Cell membrane coated nanoparticles (NPs) have recently been recognized as attractive nanomedical tools because of their unique properties such as immune escape, long blood circulation time, specific ...molecular recognition and cell targeting. However, the integrity of the cell membrane coating on NPs, a key metrics related to the quality of these biomimetic-systems and their resulting biomedical function, has remained largely unexplored. Here, we report a fluorescence quenching assay to probe the integrity of cell membrane coating. In contradiction to the common assumption of perfect coating, we uncover that up to 90% of the biomimetic NPs are only partially coated. Using in vitro homologous targeting studies, we demonstrate that partially coated NPs could still be internalized by the target cells. By combining molecular simulations with experimental analysis, we further identify an endocytic entry mechanism for these NPs. We unravel that NPs with a high coating degree (≥50%) enter the cells individually, whereas the NPs with a low coating degree (<50%) need to aggregate together before internalization. This quantitative method and the fundamental understanding of how cell membrane coated NPs enter the cells will enhance the rational designing of biomimetic nanosystems and pave the way for more effective cancer nanomedicine.
Growing up on a farm is associated with an asthma-protective effect, but the mechanisms underlying this effect are largely unknown. In the Protection against Allergy: Study in Rural Environments ...(PASTURE) birth cohort, we modeled maturation using 16S rRNA sequence data of the human gut microbiome in infants from 2 to 12 months of age. The estimated microbiome age (EMA) in 12-month-old infants was associated with previous farm exposure (β = 0.27 (0.12-0.43), P = 0.001, n = 618) and reduced risk of asthma at school age (odds ratio (OR) = 0.72 (0.56-0.93), P = 0.011). EMA mediated the protective farm effect by 19%. In a nested case-control sample (n = 138), we found inverse associations of asthma with the measured level of fecal butyrate (OR = 0.28 (0.09-0.91), P = 0.034), bacterial taxa that predict butyrate production (OR = 0.38 (0.17-0.84), P = 0.017) and the relative abundance of the gene encoding butyryl-coenzyme A (CoA):acetate-CoA-transferase, a major enzyme in butyrate metabolism (OR = 0.43 (0.19-0.97), P = 0.042). The gut microbiome may contribute to asthma protection through metabolites, supporting the concept of a gut-lung axis in humans.
Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today
. The asthma-protective effect of farms appears to be ...associated with rich home dust microbiota
, which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts
that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children
and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.
Cell membrane (CM) coating technology is increasingly being applied in nanomedicine, but the entire coating procedure including adsorption, rupture, and fusion is not completely understood. ...Previously, we showed that the majority of biomimetic nanoparticles (NPs) were only partially coated, but the mechanism underlying this partial coating remains unclear, which hinders the further improvement of the coating technique. Here, we show that partial coating is an intermediate state due to the adsorption of CM fragments or CM vesicles, the latter of which could eventually be ruptured under external force. Such partial coating is difficult to self-repair to achieve full coating due to the limited membrane fluidity. Building on our understanding of the detailed coating process, we develop a general approach for fixing the partial CM coating: external phospholipid is introduced as a helper to increase CM fluidity, promoting the final fusion of lipid patches. The NPs coated with this approach have a high ratio of full coating (~23%) and exhibit enhanced tumor targeting ability in comparison to the NPs coated traditionally (full coating ratio of ~6%). Our results provide a mechanistic basis for fixing partial CM coating towards enhancing tumor accumulation.
IMPORTANCE: Atopic dermatitis is an inflammatory, pruritic skin disease that often occurs in early infancy with a chronic course. However, a specific description of subtypes of atopic dermatitis ...depending on the timing of onset and progression of the disease in childhood is lacking. OBJECTIVE: To identify different phenotypes of atopic dermatitis using a definition based on symptoms before age 6 years and to determine whether some subtypes are more at risk for developing other allergic diseases. DESIGN, SETTING, AND PARTICIPANTS: The Protection Against Allergy Study in Rural Environments (PASTURE) is a European birth cohort where pregnant women were recruited between August 2002 and March 2005 and divided in 2 groups dependent on whether they lived on a farm. Children from this cohort with data on atopic dermatitis from birth to 6 years of age were included. EXPOSURES: Atopic dermatitis, defined as an itchy rash on typical locations from birth to 6 years. MAIN OUTCOMES AND MEASURES: The latent class analysis was used to identify subtypes of atopic dermatitis in childhood based on the course of symptoms. Multivariable logistic regressions were used to analyze the association between atopic dermatitis phenotypes and other allergic diseases. RESULTS: We included 1038 children; of these, 506 were girls. The latent class analysis model with the best fit to PASTURE data separated 4 phenotypes of atopic dermatitis in childhood: 2 early phenotypes with onset before age 2 years (early transient n = 96; 9.2% and early persistent n = 67; 6.5%), the late phenotype with onset at age 2 years or older (n = 50; 4.8%), and the never/infrequent phenotype (n = 825; 79.5%), defined as children with no atopic dermatitis. Children with both parents with history of allergies were 5 times more at risk to develop atopic dermatitis with an early-persistent phenotype compared with children with parents with no history of allergies. Both early phenotypes were strongly associated with food allergy. The risk of developing asthma was significantly increased among the early-persistent phenotype (adjusted odds ratio, 2.87; 95% CI, 1.31-6.31). The late phenotype was only positively associated with allergic rhinitis. CONCLUSIONS AND RELEVANCE: Using latent class analysis, 4 phenotypes of atopic dermatitis were identified depending on the onset and course of the disease. The prevalence of asthma and food allergy by 6 years of age was strongly increased among children with early phenotypes (within age 2 years), especially with persistent symptoms. These findings are important for the development of strategies in allergy prevention.
Display omitted
•Higher greenness levels around school were associated with lower prevalence of asthma and wheeze in schoolchildren.•The protective association was stronger in children living in high ...air polluted areas.•The observed association was mediated by air pollution level and doctor-diagnosed allergy symptom.
There is increasing interest in the effect of residential greenness on respiratory health in children with inconsistent results. However, there are no studies investigating the association between greenness around schools, a representative environment for children and childhood asthma.
To investigate the association between greenness surrounding schools and asthma in schoolchildren.
We recruited 59,754 schoolchildren from 94 schools in 2012–2013 from the Seven Northeast Cities Study, China. Greenness surrounding schools was measured using the normalized difference vegetation index (NDVI) and soil adjusted vegetation index (SAVI) at buffers from 30 to 1000 m. Asthma symptoms were collected from validated self-reported questionnaires. Logistic mixed-effects regression models were used to estimate the associations between greenness surrounding school and childhood asthma after adjustment for covariates.
We found that greenness surrounding schools in all buffered sizes was negatively associated with the prevalence of asthmatic symptoms in schoolchildren. A 0.1-unit increase in NDVI1000m was associated with lower odds of current asthma (odds ratio: 0.81, 95% confidential interval: 0.75, 0.86) and current wheeze (OR: 0.89, 95% CI: 0.84, 0.94) in children after covariate adjustments. Higher greenness was associated with less asthma symptoms in a dose-response pattern (P for trend < 0.05). The estimated associations appeared to be stronger in children exposure to higher air pollution level. The observed associations varied across seven cities.
Our findings suggest beneficial associations of greenness surrounding schools with childhood asthma. Further studies are needed to confirm our results.
Recent research indicates that exposure to pollen increases the risk and severity of respiratory infections, while studies also suggest that it may possess a protective function. Our aim was to ...investigate how exposure to common pollen modifies airway cells’ responses to viral- or bacterial-like challenges and vice versa. Cocultured A549 and THP-1 cells were exposed to three doses of four different pollens (Alnus glutinosa, Betula pendula, Phleum pratense, or Ambrosia artemisiifolia) and subsequently to Toll-like receptor (TLR) ligands mimicking bacterial and viral challenges (TLR3, TLR4, TLR7/8). The stimulation experiment was replicated in reverse order. Toxicological and immunological end points were analyzed. When cells were primed with pollen, especially with grass (P. pratense) or weed (A. artemisiifolia), the ability of cells to secrete cytokines in response to bacterial- and viral-like exposure was decreased. In contrast, cells primed with viral ligand TLR7/8 showed greater cytokine responses against pollen than cells exposed to ligands or pollen alone. Our results suggest that pollen exposure potentially weakens immune reactions to bacterial- or viral-like challenges by modulating cytokine production. They also indicate that TLR7/8-mediated viral challenges could elicit exaggerated immune responses against pollen. Both mechanisms could contribute to the acceleration and complication of infections during the pollen season.
•Long-term PM1 and PM2.5 exposure can lead to decreased lung function in children.•Association of PM1 with children's lung function are larger than PM2.5.•PM1 and PM2.5 are associated with children’s ...large/small airways in early/late life.
Experimental data suggests that PM1 is more toxic than PM2.5 although the epidemiologic evidence suggests that the health associations are similar. However, few objective exposure data are available to compare the associations of PM1 and PM2.5 with children lung function. Our objectives are a) to evaluate associations between long-term exposure to PM1, PM2.5 and children’s lung function, and b) to compare the associations between PM1 and PM2.5. From 2012 to 2013, we enrolled 6,740 children (7–14 years), randomly recruited from primary and middle schools located in seven cities in northeast China. We measured lung function including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), and maximal mid-expiratory flow (MMEF) utilizing two portable electronic spirometers. We dichotomized continuous lung function measures according the expected values for gender and age. The spatial resolution at which PM1 and PM2.5 estimated were estimated using a machine learning method and the temporal average concentrations were averaged from 2009 to 2012. A multilevel regression model was used to estimate the associations of PM1, PM2.5 exposure and lung function measures, adjusted for confounding factors. Associations with lower lung function were consistently larger for PM1 than for PM2.5. Adjusted odds ratios (OR) per interquartile range greater PM1 ranged from 1.53 for MMEF (95% confidence interval CI: 1.20–1.96) to 2.14 for FEV1 (95% CI: 1.66–2.76) and ORs for PM2.5 ranged from 1.36 for MMEF (95%CI: 1.12–1.66) to 1.82 for FEV1 (95%CI: 1.49–2.22), respectively. PM1 and PM2.5 had significant associations with FVC and FEV1 in primary school children, and on PEF and MMEF in middle school children. Long-term PM1 and PM2.5 exposure can lead to decreased lung function in children, and the associations of PM1 are stronger than PM2.5. Therefore, PM1 may be more hazardous to children’s respiratory health than PM2.5 exposure.
Background Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection. Objectives To investigate associations ...between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families. Methods Supernatants from phorbol 12-myristate 13-acetate/ionomycin–stimulated CB mononuclear cells were assessed for the production of IFN-γ, TNF-α, IL-5, IL-10, and IL-12. Results Significantly higher levels of IFN-γ and TNF-α in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-γ and TNF-α in umbilical blood. Conclusion Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth.
Background European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still ...not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells. Objective We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant. Methods From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4+ CD25+ forkhead box protein 3 (FOXP3)+ (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctor's diagnosis. Results Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4+ CD25+ , FOXP3+ T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells. Conclusions Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases.
PDF
