increasing the risk of casing deformation. This research method can provide computational guidance for preventing casing deformation in field fracturing construction.

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Respiratory syncytial virus (RSV)-induced viral pneumonia in children is common worldwide. Its high occurrence and lack of an effective vaccine make it a leading cause of death in children. Severe RSV infection can trigger uncontrolled inflammatory responses in patients, so the development of small molecule drugs with the dual function of "direct antivirus" and "inflammatory response regulation" is welcome. Resveratrol (Res) has been reported to have antiviral and anti-inflammatory pharmacological effects, but its application is limited because of its poor water solubility and oral bioavailability. Based on small-molecule nanotechnology, we developed a sonication-assisted self-assembly method for preparing insoluble Res into highly soluble resveratrol nanoparticles (Res NPs). The obtained Res NPs exhibited a higher water solubility and a faster dissolution rate, which was more conducive to the effectiveness of Res in addressing RSV-induced viral pneumonia. In vitro studies had shown that Res NPs played an antiviral role by inhibiting RSV replication and reducing the production of pro-inflammatory cytokines. Nebulized inhalation administration of Res NPs prolonged the drug's residence time in the lungs, which appears to increase the accumulation and effectiveness of Res NPs. Additionally, in vivo studies had demonstrated significant benefits of Res NPs in inhibiting RSV viral load and improving the pulmonary microenvironment in RSV-infected mice. Both antiviral and anti-inflammatory experiments had confirmed that the pharmacological activity of Res NPs is superior to that of Res. This suggested that nanosizing Res was an effective way to enhance the original pharmacological activity of Res and also offered a new formulation strategy for treating viral pneumonia.

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Background: The preoperative predictors of residual or recurrent tricuspid regurgitation (TR) after cone reconstruction (CR) remains unclear in patients with Ebstein anomaly (EA). We aimed to determine the predictive value of right ventricular longitudinal strain, assessed using cardiac magnetic resonance (CMR) imaging, for residual or recurrent TR after CR in patients with EA. Methods: This single-centre, retrospective study analysed data from 48 patients with EA [mean ± standard deviation (SD), age, 35.0±13.6 years; 13 males] who underwent CMR before CR between January 2017 and February 2023. Two-dimensional colour Doppler echocardiography was performed before CR and mid-term (>6 months) after CR to evaluate the degree of TR in patients with EA. Thirty healthy volunteers served as controls. Univariate and multivariate logistic regression analyses were performed to identify CMR predictors of moderate or severe TR >6 months after CR. Results: Mid-term postoperative results revealed severe, moderate, and mild TR in 8 (17%), 7 (15%), and 33 (69%) patients, respectively. For patients with EA and moderate or severe TR after CR, left ventricular global longitudinal strain (GLS), left ventricular ejection fraction, right ventricular global longitudinal strain (RVGLS), and right ventricular ejection fraction (RVEF) were significantly worse compared to patients with mild TR (all P<0.05). Multivariate logistic regression analyses revealed that RVGLS was independently associated with moderate or severe TR >6 months after CR [odds ratio (OR) 1.193, 95% confidence interval (CI): 1.025-1.388; P=0.02]. Conclusions: RVGLS was a significant predictor of moderate or severe TR >6 months after CR. This finding emphasizes that early and accurate measurement of RV function may help to identify patients at high risk for severe residual or recurrent TR.

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Background: The global incidence of pulmonary fungal diseases is on the rise. Individuals harboring underlying immunocompromised conditions such as human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), malignant tumors, or those who have undergone organ transplantation, among others, are particularly susceptible to fungal infections. However, in clinical practice, certain patients diagnosed with pulmonary fungal infections exhibit no discernible risk factors for immunosuppression. GATA2, a pivotal transcription factor governing hematopoiesis, is implicated in GATA2 deficiency, predisposing individuals to fungal infections. This study aims to scrutinize GATA2 variants in adult patients afflicted with pulmonary fungal infections devoid of recognized risk factors for immunosuppression. Methods: A cohort of adult patients (aged 18-65 years old, n=22) diagnosed with pulmonary fungal diseases lacking underlying immunosuppression risk factors, treated at Sun Yat-sen Memorial Hospital from January 2016 to December 2021, underwent Sanger sequencing of the GATA2 gene. Results: Among the 22 patients devoid of immunocompromised risk factors and diagnosed with pulmonary fungal diseases, 17 patients (77.3%) exhibited single nucleotide variants (SNVs) within the exons of the GATA2 gene. Notably, exon 3 variants were present in 7 cases (41.2%), exon 4 variants in 10 cases (58.8%), and exon 5 variants in 11 cases (64.7%), emerging as the most prevalent exonic variants within GATA2. Among the 17 patients harboring GATA2 SNVs, a total of 28 SNVs were identified. Of these, eight variants (NM_001145661.2:c.33G>A, NM_001145661.2:c.523C>T, NM_001145661.2:c.77A>G, NM_001145661.2:c.545C>T, NM_001145661.2:c.7G>A, NM_001145661.2:c.1406A>G, NM_001145661.2:c.977A>G, NM_001145661.2:c.742A>C) were identified as missense mutations with the potential to alter the structure and function of the GATA2 protein on the basis of multiple in silico predictive programs interpretation. One nonsense mutation (NM_001145661.2:c.664A>T) was classified as "likely pathogenic" according to 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Conclusions: GATA2 variants are prevalent among patients afflicted with pulmonary fungal infections in the absence of traditional immunosuppressive risk factors. Further investigations are warranted to elucidate the impact of GATA2 variants on the expression and functionality of the GATA2 protein.

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Objective: This study aimed to predict the level of stemness index (mRNAsi) and survival prognosis of lung adenocarcinoma (LUAD) using pathomics model. Methods: From The Cancer Genome Atlas (TCGA) database, 327 LUAD patients were randomly assigned to a training set (n = 229) and a validation set (n = 98) for pathomics model development and evaluation. PyRadiomics was used to extract pathomics features, followed by feature selection using the mRMR-RFE algorithm. In the training set, Gradient Boosting Machine (GBM) was utilized to establish a model for predicting mRNAsi in LUAD. The model's predictive performance was evaluated using ROC curves, calibration curves, and decision curve analysis (DCA). Prognostic analysis was conducted using Kaplan-Meier curves and cox regression. Additionally, gene enrichment analysis, tumor microenvironment analysis, and tumor mutational burden (TMB) analysis were performed to explore the biological mechanisms underlying the pathomics prediction model. Results: Multivariable cox analysis (HR = 1.488, 95 % CI 1.012-2.187, P = 0.043) identified mRNAsi as a prognostic risk factor for LUAD. A total of 465 pathomics features were extracted from TCGA-LUAD histopathological images, and ultimately, the most representative 8 features were selected to construct the predictive model. ROC curves demonstrated the significant predictive value of the model for mRNAsi in both the training set (AUC = 0.769) and the validation set (AUC = 0.757). Calibration curves and Hosmer-Lemeshow goodness-of-fit test showed good consistency between the model's prediction of mRNAsi levels and the actual values. DCA indicated a good net benefit of the model. The prediction of mRNAsi levels by the pathomics model is represented using the pathomics score (PS). PS was strongly associated with the prognosis of LUAD (HR = 1.496, 95 % CI 1.008-2.222, P = 0.046). Signaling pathways related to DNA replication and damage repair were significantly enriched in the high PS group. Prediction of immune therapy response indicated significantly reduced Dysfunction in the high PS group (P < 0.001). The high PS group exhibited higher TMB values (P < 0.001). Conclusions: The predictive model constructed based on pathomics features can forecast the mRNAsi and survival risk of LUAD. This model holds promise to aid clinical practitioners in identifying high-risk patients and devising more optimized treatment plans for patients by jointly employing therapeutic strategies targeting cancer stem cells (CSCs).

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Background: Testosterone (T) therapy increases lean mass and reduces total body and truncal fat mass in hypogonadal men. However, the underlying molecular mechanisms for the reciprocal changes in fat and lean mass in humans are not entirely clear. Methods: Secondary analysis of specimens obtained from a single-arm, open-label clinical trial on pharmacogenetics of response to T therapy in men with late-onset hypogonadism, conducted between 2011 and 2016 involving 105 men (40-74 years old), who were given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subcutaneous fat (SCF), peripheral blood mononuclear cells (PBMC) and serum were obtained from the participants at different time points of the study. We measured transcription factors for adipogenesis and myogenesis in the SCF, and PBMC, respectively, by real-time quantitative PCR at baseline and 6 months. Serum levels of FOLLISTATIN, PAX7, MYOSTATIN, ADIPSIN, and PRDM16 were measured by ELISA. Results: As expected, there was a significant increase in T and estradiol levels after 6 months of T therapy. There was also a reduction in fat mass and an increase in lean mass after 6 months of T therapy. Gene-protein studies showed a significant reduction in the expression of the adipogenic markers PPARγ in SCF and ADIPSIN levels in the serum, together with a concomitant significant increase in the expression of myogenic markers, MYOD in PBMC and PAX7 and FOLLISTATIN levels in the serum after 6 months of T therapy compared to baseline. Interestingly, there was a significant increase in the adipo-myogenic switch, PRDM16, expression in SCF and PBMC, and in circulating protein levels in the serum after 6 months of T therapy, which is likely from increased estradiol. Conclusion: Our study supports that molecular shift from the adipogenic to the myogenic pathway in men with hypogonadism treated with T could be mediated directly or indirectly by enhanced PRDM16 activity, in turn a result from increased estradiol level. This might have led to the reduction in body fat and increase in lean mass commonly seen in hypogonadal men treated with T.

Asunto(s)

Composición Corporal , Proteínas de Unión al ADN , Hipogonadismo , Testosterona , Factores de Transcripción , Humanos , Masculino , Testosterona/sangre , Persona de Mediana Edad , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/metabolismo , Hipogonadismo/sangre , Adulto , Anciano , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Composición Corporal/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Transducción de Señal/efectos de los fármacos , Terapia de Reemplazo de Hormonas

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Citrullination plays an essential role in various physiological or pathological processes, however, whether citrullination is involved in regulating tumour progression and the potential therapeutic significance have not been well explored. Here, we find that peptidyl arginine deiminase 4 (PADI4) directly interacts with and citrullinates hypoxia-inducible factor 1α (HIF-1α) at R698, promoting HIF-1α stabilization. Mechanistically, PADI4-mediated HIF-1αR698 citrullination blocks von Hippel-Lindau (VHL) binding, thereby antagonizing HIF-1α ubiquitination and subsequent proteasome degradation. We also show that citrullinated HIF-1αR698, HIF-1α and PADI4 are highly expressed in hepatocellular carcinoma (HCC) tumour tissues, suggesting a potential correlation between PADI4-mediated HIF-1αR698 citrullination and cancer development. Furthermore, we identify that dihydroergotamine mesylate (DHE) acts as an antagonist of PADI4, which ultimately suppresses tumour progression. Collectively, our results reveal citrullination as a posttranslational modification related to HIF-1α stability, and suggest that targeting PADI4-mediated HIF-1α citrullination is a promising therapeutic strategy for cancers with aberrant HIF-1α expression.

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Carcinoma Hepatocelular , Citrulinación , Progresión de la Enfermedad , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Hepáticas , Arginina Deiminasa Proteína-Tipo 4 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Animales , Línea Celular Tumoral , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Ubiquitinación , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Ratones , Células HEK293 , Estabilidad Proteica/efectos de los fármacos , Desiminasas de la Arginina Proteica/metabolismo , Desiminasas de la Arginina Proteica/genética , Ratones Desnudos , Masculino

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Anastomosis Quirúrgica , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Anastomosis Quirúrgica/efectos adversos , Preescolar , Masculino , Endoscopía del Sistema Digestivo/métodos

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Light-emitting electrochemical cells (LECs) are appealing for cost-effective, large-area emission applications; however, their luminescence efficiency is significantly limited by exciton annihilation caused by high concentration polarons. Here, we present thermally activated delayed fluorescence (TADF) sensitized fluorescence LECs (TSF-LECs) that achieve a record 9% EQE. The TADF sensitizers with rapid reverse intersystem crossing (RISC) rates can effectively convert triplet excitons to singlet excitons in LECs, thereby establishing a more efficient overall energy transfer pathway. Importantly, magneto-electroluminescence measurements indicate that the additional RISC route in TSF-LECs significantly suppresses the annihilation of triplet excitons and thus reduces exciton loss under high concentration polaron conditions. Compared to LECs without a sensitizer, TSF-LECs exhibit improved EQE and luminance, extended operational lifetimes, and suppressed efficiency roll-off. A flexible display prototype based on TSF-LECs was further fabricated, capable of stably displaying high-brightness preset patterns for extended periods. The exploration of the exciton dynamics in high concentration polaron environments offers valuable insights for future developments in high-efficiency LEC technology.

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In the field of soil remediation, the importance of bioavailability of pollutants has not received adequate attention, leading to the excessive application of remediation measures. Therefore, to ensure the safe use of farmland soil, a scientific method is needed to assess labile contaminants and their translocation in plants. To evaluate soil remediation effect based on bioavailability, the concentrations of these heavy metals in soil were analyzed using by the method for total metal content, the Community Bureau of Reference (BCR) extraction, and the diffusive gradients in thin films (DGT) technique. The results reveal that the correlation coefficients between metal concentrations measured by DGT and those accumulated in rice grains are the highest (Cr-R2 = 0.8966, Pb-R2 = 0.9045). However, the capability of method for total metal content to evaluate the remediation effect of heavy metals is very limited. In contrast, although Cr and Pb measured by BCR show a high correlation with HMs in rice plants, the method still falls short in precisely assessing bioavailability. Significantly, DGT proves to be more effective, successfully distinguishing the remediation effects of different treatments. Generally, DGT offers a more accurate and simpler assessment method, underscoring its practical significance for monitoring soil remediation and environmental management.

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BACKGROUND: Middle cerebral artery (MCA) plaques are a leading cause of ischemic stroke (IS). Plaque inflammation is crucial for plaque stability and urgently needs quantitative detection. PURPOSE: To explore the utility of Controlled Aliasing in Parallel Imaging Results in Higher Acceleration (CAIPIRINHA)-Dixon-Time-resolved angiography With Interleaved Stochastic Trajectories (TWIST) (CDT) dynamic contrast-enhanced MRI (DCE-MRI) for evaluating MCA culprit plaque inflammation changes over stroke time and with diabetes mellitus (DM). STUDY TYPE: Prospective. POPULATION: Ninety-four patients (51.6 ± 12.23 years, 32 females, 23 DM) with acute IS (AIS; N = 43) and non-acute IS (non-AIS; 14 days < stroke time ≤ 3 months; N = 51). FIELD STRENGTH/SEQUENCE: 3-T, CDT DCE-MRI and three-dimensional (3D) Sampling Perfection with Application optimized Contrast using different flip angle Evolution (3D-SPACE) T1-weighted imaging (T1WI). ASSESSMENT: Stroke time (from initial IS symptoms to MRI) and DM were registered. For 94 MCA culprit plaques, Ktrans from CDT DCE-MRI and enhancement ratio (ER) from 3D-SPACE T1WI were compared between groups with and without AIS and DM. STATISTICAL TESTS: Shapiro-Wilk test, Bland-Altman analysis, Passing and Bablok test, independent t-test, Mann-Whitney U test, Chi-squared test, Fisher's exact test, receiver operating characteristics (ROC) with the area under the curve (AUC), DeLong's test, and Spearman rank correlation test with the P-value significance level of 0.05. RESULTS: Ktrans and ER of MCA culprit plaques were significantly higher in AIS than non-AIS patients (Ktrans = 0.098 s-1 vs. 0.037 s-1; ER = 0.86 vs. 0.55). Ktrans showed better AUC for distinguishing AIS from non-AIS patients (0.87 vs. 0.75) and stronger negative correlation with stroke time than ER (r = -0.60 vs. -0.34). DM patients had significantly higher Ktrans and ER than non-DM patients in IS and AIS groups. DATA CONCLUSION: Imaging by CDT DCE-MRI may allow to quantitatively evaluate MCA culprit plaques over stroke time and DM. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

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KEY MESSAGE: Rice OsSPL11 activates the expression of GW5L through binding to its promoter and positively regulates grain size. Grain size (GS) is an important determinant of grain weight and yield potential in cereal. Here, we report the functional analysis of OsSPL11 in grain length (GL), grain width (GW), and 1000-grain weight (TGW). OsSPL11 mutant plants, osspl11 lines, exhibited a decrease in GL, GW, and TGW, and OsSPL11-OE lines showed an increase in GL and TGW. Expression analysis revealed that OsSPL11 was located in the nucleus and highly expressed in spikelet hull and young development grains, consistent with its function in determining GS. Further analysis confirmed that OsSPL11 directly activates the expression of GW5L to regulate GS, meanwhile OsSPL11 expression is negatively regulated by OsGBP3. Taken together, our findings demonstrate that OsSPL11 could be a key regulator of affecting GS during the spikelet hull development and facilitate the process of improving grain yield by GS modification in rice.

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Grano Comestible , Regulación de la Expresión Génica de las Plantas , Oryza , Proteínas de Plantas , Oryza/genética , Oryza/metabolismo , Oryza/crecimiento & desarrollo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Grano Comestible/genética , Grano Comestible/crecimiento & desarrollo , Grano Comestible/metabolismo , Plantas Modificadas Genéticamente , Regiones Promotoras Genéticas/genética , Mutación/genética

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Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC(0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC(0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions.