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Atopic Dermatitis is a chronic relapsing inflammatory skin disease with multiple environmental and genetic factors involved in its etiology. Although lots of genetic loci associated with atopic dermatitis have been reported by genome-wide association studies (GWASs), only a small part of phenotypic variations can be explained. To identify additional susceptibility genes on atopic dermatitis, we conducted a large-scale transcriptome-wide association study (TWAS) using joint-tissue imputation (JTI) approach in ∼840,000 European individuals combined with six precomputed gene expression weights of four atopic dermatitis-relevant tissues, including skin fibroblast, lymphocyte, and whole blood. The Mendelian randomization (MR) causal inference analysis was performed to estimate the causal effect of TWAS-identified genes. We identified 51 genes significantly associated with atopic dermatitis after Bonferroni corrections and 19 genes showed putatively causal associations, such as an established gene FLG (P = 3.98×10

Graphical abstract, Detecting SNPs associated with drug efficacy or toxicity is helpful to facilitate personalized medicine. Previous studies usually find SNPs associated with clinical outcome only in patients received a specific treatment. However, without information from patients without drug treatment, it is possible that the detected SNPs are associated with patients’ clinical outcome even without drug treatment. Here we aimed to detect drug response SNPs based on data from patients with and without drug treatment through combing the cox proportional-hazards model and pairwise Kaplan-Meier survival analysis. A pipeline named Detection of Drug Response SNPs (DDRS) was built and applied to TCGA breast cancer data including 363 patients with doxorubicin treatment and 321 patients without any drug treatment. We identified 548 doxorubicin associated SNPs. Drug response score derived from these SNPs were associated with drug-resistant level (indicated by IC50) of breast cancer cell lines. Enrichment analyses showed that these SNPs were enriched in active epigenetic regulation markers (e.g., H3K27ac). Compared with random genes, the cis-eQTL genes of these SNPs had a shorter protein–protein interaction distance to doxorubicin associated genes. In addition, linear discriminant analysis showed that the eQTL gene expression levels could be used to predict clinical outcome for patients with doxorubicin treatment (AUC = 0.738). Specifically, we identified rs2817101 as a drug response SNP for doxorubicin treatment. Higher expression level of its cis-eQTL gene GSTA1 is associated with poorer survival. This approach can also be applied to identify new drug associated SNPs in other cancers.

MicroRNAs bind to the 3′ untranslated regions of mRNAs, affecting translation, tumorigenesis, and apoptosis. This study evaluated the role of TYMS (rs1059394, C > T, and rs2847153, G > A), RYR3 (rs1044129, G > A), KIAA0423 (rs1053667, T > C), and GOLGA7 (rs11337, G > T) polymorphisms for assessment of glioma risk and prognosis among the Chinese Han population. Five single-nucleotide polymorphisms were assessed in 605 glioma patients and 1,300 controls. We found a significant correlation between rs1059394 and glioma susceptibility in the homozygote and dominant genetic models (TT versus CC, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.52–0.97, p = 0.03; CT+TT versus CC, OR = 0.74, 95% CI = 0.55–0.99, p = 0.04). The results of the Kaplan-Meier and log rank tests revealed that the rs11337 GG genotype correlated with better overall survival of glioma patients (p = 0.017) than the GT genotype. Multivariate Cox regression analysis results also showed that the rs11337 GT genotype correlated with worse overall survival (p = 0.017, hazard ratio [HR] = 1.25, 95% CI = 1.04–1.5) than the GG genotype. These results suggest that GOLGA7 (rs11337) polymorphism may play a role in the prognosis of glioma patients and that TYMS (rs1059394) is associated with glioma risk. Keywords: GOLGA7, rs11337, polymorphism, cancer risk, prognosis, microRNA-binding site

Polyimide films are widely used in space with extreme environments, where high energy beam irradiation and corresponding coupling treatment could occur. The combined effect of high energy electrons (1.2 MeV) and high tensile stress (50 MPa) on the degradation behavior of polyimide films was studied by means of scanning electron microscopy, atomic force microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and mechanical testing. The degradation of polyimide films was evaluated by analyzing the microstructure and mechanical properties. The results indicated that the external tensile stress and irradiation coupling treatment resulted in the breakage of a larger number of chemical bonds and greater deterioration of the surface quality when compared with the irradiated polyimide samples. After irradiation-load coupling treatment, numerous micro-cracks were formed on the polyimide surface, facilitating the diffusion of oxygen into polyimide films and thus increasing the probability of free radical reactions. Moreover, the coupling treatment led to a more significant decrease in tensile strength and elongation of polyimide films by 10% and 35%, respectively. The mechanism of molecular chains' scission and crosslinking as well as correlations between molecular chains and mechanical performances were discussed. The obtained results indicated that the external tensile stress accelerates the degradation process during electron beam irradiation; thus, the tensile stress potentially seriously deteriorates polyimide film properties in irradiated environments.

Human papillomavirus (HPV) type 18 is predominantly associated with the development of cervical adenocarcinomas, whereas data on HPV18 genetic variability in China are limited. HPV18 genetic variants were formed phylogenetic tree, including lineages A, B, and C. We aimed to evaluate the diversity of HPV18 genetic variants by sequencing the entire E6, E7 and L1 genes. Between 2012 and 2015, a total of 138 (0.8%, 138/17669) women with single HPV18 infection were selected in this study. Finally, we observed 122 HPV18 isolates of the complete E6-E7-L1 sequences, and obtained 36 distinct variation patterns which the accession GenBank numbers as KY457805-KY457840. Except KY457805, KY457813, KY457819, KY457827, KY457829, the rest of HPV18 isolates (81.1%, 31/36) are novel variants. All of HPV18 variants belong to lineage A, while no lineage B, and C was found in our population of Taizhou region, Southeast China. Sublineage A1 was the most common variants (85.2%, 104/122), followed by sublineage A4, A3 and A5, while no sublineage A2 was obtained. Based on the tree topologies, there were three newly identified candidates' sublineages A6-A8. Out of 122 women, 67 (54.9%) had diagnosed by biopsy, including 49 women who diagnosed with cervicitis, 12 with cervical intraepithelial neoplasia (CIN)1, 4 with CIN2/3, and 2 with adenocarcinomas, respectively. Nevertheless, there was no association between HPV18 (sub) lineages and CIN1 or worse (CIN1+) lesions comparing with normal biopsies (P = .469). In conclusion, knowledge of the distribution of geographic/ethnical HPV18 genetic diversity provides critical information for developing diagnostic probes, epidemiologic correlate of cervical cancer risk and design of HPV vaccines for targeted populations.

Background: The causal effects of childhood obesity have not been systematically characterized. We aimed to assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR). Methods: Over 5,000 datasets for adult outcomes were obtained from various resources. After data filtering, 269 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. The number of independent outcomes was 148, setting the significant threshold as P < 3.38 × 10-4. Inverse-variance weighted method, MR-Egger, weighted median method, and weighted mode method were used to estimate the causal effects. Findings: We identified potential causal effects of childhood obesity on 92 adult traits (48 disease-related traits, 35 lifestyle factors, and 9 other traits). Higher childhood BMI was associated with a reduced overall health rating (β = −0.10, 95% CI: −0.13 to −0.07, P = 6.26 × 10-11) and lower average total household income before tax (β = −0.0576, 95% CI: −0.0862 to −0.0291, P = 7.57 × 10 -5 ). Findings on diseases included some novel effects, such as the adverse effects of higher childhood BMI on venous thromboembolic disease (OR = 1.06, 95% CI: 1.03 to 1.09, P = 2.09 × 10 -4). For dietary habits, we found that higher childhood BMI was positively associated adult diet portion size (β = 0.26, 95% CI: 0.18 to 0.34, P= 7.34 × 10-11) and variation in diet (β = 0.06, 95% CI: 0.03 to 0.09, P = 3.15 × 10-5). The association between adulthood BMI and heel bone mineral density no longer existed after excluding the SNPs existing in or in linkage disequilibrium with childhood BMI. Network MR analyses suggested that past tobacco smoking, variation in diet and portion size mediated 6.39%, 3.29%, and 10.90% of the associations between childhood BMI and Type 2 Diabetes, respectively. Interpretation: In summary, childhood obesity is a risk factor for general health outcomes and socioeconomic status. The importance of control portion size and reduce dietary variation is noted. The positive association between adulthood BMI and heel BMD depend on childhood BMI. Our results highlight the need to intervene in childhood to reduce obesity from a young age and its later-life effects. Funding Statement: This study is supported by the National Natural Science Foundation of China: (31871264, 31701095); Natural Science Basic Research Program Shaanxi Province (2018JQ3058,); Innovative Talent Promotion Plan of Shaanxi Province for Young Sci-Tech New Star (2018KJXX-010), the Fundamental Research Funds for the Central Universities. This work was also supported by the high performance computing platform of Xi’an Jiaotong University. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: All data are publicly available through data resources indicated in the methods.

Over 90% of autoimmune diseases risk variants are located in the noncoding region, leading to great challenge in deciphering the underlying causal functional variants/genes and biological mechanisms. Here we devised an integrative analysis strategy named fGWASAD for identifying not only noncoding functional variants but also gene targets, and underlying biological mechanisms as well as functional roles and clinical implications of gene targets on 20 autoimmune diseases. We demonstrated the credibility of our approach, and further decoded immunologically functional clues for 72.2% of target genes and regulatory mechanisms underlying 71.2% of functional variants. By leveraging pleiotropic effect among target genes, we predicted many candidate drug target genes and new indications for known drugs on several autoimmune diseases. We also suggested the crucial regulatory roles of super enhancers on autoimmune diseases network involving several key master TFs. Together, our analysis provided valuable comprehensive resource for autoimmune diseases, which are freely available online.

Poor thermal stability and thermoplastic processability are the main obstacles for wide application of polyvinyl alcohol, which is a typically water-soluble polymer with excellent mechanical properties, biocompatibility, barrier properties and biodegradability. In this work, a novel method was demonstrated for preparing PVA based material with improved thermal stability, low additive loading, and without impairing the inherent good properties of PVA. Poly (1-vinyl-3-ethyl-imidazolium bromide) (PEtVIm-Br) was synthesized and used as both a thermal stabilizer for PVA and a compatibilizer for PVA/graphene nanocomposites. A 49% improvement in tensile strength and 65% improvement in the elongation at break were achieved by incorporating 2.5 wt% of PEtVIm-Br and 0.5 wt% of graphene into PVA matrix. The thermal stability of the PVA/PEtVIm-Br-graphene composite has been investigated by thermogravimetric analysis (TGA), TGA-DSC simultaneous thermal analysis, and TGA coupled with FTIR. With the addition of PEtVIm-Br-graphene, the elimination reaction of PVA at the initial stage of pyrolysis was suppressed remarkably, while the activation energy for pyrolysis of the nanocomposite increased obviously, resulted in a much improved thermal stability, comparing to pure PVA. The volatile products of pure PVA and PVA composites were detected by TGA/FTIR and Py-GC/MS. The improvement in thermal stability of PVA/PEtVIm-Br and PVA/PEtVIm-Br-graphene composite comparing to pure PVA may attribute to the ability of capturing free radicals of PEtVIm-Br and the barrier effect of well-dispersed graphene.

Both systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying them are still largely unknown. Through a series of bioinformatics and functional analyses, we prioritized a potential independent functional single-nucleotide polymorphism (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element and validated that IRF5 is the distal target gene (∼118 kb) of rs13239597, which is a key regulator involved in pathogenic autoantibody dysregulation, increasing risk of both SLE and SSc. We experimentally validated the long-range chromatin interactions between rs13239597 and IRF5 using chromosome conformation capture assay. We further demonstrated that rs13239597-A acted as an allele-specific enhancer regulating IRF5 expression, independently of TNPO3 by using dual-luciferase reporter assays and CRISPR-Cas9. Particularly, the transcription factor EVI1 could preferentially bind to rs13239597-A allele and increase the enhancer activity to regulate IRF5 expression. Taken together, our results uncovered a mechanistic insight of a noncoding functional variant acting as an allele-specific distal enhancer to directly modulate IRF5 expression, which might obligate in understanding of complex genetic architectures of SLE and SSc pathogenesis.

We recently showed that by introduction of a second distal histidine (Leu29 to His29 mutation) in the heme pocket of sperm whale myoglobin (Mb), L29H Mb mutant exhibits an enhanced peroxidase activity compared to wild type (WT) Mb using H 2 O 2 as an oxidant. In this study, we further showed that when L29H Mb was immobilized in didecyldimethylammonium bromide (DDAB) on glassy carbon electrode (GCE), it can efficiently reduce O 2 in aerobic buffer solution to H 2 O 2 , followed by electrode-driven oxidation of guaiacol, a common peroxidase substrate, which is more effective (∼3.6-fold at pH = 7.0) than that of WT Mb with a single distal His64. Moreover, the peroxidase-like activity of immobilized L29H Mb was found to be affected by pH values, i.e., the slope of the plot of reduction peak vs. guaiacol concentration was increased from (0.83 ± 0.04) × 10 −3 μA/mM at pH = 8.0 to (3.08 ± 0.07) × 10 −3 μA/mM at pH = 6.0, which suggests that the distal histidines play a key role in reductive activation of O 2 by providing protons. Since there is no native peroxidase with two distal histidines and native peroxidase usually uses H 2 O 2 as an oxidant, this study is thus instructive for creating functional enzymes beyond those in nature.

Rationally designed biosynthetic models provide fantastic advantages for addressing important issues in chemistry and biology. Previously, two distal histidines were introduced in the heme pocket of myoglobin (Mb) at positions 29 and 43. The resultant His29 and His43, together with the native His64, formed a metal-binding site in the designed L29H/F43H Mb mutant, which closely mimics the heterobinuclear center of native cytochrome c oxidase (C c O). Instead of studying the oxidase activity, we herein investigated the cross-reactivity, i.e., the peroxidase activity of this mutant, as well as the effect of metal ions binding to the designed metal-binding site on protein reactivity. It was found that the introduced two distal histidines with no bound metal ion serve to improve the peroxidase activity of L29H/F43H Mb compared with that of WT Mb containing a single distal histidine, whereas the binding of metal ions such as Cu(II) and Zn(II) to L29H/F43H Mb inhibits the catalytic activity to a different extent. These findings provide valuable insights into the peroxidase activity observed for the native C c O, as well as the role of metal ion in fine-tuning the protein cross-reactivity.

Objective Highly pathogenic avian influenza A virus H5N1 has the potential to cause a pandemic. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults in recent years. However, data in children are limited. Herein we evaluate the safety and immunogenicity of adjuvanted split-virion and whole-virion H5N1 vaccines in children. Methods An open-labelled phase I trial was conducted in children aged 3–11 years to receive aluminum-adjuvated, split-virion H5N1 vaccine (5–30 μg) and in children aged 12–17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5–15 μg). Safety of the two formulations was assessed. Then a randomized phase II trial was conducted, in which 141 children aged 3–11 years received the split-virion vaccine (10 or 15 μg) and 280 children aged 12–17 years received the split-virion vaccine (10–30 μg) or the whole-virion vaccine (5 μg). Serum samples were collected for hemagglutination-inhibition (HI) assays. Findings 5–15 μg adjuvated split-virion vaccines were well tolerated in children aged 3–11 years and 5–30 μg adjuvated split-virion vaccines and 5 μg adjuvated whole-virion vaccine were well tolerated in children aged 12–17 years. Most local and systemic reactions were mild or moderate. Before vaccination, all participants were immunologically naive to H5N1 virus. Immune responses were induced after the first dose and significantly boosted after the second dose. In 3–11 years children, the 10 and 15 μg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer ≥1:40) rates. In 12–17 years children, the 30 μg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 μg whole-virion vaccine induced higher response than the 10 μg split-virion vaccine did. Interpretation The aluminum-adjuvanted, split-virion prototype pandemic influenza A (H5N1) vaccine showed good safety and immunogenicity in children and 30 μg dose induced immune response complying with European Union licensure criteria. [ClinicalTrials.gov identifiers: NCT00900588 and NCT00900991 ].