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Background Mesenchymal stromal cells-derived small extracellular vesicles (MSC-sEVs) have recently attracted considerable attention because of their therapeutic potential in various immune diseases. We previously reported that MSC-sEVs could exert immunomodulatory roles in allergic airway inflammation by regulating group 2 innate lymphoid cell (ILC2) and dendritic cell (DC) functions. Therefore, this study aimed to investigate the therapeutic effects of MSC-sEVs on mature DC (mDC)-ILC2 interplay in allergic rhinitis (AR). Methods Here, we isolated MSC-sEVs from induced pluripotent stem cells (iPSC)-MSCs using anion-exchange chromatography for the generation of sEV-mDCs. sEV-mDCs were co-cultured with peripheral blood mononuclear cells (PBMCs) from patients with AR or purified ILC2s. The levels of IL-13 and GATA3 in ILC2s were examined by flow cytometry. Bulk RNA-sequence for mDCs and sEV-mDCs was employed to further probe the potential mechanisms, which were then validated in the co-culture systems. Results sEV-mDCs showed weaker capacity in priming the levels of IL-13 and GATA3 in ILC2s when compared with mDCs. Furthermore, there was higher PGE2 and IL-10 production from sEV-mDCs, and the blockade of them especially the former one could reverse the inhibitory effects of sEV-mDCs. Conclusions We demonstrated that MSC-sEVs were able to dampen the activating effects of mDCs on ILC2s in patients with AR. Mechanismly, the PGE2-EP2/4 axis played an essential role in the immunomodulatory effects of sEV-mDCs on ILC2s. Herein, we provided new insights into the mechanism underlying the therapeutic effects of MSC-sEVs in allergic airway inflammation.

Owing to the development of modern display technology, micro- and mini-light-emitting diodes (LEDs) have affected technological advancements in the display industry. The structure of mini-LEDs is completely different than that of traditional LED backlights because the former employs a display technology with an LED array structure, optical resonant cavity, and color conversion layer. Display backlight technology encounters difficulty in achieving a truly effective energy-loss mechanism when designing or measuring mini-LED performance. The present study proposes three major mini-LED energy loss mechanisms: cross-talk, resonant, and quantum conversion losses. Herein, the spectrum was obtained through the integrating sphere system, and the calculation mechanism was formed by the down-conversion theorem as the decoupling principle, which successfully calculated the independent energy-loss efficiency of each mechanism and effectively deduced the brightness and color saturation performance of this design combination.

BackgroundAllergic rhinitis (AR) is characterized by IgE-mediated mucosa response after exposure to allergens. Extracellular vesicles (EVs) are nano-size vesicles containing biological cargos for intercellular communications. However, the role of plasma EVs in pathogenesis of AR remains largely unknown.MethodsPlasma EVs from patients with AR were isolated, quantified, and characterized. The expression of Der p 1 and antigen-presenting molecules on EVs was determined by Western blot, flow cytometry, or ELISA. PKH26- and CFSE (carboxyfluorescein succinimidyl ester)-stained AR-EVs were used to determine the uptake of EVs by CD4+T cells and their effects on CD4+T cell proliferation, respectively.ResultsPlasma EVs in healthy control (HC) and AR patients were similar in the concentration of particles, expression for specific EV markers, and both had structural lipid bilayer. However, the levels of Der p 1 on plasma EVs from both mild and moderate-severe AR patients were significantly higher than that on HC. The levels of antigen-presenting molecules on plasma EVs were similar from three subjects. Moreover, levels of Der p 1 on EVs in plasma, but not nasal secretion, were significantly associated with the symptom score of AR patients and level of plasma IL-13. Additionally, plasma EVs from patients with AR promoted the development of Th2 cells, while no effect was found on CD4+ T-cell proliferation.ConclusionsPlasma EVs derived from patients with AR exhibited antigen-presenting characteristics and promoted differentiation of Th2 cells, thus providing novel understanding of the pathogenesis of AR.

The non-visual effects of blue light in displays mean that excessive use of smartphones can disturb the human circadian rhythm. Thus, the impact of virtual reality (VR) headsets, which are worn closer to the human eye, may be even more serious. In this paper, based on non-visual parameters, such as the circadian action factor (CAF) and circadian illuminance, the circadian performance of smartphone-based VR displays is quantitatively evaluated by an evaluation system we designed. Moreover, we investigate the improvements in the circadian performance of VR headsets resulting from three practical methods for reducing the blue light content. Finally, a theoretical method of shifting the green-light wavelength of the screen close to 555 nm to optimize the CAF of VR headsets is proposed. Overall, the results of this paper are of significant value in quantifying the effects of VR displays on circadian rhythms and improving the safety of VR headsets with regard to human health.

Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. Dodecanoic acid treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (eg,10, 100 μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

Although gut microbiota influences osteoporosis risk, the individual species involved, and underlying mechanisms, are unknown. We performed integrative analyses in a Chinese cohort with metagenomics/targeted metabolomics/whole-genome sequencing. Bacteroides vulgatus was found negatively associated with bone mineral density (BMD), this association was validated in US Caucasians. Serum valeric acid was positively associated with BMD, and B.vulgatus causally downregulated it. Ovariectomized mice fed B.vulgatus had decreased bone formation and increased bone resorption, lower BMD and poorer bone micro-structure. Valeric acid suppressed NF-κB p65 protein production (pro-inflammatory), and enhanced IL-10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells, and enhanced maturation of osteoblasts in vitro. B.vulgatus and valeric acid represent promising targets for osteoporosis prevention/treatment.

Background The dose and dosing time of indocyanine green (ICG) vary among fluorescence cholangiography (FC) studies. The purpose of this prospective, randomized, exploratory clinical trial was to optimize the dose and dosing time of ICG. Methods PubMed was searched to determine the optimal dose. To optimize the dosing time of ICG, a clinical trial was designed with two parts. The first part included patients with T tubes for more than 1 month. After the patient was injected with ICG, bile was collected at 10 time points to explore the change and trends of bile fluorescence intensity (FI). In addition, the results of the first experiment were used to setup a randomized controlled trial (RCT) that aimed to find the optimal dosing timing for ICG injections for laparoscopic cholecystectomy (LC). During surgery, imaging data were collected for analysis. Results After performing a systematic review, the ICG injection dose for each patient in the clinical trial was 10 mg. Five patients were included in the first part of the study. Bile collected 8 h after ICG injection had a higher FI than bile collected at other time points (p p = 0.001), liver FI (p p = 0.001) were not the same in each group. Further analysis with the Bonferroni method revealed the following: (1) the FI of the CBD in the 8 h group was significantly different from that in the 14 h group (adjusted p p = 0.042) and the 14 h group (adjusted p p = 0.013) and the 14 h group (adjusted p = 0.001). Conclusion ICG FC enables the real-time identification of extrahepatic bile ducts. The optimal effect of FC can be achieved by performing 10 mg ICG injections 10 to 12 h prior to surgery.

BACKGROUND: Both type 2 diabetes (T2D) and Alzheimer’s disease (AD) occur commonly in the aging populations and T2D has been considered as an important risk factor for AD. The heritability of both diseases is estimated to be over 50%. However, common pleiotropic single-nucleotide polymorphisms (SNPs)/loci have not been well-defined. The aim of this study is to analyze two large public accessible GWAS datasets to identify novel common genetic loci for T2D and/or AD. METHODS AND MATERIALS: The recently developed novel conditional false discovery rate (cFDR) approach was used to analyze the summary GWAS datasets from International Genomics of Alzheimer’s Project (IGAP) and Diabetes Genetics Replication And Meta-analysis (DIAGRAM) to identify novel susceptibility genes for AD and T2D. RESULTS: We identified 78 SNPs (including 58 novel SNPs) that were associated with AD in Europeans conditional on T2D (cFDR < 0.05). 66 T2D SNPs (including 40 novel SNPs) were identified by conditioning on SNPs association with AD (cFDR < 0.05). A conjunction-cFDR (ccFDR) analysis detected 8 pleiotropic SNPs with a significance threshold of ccFDR < 0.05 for both AD and T2D, of which 5 SNPs (rs6982393, rs4734295, rs7812465, rs10510109, rs2421016) were novel findings. Furthermore, among the 8 SNPs annotated at 6 different genes, 3 corresponding genes TP53INP1, TOMM40 and C8orf38 were related to mitochondrial dysfunction, critically involved in oxidative stress, which potentially contribute to the etiology of both AD and T2D. CONCLUSION: Our study provided evidence for shared genetic loci between T2D and AD in European subjects by using cFDR and ccFDR analyses. These results may provide novel insight into the etiology and potential therapeutic targets of T2D and/or AD.

Background Clinical and epidemiological findings point to an association between type 2 diabetes (T2D) and low birth weight (BW). However, the nature underlying their relationship is largely unknown. Here, we aim to identify novel single-nucleotide polymorphisms (SNPs) in T2D, BW and their pleiotropic loci. Methods We applied a pleiotropy-informed conditional false discovery rate (cFDR) method to two independent GWAS summary statistics of T2D (n = 149,821) and BW (n = 26,836). Results Conditional Q-Q plot shows a strong enrichment of genetic variants in T2D conditioned on different levels of association with BW. We identified 133 SNPs with a significance threshold of cFDR

Calcium is an important integrative component of the human body and critical for human health. It has been well established that calcium intake is helpful in the prevention and treatment of osteoporosis, which has become one of the most serious public health problems across the world. However, community-dwelling adults with and without osteoporosis are rarely concerned or even not aware of the potential side effects of high or inappropriate doses of calcium intake. Some recent studies have revealed that excessive calcium intake might increase the risks of cardiovascular diseases. The purpose of this article was to review the health benefits, costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures, cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In the end, we suggest that calcium supplementation should be prescribed and taken cautiously, accounting for individual patients' risks and benefits. Clearly, further studies are needed to examine the health effects of calcium supplementation to make any solid recommendations for people of different genders, ages, and ethnicities.

Osteoporosis is known to be highly heritable. However, to date, the findings from more than 20 genome-wide association studies (GWASs) have explained less than 6% of genetic risks. Studies suggest that the missing heritability data may be because of joint effects among genes. To identify novel heritability for osteoporosis, we performed a system-level study on bone mineral density (BMD) by weighted gene coexpression network analysis (WGCNA), using the largest GWAS data set for BMD in the field, Genetic Factors for Osteoporosis Consortium (GEFOS-2), and a transcriptomic gene expression data set generated from transiliac bone biopsies in women. A weighted gene coexpression network was generated for 1574 genes with GWAS nominal evidence of association (p ≤ 0.05) based on dissimilarity measurement on the expression data. Twelve distinct gene modules were identified, and four modules showed nominally significant associations with BMD (p ≤ 0.05), but only one module, the yellow module, demonstrated a good correlation between module membership (MM) and gene significance (GS), suggesting that the yellow module serves an important biological role in bone regulation. Interestingly, through characterization of module content and topology, the yellow module was found to be significantly enriched with contractile fiber part (GO:044449), which is widely recognized as having a close relationship between muscle and bone. Furthermore, detailed submodule analyses of important candidate genes (HOMER1, SPTBN1) by all edges within the yellow module implied significant enrichment of functional connections between bone and cytoskeletal protein binding. Our study yielded novel information from system genetics analyses of GWAS data jointly with transcriptomic data. The findings highlighted a module and several genes in the model as playing important roles in the regulation of bone mass in females, which may yield novel insights into the genetic basis of osteoporosis. © 2016 American Society for Bone and Mineral Research.

Previous studies have demonstrated the genetic correlations between type 2 diabetes, obesity and dyslipidemia, and indicated that many genes have pleiotropic effects on them. However, these pleiotropic genes have not been well-defined. It is essential to identify pleiotropic genes using systematic approaches because systematically analyzing correlated traits is an effective way to enhance their statistical power. To identify potential pleiotropic genes for these three disorders, we performed a systematic analysis by incorporating GWAS (genome-wide associated study) datasets of six correlated traits related to type 2 diabetes, obesity and dyslipidemia using Meta-CCA (meta-analysis using canonical correlation analysis). Meta-CCA is an emerging method to systematically identify potential pleiotropic genes using GWAS summary statistics of multiple correlated traits. 2,720 genes were identified as significant genes after multiple testing (Bonferroni corrected p value < 0.05). Further, to refine the identified genes, we tested their relationship to the six correlated traits using VEGAS-2 (versatile gene-based association study-2). Only the genes significantly associated (Bonferroni corrected p value < 0.05) with more than one trait were kept. Finally, 25 genes (including two confirmed pleiotropic genes and eleven novel pleiotropic genes) were identified as potential pleiotropic genes. They were enriched in 5 pathways including the statin pathway and the PPAR (peroxisome proliferator-activated receptor) Alpha pathway. In summary, our study identified potential pleiotropic genes and pathways of type 2 diabetes, obesity and dyslipidemia, which may shed light on the common biological etiology and pathogenesis of these three disorders and provide promising insights for new therapies.

Interactions between multiple genes are involved in the development of complex diseases. However, there are few analyses of gene interactions associated with papillary thyroid cancer (PTC). Weighted gene co-expression network analysis (WGCNA) is a novel and powerful method that detects gene interactions according to their co-expression similarities. In the present study, WGCNA was performed in order to identify functional genes associated with PTC using R package. First, differential gene expression analysis was conducted in order to identify the differentially expressed genes (DEGs) between PTC and normal samples. Subsequently, co-expression networks of the DEGs were constructed for the two sample groups, respectively. The two networks were compared in order to identify a poorly preserved module. Concentrating on the significant module, validation analysis was performed to confirm the identified genes and combined functional enrichment analysis was conducted in order to identify more functional associations of these genes with PTC. As a result, 1062 DEGs were identified for network construction. A brown module containing 118 highly related genes was selected as it exhibited the lowest module preservation. After validation analysis, 61 genes in the module were confirmed to be associated with PTC. Following the enrichment analysis, two PTC-related pathways were identified: Wnt signal pathway and transcriptional misregulation in cancer. LRP4, KLK7, PRICKLE1, ETV4 and ETV5 were predicted to be candidate genes regulating the pathogenesis of PTC. These results provide novel insights into the etiology of PTC and the identification of potential functional genes.

Full-color displays based on micro light-emitting diodes (μLEDs) can be fabricated on monolithic epitaxial wafers. Nanoring (NR) structures were fabricated on a green LED epitaxial wafer; the color of NR-μLEDs was tuned from green to blue through strain relaxation. An Al2O3 layer was deposited on the sidewall of NR-μLEDs, which improved the photoluminescence intensity by 143.7%. Coupling with the exposed multiple quantum wells through nonradiative resonant energy transfer, red quantum dots were printed to NR-μLEDs for a full-color display. To further improve the color purity of the red light, a distributed Bragg reflector is developed to reuse the excitation light.

Clinical and epidemiological findings point to an association between type 2 diabetes (T2D) and low birth weight. However, the nature of the relationship is largely unknown. The aim of this study was to identify novel single nucleotide polymorphisms (SNPs) in T2D and birth weight, and their pleiotropic loci.A pleiotropy-informed conditional false discovery rate (cFDR) method was applied to two independent genome-wide association studies (GWAS) summary statistics of T2D (n = 149 821) and birth weight (n = 26 836).A conditional Q-Q plot showed strong enrichment of genetic variants in T2D conditioned on different levels of association with birth weight. 133 T2D-associated SNPs, including 120 novel SNPs, were identified with a significance threshold of cFDR 0.05; 13 significant birth weight-associated SNPs, including 12 novel SNPs (cFDR 0.05) were identified. Conjunctional cFDR (ccFDR) analysis identified nine pleiotropic loci, including seven novel loci, shared by both T2D and birth weight (ccFDR 0.05). Two novel SNPs located at the CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1; rs1012635; cFDR 0.05) and adenylate cyclase 5 (ADCY5; rs4677887; cFDR 0.05) genes are of note. These two genes increase the risk of T2D and low birth weight through the pathway of the "fetal insulin hypothesis."Several pleiotropic loci were identified between T2D and birth weight by leveraging GWAS results. The results make it possible to explain a greater proportion of trait heritability and improve our understanding of the shared pathophysiology between T2D and birth weight.

Osteoporosis is known to be highly heritable. However, to date, the findings from more than 20 genome-wide association studies (GWASs) have explained less than 6% of genetic risks. Studies suggest that the missing heritability data may be because of joint effects among genes. To identify novel heritability for osteoporosis, we performed a system-level study on bone mineral density (BMD) by weighted gene coexpression network analysis (WGCNA), using the largest GWAS data set for BMD in the field, Genetic Factors for Osteoporosis Consortium (GEFOS-2), and a transcriptomic gene expression data set generated from transiliac bone biopsies in women. A weighted gene coexpression network was generated for 1574 genes with GWAS nominal evidence of association (p ≤ 0.05) based on dissimilarity measurement on the expression data. Twelve distinct gene modules were identified, and four modules showed nominally significant associations with BMD (p ≤ 0.05), but only one module, the yellow module, demonstrated a good correlation between module membership (MM) and gene significance (GS), suggesting that the yellow module serves an important biological role in bone regulation. Interestingly, through characterization of module content and topology, the yellow module was found to be significantly enriched with contractile fiber part (GO:044449), which is widely recognized as having a close relationship between muscle and bone. Furthermore, detailed submodule analyses of important candidate genes (HOMER1, SPTBN1) by all edges within the yellow module implied significant enrichment of functional connections between bone and cytoskeletal protein binding. Our study yielded novel information from system genetics analyses of GWAS data jointly with transcriptomic data. The findings highlighted a module and several genes in the model as playing important roles in the regulation of bone mass in females, which may yield novel insights into the genetic basis of osteoporosis. © 2016 American Society for Bone and Mineral Research.

There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile-quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.

In this paper, We measured the relationship between game UI and graphics playing mobile game using in eye tracking technology and verified that user interface arrangement useful to design game is important factor according to the experimental results.