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The association between composite dietary antioxidant index (CDAI) and asthma remains unclear. Our study aimed to investigate the association of CDAI with asthma in children aged 3–18 years in the United States. Cross-sectional analyses were carried out on 18,118 children aged 3–18 years old. Data was obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2003 and 2020. The Composite Dietary Antioxidant Index (CDAI) was measured by assessing the consumption of six dietary antioxidants (vitamin A, vitamin C, vitamin E, zinc, selenium and carotenoids). The association between CDAI and asthma was explored using multivariate weighted logistic regression, subgroup analyses, and sensitivity analyses. Among the 18,118 participants, 2045 (11.3%) reported a diagnosis of asthma by a healthcare provider. In both the crude and adjusted models, the odds ratios (ORs) for asthma with CDAI were not significant. Specifically, in the fully adjusted model, the OR for T2 was 0.98 (95% CI 0.83, 1.17) and the OR for T3 was 1.00 (95% CI 0.76, 1.31). Subgroup analyses by sex, age and BMI category also showed no significant associations. Sensitivity analyses, including weighted logistic multivariate analyses adjusting for family history of asthma, confirmed the absence of a significant association between CDAI and asthma. Our study showed no significant association between CDAI and asthma in children and adolescents.

Background Exosomes as the main therapeutic vectors of mesenchymal stem cells (MSC) for inflammatory bowel disease (IBD) treatment and its mechanism remain unexplored. Tumor necrosis factor-α stimulated gene 6 (TSG-6) is a glycoprotein secreted by MSC with the capacities of tissue repair and immune regulation. This study aimed to explore whether TSG-6 is a potential molecular target of exosomes derived from MSCs (MSCs-Exo) exerting its therapeutic effect against colon inflammation and repairing mucosal tissue. Methods Two separate dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD mouse models were intraperitoneally administered MSCs-Exo extracted from human umbilical cord MSC (hUC-MSC) culture supernatant. Effects of MSCs-Exo on intestinal inflammation, colon barrier function, and proportion of T cells were investigated. We explored the effects of MSCs-Exo on the intestinal barrier and immune response with TSG-6 knockdown. Moreover, recombinant human TSG-6 (rhTSG-6) was administered exogenously and colon inflammation severity in mice was evaluated. Results Intraperitoneal injection of MSCs-Exo significantly ameliorated IBD symptoms and reduced mortality rate. The protective effect of MSCs-Exo on intestinal barrier was demonstrated evidenced by the loss of goblet cells and intestinal mucosa permeability, thereby improving the destruction of tight junctions (TJ) structures and microvilli, as well as increasing the expression of TJ proteins. Microarray analysis revealed that MSCs-Exo administration downregulated the level of pro-inflammatory cytokines and upregulated the anti-inflammatory cytokine in colon tissue. MSCs-Exo also modulated the response of Th2 and Th17 cells in the mesenteric lymph nodes (MLN). Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSCs-Exo on mucosal barrier maintenance and immune regulation, whereas rhTSG-6 administration showed similar efficacy to that of MSCs-Exo. Conclusions Our findings suggested that MSCs-Exo protected against IBD through restoring mucosal barrier repair and intestinal immune homeostasis via TSG-6 in mice.

Mitogen-activated protein kinase (MAPK) is a form of serine/threonine protein kinase that activated by extracellular stimulation acting through the MAPK cascade (MAPKKK-MAPKK-MAPK). The MAPK cascade gene family, an important family of protein kinases, plays a vital role in responding to various stresses and hormone signal transduction processes in plants. In this study, we identified 14 CmMAPKs, 6 CmMAPKKs and 64 CmMAPKKKs in melon genome. Based on structural characteristics and a comparison of phylogenetic relationships of MAPK gene families from Arabidopsis, cucumber and watermelon, CmMAPKs and CmMAPKKs were categorized into 4 groups, and CmMAPKKKs were categorized into 3 groups. Furthermore, chromosome location revealed an unevenly distribution on chromosomes of MAPK cascade genes in melon, respectively. Eventually, qRT-PCR analysis showed that all 14 CmMAPKs had different expression patterns under drought, salt, salicylic acid (SA), methyl jasmonate (MeJA), red light (RL), and Podosphaera xanthii (P. xanthii) treatments. Overall, the expression levels of CmMAPK3 and CmMAPK7 under different treatments were higher than those in control. Our study provides an important basis for future functional verification of MAPK genes in regulating responses to stress and signal substance in melon.

The peripheral hematologic parameters of patients can be prognostic for many malignant tumors, including breast cancer, although their value has not been investigated among the different molecular subtypes of breast cancer. The purpose of this study was to examine the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) in different molecular subtypes of breast cancer. A retrospective cohort of 1570 operable breast cancer patients was recruited between January 2000 and December 2010. The counts of peripheral neutrophils, lymphocytes, monocytes and platelets were collected and applied to calculate the NLR and the LMR. Univariate and multivariate Cox proportional hazard analyses were used to assess the relationship of the NLR and the LMR with disease-free survival (DFS) and overall survival (OS) in all patients and triple negative breast cancer (TNBC) patients. Univariate analysis revealed that lower NLR (≤2.0) and higher LMR (>4.8) were significantly associated with superior DFS in all patients (NLR, P = 0.005; LMR, P = 0.041) and in TNBC patients (NLR, p = 0.007; LMR, P = 0.011). However, multivariate analysis revealed that only lower NLR was a significant independent predictor of superior DFS and OS in all breast cancer patients (DFS, HR = 1.50 95% CI: 1.14-1.97, P = 0.004; OS, HR = 1.63, 95% CI: 1.07-2.49, P = 0.022) and in TNBC patients (DFS, HR = 2.58, 95% CI: 1.23-5.42, P = 0.012; OS, HR = 3.05, 95% CI: 1.08-8.61, P = 0.035). Both univariate and multivariate analysis revealed that neither the NLR nor the LMR significantly predicted DFS and OS among the patients with other molecular subtypes of breast cancer. A higher pretreatment peripheral NLR significantly and independently indicated a poor prognosis for breast cancer and TNBC, and this measurement exhibited greater prognostic value than a lower LMR. The NLR was not a prognostic factor for other breast cancer subtypes.

Cucumber (Cucumis sativus L.) is an important vegetable crop species with great economic value. Shoot architecture determines the visual appearance of plants and has a strong impact on crop management and yield. Unlike most model plant species, cucumber undergoes vegetative growth and reproductive growth simultaneously, in which leaves are produced from the shoot apical meristem and flowers are generated from leaf axils, during the majority of its life, a feature representative of the Cucurbitaceae family. Despite substantial advances achieved in understanding the regulation of plant form in Arabidopsis thaliana, rice, and maize, our understanding of the mechanisms controlling shoot architecture in Cucurbitaceae crop species is still limited. In this review, we focus on recent progress on elucidating the genetic regulatory pathways underlying the determinant/indeterminant growth habit, leaf shape, branch outgrowth, tendril identity, and vine length determination in cucumber. We also discuss the potential of applying biotechnology tools and resources for the generation of ideal plant types with desired architectural features to improve cucumber productivity and cultivation efficiency.

Background and Aims. Recent evidences reveal that epithelial to mesenchymal transition (EMT) exacerbates the process of intestinal fibrosis. Tumor necrosis factor-like ligand 1A (TL1A) is a member of the tumor necrosis family (TNF), which can take part in the development of colonic inflammation and fibrosis by regulating immune response or inflammatory factors. The purpose of this study was to elucidate the possible contribution of TL1A in onset and progression of intestinal inflammation and fibrosis through EMT. Methods. Colonic specimens were obtained from patients with inflammatory bowel disease (IBD) and control individuals. The expression levels of TL1A and EMT-related markers in intestinal tissues were evaluated. Furthermore, the human colorectal adenocarcinoma cell line, HT-29, was stimulated with TL1A, anti-TL1A antibody, or BMP-7 to assess EMT process. In addition, transgenic mice expressing high levels of TL1A in lymphoid cells were used to further investigate the mechanism of TL1A in intestinal fibrosis. Results. High levels of TL1A expression were detected in the intestinal specimens of patients with ulcerative colitis and Crohn’s disease and were negatively associated with the expression of an epithelial marker (E-cadherin), while it was positively associated with the expression of interstitial markers (FSP1 and α-SMA). Transgenic mice with high expression of TL1A were more sensitive to dextran sodium sulfate and exhibited severe intestinal inflammation and fibrosis. Additionally, the TGF-β1/Smad3 pathway may be involved in TL1A-induced EMT, and the expression of IL-13 and EMT-related transcriptional molecules (e.g., ZEB1 and Snail1) was increased in the intestinal specimens of the transgenic mice. Furthermore, TL1A-induced EMT can be influenced by anti-TL1A antibody or BMP-7 in vitro. Conclusions. TL1A participates in the formation and process of EMT in intestinal fibrosis. This new knowledge enables us to better understand the pathogenesis of intestinal fibrosis and identify new therapeutic targets for its treatment.

The activating and repressing nucleotides of regulatory regions are identified at a genome-wide scale using tiling reporter assays. Massively parallel reporter assays (MPRAs) enable nucleotide-resolution dissection of transcriptional regulatory regions, such as enhancers, but only few regions at a time. Here we present a combined experimental and computational approach, Systematic high-resolution activation and repression profiling with reporter tiling using MPRA (Sharpr-MPRA), that allows high-resolution analysis of thousands of regions simultaneously. Sharpr-MPRA combines dense tiling of overlapping MPRA constructs with a probabilistic graphical model to recognize functional regulatory nucleotides, and to distinguish activating and repressive nucleotides, using their inferred contribution to reporter gene expression. We used Sharpr-MPRA to test 4.6 million nucleotides spanning 15,000 putative regulatory regions tiled at 5-nucleotide resolution in two human cell types. Our results recovered known cell-type-specific regulatory motifs and evolutionarily conserved nucleotides, and distinguished known activating and repressive motifs. Our results also showed that endogenous chromatin state and DNA accessibility are both predictive of regulatory function in reporter assays, identified retroviral elements with activating roles, and uncovered 'attenuator' motifs with repressive roles in active chromatin.

Background Intestinal hyper-permeability plays a critical role in the etiopathogenesis of inflammatory bowel disease (IBD) by affecting the penetration of pathogens, toxic compounds and macromolecules. 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the active form of vitamin D, has been shown to be an important regulator of IBD and recent epidemiology suggests that patients with IBD have an impaired vitamin D status. The purpose of this study is to investigate the possible protective effects of 1,25(OH) 2 D 3 on mucosal injury and epithelial barrier disruption on dextran sulfate sodium (DSS)-induced acute colitis model. Methods We used DSS-induced acute colitis model to investigate the protective effects of 1,25(OH) 2 D 3 on mucosal injury and epithelial barrier integrity. Severity of colitis was evaluated by disease activity index (DAI), body weight (BW) change, colon length, histology, myeloperoxidase (MPO) activity, and proinflammatory cytokine production including tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In vitro the protective role of 1,25(OH) 2 D 3 was assessed by incubating Caco-2 cells with or without DSS and measuring transepithelial electrical resistance (TEER) and fluorescein isothiocyanate dextran (FITC-D). The intestinal permeability was analyzed by FITC-D, bacterial translocation and measurement of lipopolysaccharide (LPS). Ultrastructural features of the colon tissue and Caco-2 cell monolayer were observed by electron microscopy. Expressions of tight junction (TJ) proteins in the colon mucosa and Caco-2 cells were detected by immunohistochemistry, immunofluorescence, Western blot and real-time fluorescent quantitative PCR, respectively. Results DSS-induced acute colitis model was characterized by a reduced BW, AUC of BW, serum calcium, higher DAI, AUC of DAI, shortened colon length, elevated MPO activity, worsened histologic inflammation, increased mononuclear cell numbers in mesenteric lymph nodes (MLNs) and colonic lamina propria (LP), and enhanced proteins and mRNA levels of TNF-α and IFN-γ. 1,25(OH) 2 D 3 markedly increased expressions of TJ proteins and mRNA and decreased the FITC-D permeability and the level of LPS. Furthermore, 1,25(OH) 2 D 3 abrogated bacterial translocation to MLNs and ameliorated ultrastructural features of the colon epithelium by scanning electron microscopy (SEM). In vitro , 1,25(OH) 2 D 3 increased TEER, TJ proteins and mRNA expressions, decreased the FITC-D permeability, and preserved structural integrity of the TJ in Caco-2 cells. Conclusions 1,25(OH) 2 D 3 may play a protective role in mucosal barrier homeostasis by maintaining the integrity of junction complexes and in healing capacity of the colon epithelium. 1,25(OH) 2 D 3 may represent an attractive and novel therapeutic agent for the adjuvant therapy of IBD.

Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG 2k -Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo . More importantly, systemic delivery of paclitaxel (PTX) using the PEG 2k -Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models. The use of immunostimulatory agents to enhance the efficacy of chemotherapy is a promising strategy in cancer therapy. Here, the authors report on a micellar nanoparticle that can effectively co-deliver chemo- and immunotherapeutics, resulting in an improved in vivo antitumour response.

Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis -regulatory connections and their roles in disease. Genome annotation using chromatin profiles Large-scale chromatin profiling can be used to distinguish functional genomic elements. Here, a compendium of chromatin maps for various histone marks in multiple human cell types is presented. Using the resulting data it is possible to identify different chromatin states corresponding to distinct regulatory elements such as repressed and active promoters, enhancers and insulators. Several disease-associated single nucleotide polymorphisms are shown to overlap with regulatory elements. This work has implications for human disease, and in particular for interpreting genome-wide association studies.