RESUMEN
Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned periodically by microtubule inner proteins (MIPs). Here we present an atomic model of the 48-nm repeat of a mammalian DMT, derived from a cryoelectron microscopy (cryo-EM) map of the complex isolated from bovine respiratory cilia. The structure uncovers principles of doublet microtubule organization and features specific to vertebrate cilia, including previously unknown MIPs, a luminal bundle of tektin filaments, and a pentameric dynein-docking complex. We identify a mechanism for bridging 48- to 24-nm periodicity across the microtubule wall and show that loss of the proteins involved causes defective ciliary motility and laterality abnormalities in zebrafish and mice. Our structure identifies candidate genes for diagnosis of ciliopathies and provides a framework to understand their functions in driving ciliary motility.
Asunto(s)
Cilios/ultraestructura , Microscopía por Crioelectrón , Mamíferos/metabolismo , Proteínas/metabolismo , Proteínas/ultraestructura , Secuencia de Aminoácidos , Animales , Bovinos , Cilios/metabolismo , Dineínas/metabolismo , Embrión de Mamíferos/metabolismo , Femenino , Masculino , Ratones Endogámicos C57BL , Proteínas de Microtúbulos/química , Microtúbulos/metabolismo , Microtúbulos/ultraestructura , Modelos Moleculares , Mutación/genética , Tráquea/anatomía & histología , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Pulmón/patología , Macrófagos Alveolares/metabolismo , Células Epiteliales Alveolares/metabolismo , Animales , Apoptosis/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Chaperón BiP del Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico/fisiología , Femenino , Homeostasis , Inflamación , Péptidos y Proteínas de Señalización Intercelular/fisiología , Pulmón/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Fagocitosis/fisiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfisema Pulmonar/metabolismo , Humo/efectos adversos , Fumar/efectos adversos , Nicotiana/efectos adversosRESUMEN
A noninvasive sampling technology was conceived, employing a disposable acupuncture needle in conjunction with high-resolution mass spectrometry (termed as noninvasive direct sampling extractive electrospray ionization mass spectrometry, NIDS-EESI-MS) to scrutinize the epidermal mucus of Nile tilapia for insights into the metabolic dysregulation induced by polypropylene nano- and microplastics. This analytical method initiates with the dispensing of an extraction solvent onto the needles coated with the mucus sample, almost simultaneously applying a high voltage to generate analyte ions. This innovative strategy obliterates the necessitation for laborious sample preparation, thereby simplifying the sampling process. Employing this technique facilitated the delineation of a plethora of metabolites, encompassing, but not confined to, amino acids, peptides, carbohydrates, ketones, fatty acids, and their derivatives. Follow-up pathway enrichment analysis exposed notable alterations within key metabolic pathways, including the biosynthesis of phenylalanine, tyrosine, and tryptophan, lysine degradation, as well as the biosynthesis and metabolism of valine, leucine, and isoleucine pathways in Nile tilapia, consequent to increased concentrations of polypropylene nanoplastics. These metabolic alterations portend potential implications such as immune suppression, among other deleterious outcomes. This trailblazing application of this methodology not only spares aquatic life from sacrifice but also inaugurates an ethical paradigm for conducting longitudinal studies on the same organisms, facilitating detailed investigations into the long-term effects of environmental pollutants. This technique enhances the ability to observe and understand the subtle yet significant impacts of such contaminants over time.
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Cíclidos , Microplásticos , Moco , Polipropilenos , Animales , Microplásticos/análisis , Polipropilenos/química , Cíclidos/metabolismo , Moco/metabolismo , Moco/química , Epidermis/metabolismo , Epidermis/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
BACKGROUND: The significant death rate of glioblastoma is well-known around the world. The link between gut microbiota and glioma is becoming more studied. The goal of this study was to look at the relationships between intestinal flora and glioblastoma, and to provide a new perspective for the diagnosis as well as treatment of glioblastoma. METHODS: Fecal samples from 80 participants with glioblastoma (n = 40) and healthy individuals (n = 40) in this study were collected as well as analyzed utilizing 16S rRNA gene amplicon sequencing in order to characterize the gut microbial community. RESULTS: Each group has its own microbial community, and the microbial environment of glioblastoma patients had lower richness and evenness. The structure of gut microbiota community in glioblastoma patients showed profound changes, which includes the increase of pathogens in Fusobacteria and Bacteroidetes, and the reduction of probiotic bacteria in Firmicutes, Actinobacteria and Verrucomicrobia. Meanwhile, the significant correlations and clustering of OTUS (operational taxonomic units) in glioblastoma patients were discovered, and a biomarker panel (Fusobacterium, Escherichia/Shigella, Ruminococcus gnavus group, Lachnospira, Akkermansia, Parasutterella) had been used to discriminate the patients with glioblastoma from the healthy subjects (AUC: 0.80). Furthermore, the glioblastoma group exhibited multiple disturbed pathways through KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis, particularly in genetic information processing. Moreover, the prediction of phenotypic characteristics of microbiome proposed that the glioblastoma patients might have more Gram-negative bacteria and opportunistic pathogens than the healthy controls. CONCLUSIONS: When compared to healthy people, glioblastoma sufferers have a different host-microbe interaction. Furthermore, certain types of intestinal flora could be regarded as biomarkers and drug targets for the diagnosis as well as treatment of glioblastomas.
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Bacterias , Disbiosis , Heces , Microbioma Gastrointestinal , Glioblastoma , ARN Ribosómico 16S , Humanos , Glioblastoma/microbiología , Microbioma Gastrointestinal/genética , Disbiosis/microbiología , ARN Ribosómico 16S/genética , Heces/microbiología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Masculino , Persona de Mediana Edad , Medición de Riesgo , Femenino , Biomarcadores , Adulto , Anciano , Estudios de Casos y ControlesRESUMEN
OBJECTIVE: This study aimed to construct and validate a simple and accurate clinical nomogram for predicting the occurrence of post-percutaneous nephrolithotomy sepsis, aiming to assist urologists in the early identification, warning, and early intervention of urosepsis, and to provide certain evidence-based medicine basis. METHODS: This study included patients who underwent PCNL surgery due to kidney or upper ureteral stones at the Department of Urology, Affiliated Hospital of Zunyi Medical University, from January 2019 to September 2022. This study utilized univariate and multivariate logistic regression analysis to screen and evaluate the risk factors for sepsis and construct a predictive model. An evaluation was performed using the receiver operating characteristic curve, calibration curve, and decision curve analysis curve. All statistical analyses were conducted using R version 4.2. RESULTS: A total of 946 patients who underwent post-PCNL were included in this study, among whom 69 patients (7.29%) developed post-PCNL urinary sepsis. Multiple-factor logistic regression analysis identified four independent risk factors associated with post-PCNL urinary sepsis, including positive urinary nitrite (OR = 5.9, P < 0.001), positive urine culture (OR = 7.54, P < 0.001), operative time ≥ 120 min (OR = 20.93, P = 0.0052), and stone size ≥ 30 mm (OR = 13.81, P = 0.0015). The nomogram model demonstrated good accuracy with an AUC value of 0.909, and in the validation cohort, the AUC value was 0.922. The calibration curve indicated a better consistency between the predictive line chart and the actual occurrence of post-PCNL urinary sepsis. The decision curve analysis curve showed favorable clinical utility. CONCLUSION: Preoperative positive urine culture, positive urinary nitrite, operative time ≥ 120 min, and stone size ≥ 30 mm are independent risk factors for developing post-PCNL urinary sepsis. The constructed line chart based on these factors effectively assesses the risk of urinary sepsis in patients after PCNL.
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Cálculos Renales , Nefrolitotomía Percutánea , Sepsis , Humanos , Nefrolitotomía Percutánea/efectos adversos , Nomogramas , Nitritos , Cálculos Renales/complicaciones , Sepsis/epidemiología , Sepsis/etiología , Estudios RetrospectivosRESUMEN
Healthcare disparities are common among people living with HIV (PLWH) in China and likely impact access to HIV services. This study aimed to assess the current status of access to HIV services among PLWH and explore the correlates of service uptake using baseline data from a prospective cohort study among PLWH in Jiangsu Province. Guided by Andersen's behavioral model, univariable and multivariable logistic regressions were conducted to identify factors associated with access to HIV services. Out of 8989 eligible PLWH included in this study, 46.4% perceived difficulty in seeing a healthcare professional for HIV treatment services in 2021-2022. PLWH aged 18-34 years (adjusted odds ratio [AOR] = 1.69, 95% CI 1.32-2.15), 35-39 years (AOR = 1.33, 95% CI 1.08-1.65), identified as a bisexual/other (AOR = 1.14, 95% CI 1.01-1.29), had a college and above education (AOR = 1.32, 95% CI 1.07-1.63), and perceived moderate (AOR = 1.70, 95% CI 1.51-1.91) and severe (AOR = 2.20, 95% CI 1.94-2.49) levels of HIV stigma were more likely to perceive difficulty in seeing healthcare professionals for HIV treatment in 2021-2022. Living in northern Jiangsu was also associated with increased odds of perceiving difficulty in seeing healthcare professionals for HIV treatment (AOR = 1.12, 95% CI 1.00-1.26). These findings underscore the need for innovative solutions to eliminate the practical barriers to HIV services utilization among PLWH who are bisexual, well-educated, and effective HIV-related stigma reduction interventions.
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Infecciones por VIH , Accesibilidad a los Servicios de Salud , Aceptación de la Atención de Salud , Estigma Social , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Infecciones por VIH/epidemiología , Masculino , Adulto , Femenino , China/epidemiología , Estudios Transversales , Adolescente , Estudios Prospectivos , Aceptación de la Atención de Salud/estadística & datos numéricos , Aceptación de la Atención de Salud/psicología , Adulto Joven , Persona de Mediana Edad , Disparidades en Atención de SaludRESUMEN
Ischaemic stroke is a common condition that can lead to cerebral ischaemia-reperfusion injury. Phillygenin (PHI), a natural bioactive compound derived from Forsythia suspensa, has been shown to play a crucial role in regulating inflammation across various diseases. However, its specific regulatory effects in ischaemic stroke progression remain unclear. In this study, we established a middle cerebral artery occlusion (MCAO) rat model. Treatment with PHI (50 or 100 mg/kg) significantly reduced cerebral infarction in MCAO rats. PHI treatment also mitigated the increased inflammatory response observed in these rats. Additionally, PHI suppressed microglial activation by reducing iNOS expression, a marker of M1-type polarization of microglia, and attenuated increased brain tissue apoptosis in MCAO rats. Furthermore, PHI's anti-inflammatory effects in MCAO rats were abrogated upon co-administration with GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor. In summary, PHI attenuated microglial activation and apoptosis in cerebral ischaemia-reperfusion injury through PPARγ activation, suggesting its potential as a therapeutic agent for mitigating cerebral ischaemia-reperfusion injury.
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Apoptosis , Infarto de la Arteria Cerebral Media , Microglía , PPAR gamma , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , PPAR gamma/metabolismo , Apoptosis/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Ratas , Masculino , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , LignanosRESUMEN
As the global incidence of diabetes rises and diagnoses among younger patients increase, transplant centers worldwide are encountering more organ donors with diabetes. This study examined 80 donors and 160 recipients, including 30 donors with diabetes (DD) and their 60 recipients (DDR). The control group comprised 50 non-diabetic donors (ND) and 100 recipients (NDR). We analyzed clinical, biochemical, and pathological data for both diabetic and control groups, using logistic regression to identify risk factors for delayed graft function (DGF) after kidney transplantation. Results showed that pre-procurement blood urea nitrogen levels were significantly higher in DD [18.20 ± 10.63 vs. 10.86 ± 6.92, p = 0.002] compared to ND. Renal pathological damage in DD was notably more severe, likely contributing to the higher DGF incidence in DDR compared to NDR. Although DDR had poorer renal function during the first three months post-transplant, both groups showed similar renal function thereafter. No significant differences were observed in 1-year or 3-year mortality rates or graft failure rates between DDR and NDR. Notably, according to the Renal Pathology Society (RPS) grading system, kidneys from diabetic donors with a grade > IIb are associated with significantly lower postoperative survival rates. Recipient gender [OR: 5.452 (1.330-22.353), p = 0.013] and pre-transplant PRA positivity [OR: 34.879 (7.698-158.030), p < 0.001] were identified as independent predictors of DGF in DDR. In conclusion, transplant centers may consider utilizing kidneys from diabetic donors, provided they are evaluated pathologically, without adversely impacting recipient survival and graft failure rates.
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Funcionamiento Retardado del Injerto , Supervivencia de Injerto , Trasplante de Riñón , Complicaciones Posoperatorias , Donantes de Tejidos , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Funcionamiento Retardado del Injerto/epidemiología , Funcionamiento Retardado del Injerto/etiología , Factores de Riesgo , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Diabetes Mellitus/epidemiología , Estudios Retrospectivos , Riñón/fisiopatología , Riñón/patología , Tasa de Supervivencia , Modelos Logísticos , IncidenciaRESUMEN
OBJECTIVES: Transplant renal artery stenosis (TRAS) is now recognized as a curable disease with a good prognosis if intervention occurs in the early stage. However, the mid-term outcomes of TRAS when treated by percutaneous transluminal angioplasty with stent placement have yet to be fully elucidated. The purpose of this study was to compare mid-term graft and patient survival of TRAS group with a control group. PATIENTS AND METHODS: Ninety-two patients were diagnosed of TRAS between January 2016 and January 2022 in our center. Fifty-six pairs of recipients with grafts from the same donor were selected as a study group with TRAS and a control group without TRAS, respectively. All donor kidneys were from deceased organ donation rather than living donors. The primary endpoints were graft and patient survival. The secondary outcomes were changes in renal graft function. RESULTS: The mean follow-up time for the TRAS group was 43.6 months, while the mean follow-up time for the control group was 45.3 months. In the TRAS group, the age of patients ranged from 11 to 62 years with 39 males and 17 females. In the control group, the age of patients ranged from 18 to 67 years with 40 males and 16 females. In the TRAS group, there were more patients with diabetic nephropathy as the primary renal disease compared to the control group (5/56 vs 0/56), and the incidence of acute rejection was higher in the TRAS group than in the control group (12/56 vs 3/56). Eight patients in the TRAS group and one patient in the control group experienced graft loss (p = .019). Four patients in the TRAS group and four patients in the control group died with functional renal allograft during the follow-up time (p = .989). The levels of eGFR did not differ significantly between the two groups in the first three years after kidney transplant (p > .05). Patients in the TRAS group had worse graft functionality (eGFR, 44.96 ± 18.9 vs 54.9 ± 19.6 mL/min) in the fourth year when compared with the control group (p = .01). CONCLUSIONS: The graft function deteriorated faster, and graft survival was lower in the TRAS group treated by stent placement when compared with a control group without TRAS over the mid-term.
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Supervivencia de Injerto , Trasplante de Riñón , Obstrucción de la Arteria Renal , Stents , Humanos , Masculino , Femenino , Obstrucción de la Arteria Renal/cirugía , Obstrucción de la Arteria Renal/etiología , Obstrucción de la Arteria Renal/terapia , Obstrucción de la Arteria Renal/mortalidad , Persona de Mediana Edad , Trasplante de Riñón/efectos adversos , Adulto , Estudios Retrospectivos , Anciano , Adulto Joven , Adolescente , Niño , Cadáver , Angioplastia/métodos , Tasa de Filtración GlomerularRESUMEN
Random guessing behaviors are frequently observed in low-stakes assessments, often attributed to factors such as test-takers lacking motivation or experiencing time constraints and fatigue. Existing research suggests that responses stemming from random guessing behaviors introduce biases into the constructs and relationships of interest. This is particularly problematic when estimating the relationship between speed and ability. This study introduces a Mixture Fluency model designed to account for random guessing behaviors while utilizing valid response accuracy and response time to uncover students' latent attribute profiles. The model directly addresses a limitation present in the Fluency cognitive diagnostic model (Wang & Chen, Psychometrika, 85, 600-629, (2020), which assumes that test-takers consistently employ solution behaviors when answering questions. To investigate the effectiveness of the proposed Mixture Fluency model, we conducted a simulation study encompassing various simulation conditions. Results from this study not only confirm the model's ability to detect potential random guessing behaviors but also demonstrate its capacity to enhance the inference of targeted latent constructs within the assessment. Additionally, we showcase the practical utility of the proposed model through an application to real data.
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Tiempo de Reacción , Humanos , Tiempo de Reacción/fisiología , Cognición/fisiología , Modelos Estadísticos , Simulación por Computador , Evaluación Educacional/métodos , Modelos Psicológicos , Psicometría/métodos , Psicometría/instrumentaciónRESUMEN
BACKGROUND AND AIMS: Ischemia-reperfusion (I/R) injury is an inevitable complication of liver transplantation (LT) and compromises its prognosis. Glycosyltransferases have been recognized as promising targets for disease therapy, but their roles remain open for study in hepatic I/R (HIR) injury. Here, we aim to demonstrate the exact function and molecular mechanism of a glycosyltransferase, N-acetylgalactosaminyltransferase-4 (GALNT4), in HIR injury. APPROACH AND RESULTS: By an RNA-sequencing data-based correlation analysis, we found a close correlation between GALNT4 expression and HIR-related molecular events in a murine model. mRNA and protein expression of GALNT4 were markedly up-regulated upon reperfusion surgery in both clinical samples from subjects who underwent LT and in a mouse model. We found that GALNT4 deficiency significantly exacerbated I/R-induced liver damage, inflammation, and cell death, whereas GALNT4 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration clarified that GALNT4 directly binds to apoptosis signal-regulating kinase 1 (ASK1) to inhibit its N-terminal dimerization and subsequent phosphorylation, leading to a robust inactivation of downstream c-Jun N-terminal kinase (JNK)/p38 and NF-κB signaling. Intriguingly, the inhibitory capacity of GALNT4 on ASK1 activation is independent of its glycosyltransferase activity. CONCLUSIONS: GALNT4 represents a promising therapeutic target for liver I/R injury and improves liver surgery prognosis by inactivating the ASK1-JNK/p38 signaling pathway.
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Hígado , MAP Quinasa Quinasa Quinasa 5 , N-Acetilgalactosaminiltransferasas , Daño por Reperfusión , Animales , Apoptosis , Hígado/patología , MAP Quinasa Quinasa Quinasa 5/metabolismo , Ratones , N-Acetilgalactosaminiltransferasas/genética , Multimerización de Proteína , Daño por Reperfusión/genética , Daño por Reperfusión/prevención & control , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
Since the discovery of apoptosis signal-regulated kinase 1 (ASK1), the signal transduction mechanism and pathophysiological process involved in its regulation have been continuously revealed. Many previous studies have identified that ASK1 is involved and plays a critical role in the development of diseases affecting the nervous, cardiac, renal, and other systems. As a mitogen-activated protein kinase (MAPK) kinase kinase, ASK1 mediates apoptosis, necrosis, inflammation, and other pathological processes by activating its downstream c-Jun N-terminal kinase (JNK)/p38 MAPK. Owing to the important role of ASK1, an increasing number of studies in recent years have focused on its status in liver-related diseases. In this paper, we review the mechanisms and targets of ASK1 in liver-related diseases to emphasize its important role in the development of liver disease.
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Vías Clínicas , Hepatopatías , Humanos , Transducción de Señal/fisiología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Apoptosis/fisiología , Quinasas Quinasa Quinasa PAM/metabolismoRESUMEN
NCOA7 is a nuclear receptor coactivator that is downregulated in a variety of cancers. However, the expression and prognostic significance of NCOA7 in clear cell renal cell carcinoma (ccRCC) remain unknown. The expression of NCOA7 in ccRCC tissues was analyzed using bioinformatics analysis, Western blotting, and immunohistochemistry. Kaplan-Meier analysis, the receiver operating characteristic (ROC) curve, and clinicopathological correlation analysis were used to assess the predictive power of NCOA7. Overexpression function tests were conducted in cells and mouse models to clarify the function and mechanism of NCOA7 in inhibiting the progression of ccRCC. NCOA7 expression was downregulated in all three subtypes of renal cell carcinoma, and only had significant prognostic value for patients with ccRCC. NCOA7 overexpression inhibited the proliferation, invasion, and metastasis of ccRCC cells in vivo and in vitro. Mechanistically, NCOA7 inhibited the MAPK/ERK pathway to regulate epithelial-mesenchymal transformation (EMT) and apoptosis, thereby inhibiting the progression of ccRCC. NCOA7 inhibits tumor growth and metastasis of ccRCC through the MAPK/ERK pathway, thus indicating its potential as a prognostic marker and therapeutic target for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Ratones , Carcinoma , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Sistema de Señalización de MAP Quinasas , Transducción de Señal , HumanosRESUMEN
Migraine is the second highest cause of disability worldwide, bringing a huge socioeconomic burden. Improving mitochondrial function has promise as an effective treatment strategy for migraine. Szeto-Schiller peptide (SS-31) is a new mitochondria-targeted tetrapeptide molecule that has been shown to suppress the progression of diseases by restoring mitochondrial function, including renal disease, cardiac disease, and neurodegenerative disease. However, whether SS-31 has a therapeutic effect on migraine remains unclear. The aim of this study is to clarify the treatment of SS-31 for headache and its potential mechanisms. Here we used a mouse model induced by repeated dural infusion of inflammatory soup (IS), and examined roles of Sirt3/Pgc-1α positive feedback loop in headache pathogenesis and mitochondrial function. Our results showed that repeated IS infusion impaired mitochondrial function, mitochondrial ultrastructure and mitochondrial homeostasis in the trigeminal nucleus caudalis (TNC). These IS-induced damages in TNC were reversed by SS-31. In addition, IS-induced nociceptive responses were simultaneously alleviated. The effects of SS-31 on mitochondrial function and mitochondrial homeostasis (mainly mitochondrial biogenesis) were attenuated partially by the inhibitor of Sirt3/Pgc-1α. Overexpression of Sirt3/Pgc-1α increased the protein level of each other. These results indicated that SS-31 alleviated nociceptive responses and restored mitochondrial function in an IS-induced headache mouse model via Sirt3/Pgc-1α positive feedback loop. SS-31 has the potential to be an effective drug candidate for headache treatment.
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Trastornos Migrañosos , Enfermedades Neurodegenerativas , Sirtuina 3 , Ratones , Animales , Sirtuina 3/metabolismo , Sirtuina 3/farmacología , Retroalimentación , Enfermedades Neurodegenerativas/metabolismo , Nocicepción , Mitocondrias/metabolismo , Modelos Animales de Enfermedad , Cefalea/metabolismo , Trastornos Migrañosos/metabolismoRESUMEN
The microtubular scaffold of motile cilia-the axoneme, is decorated with dynein arms, which are large multiprotein complexes essential for ciliary motility. Dynein arms are arranged along the length of the axoneme in a precise repeating pattern, converting chemical energy from ATP hydrolysis into ciliary mechanical movement. How these complicated molecular machines are assembled coordinately and accurately, starting from mere polypeptide chains in the cytoplasm, remains a fascinating yet perplexing question. Rapidly emerging evidence, from multiple studies carried out with different model organisms and with various methodologies, has highlighted the existence of a dedicated assembly pathway. Here, we summarize recent progress made in clarifying the axonemal dynein arm assembly process, focusing on individual assembly steps, including cytoplasmic preassembly, intraflagellar transport, and axonemal docking.
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Axonema , Dineínas , Axonema/metabolismo , Transporte Biológico , Cilios/metabolismo , Citoplasma/metabolismo , Dineínas/metabolismoRESUMEN
BACKGROUND: Acute vestibular syndrome (AVS) is a common clinical syndrome in neurology clinics and emergency department. Canonical standard for AVS diagnosis requires the presence of persistent vertigo for more than 24 h. HINTS (head impulse-nystagmus-test of skew) is an emerging scheme in the diagnosis of AVS. In this prospective study, we evaluated the specificity and sensitivity of HINTS in distinguishing between central and peripheral AVS. METHODS: A cohort of 239 cases with complete clinical record was recruited in the study. All patients completed emergency brain CT examination to exclude hemorrhagic stroke. HINTS examination was conducted to distinguish between central AVS and peripheral AVS, and all patients completed head MRI, BAEP and vestibular function examinations within one week. Patients diagnosed as central AVS were subject to angiography (CTA/MRA/DSA), and patients with peripheral AVS were considered for a 3-month follow-up to correct the initial diagnosis. RESULTS: Patients with central AVS were associated with an elder age, higher incidences of hypertension, atrial fibrillation, family history of stroke and previous history of stroke. Posterior circulation cerebral infarction, vestibular migraine and cerebellitis were the dominant diseases associated with central AVS. The sensitivities of HIT, GE, and TS in the diagnosis of central AVS were 73.5%, 61.2%, and 26.5%, and the specificities were 97.9%, 92.6%, and 93.2% respectively. CONCLUSIONS: The sensitivity of HINTS for central AVS diagnosis is 89.8% and the specificity is 84.2%. HINTS is an easy-to-operate, low-cost, high-sensitivity and specific examination technique, which is practical in neurology outpatient clinics and emergency departments.
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Nistagmo Patológico , Accidente Cerebrovascular , Enfermedades Vestibulares , Enfermedad Aguda , Anciano , Humanos , Estudios Prospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Vértigo/complicaciones , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/etiologíaRESUMEN
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with no effective pharmaceutical therapies currently available. Inflammation plays a key role in the progression of aneurysms. Dexamethasone (DEX), a synthetic glucocorticoid, has showed alleviating effects on cells in vitro from TAAD patients. Here we performed a study aiming at investigating the protective role of DEX in a ß-aminopropionitrile monofumarate (BAPN)-induced TAAD mouse model. DEX (dose: 0.04 mg/kg/day) treatment significantly reduced the aortic diameter and inhibited TAAD formation. DEX reduced infiltration of macrophages and neutrophils, apoptosis of vascular smooth muscle cells (VSMCs), expression of metalloproteinase 2/9, and extracellular matrix degradation in BAPN-treated TAAD mice. Furthermore, DEX therapy downregulated the expression of p-p65 in macrophages and VSMCs, which suggested that DEX might ameliorate BAPN-induced TAAD by suppressing NF-κB signaling. Therefore, DEX therapy attenuates the progression of BAPN-induced TAAD murine model and could be used as an effective adjuvant therapy for treating TAAD.
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Aneurisma de la Aorta Torácica/tratamiento farmacológico , Disección Aórtica/tratamiento farmacológico , Dexametasona/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Aminopropionitrilo/metabolismo , Disección Aórtica/metabolismo , Animales , Aneurisma de la Aorta Torácica/metabolismo , Macrófagos/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/metabolismoRESUMEN
In industrial application, an engine group with several engines running in parallel produces emissions, and because of its variable operation conditions and the number of engines being run, it produces great pollution. This study proposes a distributed control system (DCS) method to deal with NOx emissions from a diesel engine group. This DCS method contains several diesel engine test benches in parallel, and each engine is connected to an independent DCS unit with a selective catalytic reduction (SCR) device, and the central processing unit (CPU) distributes controlling quantities to each DCS unit. A dimensionless parameter, coefficient of difficulty K, is introduced to evaluate the NOx conversion efficiency of each unit. A control algorithm adopting the minimum K as the optimization control object to distribute the real-time NOx conversion efficiency for each unit is presented. This DCS deNOx technology has been applied in 10-engine test benches in parallel, and the results show that the DCS method not only controls NOx emissions of the engine group within the emission standard limit but also exhibits a good economic performance for suitable NOx conversion efficiency distribution and economical urea injection dose. This DCS emission control method is suitable for multiple diesel engines running in parallel under conditions of varied speeds and loads.
Asunto(s)
Gasolina , Emisiones de Vehículos , Catálisis , Óxidos de Nitrógeno/análisis , TecnologíaRESUMEN
BACKGROUND: The COVID-19 pandemic seriously threatens general public health services globally. This study aimed to evaluate the impact of the COVID-19 pandemic on the HIV care continuum in Jiangsu province, China. METHODS: Data on newly diagnosed HIV persons for analysis were retrieved from Chinas' web-based Comprehensive Response Information Management System (CRIMS) for HIV/AIDS from 2016 to 2020. We recorded data for the first 3 months (January to March, 2020) of strictly implementing COVID-19 measures from publicly available disease databases of the Jiangsu provincial Health Committee. We used seasonal autoregressive integrated moving average (SARIMA) and exponential smoothing in forecasting the parameters. Subgroup differences were accessed using Chi-square tests. RESULTS: Compared to the estimated proportions, the HIV testing rates decreased by 49.0% (919,938) in the first three months of implementing COVID-19 measures. Of an estimated 1555 new HIV diagnosis expected in the same period, only 63.0% (980) new diagnoses were recorded. According to actual data recorded during the said period, 980 positively tested persons received confirmatory tests, of which 71.4% (700) were reportedly linked to care. And only 49.5% (235) out of the expected 475 newly diagnosed HIV persons received CD4 cell count testing. Meanwhile 91.6% (208) of newly diagnosed HIV persons who received CD4 count tests reportedly initiated antiretroviral therapy (ART) compared to the 227 expected. Compared to the same period from 2016 to 2019, PLWH less than 30 years old and migrants were more likely to be affected by the COVID-19 policies. CONCLUSIONS: The COVID-19 pandemic negatively impacted HIV healthcare systems in Jiangsu, China. Further measures that can counter the impact of the pandemic are needed to maintain the HIV care continuum.
Asunto(s)
COVID-19 , Continuidad de la Atención al Paciente , Infecciones por VIH , Adulto , COVID-19/epidemiología , China/epidemiología , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Masculino , Persona de Mediana Edad , PandemiasRESUMEN
BACKGROUND: Late presentation to HIV/AIDS care presents serious health concerns, like increased transmission and high healthcare costs, increased mortality, early development of opportunistic infection, increased risk of antiretroviral therapy drug resistance. Despite the effort to contain the HIV/AIDS epidemic, LP has remained an impediment to individual immune reconstitution and public health. OBJECTIVE: This review aimed to estimate the prevalence and determine the factors associated with late presentation to HIV/AIDS care. METHODS: We searched PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Wanfang, and Weipu database for articles published from 2010 to 2020. We utilized I2 statistics and Q-test to estimate heterogeneity between studies. Random-effects meta-analysis models were used to calculate the aggregate odds ratio of late presentation to HIV/AIDS care. RESULTS: Of 9563 titles and abstracts retrieved, 189 were identified as potentially eligible and 39 fulfilled the inclusion criteria. The pooled prevalence of late presentation to HIV/AIDS care was 43.26%. The major risk factors were patients ≥ 50 years old (OR = 2.19, 95% CI: 1.85-2.58; I2 = 97.44%), married (OR = 1.50, 95% CI: 1.35-1.68; I2 = 96.58%), with heterosexual contact as risk factor for infection (OR = 1.91, 95% CI: 1.73-2.11; I2 = 90.74%) and diagnosed in medical institutions (OR = 2.35,95% CI: 2.11-2.62; I2 = 96.05%). In middle or low HIV prevalence areas, patients ≥ 50 years old (P = 0.01), married (P < 0.01) and diagnosed in medical institutions (P = 0.01) were more likely to be presented late than in high prevalence areas. From 2016-2020, the OR of patients who were married and diagnosed in medical facilities were significantly lower than before (P < 0.01). CONCLUSION: Patients ≥ 50 years old, married, with heterosexual contact as risk factor for infection, and diagnosed in medical institutions were risk factors of LP. Gender had no significant relationship with LP. In middle or low prevalence areas, patients who were ≥ 50 years old, married, and diagnosed in medical institutions were more likely to be presented late than in other areas. Married patients and those diagnosed in medical institutions after 2015 have a lower risk of LP than before.