Summary
What is known and objectives
Different population pharmacokinetics (PPK) models of tacrolimus have been established in various populations. However, the tacrolimus PPK model in paediatric ...systemic lupus erythematosus (PSLE) is still undefined. This study aimed to establish the tacrolimus PPK model in Chinese PSLE.
Methods
A total of nineteen Chinese patients with PSLE from real‐world study were characterized with nonlinear mixed‐effects modelling (NONMEM). The impact of demographic features, biological characteristics, and concomitant medications was evaluated. Model validation was assessed by bootstrap and prediction‐corrected visual predictive check (VPC).
Results
A one‐compartment model with first‐order absorption and elimination was determined to be the most suitable model in PSLE. The typical values of apparent oral clearance (CL/F) and the apparent volume of distribution (V/F) in the final model were 2.05 L/h and 309 L, respectively. Methylprednisolone and simvastatin were included as significant.
What is new and conclusion
The first validated tacrolimus PPK model in patients with PSLE is presented.
The first tacrolimus population pharmacokinetics model in patients with paediatric systemic lupus erythematosus
Abstract
Bladder cancer (BLCA) is one of the most frequent genitourinary cancers, with a high rate of morbidity and mortality. The connection of m6A-related lncRNAs with PD-L1 and tumor immune ...microenvironment (TIME) in BLCA prognosis was extensively investigated in this study, which could suggest novel therapeutic targets for further investigation. 30 m6A-associated lncRNAs with predictive values from the TCGA data set were identified with co-expression analysis. Cluster2 was correlated with a poor prognosis, upregulated PD-L1 expression, and higher immune ratings. Cluster2 had larger amounts of resting CD4 memory-activated T cells, M2 macrophages, neutrophils, and NK cells infiltration. “CHEMOKINE SIGNALING PATHWAY” was the most significantly enriched signaling pathway according to GSEA, which may play an important role in the different immune cell infiltrates between cluster1/2. The risk model for m6A-related lncRNAs could be employed in a prognostic model to predict BLCA prognosis, regardless of other clinical features. Collectively, m6A-related lncRNAs were linked to PD-L1 and TIME, which would dynamically affect the number of tumor-infiltrating immune cells. m6A-related lncRNAs may be key mediators of PD-L1 expression and immune cells infiltration and may strongly affect the TIME of BLCA.
The astrocyte odyssey Wang, Doris D; Bordey, Angélique
Progress in neurobiology,
12/2008, Letnik:
86, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Neurons have long held the spotlight as the central players of the nervous system, but we must remember that we have equal numbers of astrocytes and neurons in the brain. Are these cells only filling ...up the space and passively nurturing the neurons, or do they also contribute to information transfer and processing? After several years of intense research since the pioneer discovery of astrocytic calcium waves and glutamate release onto neurons in vitro, the neuronal-glial studies have answered many questions thanks to technological advances. However, the definitive in vivo role of astrocytes remains to be addressed. In addition, it is becoming clear that diverse populations of astrocytes coexist with different molecular identities and specialized functions adjusted to their microenvironment, but do they all belong to the umbrella family of astrocytes? One population of astrocytes takes on a new function by displaying both support cell and stem cell characteristics in the neurogenic niches. Here, we define characteristics that classify a cell as an astrocyte under physiological conditions. We will also discuss the well-established and emerging functions of astrocytes with an emphasis on their roles on neuronal activity and as neural stem cells in adult neurogenic zones.
Precision nutrition aims to prevent and manage chronic diseases by tailoring dietary interventions or recommendations to one or a combination of an individual's genetic background, metabolic profile, ...and environmental exposures. Recent advances in genomics, metabolomics, and gut microbiome technologies have offered opportunities as well as challenges in the use of precision nutrition to prevent and manage type 2 diabetes. Nutrigenomics studies have identified genetic variants that influence intake and metabolism of specific nutrients and predict individuals' variability in response to dietary interventions. Metabolomics has revealed metabolomic fingerprints of food and nutrient consumption and uncovered new metabolic pathways that are potentially modified by diet. Dietary interventions have been successful in altering abundance, composition, and activity of gut microbiota that are relevant for food metabolism and glycaemic control. In addition, mobile apps and wearable devices facilitate real-time assessment of dietary intake and provide feedback which can improve glycaemic control and diabetes management. By integrating these technologies with big data analytics, precision nutrition has the potential to provide personalised nutrition guidance for more effective prevention and management of type 2 diabetes. Despite these technological advances, much research is needed before precision nutrition can be widely used in clinical and public health settings. Currently, the field of precision nutrition faces challenges including a lack of robust and reproducible results, the high cost of omics technologies, and methodological issues in study design as well as high-dimensional data analyses and interpretation. Evidence is needed to support the efficacy, cost-effectiveness, and additional benefits of precision nutrition beyond traditional nutrition intervention approaches. Therefore, we should manage unrealistically high expectations and balance the emerging field of precision nutrition with public health nutrition strategies to improve diet quality and prevent type 2 diabetes and its complications.
Americans have a shorter life expectancy compared with residents of almost all other high-income countries. We aim to estimate the impact of lifestyle factors on premature mortality and life ...expectancy in the US population.
Using data from the Nurses' Health Study (1980-2014; n=78 865) and the Health Professionals Follow-up Study (1986-2014, n=44 354), we defined 5 low-risk lifestyle factors as never smoking, body mass index of 18.5 to 24.9 kg/m
, ≥30 min/d of moderate to vigorous physical activity, moderate alcohol intake, and a high diet quality score (upper 40%), and estimated hazard ratios for the association of total lifestyle score (0-5 scale) with mortality. We used data from the NHANES (National Health and Nutrition Examination Surveys; 2013-2014) to estimate the distribution of the lifestyle score and the US Centers for Disease Control and Prevention WONDER database to derive the age-specific death rates of Americans. We applied the life table method to estimate life expectancy by levels of the lifestyle score.
During up to 34 years of follow-up, we documented 42 167 deaths. The multivariable-adjusted hazard ratios for mortality in adults with 5 compared with zero low-risk factors were 0.26 (95% confidence interval CI, 0.22-0.31) for all-cause mortality, 0.35 (95% CI, 0.27-0.45) for cancer mortality, and 0.18 (95% CI, 0.12-0.26) for cardiovascular disease mortality. The population-attributable risk of nonadherence to 5 low-risk factors was 60.7% (95% CI, 53.6-66.7) for all-cause mortality, 51.7% (95% CI, 37.1-62.9) for cancer mortality, and 71.7% (95% CI, 58.1-81.0) for cardiovascular disease mortality. We estimated that the life expectancy at age 50 years was 29.0 years (95% CI, 28.3-29.8) for women and 25.5 years (95% CI, 24.7-26.2) for men who adopted zero low-risk lifestyle factors. In contrast, for those who adopted all 5 low-risk factors, we projected a life expectancy at age 50 years of 43.1 years (95% CI, 41.3-44.9) for women and 37.6 years (95% CI, 35.8-39.4) for men. The projected life expectancy at age 50 years was on average 14.0 years (95% CI, 11.8-16.2) longer among female Americans with 5 low-risk factors compared with those with zero low-risk factors; for men, the difference was 12.2 years (95% CI, 10.1-14.2).
Adopting a healthy lifestyle could substantially reduce premature mortality and prolong life expectancy in US adults.
Background
IL‐25 has been proposed to play a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the association of IL‐25 with the ...Th2‐biased inflammatory profiles in CRSwNP.
Methods
Nasal polyp (NP) tissues and control uncinate process tissues were collected from 92 patients with CRSwNP, 20 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 16 normal control subjects. IL‐25 expression was examined using immunohistochemistry and immunofluorescence staining, flow cytometry, RT‐qPCR, and ELISA. The inflammatory profiles and clinical characteristics of 2 NP subtypes (IL‐25high and IL‐25low) were evaluated, and the effects of IL‐25 on Th2 cytokine production in cultured dispersed polyp cells were examined in vitro.
Results
The mRNA and protein levels of IL‐25 were significantly increased in the polyp tissues compared with the control uncinate process tissues. The IL‐25high subtype showed greater computed tomography scores, endoscopic scores, and Th2 response. Exposure to IL‐25 activated type 2 innate lymphoid cells and Th2 cells in NP simultaneously which further increased Th2 cytokine production in vitro.
Conclusions
Local IL‐25 plays a crucial role in promoting Th2‐biased inflammatory profiles in NP and may serve as a promising therapeutic target in CRSwNP patients.
To cite this article: Xu G, Zhang L, Wang DY, Xu R, Liu Z, Han DM, Wang XD, Zuo KJ, Li HB. Opposing roles of IL-17A and IL-25 in the regulation of TSLP production in human nasal epithelial cells. ...Allergy 2010; 65: 581-589. The importance of IL-17A, IL-17F, and IL-25 in allergic rhinitis (AR), as well as their possible role in regulation on thymic stromal lymphopoietin (TSLP) production in nasal epithelial cells, is not well understood. To determine the possible regulation of IL-17A, IL-17F, and IL-25 on TSLP production in the initiation of allergic responses. The levels of IL-17A, IL-17F, IL-25, and TSLP in nasal lavages of patients with AR were measured using an enzyme-linked immunosorbent assay (ELISA) and compared with that in normal controls. Then, primary human nasal epithelial cells (HNECs) were stimulated with dsRNA (0-75 μg/ml), as well as IL-17A (100 ng/ml), IL-17F (100 ng/ml), and IL-25(100 ng/ml). The mRNA expression of IL-17A, IL-17F, IL-25, TSLP, as well as the chemokines CCL20, IL-8, and eotaxin was analyzed using quantitative real-time PCR, and their protein levels in the supernatants of cultured HNECs were determined by ELISA. Both TSLP and IL-17 cytokines are significantly elevated in patients with AR. dsRNA was found to increase the production of IL-17F, IL-25, TSLP, CCL20, and IL-8 in HNECs. Furthermore, IL-25 significantly enhanced dsRNA-induced TSLP production in primary HNECs and was dominant to the inhibitory effect of IL-17A on TSLP regulation. Our study provides the first evidence that both IL-17F and IL-25 can be induced by dsRNA in HNECs. Despite of the opposing effects of IL-17A and IL-25 on TSLP regulation in HNECs, IL-25 was dominant to IL-17A, providing a plausible explanation for the simultaneous upregulation of IL-17 cytokines and TSLP in patients with AR.
Highlights • Guanabenz extended the lifespan of SOD1 G93A mice. • Guanabenz delayed the disease onset of SOD1 G93A mice. • Guanabenz improved motor performance in SOD1 G93A mice. • Guanabenz ...attenuated motor neuron loss in SOD1 G93A mice. • Guanabenz attenuated ER stress and mitochondrial stress.
The relationship between microstructure and crack arrest characteristics of a microalloyed steel with a yield strength of 460 MPa was elucidated in this study with particular focus on the effect of ...the microstructure on the propagation of brittle cracks. The study emphasized that the acicular ferrite (AF) content could be increased to 41% by lowering the final rolling temperature and final cooling temperature, which reduces the average effective grain size (EGS) to as small as ~4.1 μm and increases the high-angle grain boundaries (HAGB) proportion to as high as ~48.8%. The presence of AF in large numbers could reduce the ductile-to-brittle transition temperature to approximately −87 °C through refinement of the microstructure. The presence of HAGB between adjacent grains could significantly arrest cracks by changing the propagation direction of brittle cracks and was a decisive factor in determining the characteristics of brittle fracture. Moreover, the fracture roughness varied directly with the proportion of the HAGB and inversely with the average EGS. Martensite/austenite islands with low content (0.92%) and small size (~1.5 μm) reduced the stress concentration significantly at the crack tip. The excellent crack arrestability was attributed to AF, which minimized the expansion of cleavage facets by the split nail effect ahead of the growth direction, so that the cleavage facets were divided into two or more branches, considerably reducing the stress concentration and retarding brittle crack growth during crack propagation at low ambient temperature.
The Advanced Small Analyzer for Neutrals (ASAN) is a compact mass resolving energetic neutral atom analyzer flown on the Yutu-2 rover of the Chinese Chang’E-4 mission to the Moon. ASAN measures ...energetic neutral atoms in the energy range from 10 eV to 10 keV with typically 30% energy resolution. The field-of-view is a single angular pixel of 37° × 30° pointing at lunar surface. Energetic neutral atoms enter the instrument through a charge particle deflection system and are then ionized on a diamond-like carbon conversion surface. Positive ions from the conversion surface are energy analyzed using an electrostatic analyzer and their velocity is subsequently determined in a time-of-flight section using ceramic channel electron multipliers as detectors. The obtained mass resolution m/
Δ
m is about 2, comfortably separating neutral hydrogen, helium, and the oxygen-group (≥16 amu). A full energy spectrum for energetic neutral atoms is obtained in 3 seconds. Switching the charged particle deflection system off, ASAN also directly measures positive ions with similar performance as for energetic neutral atoms. Including electronics the instrument weighs 970 g and consumes 3.4 W.
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