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Success in plant reproduction is highly dependent on the correct timing of the floral transition, which is tightly regulated by the flowering pathways. In the model plant Arabidopsis thaliana, the central flowering repressor FLOWERING LOCUS C (FLC) is precisely regulated by multiple flowering time regulators in the vernalization pathway and autonomous pathway, including FPA. Here we report that Arabidopsis MEDIATOR SUBUNIT 8 (MED8) promotes floral transition in Arabidopsis by recruiting FPA to the FLC locus to repress FLC expression. Loss of MED8 function leads to a significant late-flowering phenotype due to increased FLC expression. We further show that MED8 directly interacts with FPA in the nucleus and recruits FPA to the FLC locus. Moreover, MED8 is indispensable for FPA's function in controlling flowering time and regulating FLC expression. Our study thus reveals a flowering mechanism by which the Mediator subunit MED8 represses FLC expression by facilitating the binding of FPA to the FLC locus to ensure appropriate timing of flowering for reproductive success.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Flores/fisiología , Regulación de la Expresión Génica de las Plantas , Proteínas de Dominio MADS/genética , Proteínas de Dominio MADS/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
PURPOSE: To explore the potential causal links between obesity, type 2 diabetes (T2D), and lifestyle choices (such as smoking, alcohol and coffee consumption, and vigorous physical activity) on stress urinary incontinence (SUI), this study employs a Mendelian Randomization approach. This research aims to clarify these associations, which have been suggested but not conclusively established in prior observational studies. METHODS: Genetic instruments associated with the exposures at the genome-wide significance (p < 5 × 10-8) were selected from corresponding genome-wide association studies. Summary-level data for SUI, was obtained from the UK Biobank. A two-sample MR analysis was employed to estimate causal effects, utilizing the inverse-variance weighted (IVW) method as the primary analytical approach. Complementary sensitivity analyses including MR-PRESSO, MR-Egger, and weighted median methods were performed. The horizontal pleiotropy was detected by using MR-Egger intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran's Q statistics. RESULTS: Our findings demonstrate a significant causal relationship between higher body mass index (BMI) and the risk of SUI, with increased abdominal adiposity (WHRadjBMI) similarly linked to SUI. Smoking initiation is also causally associated with an elevated risk. However, our analysis did not find definitive causal connections for other factors, including T2D, alcohol consumption, coffee intake, and vigorous physical activity. CONCLUSIONS: These findings provide valuable insights for clinical strategies targeting SUI, suggesting a need for heightened awareness and potential intervention in individuals with higher BMI, WHR, and smoking habits. Further research is warranted to explore the complex interplay between genetic predisposition and lifestyle choices in the pathogenesis of SUI.
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Diabetes Mellitus Tipo 2 , Incontinencia Urinaria de Esfuerzo , Humanos , Análisis de la Aleatorización Mendeliana , Café , Estudio de Asociación del Genoma Completo , Estilo de VidaRESUMEN
BACKGROUND AND OBJECTIVE: Noninvasive neuromodulation, particularly through low-intensity ultrasound, holds promise in the fields of neuroscience and neuro-engineering. Ultrasound can stimulate the central nervous system to treat neurologic disorders of the brain and activate peripheral nerve activity. The aim of this study is to investigate the inhibitory effect of low-intensity ultrasonic tibial nerve stimulation on both the physiological state and the overactive bladder (OAB) model in rats. MATERIALS AND METHODS: A total of 28 female Sprague-Dawley rats were used in this study. Continuous transurethral instillation of 0.9% normal saline into the bladder was initially performed to stimulate physiological bladder activity. Subsequently, a solution containing 0.3% acetic acid dissolved in saline was instilled to induce rat models of OAB. The study comprised two phases: initial observation of bladder response to low-intensity ultrasound (1 MHz, 1 W/cm2, 50% duty cycle) in seven rats; subsequent exploration of ultrasound frequency (3 MHz) and intensity (2 W/cm2 and 3 W/cm2) effects in 21 rats. The intercontraction intervals (ICIs) were the primary outcome measure. Histologic analysis of tibial nerves and surrounding muscle tissues determined safe ultrasound parameters. RESULTS: Low-intensity ultrasound tibial nerve stimulation significantly inhibited normal and OAB activity. Ultrasound stimulation at 1 MHz, 1 W/cm2, with a 50% duty cycle significantly prolonged the ICI in both normal (p < 0.0001) and OAB rats (p < 0.01), as did transitioning to a 3 MHz frequency (p = 0.001 for normal rats; p < 0.01 for OAB rats). Similarly, at an intensity of 2 W/cm2 and 1 MHz frequency with a 50% duty cycle, ultrasound stimulation significantly prolonged the ICI in both normal (p < 0.01) and OAB rats (p < 0.005). Furthermore, switching to a 3 W/cm2 ultrasound intensity also significantly extended the ICI in both normal (p < 0.05) and OAB rats (p = 0.01). However, after different ultrasound intensities and frequencies, there was no statistical difference in ICI ratios (preultrasound stimulation vs postultrasound stimulation/preultrasound stimulation ∗ 100%) in all rats (p > 0.05). Low-intensity ultrasound tibial nerve stimulation did not influence baseline pressure, threshold pressure, or maximum pressure. In addition, a latency period in bladder reflex inhibition was induced by low-intensity ultrasound tibial nerve stimulation in some rats. Histologic analysis indicated no evident nerve or muscle tissue damage or abnormalities. CONCLUSIONS: This study confirmed the potential of transcutaneous ultrasound tibial nerve stimulation to improve bladder function. According to the findings, the ultrasonic intensities ranging from 1 to 3 W/cm2 and frequencies of 1 MHz and 3 MHz are both feasible and safe treatment parameters. This study portended the promise of low-intensity ultrasound tibial nerve stimulation as a treatment for OAB and provides a basis and reference for future clinical applications.
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Metal-modified catalysts have attracted extraordinary research attention in heterogeneous catalysis due to their enhanced geometric and electronic structures and outstanding catalytic performances. Silver (Ag) possesses necessary active sites for ethylene epoxidation, but the catalyst activity is usually sacrificed to obtain high selectivity towards ethylene oxide (EO). Herein, we report that using Al can help in tailoring the unoccupied 3d state of Ag on the MnO2 support through strong electronic metal-support interactions (EMSIs), overcoming the activity-selectivity trade-off for ethylene epoxidation and resulting in a very high ethylene conversion rate (~100 %) with 90 % selectivity for EO under mild conditions (170 °C and atmospheric pressure). Structural characterization and theoretical calculations revealed that the EMSIs obtained by the Al modification tailor the unoccupied 3d state of Ag, modulating the adsorption of ethylene (C2H4) and oxygen (O2) and facilitating EO desorption, resulting in high C2H4 conversion. Meanwhile, the increased number of positively charge Ag+ lowers the energy barrier for C2H4(ads) oxidation to produce oxametallacycle (OMC), inducing the unexpectedly high EO selectivity. Such an extraordinary electronic promotion provides new promising pathways for designing advanced metal catalysts with high activity and selectivity in selective oxidation reactions.
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Copper (Cu), a promising catalyst for electrochemical CO2 reduction (CO2R) to multi-electron reduction products, suffers from an unavoidable and uncontrollable reconstruction process during the reaction, which not only may lead to catalyst deactivation but also brings great challenges to the exploration of the structure-performance relationship. Herein, we present an efficient strategy for stabilizing Cu with silica and synthesize reconstruction-resistant CuSiOx amorphous nanotube catalysts with abundant atomic Cu-O-Si interfacial sites. The strong interfacial interaction between Cu and silica makes the Cu-O-Si interfacial sites ultrastable in the CO2R reaction without any apparent reconstruction, thus exhibiting high CO2-to-CH4 selectivity (72.5%) and stability (FECH4 remains above 60% after 12 h of test). A remarkable CO2-to-CH4 conversion rate of 0.22 µmol cm-2 s-1 was also achieved in a flow cell device. This work provides a very promising route for the design of highly active and stable Cu-based CO2R catalysts.
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Developing efficient and simple catalysts to reveal the key scientific issues in the epoxidation of ethylene has been a long-standing goal for chemists, whereas a heterogenized molecular-like catalyst is desirable which combines the best aspects of homogeneous and heterogeneous catalysts. Single-atom catalysts can effectively mimic molecular catalysts on account of their well-defined atomic structures and coordination environments. Herein, we report a strategy for selective epoxidation of ethylene, which exploits a heterogeneous catalyst comprising iridium single atoms to interact with the reactant molecules that act analogously to ligands, resulting in molecular-like catalysis. This catalytic protocol features a near-unity selectivity (99%) to produce value-added ethylene oxide. We investigated the origin of the improvement of selectivity for ethylene oxide for this iridium single-atom catalyst and attributed the improvement to the π-coordination between the iridium metal center with a higher oxidation state and ethylene or molecular oxygen. The molecular oxygen adsorbed on the iridium single-atom site not only helps to strengthen the adsorption of ethylene molecule by iridium but also alters its electronic structure, allowing iridium to donate electrons into the double bond π* orbitals of ethylene. This catalytic strategy facilitates the formation of five-membered oxametallacycle intermediates, leading to the exceptionally high selectivity for ethylene oxide. Our model of single-atom catalysts featuring remarkable molecular-like catalysis can be utilized as an effective strategy for inhibiting the overoxidation of the desired product. Implementing the concepts of homogeneous catalysis into heterogeneous catalysis would provide new perspectives for the design of new advanced catalysts.
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PURPOSE: To establish typical value ranges (TVRs) of the air-charged catheter (ACC) system, and analyze the typical signal patterns (TSPs) of cough under different bladder volumes for quality control of a urodynamic study using the ACC system. MATERIALS AND METHODS: The urodynamic traces of 1977 patients with neurogenic bladder (NB) were analyzed for intravesical pressure (pves ), abdominal pressure (pabd ), and detrusor pressure (pdet ) in the cough test at our center from July 2017 to December 2021. The pdet cough signals were described and classified. The pdet cough signal patterns in different bladder volumes and postures were analyzed. RESULTS: The 50% range of the initial resting pves , pabd , and pdet in the supine and sitting positions were 7-15, 7-14, and 0-0 cmH2 O, and 24-33, 24-33, and 0-0 cmH2 O, respectively. The cough amplitudes for pves and pabd were similar in the 50% range, as follows: 10-27 and 8-25 cmH2 O in the supine position, respectively; and 18-43 and 17-40 cmH2 O in the sitting position, respectively. The cough amplitude of pves and pabd was not related to bladder volume (p > 0.05). The cough spikes of pdet were divided into three types: type I, in which pdet has a minimal change (<5 cmH2 O); type II, a monophasic cough spike, in which could be a positive (IIa, ≥5 cmH2 O) or negative spike (IIb, ≥5 cmH2 O); and type III, a biphasic spike, in which could be a positive-to-negative biphasic (IIIa) or negative-to-positive spike (IIIb). Under different bladder volumes, the cough signals of pdet were all expressed as type I, II, or III, and the cough signals were unrelated to bladder volume (p > 0.05). CONCLUSIONS: TVRs of the initial resting state in patients with NB were established to provide guidance for quantitative quality control of the ACC system. The TSPs of the pdet cough signal under different bladder volume and posture were described, which could be used for qualitative quality control of the ACC system.
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Vejiga Urinaria Neurogénica , Humanos , Vejiga Urinaria Neurogénica/terapia , Catéteres , Urodinámica , Tos , Presión , Control de CalidadRESUMEN
Floral transition, the change from vegetative growth to reproductive development, is dramatic in flowering plants. Here, we show that one subgroup III member of the B-box (BBX) family, BBX17, is a repressor of floral transition under long-day conditions. BBX17 contains a B-box domain and a CCT domain. Although the phenotype of the BBX17 loss-of-function plants was comparable to that of wild-type plants, BBX17-overexpression plants displayed a delayed-flowering phenotype under long-day conditions. The delayed-flowering phenotype was not the result of an altered CONSTANS (CO) expression level but rather the repression of the FLOWERING LOCUS T (FT) expression level. BBX17 physically associated with CO and repressed its ability to control FT expression. Furthermore, the BBX17 protein degraded in the dark, but irradiating seedlings with white, blue, red or far-red light stabilized the BBX17 level. We also proved that the degradation of BBX17 was via 26S proteasome and requires COP1. Thus, BBX17 acts as a key factor in the CO-FT regulatory system to control Arabidopsis thaliana flowering.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Unión al ADN/metabolismo , Flores/fisiología , Regulación de la Expresión Génica de las Plantas , Fotoperiodo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: To assess the inter-observer and intra-observer reliability of the magnetic resonance urography (MRU)-upper urinary tract dilation (UUTD) grading system. METHODS: A total of 40 patients with a diagnosis of NB were enrolled in this study. The images were assembled in an electronic presentation randomly. The presentations were reviewed and graded by 4 junior and 4 senior urologists. One week later, the images were randomized again and reassessed. The inter-observer reliability was estimated by Kendall's coefficient of concordance and intra-class correlation coefficient (ICC), and the intra-observer reliability was estimated by weighted Cohen's kappa. RESULTS: The inter-observer reliability strength was excellent for all urologists, with the ICC value of 0.939 (0.908-0.963) and Kendall's W value of 0.967. The highest agreement was shown in Grade 4 at 92.50%, and the lowest in Grade 2 at 82.14%. All disagreements were within one grade of difference. Moreover, the Intra-observer reliability was excellent, with the weighted kappa value ranging from 0.904 to 0.954. CONCLUSIONS: The inter-observer and intra-observer reliability of this novel MRU-UUTD grading system is confirmed, providing adequate evidence for broader clinical application.
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Vejiga Urinaria Neurogénica , Sistema Urinario , Dilatación , Humanos , Espectroscopía de Resonancia Magnética , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Vejiga Urinaria Neurogénica/diagnóstico por imagen , Sistema Urinario/diagnóstico por imagen , Urografía/métodosRESUMEN
BACKGROUND: RNA polymerase II plays critical roles in transcription in eukaryotic organisms. C-terminal Domain Phosphatase-like 1 (CPL1) regulates the phosphorylation state of the C-terminal domain of RNA polymerase II subunit B1, which is critical in determining RNA polymerase II activity. CPL1 plays an important role in miRNA biogenesis, plant growth and stress responses. Although cpl1 mutant showes delayed-flowering phenotype, the molecular mechanism behind CPL1's role in floral transition is still unknown. RESULTS: To study the role of CPL1 during the floral transition, we first tested phenotypes of cpl1-3 mutant, which harbors a point-mutation. The cpl1-3 mutant contains a G-to-A transition in the second exon, which results in an amino acid substitution from Glu to Lys (E116K). Further analyses found that the mutated amino acid (Glu) was conserved in these species. As a result, we found that the cpl1-3 mutant experienced delayed flowering under both long- and short-day conditions, and CPL1 is involved in the vernalization pathway. Transcriptome analysis identified 109 genes differentially expressed in the cpl1 mutant, with 2 being involved in floral transition. Differential expression of the two flowering-related DEGs was further validated by qRT-PCR. CONCLUSIONS: Flowering genetic pathways analysis coupled with transciptomic analysis provides potential genes related to floral transition in the cpl1-3 mutant, and a framework for future studies of the molecular mechanisms behind CPL1's role in floral transition.
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Proteínas de Arabidopsis , Arabidopsis , Flores/fisiología , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Flores/genética , Regulación de la Expresión Génica de las Plantas , Mutación , Fosfoproteínas Fosfatasas/genética , Proteínas de Unión al ARN/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: The TGACG-binding (TGA) family has 10 members that play vital roles in Arabidopsis thaliana defense responses and development. However, their involvement in controlling flowering time remains largely unknown and requires further investigation. RESULTS: To study the role of TGA7 during floral transition, we first investigated the tga7 mutant, which displayed a delayed-flowering phenotype under both long-day and short-day conditions. We then performed a flowering genetic pathway analysis and found that both autonomous and thermosensory pathways may affect TGA7 expression. Furthermore, to reveal the differential gene expression profiles between wild-type (WT) and tga7, cDNA libraries were generated for WT and tga7 mutant seedlings at 9 days after germination. For each library, deep-sequencing produced approximately 6.67 Gb of high-quality sequences, with the majority (84.55 %) of mRNAs being between 500 and 3,000 nt. In total, 325 differentially expressed genes were identified between WT and tga7 mutant seedlings. Among them, four genes were associated with flowering time control. The differential expression of these four flowering-related genes was further validated by qRT-PCR. CONCLUSIONS: Among these four differentially expressed genes associated with flowering time control, FLC and MAF5 may be mainly responsible for the delayed-flowering phenotype in tga7, as TGA7 expression was regulated by autonomous pathway genes. These results provide a framework for further studying the role of TGA7 in promoting flowering.
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Arabidopsis/genética , Flores/genética , Arabidopsis/crecimiento & desarrollo , Flores/crecimiento & desarrollo , Regulación de la Expresión Génica de las Plantas , Mutación , Plantones/genética , Plantones/crecimiento & desarrollo , TranscriptomaRESUMEN
AIMS: Cell death and inflammation are involved in the development of bladder dysfunction. Pyroptosis is programmed cell death, causing cytotoxic effects and local inflammation. As one of the biggest health threats in the world, smoking is also closely related to urinary system diseases. The aims of this study were to investigate the role of NLRP3 inflammasome-mediated pyroptosis in the bladder after cigarette smoke exposure. METHODS: The expression of NLRP3 inflammasome and the activity of caspase-1 in bladder tissue was investigated after cigarette smoke exposure. In vitro, bladder urothelial cells were stimulated by cigarette smoke extract and then the activity of caspase-1 and the expression of NLRP3 inflammasome were measured. The role of oxidative stress was also assessed. RESULTS: The activity of caspase-1 in bladder tissue increased by 50% after cigarette smoke exposure. Cigarette smoke caused oxidative stress injury and the activation of NLRP3 inflammasome. In addition, reactive oxygen species (ROS) inhibitor N-acetyl-cysteine alleviated the pyroptosis of urothelial cells. CONCLUSIONS: Cigarette smoke-induced pyroptosis of bladder tissue by activating ROS/NLRP3/caspase-1 signaling pathway. Inhibition of bladder urothelial cell pyroptosis may be a new approach to alleviate bladder damage caused by smoking.
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Caspasa 1/metabolismo , Células Epiteliales/metabolismo , Piroptosis/fisiología , Transducción de Señal/fisiología , Urotelio/metabolismo , Animales , Línea Celular , Células Epiteliales/citología , Humanos , Inflamasomas/metabolismo , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Humo , Urotelio/citologíaRESUMEN
PURPOSE: Cannabinoids have been shown to exert analgesic and anti-inflammatory effects, and the effects of cannabinoids are mediated primarily by cannabinoid receptors 1 and 2 (CB1 and CB2). The objective of this study was to determine efficacy and mechanism of CB2 activation on cyclophosphamide (CYP)-induced cystitis in vivo. METHODS: Cystitis was induced by intraperitoneal (IP) injection of CYP in female C57BL/6J mice. Mice were pretreated with CB2 agonist JWH-133 (1 mg/kg, intraperitoneally), CB2 antagonist AM-630 (1 mg/kg, intraperitoneally) or autophagy inhibitor 3-methyladenine (3-MA) (50 mM, intraperitoneally) before IP injection of CYP. Peripheral nociception and spontaneous voiding were investigated in these mice. Bladders were collected, weighed, and processed for real-time polymerase chain reaction, immunoblotting analysis, histological and immunohistochemical analysis. RESULTS: Twenty-four hours after IP injection of CYP, the bladder of CYP-treated mice showed histological evidence of inflammation. The expression of CB2 in bladder was significantly increased in CYP-treated mice. Mechanical sensitivity was significantly increased in CYP-treated mice and CB2 agonist JWH-133 attenuated this effect (P < .05). The number of urine spots was significantly increased after CYP treatment and it was decreased in JWH-133 treated mice (P < .05). Activating CB2 with JWH-133 significantly alleviated bladder tissue inflammatory responses and oxidative stress induced by CYP. Activation of CB2 by JWH-133 increased the expression of LC3-II/LC3-I ratio, and decreased the expression of SQSTM1/p62 in the bladder of cystitis mice, whereas AM-630 induced inverse effects. Further study indicated that JWH-133 could promote autophagy and blocking autophagy by 3-MA dismissed the effort of CB2 in alleviating bladder tissue inflammatory responses and oxidative stress injury. Furthermore, treatment with 3-MA decreased the expression of p-AMPK and induced the phosphorylation of mTOR in the presence of JWH-133 stimulation in cystitis model. CONCLUSIONS: Activation of CB2 decreased severity of CYP-induced cystitis and ameliorated bladder inflammation. CB2 activation is protective in cystitis through the activation of autophagy and AMPK-mTOR pathway may be involved in the initiation of autophagy.
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Autofagia/efectos de los fármacos , Cistitis/metabolismo , Receptor Cannabinoide CB2/agonistas , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Ciclofosfamida , Cistitis/inducido químicamente , Femenino , Indoles/farmacología , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Receptor Cannabinoide CB2/antagonistas & inhibidores , Micción/efectos de los fármacosRESUMEN
Bladder cancer is one of the most commonly diagnosed tumors and is results from the accumulation of somatic mutations in the DNA. Tumor mutation burden (TMB) has been associated with cancer immunotherapeutic response. In this study, we attempted to explore the correlation between TMB and cancer prognosis. Identify the different expressed genes and immune cell infiltration signatures between low and high TMB group. Mutation data, gene expression profiles and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high and low TMB groups, allowing differentially expressed genes (DEGs) to be identified. Functional enrichment and protein-protein interaction (PPI) network analysis were used to identify the functions of the DEGs. And immune cell infiltration signatures were evaluated by CIBERSORT algorithm. These results shown that high TMB was significantly associated with prognosis. We obtained a list of TMB related genes which may influence the infiltrations of immune cells. We also found a higher proportion of CD8 T cells, CD4 T cells and NK cells in the high TMB group. Our data suggest that higher TMB tends to promote the infiltrations of T cells and NK cells and patients with higher TMB may achieve a more favorable prognosis in bladder cancer.
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Biomarcadores de Tumor/genética , Quimiocina CXCL10/genética , Proteínas de Neoplasias/genética , Neoplasias de la Vejiga Urinaria/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Mutación/genética , Pronóstico , Transducción de Señal/genética , Transcriptoma/genética , Transcriptoma/inmunología , Carga Tumoral/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Tumor-infiltrating immune cells are closely related to the prognosis of bladder cancer. Analysis of tumor infiltrating immune cells is usually based on immunohistochemical analysis. Since many immune cell marker proteins are not specific for different immune cells, which may induce misleading or incomplete. CIBERSORT is an algorithm to estimate specific cell types in a mixed cell population using gene expression data. In this study, the CIBERSORT algorithm was used to identify the immune cell infiltration signatures. The gene expression profiles, mutation data, and clinical data were collected from The Cancer Genome Atlas (TCGA) database. Unsupervised consensus clustering was used to acquire the immune cell infiltration subtypes of bladder cancer based on the fractions of 22 immune cell types. Four immune cell clusters with different immune infiltrate and mutation characteristics were identified. In addition, this stratification has a prognostic relevance, with cluster 2 having the best outcome, cluster 1 the worst. These clusters showed distinct mRNA expression patterns. The characteristic genes in subtype cluster 1 were mainly involved in cell division, those in subtype cluster 2 were mainly related in antigen processing and presentation, those in subtype cluster 3 were mainly involved in epidermal cell differentiation, and those in subtype cluster 4 were mainly related in the humoral immune response. These differences may affect the development of the bladder cancer, the sensitivity to treatment as well as the prognosis. Through further validation, this study may contribute to the development of personalized therapy and precision medical treatments.
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Linaje de la Célula/inmunología , Genómica , Proteínas de Neoplasias/genética , Neoplasias de la Vejiga Urinaria/genética , Linfocitos B/metabolismo , Linfocitos B/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Linaje de la Célula/genética , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Genoma Humano/genética , Humanos , Mutación/genética , Proteínas de Neoplasias/inmunología , Medicina de Precisión , Pronóstico , Linfocitos T/metabolismo , Linfocitos T/patología , Neoplasias de la Vejiga Urinaria/clasificación , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
The specific regulatory mechanism of bladder urothelial barrier dysfunction after infection with uropathogenic Escherichia coli (UPEC) is still unclear. The cross talk between bladder urothelial cells and mast cells may play an important role during UPEC infection. In this study, the pyroptosis of urothelial cells was investigated after UPEC infection both in vivo and in vitro. The levels of IL-1ß and IL-18 in exosomes derived from bladder urothelial cells after UPEC infection were detected. The role of these processes in the recruitment and activation of mast cells was measured. The mechanism of mast cell-induced disruption of bladder epithelial barrier function was also assessed. We found that UPEC infection induced pyroptosis of bladder urothelial cells and led to the release of IL-1ß and IL-18 in the form of exosomes, which promoted the migration of mast cells. Tryptase secreted by mast cells aggravated the damage to the barrier function of the bladder urothelium by acting on protease-activated receptor 2 (PAR2). Inhibition of pyroptosis or the tryptase-PAR2 axis reduced the disruption of bladder urothelial barrier function and decreased the bacterial burden. The present study supports a novel mechanism by which pyroptosis-dependent release of exosomes from bladder urothelial cells activates mast cells and regulates bladder urothelial barrier function during UPEC infection.
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Infecciones por Escherichia coli/metabolismo , Exosomas/metabolismo , Mastocitos/metabolismo , Piroptosis/fisiología , Infecciones Urinarias/metabolismo , Urotelio/metabolismo , Animales , Línea Celular , Infecciones por Escherichia coli/inmunología , Exosomas/inmunología , Femenino , Humanos , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Vejiga Urinaria/inmunología , Vejiga Urinaria/metabolismo , Vejiga Urinaria/microbiología , Infecciones Urinarias/inmunología , Escherichia coli Uropatógena , Urotelio/inmunología , Urotelio/microbiologíaRESUMEN
As an important chemokine receptor, the role of CCR4 in the progression of bladder cancer (BC) remains unknown. In this study, we have shown that CCR4 expression was upregulated in bladder carcinoma tissues compared with adjacent nontumor tissues. Kaplan-Meier survival analysis revealed that CCR4 expression was an independent prognostic risk factor in BC patients, and the addition of CCL17 induced CCR4 production and promoted migration and invasion of BC cells. In addition, CCR4 knockdown significantly attenuated the migratory and invasive capabilities of BC cells. Mechanistically, CCL17-CCR4 axis is involved in ERK1/2 signaling and could mediate the migration and invasion of BC cells by regulating MMP13 activation. This study suggests that CCR4 might represent a promising prognostic biomarker and a potential therapeutic option for BC.
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The etiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still unknown. Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to play an important role in the development of autoimmune and inflammatory diseases. Here, we investigated the expression and function of GM-CSF in patients with CP/CPPS and in a mouse model of experimental autoimmune prostatitis (EAP). GM-CSF mRNA levels were detected in expressed prostatic secretions samples from patients with CP/CPPS and in prostate tissue from a mouse model of EAP. The expression of GM-CSF receptor in mouse prostate and dorsal root ganglia were determined using PCR and immunohistochemistry. Behavioral testing and inflammation scoring were performed to evaluate the role of GM-CSF in disease development and symptom severity of EAP using GM-CSF knockout mice. mRNA levels of putative nociceptive and inflammatory markers were measured in the prostate after the induction of EAP. Elevated GM-CSF mRNA levels were observed in expressed prostatic secretions samples from patients with CP/CPPS compared with healthy volunteers. GM-CSF mRNA was also significantly increased in prostate tissue of the EAP mice model. The expression of GM-CSF receptors was confirmed in mouse prostate and dorsal root ganglia. GM-CSF knockout mice showed fewer Infiltrating leukocytes and pain symptoms after the induction of EAP. Deletion of GM-CSF significantly diminished EAP-induced increases of chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 3, and nerve growth factor mRNA expression. The results indicated that GM-CSF plays a functional role in the pathogenesis of EAP. GM-CSF may function as a signaling mediator for both inflammation and pain transduction in CP/CPPS.
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Enfermedades Autoinmunes/fisiopatología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Prostatitis/inmunología , Animales , Enfermedades Autoinmunes/etiología , Dolor Crónico , Modelos Animales de Enfermedad , Ganglios Espinales/química , Ganglios Espinales/metabolismo , Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Humanos , Masculino , Ratones , Ratones Noqueados , Dolor Pélvico , Próstata/química , Próstata/metabolismo , Prostatitis/fisiopatología , ARN Mensajero/análisis , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/análisis , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Semen/químicaRESUMEN
Histidine works as an important mediator in the charge transport process through proteins via its conjugate side group. It can also stabilize a peptide's secondary structure through hydrogen bonding of the imidazole group. In this study, the conformation of the self-assembled monolayer (SAM) and the charge transport of the tailor-made oligopeptide hepta-histidine derivative (7-His) were modulated through the pH control of the assembly environment. Histidine is found to be an efficient tunneling mediator in monolayer junctions with an attenuation factor of ß = â¼0.5 Å-1. Successful theoretical model fitting indicates a linear increase in the number of tunneling sites as the 7-His SAM thickness increases, following the deprotonation of histidine. Combined with the ultraviolet photoelectron spectroscopy (UPS) measurements, a modulable charge transport pathway through 7-His with imidazole groups of histidine as tunneling foot stones is revealed. Histidine therefore possesses a large potential for modulable functional (bio)electronic devices.
RESUMEN
A novel surface plasmon resonance (SPR) biosensor based on Ag-Au bimetallic films with a hybrid structure of blue phosphorene (BlueP)/transition metal dichalcogenides (TMDCs) and graphene is presented. In order to improve the sensitivity, the thickness of silver and gold films is optimized to achieve minimum reflectivity and an adequate level of sensitivity; further, sensitivity for the monolayer BlueP/MoS2 and graphene structure is enhanced by 19.73%, with respect to a traditional sensor. Besides, the effect of layers of different Blue/TMDCs heterostructures to the sensitivity of the SPR biosensor is investigated, and the highest sensitivity with 335.4°/RIU for the bilayer BlueP/WS2 is obtained. Furthermore, distributions of the electric field and the changes of resonance angle to the refractive index of the sensing medium and prism in the visible regime are illustrated at optimal configuration. In virtue of highly sensitive characteristics, the proposed sensor structure will be a much better option to be employed for further biological detection.