Schizophrenia is a common psychiatric disorder with high heritability and complex genetic architecture. Genome-wide association studies (GWAS) have identified several significant loci associated with schizophrenia. However, the explained heritability is still low. Growing evidence has shown schizophrenia is attributable to multiple genes with moderate effects. In-depth mining and integration of GWAS data is urgently expected to uncover disease-related gene combination patterns. Network-based analysis is a promising strategy to better interpret GWAS to identify disease-related network modules. We performed a network-based analysis on three independent schizophrenia GWASs by using a refined analysis framework, which included a more accurate gene P-value calculation, dynamic network module searching algorithm and detailed functional analysis for the obtained modules genes. The result generated 79 modules including 238 genes, which form a highly connected subnetwork with more statistical significance than expected by chance. The result validated several reported disease genes, such as MAD1L1, MCC, SDCCAG8, VAT1L, MAPK14, MYH9 and FXYD6, and also obtained several novel candidate genes and gene-gene interactions. Pathway enrichment analysis of the module genes suggested they were enriched in several neural and immune system related pathways/GO terms, such as neurotrophin signaling pathway, synaptosome, regulation of protein ubiquitination, and antigen processing and presentation. Further crosstalk analysis revealed these pathways/GO terms were cooperated with each other, and identified several important genes, which might play vital roles to connect these functions. Our network-based analysis of schizophrenia GWASs will facilitate the understanding of genetic mechanisms of schizophrenia.

Cerenkov luminescence imaging utilizes visible photons emitted from radiopharmaceuticals to achieve in vivo optical molecular-derived signals. Since Cerenkov radiation is weak, non-optimum for tissue penetration and continuous regardless of biological interactions, it is challenging to detect this signal with a diagnostic dose. Therefore, it is challenging to achieve useful activated optical imaging for the acquisition of direct molecular information. Here we introduce a novel imaging strategy, which converts γ and Cerenkov radiation from radioisotopes into fluorescence through europium oxide nanoparticles. After a series of imaging studies, we demonstrate that this approach provides strong optical signals with high signal-to-background ratios, an ideal tissue penetration spectrum and activatable imaging ability. In comparison with present imaging techniques, it detects tumour lesions with low radioactive tracer uptake or small tumour lesions more effectively. We believe it will facilitate the development of nuclear and optical molecular imaging for new, highly sensitive imaging applications.

Cornea transplant technology has progressed markedly in recent decades, allowing surgeons to replace diseased corneal endothelium by a thin lamellar structure. A thin, transparent, biocompatible, tissue-engineered substratum with corneal endothelial cells for endothelial keratoplasty is currently of interest. Electrospinning a nanofibrous structure can simulate the extracellular matrix and have beneficial effects for cell culture. Silk fibroin (SF) has good biocompatibility but poor mechanical properties, while poly(L-lactic acid-co-ε-caprolactone) (P(LLA-CL)) has good mechanical properties but poor biocompatibility. Blending SF with P(LLA-CL) can maintain the advantages of both these materials and overcome their disadvantages. Blended electrospun nanofibrous membranes may be suitable for regeneration of the corneal endothelium. The aim of this study was to produce a tissue-engineered construct suitable for endothelial keratoplasty.

While >200 types of etiologies have been shown to be involved in the pathogenesis of infantile spasms, the pathophysiology of infantile spasms remains largely elusive. Pre-natal stress and hypothalamic-pituitary-adrenal axis dysfunction were shown to be involved in the development of infantile spasms. To test the genetic association between the CRHR1 gene, which encodes the corticotrophin-releasing hormone (CRH) receptor, and infantile spasms, five single nucleotide polymorphisms (SNPs) in the CRHR1 gene were genotyped in a sample set of 128 cases with infantile spasms and 131 healthy controls. Correlation analysis was performed on the genotyped data. Under the assumption of the dominant model, the selected five SNPs, rs4458044, rs171440, rs17689966, rs28364026 and rs242948, showed no association with the risk of infantile spasms and the effectiveness of adrenocorticotropic hormone treatment. In addition, subsequent haplotype analysis suggested none of them was associated with infantile spasms. In conclusion, the experimental results of the present study suggested no association between the CRHR1 gene and infantile spasms in a Chinese population.

Auditory neuropathy spectrum disorder (ANSD) is a form of hearing loss in which auditory signal transmission from the inner ear to the auditory nerve and brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. For many cases of ANSD, the underlying molecular pathology and the site of lesion remain unclear. The X-linked form of the condition, AUNX1, has been mapped to Xq23-q27.3, although the causative gene has yet to be identified.

Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.

The potato (Solanum tuberosum) cultivar 'Xin Daping' is tetraploid with white skin and white flesh, while the cultivar 'Hei Meiren' is also tetraploid with purple skin and purple flesh. Comparative transcriptome analysis of white and purple cultivars was carried out using high-throughput RNA sequencing in order to further understand the mechanism of anthocyanin biosynthesis in potato.

The aim of the present study was to evaluate the effects of the B7/cluster of differentiation (CD)28 signaling pathway on experimental lupus nephritis and examine the molecular mechanism involved by inhibiting the B7/CD28 signaling pathway. A lupus nephritis model in C57BL/6 J mice was induced via intraperitoneal injection of pristane. A recombinant B7‑1 short hairpin RNA (shRNA) lentivirus vector was constructed by synthesis and splicing. A neutralizing mouse anti‑human B7‑1 antibody termed 4E5 was also prepared. The mouse model of lupus nephritis was treated with B7‑1 shRNA and 4E5 via injection through the tail vein. The silencing effects of B7‑1 shRNA lentiviral infection on target molecules were evaluated using immunofluorescence and flow cytometry. The levels of protein in the urine were detected using Albustix test paper each month over 10 months. The concentration of interleukin (IL)‑4 and interferon‑γ in the serum was determined using an ELISA. The immune complex (IC) deposits in the kidney were analyzed using direct immunofluorescence. The results demonstrated that the C57BL/6 J mouse lupus nephritis model was successfully constructed with immune cells activated in the spleen of the mice, increases in the concentration of anti‑nuclear antibody (ANA) and anti‑double stranded DNA antibodies as well as positive IC formation. Following B7‑1 shRNA lentivirus or 4E5 treatment, CD11b+B7‑1+, CD11c+B7‑1+ and CD21+B7‑1+ cells in the spleen of the mice were significantly reduced. The concentration of ANA and IL‑4 in the serum was also decreased. The concentration of urine protein was reduced and it was at its lowest level in the 4E5 early intervention group. It was also revealed that the immunofluorescence intensity of the IC deposits was weak in the 4E5 early intervention group. In conclusion, inhibiting the B7‑1/CD28 signaling pathway is able to alleviate experimental lupus nephritis and provides an experimental basis for the therapeutic use of blocking the B7‑1/CD28 signaling pathway in human lupus nephritis and other autoimmune disorders.

MG7-Ag, a specific gastric cancer-associated antigen, can be used to non-invasively monitor gastric cancer by molecular imaging with positron emission tomography/computed tomography (PET/CT). In this study, we prepared and evaluated a (68)Ga-labeled MG7 antibody as a molecular probe for nanoPET/CT imaging of gastric cancer in a BGC-823 tumor xenografted mouse model. Macrocyclic chelator 1,4,7-triazacyclononane-N,N0,N00-triacetic acid (NOTA)-conjugated MG7 antibody was synthesized and radiolabeled with (68)Ga (t1/2 = 67.71 min). Then, (68)Ga-NOTA-MG7 was tested using in vitro cytological studies, in vivo nanoPET/CT and Cerenkov imaging studies as well as ex vivo biodistribution and histology studies. The in vitro experiments demonstrated that (68)Ga-NOTA-MG7 has an excellent radiolabeling efficiency of approximately 99% without purification, and it is stable in serum after 120 min of incubation. Cell uptake and retention studies confirmed that (68)Ga-NOTA-MG7 has good binding affinity and tumor cell retention. For the nanoPET imaging study, the predominant uptake of (68)Ga-NOTA-MG7 was visualized in tumor, liver and kidneys. The tumor uptake reached at its peak (2.53 ± 0.28%ID/g) at 60 min pi. Cherenkov imaging also confirmed the specificity of tumor uptake. Moreover, the biodistribution results were consistent with the quantification data of nanoPET/CT imaging. Histologic analysis also demonstrated specific staining of BGC-823 tumor cell lines.

A better understanding of the effects of human adipocytes on breast cancer cells may lead to the development of new treatment strategies. We explored the effects of adipocytes on the migration and invasion of breast cancer cells both in vitro and in vivo.

The aim of the present study was to explore the function and interaction of differentially expressed genes (DEGs) in pulmonary embolism (PE). The gene expression profile GSE13535, was downloaded from the Gene Expression Omnibus database. The DEGs 2 and 18 h post‑PE initiation were identified using the affy package in R software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the DEGs were analyzed using Database for Annotation Visualization and Integrated Discovery (DAVID) online analytical tools. In addition, protein‑protein interaction (PPI) networks of the DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins. The PPI network at 18 h was modularized using Clusterone, and a functional enrichment analysis of the DEGs in the top three modules was performed with DAVID. Overall, 80 and 346 DEGs were identified 2 and 18 h after PE initiation, respectively. The KEGG pathways, including chemokine signaling and toll‑like receptor signaling, were shown to be significantly enriched. The five highest degree nodes in the PPI networks at 2 or 18 h were screened. The module analysis of the PPI network at 18 h revealed 11 hub nodes. A Gene Ontology terms analysis demonstrated that the DEGs in the top three modules were associated with the inflammatory, defense and immune responses. The results of the present study suggest that the DEGs identified, including chemokine‑related genes TFPI2 and TNF, may be potential target genes for the treatment of PE. The chemokine signaling pathway, inflammatory response and immune response were explored, and it may be suggested that these pathways have important roles in PE.

NAG-thiazoline (NGT) and its derivatives are well-known inhibitors against most β-acetylglucosaminidases (β-GlcNAcases) except for insect and bacterial chitinolytic β-GlcNAcases, including the molting-indispensable OfHex1 from the insect Ostrinia furnacalis. Here, we report the co-crystal structure of OfHex1 in complex with NGT. This structure reveals a large active pocket in OfHex1 that may account for the poor inhibitory activity of NGT. To test this hypothesis, a bulky substituent was designed and synthesized on the thiazoline ring of NGT. The resulting compound (NMAGT) was determined to be a submicromolar inhibitor of OfHex1 with a Ki value of 0.13 μM, which is 600-fold lower than Ki value of NGT. Molecular dynamics simulation analysis supported the good fit of NMAGT to the active pocket.

Smoking is a modifiable risk factor for morbidity and mortality caused by cancer, cardiovascular diseases, respiratory diseases, and many other diseases. Given the large population size and high prevalence of smoking in Asia, successful smoking cessation could potentially prevent the large number of premature deaths in Asians. However, most dependent smokers cannot successfully quit smoking due to nicotine addiction, and they need professional help and smoking cessation therapies. Varenicline is a highly selective partial agonist for the nicotinic acetylcholine receptor α4β2 subtype, which is believed to be responsible for mediating the reinforcing properties of nicotine. This article is a narrative review, which summarizes the smoking cessation efficacy, side effects, and cost utilities of varenicline in Asians. From this review, we conclude that varenicline is an effective medication that could assist smoking cessation in the Asian populations. The adverse events of varenicline are tolerable, and the most common events were nausea and abnormal dreams. Both the efficacy and tolerance of varenicline in Asians are similar to that in Western populations. Considering the cost utilities, varenicline should be recommended for use in smoking cessation and be covered by medical insurance in most Asian countries.

Keratinocytes proliferation is critical for the capacity to heal wounds and accumulating evidences have proved that dysregulation of microRNAs is involved in proliferation of keratinocytes. However, the molecular mechanisms remain to be completely elucidated. Here, we show that miR-136 was significantly decreased by TGF-β1 treatment in HaCaT cells and normal human epidermal keratinocytes (NHEK), and it was a Smad3-dependent manner. By cell proliferation assay and cell cycle analysis, we found that reintroduction of miR-136 by transfection, as well as PPP2R2A silencing, counteracted TGF-β-induced proliferation arrest in HaCaT cells. Further, PPP2R2A was verified as a direct target of miR-136 by dual-luciferase reporter assays and Western blotting. These data suggest that miR-136 may play an important role during TGF-β1-induced proliferation arrest by targeting PPP2R2A in keratinocytes, which might represent a potential target for improving skin wound healing.

The aim of the present study has been to critically review 22 disease scoring systems (DSSs) on oral lichen planus (OLP) that have been reported in the literature during the past decades. Although the presently available DSSs may all have some merit, particularly for research purposes, the diversity of both the objective and subjective parameters used in these systems and the lack of acceptance of one of these systems for uniform use, there is a need for an international, authorized consensus meeting on this subject. Because of the natural course of OLP characterized by remissions and exacerbations and also due to the varying distribution pattern and the varying clinical types, e.g. reticular and erosive, the relevance of a DSS based on morphologic parameters is somewhat questionable. Instead, one may consider to only look for a quality of life scoring system adapted for use in OLP patients.

The chemical composition, anti-inflammatory, cytotoxic and antioxidant activities of essential oil from leaves of Mentha piperita (MEO) grown in China were investigated. Using GC-MS analysis, the chemical composition of MEO was characterized, showing that it was mainly composed of menthol, menthone and menthy acetate. MEO exhibited potent anti-inflammatory activities in a croton oil-induced mouse ear edema model. It could also effectively inhibit nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. The cytotoxic effect was assessed against four human cancer cells. MEO was found to be significantly active against human lung carcinoma SPC-A1, human leukemia K562 and human gastric cancer SGC-7901 cells, with an IC50 value of 10.89, 16.16 and 38.76 µg/ml, respectively. In addition, MEO had moderate antioxidant activity. The results of this study may provide an experimental basis for further systematic research, rational development and clinical utilization of peppermint resources.

The data on the prognostic values of high sensitivity C-reactive protein (hsCRP) levels in patients with advanced symptomatic heart failure (HF) receiving cardiac resynchronization therapy (CRT) are scarce. The aim of present study was to investigate the association of serum hsCRP levels with left ventricle reverse remodeling after six months of CRT as well as long-term outcome.

Angiogenesis is spatially and temporally orchestrated by a myriad of signaling pathways, including the Notch signaling pathway. Here, we identified UXT as an evolutionarily conserved and developmentally expressed protein, indispensable for intersegmental vessel (ISV) formation in zebrafish. Deficiency of UXT in zebrafish embryos results in shorter ISVs, loss of tip cell behavior, and impairment of endothelial cell migration and division. Significantly, UXT attenuates the expression of the Notch-responsive genes in vitro and in vivo. Mechanistically, UXT binds to the promoters of the Notch signaling target genes and specifically interacts with the transactivation region domain of the Notch intracellular domain (NICD), impairing the interaction between NICD and the transcription factor RBP-Jκ endogenously. This prevents RBP-Jκ/CSL from activation and thus inhibits the consequent gene inductions. Furthermore, blockade of Notch signaling rescues the angiogenesis defect caused by UXT knockdown both in vitro and in vivo. Taken together, the data presented in this study characterize UXT as a novel repressor of Notch signaling, shedding new light on the molecular regulation of angiogenesis.

Degraded fucoidan (F1) was desulfated by DMSO-MeOH. And anion exchange chromatography was performed to fractionate desulfated F1 (ds-F1) into five fractions. Electrospray ionization mass spectrometry (ESI-MS) showed that each fraction contained at least one set of neutral and/or sulfated fucooligosaccharides in the form of methyl glycosides. And the structures of oligomeric fragments were characterized by ESI-CID-MS/MS and ESI-CID-MS/MS/MS. In addition, more structural features were shown by NMR. Therefore, it was concluded that LF1 contained a backbone of (1→3)-linked fucopyranose residues sulfated at C-4 and branched at C-2 by fucopyranose residues and fucoglucuronomannan, fucoglucuronan, galactan and xylan were found in LF-5. Finally, it was concluded that F1 was the middle component, which contained the information of both F0.5 and F2, indicating that the differences between F1 and F0.5, F2 might be derived primarily from the different needs of algae itself.

The growth and development of plants are sensitive to their surroundings. Although numerous studies have analyzed plant transcriptomic variation, few have quantified the effect of combinations of factors or identified factor-specific effects. In this study, we performed RNA sequencing (RNA-seq) analysis on tobacco leaves derived from 10 treatment combinations of three groups of ecological factors, i.e., climate factors (CFs), soil factors (SFs), and tillage factors (TFs). We detected 4980, 2916, and 1605 differentially expressed genes (DEGs) that were affected by CFs, SFs, and TFs, which included 2703, 768, and 507 specific and 703 common DEGs (simultaneously regulated by CFs, SFs, and TFs), respectively. GO and KEGG enrichment analyses showed that genes involved in abiotic stress responses and secondary metabolic pathways were overrepresented in the common and CF-specific DEGs. In addition, we noted enrichment in CF-specific DEGs related to the circadian rhythm, SF-specific DEGs involved in mineral nutrient absorption and transport, and SF- and TF-specific DEGs associated with photosynthesis. Based on these results, we propose a model that explains how plants adapt to various ecological factors at the transcriptomic level. Additionally, the identified DEGs lay the foundation for future investigations of stress resistance, circadian rhythm and photosynthesis in tobacco.