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1.
Am J Respir Cell Mol Biol ; 70(3): 215-225, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38061028

RESUMEN

The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity after sepsis-induced lung injury remain unclear. Sphingosine-1-phosphate receptor 2 (S1PR2) has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune responses in patients with sepsis and healthy control subjects were assessed. The impact of S1PR2 on type 2 immunity in patients with sepsis and in a murine model of sepsis was further investigated. The type 2 innate immune responses were significantly increased in the circulation of patients 24 hours after sepsis, which was positively related to clinical complications and negatively correlated with S1PR2 mRNA expression. Animal studies showed that genetic deletion or pharmacological inhibition of S1PR2 induced type 2 innate immunity accumulation in the post-septic lungs. Mechanistically, S1PR2 deficiency promoted macrophage-derived interleukin (IL)-33 increase and the associated type 2 response in the lung. Furthermore, S1PR2-regulated IL-33 from macrophages mitigated lung injury after sepsis in mice. In conclusion, a lack of S1PR2 modulates the type 2 immune response by upregulating IL-33 release from macrophages and alleviates sepsis-induced lung injury. Targeting S1PR2 may have potential therapeutic value for sepsis treatment.


Asunto(s)
Lesión Pulmonar , Sepsis , Animales , Humanos , Ratones , Interleucina-33 , Macrófagos , Sepsis/complicaciones , Receptores de Esfingosina-1-Fosfato
2.
J Am Chem Soc ; 146(34): 24053-24060, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39136646

RESUMEN

Macrocyclic peptides are promising scaffolds for the covalent ligand discovery. However, platforms enabling the direct identification of covalent macrocyclic ligands in a high-throughput manner are limited. In this study, we present an mRNA display platform allowing selection of covalent macrocyclic inhibitors using 1,3-dibromoacetone-vinyl sulfone (DBA-VS). Testcase selections on TEV protease resulted in potent covalent inhibitors with diverse cyclic structures, among which cTEV6-2, a macrocyclic peptide with a unique C-terminal cyclization, emerged as the most potent covalent inhibitor of TEV protease described to-date. This study outlines the workflow for integrating chemical functionalization─installation of a covalent warhead─with mRNA display and showcases its application in targeted covalent ligand discovery.


Asunto(s)
ARN Mensajero , ARN Mensajero/antagonistas & inhibidores , Ciclización , Sulfuros/química , Sulfuros/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/síntesis química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/síntesis química , Sulfonas/química , Sulfonas/farmacología , Descubrimiento de Drogas , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Estructura Molecular
3.
Anal Chem ; 96(28): 11557-11565, 2024 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-38959297

RESUMEN

Mitochondria (MT) and the endoplasmic reticulum (ER) maintain lipid and calcium homeostasis through membrane contacts, particularly MT-ER contacts (MERCs), spanning distances from 10 to 50 nm. However, the variation of different distance ranges and the metabolic factors influencing this variation remain poorly understood. This study employed microfluidic chip-based super-resolution microscopy in conjunction with a Moore-Neighbor tracing-incorporated organelle proximity analysis algorithm. This approach enabled precise three-dimensional localization of single-fluorescence protein molecules within narrow and irregular membrane proximities. It achieved lateral localization precision of less than 20 nm, resulting in a minimum MERC distance of approximately 8 nm in spatial and mean distances across multiple threshold ranges. Additionally, we demonstrated that the MERC distance variation was correlated with MT size rather than ER width. The proportion of each distance range varied significantly after the stimuli. Free cholesterol showed a negative correlation with various distances, while distances of 10-30 nm were associated with glucose, glutamine, and pyruvic acid. Furthermore, the 30-40 nm range was influenced by citric acid. These results underscore the role of advanced subcellular organelle analysis in elucidating the single-molecule behavior and organelle morphology in single-cell studies.


Asunto(s)
Retículo Endoplásmico , Mitocondrias , Análisis de la Célula Individual , Retículo Endoplásmico/metabolismo , Mitocondrias/metabolismo , Mitocondrias/química , Humanos , Microscopía Fluorescente/métodos , Células HeLa
4.
Anal Chem ; 96(11): 4430-4436, 2024 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-38447029

RESUMEN

Traditional single-molecule fluorescence in situ hybridization (smFISH) methods for RNA detection often face sensitivity challenges due to the low fluorescence intensity of the probe. Also, short-lived autofluorescence complicates obtaining clear signals from tissue sections. In response, we have developed an smFISH probe using highly grafted lanthanide complexes to address both concentration quenching and autofluorescence background. Our approach involves an oligo PCR incorporating azide-dUTP, enabling conjugation with lanthanide complexes. This method has proven to be stable, convenient, and cost-effective. Notably, for the mRNA detection in SKBR3 cells, the lanthanide probe group exhibited 2.5 times higher luminescence intensity and detected 3 times more signal points in cells compared with the Cy3 group. Furthermore, we successfully applied the probe to image HER2 mRNA molecules in breast cancer FFPE tissue sections, achieving a 2.7-fold improvement in sensitivity compared to Cy3-based probes. These results emphasize the potential of time-resolved smFISH as a highly sensitive method for nucleic acid detection, free of background fluorescence interference.


Asunto(s)
Elementos de la Serie de los Lantanoides , Hibridación Fluorescente in Situ/métodos , ARN/análisis , ARN Mensajero/genética , Diagnóstico por Imagen
5.
Eur J Immunol ; 53(10): e2250226, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37389889

RESUMEN

Protein arginine methyltransferase 5 (Prmt5) is essential for normal B-cell development; however, the roles of Prmt5 in tumor-infiltrating B cells in tumor therapy have not been well elucidated. Here, we revealed that CD19-cre-Prmt5fl/fl (Prmt5cko) mice showed smaller tumor weights and volumes in the colorectal cancer mouse model; B cells expressed higher levels of Ccl22 and Il12a, which attracted T cells to the tumor site. Furthermore, we used direct RNA sequencing to comprehensively profile RNA processes in Prmt5 deletion B cells to explore underline mechanisms. We found significantly differentially expressed isoforms, mRNA splicing, poly(A) tail lengths, and m6A modification changes between the Prmt5cko and control groups. Cd74 isoform expressions might be regulated by mRNA splicing; the expression of two novel Cd74 isoforms was decreased, while one isoform was elevated in the Prmt5cko group, but the Cd74 gene expression showed no changes. We observed Ccl22, Ighg1, and Il12a expression was significantly increased in the Prmt5cko group, whereas Jak3 and Stat5b expression was decreased. Ccl22 and Ighg1 expression might be associated with poly(A) tail length, Jak3, Stat5b, and Il12a expression might be modulated by m6A modification. Our study demonstrated that Prmt5 regulates B-cell function through different mechanisms and supported the development of Prmt5-targeted antitumor treatments.


Asunto(s)
Neoplasias Colorrectales , Proteína-Arginina N-Metiltransferasas , Animales , Ratones , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Isoformas de Proteínas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero
6.
Small ; 20(24): e2306725, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38287726

RESUMEN

Droplet microfluidics are extensively utilized to generate monodisperse cell-laden microgels in biomedical applications. However, maintaining cell viability is still challenging due to overexposure to harsh conditions in subsequent procedures that recover the microgels from the oil phase. Here, a gravity-oriented microfluidic device for end-to-end fabrication of cell-laden microgels is reported, which integrates dispersion, gelation, and extraction into a continuous workflow. This innovative on-chip extraction, driven by native buoyancy and kinetically facilitated by pseudosurfactant, exhibits 100% retrieval efficiency for microgels with a wide range of sizes and stiffnesses. The viability of encapsulated cells is perfectly maintained at ≈98% with minimal variations within and between batches. The end-to-end fabrication remarkably enhances the biocompatibility and practicality of microfluidics-based cell encapsulation and is promising to be compatible with various applications ranging from single-cell analysis to clinical therapy.


Asunto(s)
Materiales Biocompatibles , Células , Dispositivos Laboratorio en un Chip , Microgeles , Microgeles/química , Dispositivos Laboratorio en un Chip/normas , Gravitación , Células/química
7.
Small ; : e2404307, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39240072

RESUMEN

Free-standing micro-supercapacitor (MSC) devices without substrate or current collectors are promising for practical applications. However, it is still difficult to prepare high-performance free-standing MSC devices because of the requirement of optimized active sites, conductivity, ion diffusion, controlled patterns, moisture susceptibility, etc. Here, it is proposed that the optimization of oxygen level on graphene is promising to solve these requirements because of the balance of sp2 and sp3 hybridization. Using the medium-oxidized graphene, the flexible, conductive, hydro-stable, easy-processing film can be facilely obtained, which facilitates the preparation of free-standing MSC electrodes. After constructing with gel electrolyte, the free-standing MSC device shows a high capacitance of 898.4 mF cm-2 using aqueous-gel electrolyte and 383.6 mF cm-2 using ion-gel electrolyte with mass loading of ca. 10 mg cm-2. Correspondingly, the MSC device can achieve a landmark energy density of 42.6 µWh cm-2 at 0.85 mW cm-2 (7.1 mWh cm-3 at 141.7 mW cm-3). The advantages of high performance, facile preparation, and low inactive components make the free-standing MSC device promising for practical applications.

8.
Small ; 20(27): e2308565, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38339770

RESUMEN

Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.


Asunto(s)
Cobre , Inmunoterapia , Indoles , Nanoestructuras , Polímeros , Cobre/química , Polímeros/química , Animales , Inmunoterapia/métodos , Indoles/química , Indoles/farmacología , Ratones , Nanoestructuras/química , Línea Celular Tumoral , Humanos , Catálisis , Femenino , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo
9.
Am J Geriatr Psychiatry ; 32(5): 586-595, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38184422

RESUMEN

OBJECTIVES: Collaborative care (CC) has demonstrated effectiveness for improving late-life depression in primary care, but clinics offering this service can find it challenging to address unmet social needs that may be contributing to their patients' depression. Clinics may benefit from better coordination and communication with community-based organizations (CBO) to strengthen depression treatment and to address unmet social needs. We evaluated the feasibility of adding a CBO to enhance standard collaborative care and the impact of such partnered care on older adults. DESIGN: Multisite, prepost evaluation. SETTING: Eight (n = 8) partnerships between primary care clinics and community-based organizations in California. PARTICIPANTS: A total of 707 depressed older adults (60 years or older) as evidenced by having a score of 10 or more on the Patient Health Questionnaire (PHQ-9) received care under the Care Partners project. INTERVENTION: A CBO partner was added to augment CC for late-life depression in primary care. MEASUREMENTS: The PHQ-9 was used to identify depressed older adults and to monitor depression symptom severity during a course of care. RESULTS: At baseline, the average PHQ-9 depression score across the partnerships was 15, indicating moderate depression severity. Participating patients saw an average 7-point reduction in their PHQ-9 score, baseline to last score assessed, with nearly half of all participants (48.4%) experiencing a 50% or greater improvement from their baseline score. CONCLUSIONS: Our findings suggest that partnering with a community-based organization is a feasible and effective way for primary care clinics to address late-life depression in their patients.


Asunto(s)
Depresión , Trastorno Depresivo , Humanos , Anciano , Depresión/terapia , Cuidadores , Mejoramiento de la Calidad , Trastorno Depresivo/terapia
10.
Pharm Res ; 41(6): 1257-1270, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38844745

RESUMEN

PURPOSE: Cinchoninze hydrochloride solves the problem of the low solubility of cinchonine, but it is unstable and susceptible to deliquescence. In this study, we designed and prepared cinchonine cocrystal salts or cinchonine salts with better stability, solubility and antioxidant activity than cinchonine. METHOD: We successfully synthesized and characterized three cinchonine salts, namely, cinchonine-fumaric acid, cinchonine-isoferulic acid, and cinchonine-malic acid. The high humidity (92.5% RH) and high temperature (60°C) tests were conducted to determine the physical stability and hygroscopicity of cinchonine hydrochloride, cinchonine and three cinchonine salts. And the ultraviolet spectrophotometry was conducted to determine the equilibrium solubility and intrinsic dissolution rate of cinchonine and salts. Moreover, the DPPH, ABTS, and FRAP assays determined the antioxidant activity of cinchonine and salts. RESULT: Compared with cinchonine hydrochloride and cinchonine, all three cinchonine salts exhibited good physical stability over 15 days under high humidity (92.5% RH) and high temperature (60°C) conditions. While cinchonine and cinchonine hydrochloride are categorized as hygroscopic and deliquescent, respectively, three cinchonine salts are classified as slightly hygroscopic, meaning that they have a lower hygroscopicity than cinchonine and cinchonine hydrochloride. And three cinchonine salts had higher equilibrium solubility, faster intrinsic dissolution rates, and higher antioxidant activity in comparison to cinchonine. Moreover, they showed a "spring and parachute" pattern in the phosphate buffer (pH = 6.8). CONCLUSION: Cocrystallization technology is a viable option for improving cinchonine's poor physicochemical qualities.


Asunto(s)
Antioxidantes , Cristalización , Estabilidad de Medicamentos , Solubilidad , Antioxidantes/química , Antioxidantes/farmacología , Humectabilidad , Química Farmacéutica/métodos , Humedad , Sales (Química)/química
11.
BMC Med Res Methodol ; 24(1): 125, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38831262

RESUMEN

BACKGROUND: Mediation analysis is a powerful tool to identify factors mediating the causal pathway of exposure to health outcomes. Mediation analysis has been extended to study a large number of potential mediators in high-dimensional data settings. The presence of confounding in observational studies is inevitable. Hence, it's an essential part of high-dimensional mediation analysis (HDMA) to adjust for the potential confounders. Although the propensity score (PS) related method such as propensity score regression adjustment (PSR) and inverse probability weighting (IPW) has been proposed to tackle this problem, the characteristics with extreme propensity score distribution of the PS-based method would result in the biased estimation. METHODS: In this article, we integrated the overlapping weighting (OW) technique into HDMA workflow and proposed a concise and powerful high-dimensional mediation analysis procedure consisting of OW confounding adjustment, sure independence screening (SIS), de-biased Lasso penalization, and joint-significance testing underlying the mixture null distribution. We compared the proposed method with the existing method consisting of PS-based confounding adjustment, SIS, minimax concave penalty (MCP) variable selection, and classical joint-significance testing. RESULTS: Simulation studies demonstrate the proposed procedure has the best performance in mediator selection and estimation. The proposed procedure yielded the highest true positive rate, acceptable false discovery proportion level, and lower mean square error. In the empirical study based on the GSE117859 dataset in the Gene Expression Omnibus database using the proposed method, we found that smoking history may lead to the estimated natural killer (NK) cell level reduction through the mediation effect of some methylation markers, mainly including methylation sites cg13917614 in CNP gene and cg16893868 in LILRA2 gene. CONCLUSIONS: The proposed method has higher power, sufficient false discovery rate control, and precise mediation effect estimation. Meanwhile, it is feasible to be implemented with the presence of confounders. Hence, our method is worth considering in HDMA studies.


Asunto(s)
Análisis de Mediación , Puntaje de Propensión , Humanos , Estudios Observacionales como Asunto/métodos , Factores de Confusión Epidemiológicos , Epigenómica/métodos , Simulación por Computador , Algoritmos
12.
J Immunol ; 208(2): 501-513, 2022 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-34911774

RESUMEN

Protein arginine methyltransferase 5 (PRMT5) participates in the symmetric dimethylation of arginine residues of proteins and contributes to a wide range of biological processes. However, how PRMT5 affects the transcriptional and epigenetic programs involved in the establishment and maintenance of T cell subset differentiation and roles in antitumor immunity is still incompletely understood. In this study, using single-cell RNA and chromatin immunoprecipitation sequencing, we found that mouse T cell-specific deletion of PRMT5 had greater effects on CD8+ than CD4+ T cell development, enforcing CD8+ T cell differentiation into Klrg1+ terminal effector cells. Mechanistically, T cell deficiency of PRMT5 activated Prdm1 by decreasing H4R3me2s and H3R8me2s deposition on its loci, which promoted the differentiation of Klrg1+CD8+ T cells. Furthermore, effector CD8+ T cells that transited to memory precursor cells were decreased in PRMT5-deficient T cells, thus causing dramatic CD8+ T cell death. In addition, in a mouse lung cancer cell line-transplanted tumor mouse model, the percentage of CD8+ T cells from T cell-specific deletion of PRMT5 mice was dramatically lost, but CD8+Foxp3+ and CD8+PDL1+ regulatory T cells were increased compared with the control group, thus accelerating tumor progression. We further verified these results in a mouse colon cancer cell line-transplanted tumor mouse model. Our study validated the importance of targeting PRMT5 in tumor treatment, because PRMT5 deficiency enforced Klrg1+ terminal CD8+ T cell development and eliminated antitumor activity.


Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Carcinogénesis/genética , Lectinas Tipo C/metabolismo , Proteína-Arginina N-Metiltransferasas/deficiencia , Receptores Inmunológicos/metabolismo , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Hematopoyesis/fisiología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Activación de Linfocitos/inmunología , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , RNA-Seq , Transducción de Señal/genética , Análisis de la Célula Individual
13.
Skin Res Technol ; 30(8): e13875, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39120064

RESUMEN

BACKGROUND: Recent studies increasingly suggest that microbial infections and the immune responses they elicit play significant roles in the pathogenesis of chronic inflammatory skin diseases. This study uses Mendelian randomization (MR) and Bayesian weighted Mendelian randomization (BWMR) to explore the causal relationships between immune antibody responses and four common skin diseases: psoriasis, atopic dermatitis (AD), rosacea, and vitiligo. METHODS: We utilized summary statistics from genome-wide association studies (GWAS) for antibody responses to 13 infectious pathogens and four skin diseases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess causal relationships using multiple MR methods, including inverse variance weighted (IVW), MR Egger, and weighted median. BWMR was also employed to confirm findings and address potential pleiotropy. RESULTS: The IVW analysis identified significant associations between specific antibody responses and the skin diseases studied. Key findings include protective associations of anti-Epstein-Barr virus (EBV) IgG seropositivity and Helicobacter pylori UREA antibody levels with psoriasis and AD. anti-chlamydia trachomatis IgG seropositivity, anti-polyomavirus 2 IgG seropositivity, and varicella zoster virus glycoprotein E and I antibody levels were negatively associated with rosacea, while EBV Elevated levels of the early antigen (EA-D) antibody levels and HHV-6 IE1B antibody levels were positively associated with rosacea. H. pylori Catalase antibody levels were protectively associated with vitiligo, whereas anti-herpes simplex virus 2 (HSV-2) IgG seropositivity was positively associated with vitiligo. The BWMR analysis confirmed these associations. CONCLUSION: This study underscores the significant role of H. pylori and other pathogens in these skin diseases, suggesting both protective and exacerbating effects depending on the specific condition. Understanding these pathogen-immune interactions can lead to the development of more effective, personalized treatments and preventative strategies, ultimately improving patient outcomes and quality of life.


Asunto(s)
Teorema de Bayes , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Dermatitis Atópica/inmunología , Dermatitis Atópica/genética , Dermatitis Atópica/microbiología , Dermatitis Atópica/sangre , Rosácea/inmunología , Rosácea/genética , Vitíligo/genética , Vitíligo/inmunología , Formación de Anticuerpos/genética , Psoriasis/inmunología , Psoriasis/genética , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/genética
14.
Skin Res Technol ; 30(9): e70035, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39218780

RESUMEN

BACKGROUND: Atopic dermatitis (AD), psoriasis (PSO), rosacea, and other related immune skin diseases are affected by multiple complex factors such as genetic and microbial components. This research investigates the causal relationships between specific skin microbiota and these diseases by using Mendelian randomization (MR), and Bayesian weighted Mendelian randomization (BWMR). METHODS: We utilized genome-wide association study (GWAS) data to analyze the associations between various skin bacteria and three dermatological diseases. Single nucleotide polymorphisms (SNPs) served as instrumental variables (IVs) in MR methods, including inverse variance weighted (IVW), and MR Egger. BWMR was employed to validate results and address pleiotropy. RESULTS: The IVW analysis identified significant associations between specific skin microbiota and dermatological diseases. ASV006_Dry, ASV076_Dry, and Haemophilus_Dry were significantly positively associated with AD, whereas Kocuria_Dry was negatively associated. In PSO, ASV005_Dry was negatively associated, whereas ASV004_Dry, Rothia_Dry, and Streptococcus_Moist showed positive associations. For rosacea, ASV023_Dry was significantly positively associated, while ASV016_Moist, Finegoldia_Dry, and Rhodobacteraceae_Moist were significantly negatively associated. These results were corroborated by BWMR analysis. CONCLUSION: Bacterial species such as Finegoldia, Rothia, and Streptococcus play crucial roles in the pathogenesis of AD, PSO, and rosacea. Understanding these microbial interactions can aid in developing targeted treatments and preventive strategies, enhancing patient outcomes and quality of life.


Asunto(s)
Teorema de Bayes , Dermatitis Atópica , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Microbiota , Polimorfismo de Nucleótido Simple , Humanos , Microbiota/genética , Dermatitis Atópica/microbiología , Dermatitis Atópica/genética , Piel/microbiología , Rosácea/microbiología , Rosácea/genética , Enfermedades de la Piel/microbiología , Enfermedades de la Piel/genética , Psoriasis/microbiología , Psoriasis/genética
15.
BMC Pulm Med ; 24(1): 413, 2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-39187816

RESUMEN

BACKGROUND: Higher red blood cell distribution width (RDW) levels are associated with mortality in patients with chronic obstructive pulmonary disease (COPD). However, more convincing evidence is still lacking, and the relationship between hemoglobin-to-red blood cell distribution width ratio (HRR) and mortality in patients with COPD remains unclear. METHODS: This study is a prospective cohort study that includes 3,745 adult patients with COPD from the National Health and Nutrition Examination Survey (NHANES) database spanning from 1999 to 2018 in the United States. COX proportional hazards regression analysis, Kaplan-Meier survival curves and restricted cubic spline models were employed to investigate the association of RDW and HRR levels with mortality. Time-dependent receiver operating characteristic curve (ROC) analysis was conducted to evaluate the accuracy of RDW and HRR in predicting mortality in patients with COPD. RESULTS: Higher RDW level was positively associated with increased risk of all-cause mortality (HR = 1.16, 95% CI = 1.11-1.21, P < 0.001), cardiovascular disease (CVD) mortality (HR = 1.13, 95% CI = 1.06-1.21, P < 0.001), and chronic lower respiratory disease (CLRD) related mortality (HR = 1.15, 95% CI = 1.05-1.25, P = 0.003) after adjusting for various potential confounders. HRR was inversely associated with all-cause mortality (HR = 0.14, 95% CI = 0.08-0.25, P < 0.001), CVD mortality (HR = 0.12, 95% CI = 0.05-0.31, P < 0.001). HRR has no significant correlation with CLRD-related mortality. The time-dependent ROC curve showed that RDW exhibited area under the curves (AUCs) of the 5- and 10-year survival rates were 0.707 and 0.714 for all-cause mortality and 0.686 and 0.698, respectively, for CVD mortality. HRR yielded AUCs of the 5- and 10-year survival rates were 0.661 and 0.653 for all-cause mortality and 0.654 and 0.66, respectively, for CVD mortality. CONCLUSION: Higher RDW levels were positively associated with an increased risk of mortality in patients with COPD. HRR levels were negatively correlated with the risk of all-cause and CVD mortality. The predictive value of HRR for mortality in these patients is lower than that of RDW.


Asunto(s)
Índices de Eritrocitos , Hemoglobinas , Encuestas Nutricionales , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Estados Unidos/epidemiología , Hemoglobinas/análisis , Curva ROC , Modelos de Riesgos Proporcionales , Estimación de Kaplan-Meier , Valor Predictivo de las Pruebas
16.
Int J Cancer ; 152(3): 436-446, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36214796

RESUMEN

Esophageal cancer (EC) is a main cause of cancer-related deaths. However, genomic alterations and the clinical value of next-generation sequencing (NGS) in advanced or metastatic EC for precision therapy remain largely unclear. Herein, we performed comprehensive analyses on a cohort of 47 individuals with advanced or metastatic EC who underwent NGS between May 2017 and February 2020. Eventually, 227 mutated genes were identified in the cohort. TP53, NQO1, DPYD, GSTM1, XRCC1 and ERCC1 were the most mutated genes and associated with immune cell infiltration, autophagy and hypoxia. Patients who received NGS-guided treatments exhibited better objective remission rate (ORR) (72.22%), disease control rate (DCR) (88.89%), overall survival (OS) (P = .0019) and progression-free survival (PFS) (P = .0077) than those not receiving NGS-guided therapies. The multivariate analyses further demonstrated that the NGS-guided therapy was an independently prognostic factor (OS: hazard radio [HR] 0.31, 95% coincidence interval [CI] 0.1-0.97, P = .04). In conclusion, we depicted a comprehensive mutational landscape of 47 patients with locally advanced or metastatic EC and illustrated the utility of NGS testing to guide clinical management in improving ORR, DCR, OS and PFS.


Asunto(s)
Neoplasias Esofágicas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Genómica , Supervivencia sin Progresión , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética
17.
J Neuroinflammation ; 20(1): 183, 2023 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-37533053

RESUMEN

BACKGROUND: Protein arginine methyltransferase 5 (Prmt5) is the main type II methyltransferase, catalyzes protein arginine residue symmetric dimethylation, and modulates normal cellular physiology and disease progression. Prmt5 inhibition or deletion in CD4+ T cells has been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), but the detailed molecular mechanisms have not yet been elucidated. METHODS: EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35-55) in T cells Prmt5 conditional knockout (CD4-cre-Prmt5fl/fl, Prmt5cko) and Prmt5fl/fl (WT) mice. Flow cytometry, single-cell RNA sequencing, ATAC sequencing and chromatin immunoprecipitation assay (ChIP) approaches were used to explore the detail mechanisms. RESULTS: We find that Prmt5cko mice are resistant to EAE; infiltrating inflammatory CD4+ T cells in the central nervous system (CNS) are greatly reduced. However, in Prmt5cko mice, T cells in the spleen show much more proliferation and activation properties, the total number of CD4+ T cells in the spleen is not reduced, and the percentage of Rora+ CD4+ T cells is elevated. Also, CD4+ T cells express lower levels of S1pr1 and Klf2 than WT mice, which may influence pathogenic CD4+ T-cell egress from the spleen and migration to the CNS. Moreover, the single-cell ATAC sequence and ChIP assay reveal that the transcription factor Klf2 is enriched at the S1pr1 promoter and that Klf2 motif activity is reduced in Prmt5cko mice. CONCLUSIONS: Our study delineates the undiscovered role of Prmt5 in T-cell biology in which Prmt5 may inhibit Klf2-S1pr1 pathway to ameliorate EAE disease. Controlling T-cell Prmt5 expression may be helpful for the treatment of autoimmune diseases.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Proteína-Arginina N-Metiltransferasas , Animales , Ratones , Linfocitos T CD4-Positivos , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidad , Factores de Transcripción/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo
18.
J Org Chem ; 88(9): 5348-5358, 2023 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-37011379

RESUMEN

A facile access to isocoumarins has been established via rhodium(III)-catalyzed C-H bond activation and intramolecular C-C cascade annulation of enaminones and cyclic 1,3-dicarbonyl compounds. The synthetic protocol features a wide range of substrates with high functional group tolerance, mild reaction conditions, and the selective cleavage of the enaminone C-C bond. Notably, the cyclic 1,3-dicarbonyl compounds can in situ-generate iodonium ylide as a carbene precursor to prepare polycyclic scaffolds by reacting with PhI(OAc)2. The application of this method to prepare useful synthetic precursors and bioactive skeletons is also exemplified.

19.
Inorg Chem ; 62(5): 2228-2235, 2023 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-36689703

RESUMEN

Commercial polyketone materials are generally produced by palladium-catalyzed terpolymerization of ethylene and α-olefin with carbon monoxide (CO), and rare examples were reported regarding the incorporation of propylene into an ethylene/CO copolymer chain using a cost-effective nickel catalyst. In this study, we have developed a series of [P,O]-type cationic Pd and Ni complexes supported by a diphosphazane monoxide (PNPO) platform, and the electronic and steric effect on phosphine, amine, and phosphine oxide moieties is systematically investigated for terpolymerization in terms of activity, propylene/CO (C3) incorporation, and molecular weight control. It is observed that the melting temperature (Tm) is proportional to the number of C3 incorporations present in the polymer chain, and the incorporated propylene does not affect the degradation temperature substantially, thus broadening the processing temperature window of the resultant polyketones. Notably, in comparison with dppp-type catalysts, PNPO catalysts exhibited a higher preference for propylene consumption, which is of great importance for making more efficient use of α-olefin resources.

20.
Appl Opt ; 62(36): 9446-9453, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38108768

RESUMEN

A dual aspheric integrated beam shaper suitable for a high-power laser situation has been designed and realized. The model for this lens was derived theoretically and the performance was evaluated using a detailed simulation. The ultrasonic vibration assisted cutting and the high-precision grinding and polishing technology were used for the processing. The surface accuracy was less than 200 nm measured with a profiler, and the roughness was smaller than 20 nm with the help of the white light interferometer. Shaping experiments were carried out, which verified that the Gaussian beam has uniform intensity distribution with a uniformity of 85.13% in the near field and converges to a point in the far field, which is exactly as expected. It thus provides an actual selection for high-power laser shaping.

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