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The transition metal iron plays a crucial role in living cells. However, high levels of iron are potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungus Candida albicans for colonization in the iron-rich gastrointestinal (GI) tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications (PTMs) and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 de-repress the expression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress-adaptation of C. albicans to gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism.

Purpose This study aims to prepare a low-formaldehyde and environmentally friendly glucose-lignin-based phenolic resin. Design/methodology/approach The authors directly used lignin to substitute formaldehyde to prepare lignin-based phenolic resin (LPF) with urea as formaldehyde absorbent. To improve the performance of the adhesive, the biobased glucose was introduced and the modified glucose-LPF (GLPF) was obtained. Findings The results showed that when the replacing amount of lignin to formaldehyde reached 15 Wt.%, the physical properties of the prepared LPF met the Chinese national standard, and the bonding strength increased by 21.9%, from 0.75 to 0.96 MPa, compared with PF. The addition of glucose boost the performance of wood adhesive, for example, the free phenol content of the obtained GLPF was significantly reduced by 79.11%, from 5.60% to 1.17%, the bonding strength (1.19 MPa) of GLPF increased by 19.3% in comparison to LPF and the curing temperature of GLPF decreased by 13.08%. Practical implications The low-formaldehyde and environmentally friendly GLPF has higher bonding strength and lower curing temperature, which is profitable to industrial application. Social implications The prepared GLPF has lower free formaldehyde and formaldehyde emission, which is cost-effective and beneficial to human health. Originality/value The joint work of lignin and glucose provides the wood adhesive with increased bonding strength, decreased free phenol content and reduced curing temperature.

Cisplatin is the first-line chemotherapy drug for the treatment of gastric cancer (GC) patients. However, GC patients who are resistant to cisplatin often do not benefit from it. Therefore, finding a key molecule that affects cisplatin sensitivity is expected to enhance the efficacy of cisplatin in GC treatment.The human GC cell lines SGC-7901 and BGC-823 were used. The protein chip array was used to screen the cisplatin-resistance genes from the complete response and non-complete response GC patients' tissues, then, the differential gene expression analysis, GO function annotation analysis, and KEGG pathway enrichment analysis were performed. The GC tissue chip in the GEO database was analyzed to screen the target gene. Flow cytometry, Hoechst 33342 staining assay, Western Blot, MTT, tumor sphere formation, cell cycle, and apoptosis assays were performed to explore the effect of Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase (LHPP) on the apoptosis, stemness, and reactive oxygen species (ROS) accumulation of cisplatin-resistant GC cells treated with cisplatin. In vivo, the cisplatin-resistant GC cell lines transfected with pcDNA-LHPP or si-LHPP were injected subcutaneously into mice to construct GC subcutaneous xenograft GC models.Based on protein chip array and bioinformatics analysis, it was found that LHPP is the core molecule in the cisplatin resistance regulatory network in GC, and its expression is down-regulated in GC cisplatin-resistant tissues and cells. In vitro and in vivo experimental results show that the up-regulated expression of LHPP is closely related to the increase in sensitivity of GC to cisplatin. Mechanically, we found that overexpression of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, promote cisplatin-induced ROS accumulation, suppress stemness, and enhance the sensitivity of GC to cisplatin.Up-regulation of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, attenuate stemness, and enhance the accumulation of intracellular ROS, thereby promoting cisplatin-mediated GC cell apoptosis and enhancing cisplatin sensitivity.

Lipid droplets (LDs), the highly dynamic intracellular organelles, are critical for lipid metabolism. Dynamic alterations in the configurations and functions of LDs during innate immune responses to bacterial infections and the underlying mechanisms, however, remain largely unknown. In this study, we trace the time-course morphology of LDs in fat bodies of Drosophila after transient bacterial infection. Detailed analysis shows that perilipin1 (plin1), a core gene involved in the regulation of LDs, is suppressed by the immune deficiency signaling, one major innate immune pathway in Drosophila. During immune activation, downregulated plin1 promotes the enlargement of LDs, which in turn alleviates immune reaction–associated reactive oxygen species stress. Thus, the growth of LDs is likely an active adaptation to maintain redox homeostasis in response to immune deficiency activation. Therefore, our study provides evidence that plin1 serves as a modulator on LDs’ reconfiguration in regulating infection-induced pathogenesis, and plin1 might be a potential therapeutic target for coordinating inflammation resolution and lipid metabolism.

In this paper, a low-formaldehyde and environmentally friendly phenol-formaldehyde resin wood adhesive was prepared by directly using lignin to substitute formaldehyde, which was further modified by glucose to improve the physical, mechanical, and curing properties. The results showed that when the replacing amount of lignin to formaldehyde reached 15 wt%, the physical properties of the prepared lignin-based-phenolic resin (LPF) can meet the Chinese national standard, and the bonding strength can increase by 21.9%, from 0.75 MPa to 0.96 MPa, compared with phenolic resin (PF). The addition of glucose boost the performance of wood adhesive, for example, the free phenol content of the obtained glucose-lignin-based phenolic resin (GLPF) significantly reduced by 79.11%, from 5.60–1.17%, the bonding strength (1.19 MPa) of GLPF increased by 19.3% in comparison to LPF, and the curing temperature of GLPF decreased by 13.08%. FT-IR results showed that the main structure of the resin did not change before and after substitution by lignin and modification by glucose. The present study provides a simple and green method for preparing resins.

Transcription factors are frequently aberrantly reactivated in various cancers, including colorectal cancer (CRC). However, as a transcription factor, the role of GMEB2 in cancer is still unclear, and further studies are needed. Here, we aimed to identify the function and mechanism of GMEB2 in regulating the malignant progression of CRC. GMEB2 was found to be highly expressed in online data analyses. We demonstrated that GMEB2 was markedly upregulated at both the mRNA and protein levels in CRC cells and tissues. GMEB2 knockdown inhibited CRC cell growth in vitro and in vivo. Mechanistically, as a transcription factor, GMEB2 transactivated the ADRM1 promoter to increase its transcription. Rescue experiments showed that ADRM1 downregulation partially reversed the promoting effects of GMEB2 on CRC growth in vitro. Moreover, the GMEB2/ADRM1 axis induced nuclear translocation of NF-κB, thus activating NF-κB signalling. Finally, we further revealed that YTHDF1 recognized and bound to the m

In recent years there has been a growing interest in treating many-body systems as Bell scenarios, where lattice sites play the role of distant parties and only near-neighbor statistics are accessible. We investigate contextuality arising from three Bell scenarios in infinite, translation-invariant 1D models: nearest-neighbor with two dichotomic observables per site; nearest- and next-to-nearest neighbor with two dichotomic observables per site, and nearest-neighbor with three dichotomic observables per site. For the first scenario, we give strong evidence that it cannot exhibit contextuality, not even in non-signaling physical theories beyond quantum mechanics. For the second one, we identify several low-dimensional models that reach the ultimate quantum limits, paving the way for self-testing ground states of quantum many-body systems. For the last scenario, which generalizes the Heisenberg model, we give strong evidence that, in order to exhibit contextuality, the dimension of the local quantum system must be at least 3.

In contrast to the extensive but non-recyclable use of tetraalkoxydiboron(4) compounds as stoichiometric reagents in diverse reactions, this article reports an atom-economical reaction using a commercial diboron(4) as the catalyst. The key to success was designing a catalytic cycle for radical [3 + 2] cycloaddition involving a pyridine cocatalyst to generate from the diboron(4) catalyst and reversibly mediate the transfer of boronyl radicals. In comparison with known [3 + 2] cycloaddition with transition metal-based catalysts, the current reaction features not only metal-free conditions, inexpensive and stable catalysts, and simple operation but also remarkably broadened substrate scope. In particular, previously unusable cyclopropyl ketones without an activating group and/or alkenes with 1,2-disubstitution and 1,1,2-trisubstitution patterns were successfully used for the first time. Consequently, challenging cyclopentane compounds with various levels of substitution (65 examples, 57 new products, up to six substituents at all five ring atoms) were readily prepared in generally high to excellent yield and diastereoselectivity. The reaction was also successfully applied in concise formal synthesis of an anti-obesity drug and building natural product-like complex bridged or spirocyclic compounds. Mechanistic experiments and computational investigation support the proposed radical relay catalysis featuring a pyridine-assisted boronyl radical catalyst. Overall, this work demonstrates the first approach to use tetraalkoxydiboron(4) compounds as catalysts and may lead to the development of new, green, and efficient transition metal-like boron-catalyzed organic reactions.

Background: Bronchiolar adenoma (BA)/ciliated muconodular papillary tumors (CMPTs) was previously considered to be a benign neoplasm, with the possibility of malignant transformation reported in a few cases. Thus, the exact nature and biological potential of BA/CMPT have not been fully elucidated. We here report a case of mucinous adenocarcinoma (MA) caused by malignant transformation of BA. Case presentation: A 57-year-old woman presented with a 17.0×7.0 mm nodule in the lower lobe of the left lung. Hematoxylin-eosin (H&E) staining and immunohistochemistry were performed. The tumor was composed of two areas: BA area and MA area. In BA area, the tumor was consisted by a bilayered structure of luminal cells and basal cells. Basal cells were positive for CK5/6, p63, and p40, while they were not detected in MA area. The Ki-67 proliferation index was low (1%~2%). Finally, the patient was diagnosed with BA accompanied by MA, and had a favourable outcome.Conclusions: BA is generally considered to be a benign tumor. The present study indicated that BA may be carcinogenic and we should be vigilant for its potentiality of malignant transformation in clinical practice.

Background Previous studies have shown that the N6-methyladenosine (m6A) modification enhances the binding ability of mRNAs/long noncoding RNAs (lncRNAs) to microRNAs (miRNAs), but the impact of this modification on the competitive endogenous RNA (ceRNA) function of circular RNAs (circRNAs) is unclear. Methods We used a human circRNA microarray to detect the expression profiles of circRNAs in 3 pairs of cancer and paracancerous tissues from patients with colorectal cancer (CRC) and 3 pairs of peripheral blood specimens from patients with CRC and healthy individuals. The circRNAs highly expressed in both peripheral blood and tumour tissues of patients with CRC, including circALG1, were screened. A quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis of an expanded sample size was performed to detect the expression level of circALG1 in peripheral blood and tumour tissues of patients with CRC and determine its correlation with clinicopathological features, and circRNA loop-forming validation and stability assays were then conducted. Transwell assays and a nude mouse cancer metastasis model were used to study the function of circALG1 in CRC and the role of altered m6A modification levels on the regulation of circALG1 function. qRT-PCR, western blot (WB), Transwell, RNA-binding protein immunoprecipitation (RIP), RNA antisense purification (RAP), and dual-luciferase reporter gene assays were performed to analyse the ceRNA mechanism of circALG1 and the effect of the m6A modification of circALG1 on the ceRNA function of this circRNA. Results CircALG1 was highly expressed in both the peripheral blood and tumour tissues of patients with CRC and was closely associated with CRC metastasis. CircALG1 overexpression promoted the migration and invasion of CRC cells, and circALG1 silencing and reduction of the circALG1 m6A modification level inhibited CRC cell migration and invasion. In vivo experiments further confirmed the prometastatic role of circALG1 in CRC. Further mechanistic studies showed that circALG1 upregulated the expression of placental growth factor (PGF) by binding to miR-342-5p and that m6A modification enhanced the binding of circALG1 to miR-342-5p and promoted its ceRNA function. Conclusion M6A modification enhances the binding ability of circALG1 to miR-342-5p to promote the ceRNA function of circALG1, and circALG1 could be a potential therapeutic target in and a prognostic marker for CRC.

In contrast to the extensive but non-recyclable use of tetraalkoxydiboron(4) compounds as stoichiometric reagents in diverse reactions, this article reports an atom-economical reaction using a commercial diboron(4) as the catalyst. The key to success was designing a catalytic cycle for radical [3+2] cycloaddition involving a pyridine cocatalyst to generate from the diboron(4) catalyst and reversibly mediate the transfer of boronyl radicals. In comparison with known [3+2] cycloaddition with transition metal-based catalysts, the current reaction features not only metal-free conditions, inexpen-sive and stable catalysts, and simple operation, but also remarkably broadened substrate scope. In particular, previously unusable cyclopropyl ketones without an activating group and/or alkenes with 1,2-disubstitution and 1,1,2-trisubstitution pattern were successfully used for the first time. Consequently, challenging cyclopentane compounds with various levels of substitution (65 examples, 57 new products, up to six substituents at all five ring atoms) were readily prepared in generally high to excellent yield and diastereoselectivity. The reaction was also successfully applied in con-cise formal synthesis of an anti-obesity drug and building natural product-like complex bridged or spiralcyclic com-pounds. Mechanistic experiments and computational investigation support the proposed radical relay catalysis featuring a pyridine-assisted boronyl radical catalyst. Overall, this work demonstrates the first approach to use tetraalkoxydibo-ron(4) compounds as catalysts and may lead to the development of new, green and efficient transition metal-like boron-catalyzed organic reactions.

Elucidating the molecular mechanism of the migration and invasion is critical for identifying novel therapeutic targets and may significantly improve the prognosis of colorectal cancer. Emerging evidence suggests an involvement of dysregulated microRNAs in the process of tumorigenesis. Here, we show that miR-1225-5p prevents migration and invasion of colorectal cancer cells. Overexpression of miR-1225-5p significantly decreases the expression of Matrix Metalloproteases (MMPs)-1, 3, and 9. Knockdown of miR-1225-5p elevates ROS level via regulating Keap1/Nrf2 pathway. Furthermore, miR-1225-5p attenuates IL-17A-induced p38/AP-1-signaling pathway by suppressing IL-17RA expression. We also examined the biological effects of Rosmarinic acid (RA) on metastatic colorectal cancer cells. RA inhibited EMT via the p38/AP-1 signaling, and miR-1225-5p is essential for RA-mediated anti-metastatic effects.

Preeclampsia (PE) is one type of hypertension during pregnancy that seriously threatens maternal and infant health. Trophoblast dysfunction, such as decreased proliferation and migration, is closely related to the occurrence and development of PE. MicroRNAs (miRNAs) have been proven to play an important role in many diseases, including PE. miR-384 was reported to play a regulatory role in promoting cell apoptosis and inhibiting proliferation, migration and invasion in a variety of tumors. Previously, we found that miR-384 is upregulated in the placenta and plasma in the context of PE. In this study, we elucidated the function of miR-384 in the trophoblast cell line HTR-8/SVneo and the trophoblastic tumor cell line JEG-3. Cell proliferation and migration were inhibited by miR-384 overexpression but promoted by miR-384 downregulation. Subsequently, polypyrimidine tract-binding protein 3(PTBP3) was found to be a direct target gene of miR-384. PTBP3 was downregulated in placental tissues from PE patients, and a negative correlation was found between PTBP3 and miR-384. Our results suggest that the miR-384/PTBP3 axis plays an important role in regulating trophoblast function during the progression of PE, and these data provide novel insight into the molecular pathogenesis of this disorder.

Hypoxia plays a major role in various tumor types. However, few studies have concentrated on the prognostic model of hypoxia-related genes in rectal cancer and the effect of hypoxia on neutrophil-mediated immunosuppression. We performed Kaplan–Meier analysis, random survival forest analysis, and Cox regression analysis on 342 hypoxia-related genes, constructed hypoxia score in the Gene Expression Omnibus (GEO) cohort, and verified them in the Cancer Genome Atlas (TCGA) cohort. Then the patients were divided into two groups according to the risk level. The overall survival rate of the high-risk (HRisk) group was significantly higher than that of the low-risk (LRisk) group (GEO, p < 0.001; TCGA, p = 0.016). Through receiver operating characteristic and decision curve analysis, the nomogram based on hypoxia score has excellent prediction ability. Functional enrichment analysis showed that hypoxia, metastasis, inflammation, immunity, and other related pathways were enriched. The HRisk group was associated with lower tumor purity, higher immune and stromal score, higher neutrophils, and lower activated memory CD4 + T cells. More importantly, the checkpoint of neutrophil-mediated immunosuppression increased in the HRisk group. In conclusion, a hypoxia score based on 5 hypoxia-related genes can be used to predict the prognosis of rectal cancer and ANLN with a cancer-suppressing effect and SRPX (Sushi Repeat Containing Protein X-Linked) with a cancer-promoting effect may be potential therapeutic targets for rectal cancer.

BackgroundFerroptosis is a newly defined form of programmed cell death that plays an important role in many cancers. However, ferroptosis-related lncRNAs (FRLs) involved in the regulation of colon cancer are not thoroughly understood. This study aimed to identify a prognostic FRL signature in colon cancer and explore its potential molecular function.MethodsRNA-seq data and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database, and a list of ferroptosis-related genes was extracted from the FerrDb website. Analysis of differentially expressed FRLs was performed using the ‘limma’ package in R software. By implementing coexpression analysis and univariate Cox analysis, we then identified prognostic FRLs. Using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm, we constructed a prognostic model based on 4 FRLs. We evaluated the prognostic power of this model using Kaplan–Meier (K-M) survival curve analysis and receiver operating characteristic (ROC) curve analysis. Moreover, the relationships between the signature and immune landscape, somatic mutation and drug sensitivity were explored. Finally, in vitro experiments were conducted to validate the functions of AP003555.1 and AC000584.1.ResultsA 4-FRL signature was constructed. Two risk groups were classified based on the risk score calculated by this signature. The signature-based risk score exhibited a more powerful capacity for survival prediction than traditional clinicopathological features in colon patients. Additionally, we observed a significant difference in immune cells, such as CD4+ and CD8+ T cells and macrophages, between the two groups. Moreover, the high-risk group exhibited lower IC50 values for certain chemotherapy drugs, such as cisplatin, docetaxel, bleomycin or axitinib. Finally, the in vitro experiments showed that ferroptosis processes were suppressed after AP003555.1 and AC000584.1 knockdown.ConclusionThe proposed 4-FRL signature is a promising biomarker to predict clinical outcomes and therapeutic responses in colon cancer patients.

To investigate the influence of ROI placement methods and radiologists' experience on diffusion kurtosis imaging (DKI) and intravoxel incoherent motion (IVIM) parameters' diagnostic performance in differentiating benign and malignant lesions based on the mass and non-mass enhancement (NME).We evaluated 138 lesions in 131 patients retrospectively. The IVIM and DKI parameter values were measured by three radiologists with different experiences independently using two different ROI placement methods. IVIM parameters include diffusion coefficient (ADCIn mass lesions, inter- and intra-observer agreement were perfect for all parameters (ICC: 0.800-989). In NME, the inter-observer agreement was substantial to perfect for all parameters(ICC: 0.703-877), the intra-observer agreement of the senior and intermediate radiologists was substantial to perfect(ICC: 0.748-931) and the intra-observer agreement of the junior radiologist was moderate to substantial(ICC: 0.569-784). The diagnostic performance of ADCThe observers' experience can influence the ROI selection and the diagnostic performance of ADC

Transcription factors are frequently aberrantly reactivated in various cancers, including colorectal cancer (CRC). However, as a transcription factor, the role of GMEB2 in cancer is still unclear, and further studies are needed. Here, we aimed to identify the function and mechanism of GMEB2 in regulating the malignant progression of CRC. GMEB2 was found to be highly expressed in online data analyses. We demonstrated that GMEB2 was markedly upregulated at both the mRNA and protein levels in CRC cells and tissues. GMEB2 knockdown inhibited CRC cell growth in vitro and in vivo. Mechanistically, as a transcription factor, GMEB2 transactivated the ADRM1 promoter to increase its transcription. Rescue experiments showed that ADRM1 downregulation partially reversed the promoting effects of GMEB2 on CRC growth in vitro. Moreover, the GMEB2/ADRM1 axis induced nuclear translocation of NF-κB, thus activating NF-κB signalling. Finally, we further revealed that YTHDF1 recognized and bound to the m6A site on GMEB2 mRNA, which enhanced its stability. Taken together, our findings reveal the crucial role and regulatory mechanism of GMEB2 in CRC for the first time and provide a novel potential therapeutic target for CRC therapy.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that causes a range of social communication and behavioral impairments. ASD typically manifests in young children, often with developmental delay or intellectual disabilities (DD/ID) as comorbidities. Accruing evidence indicates that ASD is highly heritable and genomewide studies on ASD cohorts have defined numerous genetic contributors. Notably, most of these studies have been performed with individuals of European and Hispanic ancestry and thus there is a paucity of genetic analyses of ASD in the East Asian population. Here, we performed whole-exome sequencing on 772 ASD trios from China, combining with a previous study of 369 Chinese ASD trios, to identify de novo variants in a total of 1141 ASD trios. We found that ASD probands without DD/ID carried less disruptive de novo variants, including protein-truncating and missense variants, than ASD with DD/ID. Surprisingly, we showed that expression of genes with de novo variants found in ASD probands without DD/ID were enriched in a specific group of neural progenitor cells, suggesting a potential mechanism underlying high-functioning autism. Importantly, some ASD risk genes from this study are not present in the current ASD gene database, suggesting that there are novel genetic contributors to ASD in East Asian populations. We validated one such novel ASD risk gene – SLC35G1 by showing that mice harboring heterozygous deletion of Slc35g1 exhibited defects in social interaction behaviors. Together, this work nominates novel ASD risk genes and indicates that ASD genetic studies in different geographic populations are essential to reveal the comprehensive genetic architecture of ASD.

Previous studies have shown that the NWe used a human circRNA microarray to detect the expression profiles of circRNAs in 3 pairs of cancer and paracancerous tissues from patients with colorectal cancer (CRC) and 3 pairs of peripheral blood specimens from patients with CRC and healthy individuals. The circRNAs highly expressed in both peripheral blood and tumour tissues of patients with CRC, including circALG1, were screened. A quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis of an expanded sample size was performed to detect the expression level of circALG1 in peripheral blood and tumour tissues of patients with CRC and determine its correlation with clinicopathological features, and circRNA loop-forming validation and stability assays were then conducted. Transwell assays and a nude mouse cancer metastasis model were used to study the function of circALG1 in CRC and the role of altered mCircALG1 was highly expressed in both the peripheral blood and tumour tissues of patients with CRC and was closely associated with CRC metastasis. CircALG1 overexpression promoted the migration and invasion of CRC cells, and circALG1 silencing and reduction of the circALG1 mM

MicroRNAs (miRNAs) and their target genes have been shown to play an important role in gastric cancer but have not been fully clarified. Therefore, our goal was to identify the key miRNA–mRNA regulatory network in gastric cancer by utilizing a variety of bioinformatics analyses and experiments. A total of 242 miRNAs and 1080 genes were screened from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. Then, survival-related differentially expressed miRNAs and their differentially expressed target genes were screened. Twenty hub genes were identified from their protein–protein interaction network. After weighted gene co-expression network analysis was conducted, we selected miR-137-3p and its target gene, COL5A1, for further research. We found that miR-137-3p was significantly downregulated and that overexpression of miR-137-3p suppressed the proliferation, invasion, and migration of gastric cancer cells. Furthermore, we found that its target gene, COL5A1, could regulate the expression of another hub gene, FSTL1, by sponging miR-137-3p, which was confirmed by dual-luciferase reporter assays. Knockdown of COL5A1 inhibited the proliferation, invasion, and migration of gastric cancer cells, which could be rescued by the miR-137-3p inhibitor or overexpression of FSTL1. Ultimately, bioinformatics analyses showed that the expression of FSTL1 was highly correlated with immune infiltration.

To utilize carbon source and decompose the petroleum hydrocarbon substances simultaneously, adding the electrolysis to ozonation (E

Lipid droplets (LDs) are dynamic intracellular organelles critical for lipid metabolism. Alterations in the dynamics and functions of LDs during innate immune response to infections and the underlying mechanisms however, remain largely unknown. Herein, we describe the morphological dynamics of LDs in fat body of Drosophila, which vary between transient and sustained bacterial infections. Detailed analysis shows that perilipin1 (plin1), a core gene regulating lipid metabolism of LDs is suppressed by IMD/Relish, an innate immune signaling pathway via Martik (MRT) /Putzig (PZG) complex. During transient immune activation, downregulated plin1 promotes the formation of large LDs, which alleviates immune reaction-induced reactive oxygen species (ROS) stress. Thus, the growth of LDs is likely an active adaptation to maintain redox homeostasis in response to IMD activation. Whereas, under sustained inflammatory conditions, plin1 deficiency accelerates excessive decomposition of large LDs through recruitment of Brummer/ATGL lipase resulting in energy wasting, severe lipotoxicity and then deteriorated pathogenesis. Taken together, our study provides evidence that plin1 has a dual function on LDs'morphology in regulating infection-induced pathogenesis, and Plin1 might be a potential therapeutic target for coordinating inflammation resolution and lipid metabolism.

In higher plants, the light-harvesting chlorophyll a/b-binding (Lhc) proteins function in multiple processes that are critical to plant growth, development, and abiotic stress response. However, the Lhc gene family has not been well characterized in the important fruit crop, apple (Malus × domestica Borkh.). In this study, we identified 27 Lhc genes in the apple genome. Phylogenetic analysis showed that the Lhc gene family could be classified into three major subfamilies, each of whose members shared similar conserved motifs. Evolutionary analysis indicated that duplicated MdLhc genes were primarily under purifying selection. MdLhcs were expressed at varying levels in all tissues examined and showed different expression patterns under drought stress. The overexpression of MdLhcb4.3 in transgenic Arabidopsis and apple callus enhanced their tolerance to drought and osmotic stress. Taken together, these results demonstrate the important role of Lhc proteins in the regulation of plant resistance to drought and osmotic stress and provide valuable information for further study of Lhc functions in apple.

Due to the high mutation and recombination rates of the influenza virus, current clinically licensed influenza vaccines and anti-influenza drugs provide limited protection against the emerging influenza virus epidemic. Therefore, universal influenza vaccines with high efficacy are urgently needed to ensure human safety and health. Passive immunization of influenza broadly neutralizing antibodies may become an ideal option for controlling influenza infection. CR9114 isolated from the peripheral blood mononuclear cells of healthy donors is a broadly neutralizing monoclonal antibody that targets different types of influenza viruses. As the adenovirus vector is one of the most promising delivery vehicles, we employed the chimpanzee adenoviral vector, AdC68, to express CR9114 as a universal anti-influenza vaccine, termed AdC68-CR9114, and evaluated its antibody expression and its broad spectrum of prophylactic and therapeutic effects in animal models. Based on our findings, AdC68-CR9114-infected cell expressed the broadly neutralizing antibody at a high level in vitro and in vivo, exhibited biological functions, and protected mice from different types of influenza virus infection at different time points. The findings from this study shed light on a new strategy for controlling and preventing influenza infection.

Chimeric Antigen Receptor (CAR)-T cells have great efficacy against CD19+ leukemia but little success for solid tumors. This study explored the effectiveness of third generation anti-HER2 CAR-T cells alone or in combination with anti-PD1 antibody on breast tumor cells expressing HER2 in vitro and in immune competent mouse model. The PDL1-positive mouse mammary tumor cell line 4T1 engineered to express luciferase and human HER2 was used as the target cell line (4T1-Luc-HER2). Anti-HER2 CAR-T cells were generated by transducing mouse spleen T cells with recombinant lentiviruses. ELISA analysis showed that IL-2 and IFN-γ secretion was increased in CAR-T cells co-cultured with the target cells, and the secretion of these two cytokines was increased further with the addition of anti-PD1 antibody. Lactate dehydrogenase assay revealed that CAR-T cells displayed a potent cytotoxicity against the target cells, and the addition of anti-PD1 antibody further enhanced the cytotoxicity. At the effector: target ratio of 16:1, cytotoxicity was 39.8% with CAR-T cells alone, and increased to 49.5% with the addition of anti-PD1 antibody. In immune competent syngeneic mouse model, CAR-T cells were found to be present in tumor stroma, inhibited tumor growth and increased tumor apoptosis significantly. Addition of anti-PD1 antibody further enhanced these anti-tumor activities. Twenty-one days after treatment, tumor weight was reduced by 50.0% and 73.3% in CAR-T group and CAR-T plus anti-PD1 group compared with blank T group. Our results indicate that anti-PD1 antibody can greatly increase the efficacy of anti-HER2 CAR-T against HER2-positive solid tumors.

Gastrointestinal acute graft-vs.-host disease (GI aGVHD) remains a significant obstacle to the success of allogeneic hematopoietic cell transplantation and is a major cause of morbidity and mortality. In addition, GI aGVHD is often clinically indistinguishable from other causes of GI dysfunction such as conditioning regimen toxicity, infections, or medications, which complicates the diagnosis. Thus, specific biomarkers are needed to help improve diagnosis and obtain a deeper understanding of the cytokine changes in GI aGVHD. An MHC-mismatched model of aGVHD was established by transplanting 1 × 107 bone marrow nuclear cells and 3 × 107 spleen cells from C57/Bl6 mice or from BALB/c mice into lethally irradiated BALB/c recipients. The mice in the allogeneic transplantation group were intraperitoneally treated with 20 mg kg−1 day−1 cyclosporin A after aGVHD developed. Five micrograms of lipopolysaccharide were administered intraperitoneally daily to syngeneic recipients at day 11 to imitate infection; the same volume of phosphate-buffered saline was administered to control mice. The mice were killed at the indicated time points. Forty molecules derived from the GI tract were screened cytokine array. The data demonstrated that the expression of B lymphocyte chemoattractant (CXCL13) was increased by ~10-, 12-, and 16-fold upon the occurrence of aGVHD compared with infection, aGVHD after treatment, and the syngeneic control group, respectively. Thus, the elevation of BLC (CXCL13) is an indicator of acute GI GVHD.

We combine dual interval valued hesitant fuzzy sets with rough sets to construct a hybrid uncertainty theory. According to the proposed dual interval valued hesitant fuzzy relation, our paper firstly investigated the two rough approximation operators, lower and upper of dual interval valued hesitant fuzzy set. Properties of the two rough approximation operators, their relationships between three specific dual interval valued hesitant fuzzy sets as well as four special fuzzy relations, serial, reflexive, symmetric and transitive relations of the dual interval valued hesitant fuzzy are further studied. Finally, We show the proposed dual interval valued hesitant fuzzy rough set anastz can help making decisions in clinic medical diagnosis.

Rabies continues to poses serious threats to the public health in many countries. The development of novel inexpensive, safe and effective vaccines has become a high priority for rabies control worldwide. We previously generated a novel recombinant rabies vaccine by cloning rabies virus glycoprotein into a chimpanzee adenoviral vector, termed ChAd68-Gp. The present study evaluated the immune responses and protection afforded by this vaccine in beagle dogs. The results demonstrated that intramuscular immunization with both low-dose and high-dose of ChAd68-Gp induced strong immune responses and provided complete protection in beagles even at low-dose. However, when administered orally, high-dose vaccination was protective while low-dose vaccination was ineffective. Further investigation indicated that the low-pH value of gastric juice in the stomach of beagles might decompose the adenovirus. Therefore, suitable formulation for adenovirus-based oral vaccine should be considered and developed. The chimpanzee adenovirus-vectored rabies vaccine ChAd68-Gp warrants extensive test for clinical application.

To evaluate the safety and feasibility of neoadjuvant chemotherapy prior elective surgery following self-expanding metallic stents (SEMS) for complete obstructive left hemicolon cancer.This prospective, multicenter, open-labelled trial was approved by the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University(2016-ke-161-1) and registered in Clinicaltrials.gov (NCT02972541).(1)age between 18 and 75 years old;(2) adenocarcinoma confirmed by pathology;(3) left hemicolon cancer confirmed by clinical manifestations and imaging examinations with the distance to anal verge15 cm; (4) resectable cancer evaluated by imaging examination without distant metastasis; (5) Eastern Cooperative Oncology Group (ECOG) score ≤ 1 or Karnofsky Performance Scale (KPS)70, indicating tolerance of neoadjuvant chemotherapy and operation; (6) absence of chemotherapy or radiotherapy within past six months; (7) bone marrow system and hepatorenal function: hemoglobin ≥ 90 g/L, neutrophil ≥ 1.5×10(1) multiple primary colorectal cancer; (2) rejection of operation;(3) presenting peritonitis or bowel perforation before SEMS; (4) unqualified conditions proved by inspector from registration data. According to inclusion criteria, 62 consecutive patients receiving neoadjuvant chemotherapy prior to elective surgery following SEMS for complete obstructive left hemicolon cancer from Beijing Chaoyang Hospital of Capital Medical University (n=31), Qilu Hospital of Shandong University (n=14), the Third Xiangya Hospital of Central South University (n=13), Zhongnan Hospital of Wuhan University (n=2), the Fourth Hospital of Hebei Medical University (n=2) between December 2015 and December 2017 were prospectively enrolled in this study. Patients were divided into neoadjuvant chemotherapy group and elective surgery group according to the investigator's clinical experience and patient's preference. Patients in the elective surgery group received surgery within one to two weeks after SEMS placement without neoadjuvant chemotherapy. Those in the neoadjuvant chemotherapy group received 2 cycles of CapeOX or 3 cycles of mFOLFOX6 neoadjuvant chemotherapy within one to two weeks after SEMS placement, and then underwent surgery within 3 weeks after finishing neoadjuvant chemotherapy. Data between groups were compared using Student t-test, chi-square analysis or Fisher exact test analysis, including basic clinical informations, operational conditions and postoperative complications. The adverse reactions during the neoadjuvant chemotherapy were recorded. Surgical difficulty was assessed using visual analog scales ranging from 1 to 10, where 1 represented the lowest and 10 the highest degree of surgical difficulty, as judged by the surgeon.The study included 38 males and 24 females with mean age of (64.8±8.8) years. The clinical baseline data between 2 groups were not significantly different (all P0.05) except the average time interval between SEMS and surgery was significantly longer in neoadjuvant chemotherapy group [(61.6±13.5) days vs. (10.4±5.2) days, t=16.679, P0.001]. There was no stent migration in either group. Three patients had perforation in the elective surgery group; one patient had perforation and one had obstruction in the neoadjuvant chemotherapy group; and all these patients received emergent surgery. Adverse reactions of neodajuvant chemotherapy were mainly degree 1 and 2 except one patient with degree 3 diarrhea. Patients in neoadjuvant chemotherapy group had significantly lower rate of stoma [4.8%(1/21) vs. 34.1%(14/41), χ²=6.538, P=0.011], higher rate of laparoscopic surgery [71.4%(15/21) vs. 36.6%(15/41), χ²=6.751, P=0.009], shorter mean operative time (147 minutes vs. 178 minutes, t=-3.255, P=0.002), less mean intraoperative blood loss (47 ml vs. 127 ml, t=-4.129, P0.001), lower degree of surgical difficulty(3.3 vs. 5.6, t=-5.091, P0.001), shorter mean postoperative exhausting time (56.2 hours vs. 69.0 hours, t=-2.891, P=0.006), and shorter mean postoperative hospital stay (8.5 days vs. 13.5 days, t=-2.246, P=0.028) as compared with patients in the elective surgery group. Surgical site infection rate and anastomotic leakage rate did not differ significantly between two groups(all P0.05).Neoadjuvant chemotherapy prior elective surgery following SEMS is a relatively safe and feasible approach in the treatment for obstructive left hemicolon cancer, and is associated with less stoma, more laparoscopic surgery, shorter operative time, less blood loss, lower surgical difficulty, and faster postoperative recovery as compared with conventional elective surgery.

In this paper, the output feedback control problem for a genetic hypersonic vehicle is considered under the restriction that only the vehicle’s velocity and altitude are measurable. High gain observers (HGO) are utilized to provide estimation signals for unmeasurable derivatives of the vehicle’s velocity and altitude. Neural network based feedforward function is designed to compensate for model uncertainties. The proposed control design require less knowledge of the hypersonic vehicle’s dynamic model. A comprehensive stability analysis of the closed loop system under the output feedback control is carried to prove that the proposed control law yields semiglobal uniformly ultimately bounded tracking while keeping all the closed loop signals bounded. Numerical simulation results are presented to validate the proposed control design.

In this paper, a neural network based continuous control mechanism that can compensate for system uncertainties is developed for a class of robot manipulators under both repeating and non-repeating disturbances. With limited assumptions about the systems’ dynamics, Lyapunov techniques are utilized to show that a semi-global asymptotic tracking result is achieved while all the closed-loop states remain bounded. Numerical simulation results are provided to demonstrated that the proposed control design achieves a good tracking performance.

We describe CT features of our three cases with localized Castleman disease in the retroperitoneum and review literature. Besides those CT features, which have been reported before, we mainly present some newly discovered CT findings of the disease. These new CT findings include the sign of peripheral 'rim-like' enhancement at the early phase of an enhanced CT scan, a higher ratio of the left sided retroperitoneal location to the right side and the presence of local peritoneal thickening around the lesion. In addition, the feeding artery of the lesion is more visually pronounced than ever before by a 16-detector CT scanner.After reviewing the literature and comparing with their histological findings, we suggest these newly discovered findings are relatively characteristic CT features of the disease. Moreover, multi-detector helical CT can now show more details of the disease than ever before.

Mixed linage leukemia gene 2 (MLL2) is identified as a novel mutation gene in diffuse large B cell lymphoma (DLBCL). However, the significance of MLL2 protein expression for the prognosis of DLBCL is unclear. In this study, we detected MLL2 protein expression in primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) samples by using tissue microarray immunohistochemistry, and analyzed the correlation between MLL2 protein expression and tumor proliferation activity. In addition, we investigated clinical significance of MLL2 protein expression for PGI-DLBCL prognosis. We found that there was significant difference in MLL2 protein expression between PGI-DLBCL and reactive hyperplasia of lymph node. High expression of MLL2 protein indicated higher clinical stage. In older patients (>60 years) with PGI-DLBCL, MLL2 protein expression was positively correlated with Ki-67 expression and negatively correlated with patient survival. Our data suggest that MLL2 protein is overexpressed in PGI-DLBCL and appears as a prognostic factor for patients of PGI-DLBCL, especially for those older than 60 years old.

Gastric cancer is a malignant disease of the digestive system with high rates of incidence and mortality. S‑phase kinase‑associated protein 2 (Skp2) is a novel oncogene, which has been identified to be important in tumor progression and metastasis. In order to clarify the role of Skp2 in human gastric cancer, the present study detected the expression of Skp2 in human gastric cancer tissues, and investigated the molecular mechanism of Skp2 in the progression of gastric carcinoma. The results of the initial bioinformatics analysis showed that Skp2 was significantly upregulated in 31 specimens of primary gastric cancer from a UK patient cohort, and in 10 gastric cancer lines of a side population, compared with normal gastric tissues (P

Effects of the Epstein-Barr virus (EBV) on cellular protein expression are essential for viral pathogenesis. To characterize the cellular response to EBV infection, differential proteomes of gastric epithelial AGS cells were analyzed with two-dimensional gel electrophoresis (2-DE) followed by matrix-assisted laser desorption/ionization- time of flight (MALDI-TOF) and liquid chromatography electrospray/ionization ion trap (LC-ESI-IT) mass spectrometry identification. Mass spectrometry identified 9 altered cellular proteins, including 5 up-regulated and 4 down-regulated proteins after EBV infection. Notably 2-DE analysis revealed that EBV infection induced increased expression of heat shock cognate 71 kDa protein, actin cytoplasmic 1, pyridoxine-5'-phosphate oxidase, caspase 9, and t-complex protein 1 subunit alpha. In addition, EBV infection considerably suppressed those cellular proteins of zinc finger protein 2, cyclin-dependent kinase 2, macrophage-capping protein, and growth/ differentiation factor 11. Furthermore, the differential expressional levels of partial proteins (cyclin-dependent kinase 2 and caspase 9) were confirmed by Western blot analysis.Thus, this work effectively provided useful protein-related information to facilitate further investigation of the mechanisms underlying EBV infection and pathogenesis.

In this paper, the output feedback control problem for a genetic hypersonic vehicle is considered under the restriction that only the vehicle's velocity and altitude are measurable. High gain observers (HGO) are utilized to provide estimation signals for unmeasurable derivatives of the vehicle's velocity and altitude. A comprehensive stability analysis of the closed loop system under the output feedback control is carried to prove that the proposed control law yields semiglobal uniformly ultimately bounded tracking while keep all the closed loop signals bounded. Numerical simulation results are presented to validate the proposed control design.

This paper considers about the control problem for an underactuated quadrotor UAV system with model parameter uncertainty. Backstepping based techniques are utilized to design a nonlinear adaptive controller which can compensate for the mass uncertainty of the vehicle. Lyapunov based stability analysis shows that the proposed control design yields asymptotic tracking for the UAV's motion in x, y, z direction and the yaw rotation, while keep the stability of the closed loop dynamics of the quadrotor UAV. Numerical simulation results are provided to show the good tracking performance of proposed control laws.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRs) are single-stranded, noncoding RNAs that are important in many biological processes. Although the oncogenic and tumor-suppressive functions of several miRs have been characterized, their precise biological roles remain largely unexplored. In the present study, the role of miR-133b was identified in the regulation of CRC cell proliferation and apoptosis. miR-133b expression was shown to be greatly downregulated in human CRC cells compared to normal colon cells. Downregulation of miR-133b expression was also significant in six of eight human CRC tissues compared with adjacent normal tissues. In the CRC cell lines SW-620 and HT-29, ectopic expression of miR-133b potently affected tumor cell proliferation and apoptosis in vitro and in vivo by direct targeting of the receptor tyrosine kinase MET. Transfection of SW-620 and HT-29 cells with miR-133b significantly suppressed a luciferase-reporter containing the MET-3'-untranslated region. Taken together, these results provide evidence that miR-133b regulated tumor cell proliferation and apoptosis through modulation of the MET signaling pathway.

Background Mitochondrial defects have been associated with various human conditions including cancers. Methods We analyzed the mutations at the mitochondrial DNA (mtDNA) in patients with different thyroid lesions. In particular, in order to investigate if the accumulation of mtDNA mutations play a role in tumor progression, we studied the highly variable main control region of mtDNA, the displacement-loop (D-loop) in patients with non-tumor nodular goiters, with benign thyroid adenomas, and with malignant thyroid carcinomas. Total thyroid tumor or goiter samples were obtained from 101 patients, matched with nearby normal tissue and blood from the same subject. Results Noticeably, mitochondrial microsatellite instability (mtMSI) was detected in 2 of 19 nodular goiters (10.53%), and 8 of 77 (10.39%) malignant thyroid carcinomas. In addition, 6 patients, including 5 (6.49%) with malignant thyroid carcinomas and 1 (5.26%) with nodular goiter, were found to harbor point mutations. The majority of the mutations detected were heteroplasmic. General significance Our results indicate that mtDNA alterations in the D-loop region could happen before tumorigenesis in thyroid, and they might also accumulate during tumorigenesis.

We report CT features of four cases of Eosinophilic enteritis. The disease involves the jejunum in one case, the ileum in two cases, and the colon in the remaining case. Two cases demonstrate a predominantly mucosal type of eosinophilic enteritis, while the other two cases demonstrate a predominantly subserosal type. CT findings include bowel wall thickening in four cases, bowel fold thickening in two cases, layering of the bowel wall in two cases, luminal narrowing without obstruction in three cases, an intra-luminal granuloma mimicking a huge polyp in one case, an extra-luminal irregular granuloma markedly enhancing and slightly necrosing in one case, mesenteric lymphadenopathy with peripheral rim-like enhancement and marked necrosis in one case and ascites in one case. CT findings are more characteristic of an inflammatory disease rather than of a tumor, and these findings are helpful for assessing the extent and location of the disease. Moreover, combined with its typical clinical manifestations, CT findings may lead to the correct diagnosis.