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Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir).A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%).Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).

Aspergillus fungi are known to produce aflatoxins, among which aflatoxin B1 (AFB1) is the most potent carcinogen that is metabolised by cytochrome P450 (CYP450). In the liver, AFB1 is metabolised into exo-8,9-epoxide by the CYP1A2 enzymes. The resulting epoxide can react with guanine to cause DNA damage. Natural inhibitors are being identified. However, the modes of action are poorly understood. In the current study, we have investigated the mode of action of AFB1 with CYP1A2, CYP3A4 and CYP2A13 using molecular dynamic simulation (MD simulation) approaches. The interaction network and paths among CYP1A2, CYP3A4, and CYP2A13 have been investigated using the STRING database and PathLinker plugin of Cytoscape. CYP3A4 is the most active protein involved in interactions with AFB1 during its metabolism. Residues 362ARG, 445SER, 450LEU and 451PHE of CYP1A2 are important, interacting with AFB1 and converting it to toxic exo-AFB1-8,9-epoxide (AFBEX). The pathway shows that microsomal epoxide hydrolase (EPHX1) may acts as initiator in the signalling pathway where CYP1A2, CYP3A4 and CYP2A13 interact in a sequential order. The interaction network shows there to be a strong association in expression among CYP1A2, CYP3A4 and CYP2A13 along with other metabolising enzymes. The complex of AFB1 and CYP1A2 was found to be stable during the MD simulation. This study provides a better understanding of the mode of action between AFB1 and CYP1A2, CYP3A4 and CYP2A13 which relates to the effective management of AFB1 toxicity. EPHX1 in the protein network may be an ideal target when designing inhibitors to prevent the toxin’s activation. Peptide inhibitors may be designed to block the substrate site residues of CYP1A2 in order to prevent the conversion from AFB1 into AFBEX. This would either neutralise or reduce its toxicity.

Background Spatial chromatin structure is intricately linked with somatic aberrations, and somatic mutations of various cancer-related genes, termed co-mutations (CoMuts), occur in certain patterns during cancer initiation and progression. The functional mechanisms underlying these genetic events remain largely unclear in thyroid cancer (TC). With discrepant differentiation, papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) differ greatly in characteristics and prognosis. We aimed to reveal the spatial gene alterations and regulations between the two TC subtypes. Methods We systematically investigated and compared the spatial co-mutations between ATC (8305C), PTC (BCPAP and TPC-1), and normal thyroid cells (Nthy-ori-3–1). We constructed a framework integrating whole-genome sequencing (WGS), high-throughput chromosome conformation capture (Hi-C), and transcriptome sequencing, to systematically detect the associations between the somatic co-mutations of cancer-related genes, structural variations (SVs), copy number variations (CNVs), and high-order chromatin conformation. Results Spatial co-mutation hotspots were enriched around topologically associating domains (TADs) in TC. A common set of 227 boundaries were identified in both ATC and PTC, with significant overlaps between them. The spatial proximities of the co-mutated gene pairs in the two TC types were significantly greater than in the gene-level and overall backgrounds, and ATC cells had higher TAD contact frequency with CoMuts > 10 compared with PTC cells. Compared with normal thyroid cells, in ATC the number of the created novel three-dimensional chromatin structural domains increased by 10%, and the number of shifted TADs decreased by 7%. We found five TAD blocks with CoMut genes/events specific to ATC with certain mutations in genes including MAST-NSUN4, AM129B/TRUB2, COL5A1/PPP1R26, PPP1R26/GPSM1/CCDC183, and PRAC2/DLX4. For the majority of ATC and PTC cells, the HOXA10 and HIF2α signals close to the transcription start sites of CoMut genes within TADs were significantly stronger than those at the background. CNV breakpoints significantly overlapped with TAD boundaries in both TC subtypes. ATCs had more CNV losses overlapping with TAD boundaries, and noncoding SVs involved in intrachromosomal SVs, amplified inversions, and tandem duplication differed between ATC and PTC. TADs with short range were more abundant in ATC than PTC. More switches of A/B compartment types existed in ATC cells compared with PTC. Gene expression was significantly synchronized, and orchestrated by complex epigenetics and regulatory elements. Conclusion Chromatin interactions and gene alterations and regulations are largely heterogeneous in TC. CNVs and complex SVs may function in the TC genome by interplaying with TADs, and are largely different between ATC and PTC. Complexity of TC genomes, which are highly organized by 3D genome-wide interactions mediating mutational and structural variations and gene activation, may have been largely underappreciated. Our comprehensive analysis may provide key evidence and targets for more customized diagnosis and treatment of TC.

Graphical abstract, Pyrazinamide (PZA) is a component of first-line drugs, active against latent Mycobacterium tuberculosis (MTB) isolates. The prodrug is activated into the active form, pyrazinoic acid (POA) via pncA gene-encoded pyrazinamidase (PZase). Mutations in pncA have been reported, most commonly responsible for PZA-resistance in more than 70% of the resistant cases. In our previous study, we detected many mutations in PZase among PZA-resistance MTB isolates including A46V, H71Y, and D129N. The current study was aimed to investigate the molecular mechanism of PZA-resistance behind mutants (MTs) A46V, H71Y, and D129N in comparison with the wild type (WT) through molecular dynamic (MD) simulation. MTB positive samples were subjected to PZA drug susceptibility testing (DST) against critical concentration (100ug/ml). The resistant samples were subjected to pncA sequencing. Thirty-six various mutations have been observed in the coding region of pncA of PZA-resistant isolates (GenBank accession No. MH461111) including A46V, H71Y, and D129N. The post-simulation analysis revealed a significant variation in MTs structural dynamics as compared to the WT. Root means square deviations (RMSD) and Root means square fluctuation (RMSF) has been found in variation between WT and MTs. Folding effect and pocket volume were altered in MTs when compared with WT. Geometric matching supports the effect of mutation A46V, H71Y, and D129N on PZase structure that may have an insight effect on PZase dynamics, making them vulnerable to convert pro-PZA into active form, POA. In conclusion, the current analyses will provide useful information behind PZA-resistance for better management of drug-resistant TB.

Severe acute respiratory syndrome virus 2 (SARS-CoV-2) belongs to the single-stranded positive-sense RNA family. The virus contains a large genome that encodes four structural proteins, small envelope (E), matrix (M), nucleocapsid phosphoprotein (N), spike (S), and 16 nonstructural proteins (nsp1-16) that together, ensure replication of the virus in the host cell. Among these proteins, the interactions of N and Nsp3 are essential that links the viral genome for processing. The N proteins reside at CoV RNA synthesis sites known as the replication-transcription complexes (RTCs). The N-terminal of N has RNA-binding domain (N-NTD), capturing the RNA genome while the C-terminal domain (N-CTD) anchors the viral Nsp3, a component of RTCs. Although the structural information has been recently released, the residues involved in contacts between N-CTD with Nsp3 are still unknown. To find the residues involved in interactions between two proteins, three-dimensional structures of both proteins were retrieved and docked using HADDOCK. Residues at N-CTD were detected in interaction with L499, R500, K501, V502, P503, T504, D505, N506, Y507, I508, T509, K529, K530K532, S533 of Nsp3 and N-NTD to synthesize SARS-CoV-2 RNA. The interaction between Nsp3 and CTD of N protein may be a potential drug target. The current study provides information for better understanding the interaction between N protein and Nsp3 that could be a possible target for future inhibitors.

Platinum-based drugs such as cisplatin are widely used in combination chemotherapy for non-small cell lung cancer (NSCLC) owing to their high clinical response rate; however, acquired resistance to cisplatin is eventually inevitable. Circular RNAs (circRNAs) are involved in the development of diverse types of cancers, but their connection to cisplatin-resistance in NSCLC has not been studied. In the present study, two cisplatin-resistant NSCLC cell lines (A549/DDP and PC9/DDP) were established by gradually increasing concentrations of cisplatin in the media. The resulting cell lines possessed high resistance to cisplatin and strong proliferation, migration, and colony formation abilities compared to the parental cells. Microarray analysis identified 19,161 circRNAs that were dysregulated in cisplatin-resistant cell lines (fold change abs>2), including 11,915 up-regulated and 7246 down-regulated circRNAs. The expression of the top five up-regulated and down-regulated circRNAs was validated using real-time quantitative polymerase chain reaction. A circRNA-micro RNA (miRNA) network of the top 20 dysregulated circRNAs and their predicted miRNAs was constructed using Cytoscape. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the host genes of the identified circRNAs were involved in the regulation of MAP kinase kinase kinase kinase activity, 6-phosphofructo-2-kinase activity, focal adhesion, ErbB signaling, and ECM-receptor interactions, which may contribute to cisplatin resistance in NSCLC. In summary, this is the first report on circRNA profiling in cisplatin-resistant NSCLC cells and it provides new potential targets for the reversal of cisplatin resistance in NSCLC.

A 29-year-old male with pathologically confirmed extranodal NK/T cell lymphoma of the tonsil, nasal type was admitted to Xinhua hospital affiliated to Shanghai Jiao Tong University School of Medicine. The patient was provided with several cycles of anti-PD-1 immunotherapy and obtained a Complete Response (CR) outcome. Despite the response, the patient also suffered from severe adverse effects, including a worsening pulmonary inflammation and severe laryngeal edema. A tracheotomy was performed to remove the white pseudo-membrane of laryngeal. via pathological analysis, necrosis of granuloma lymphoid cells and rhabdomous granuloma was found in this removed section. Meantime, a large amount of Candida nivaria, Klebsiella pneumoniae, and carbapenem-resistant Enterobacter was present in the patient’s sputum culture. The level of inflammatory cytokines (e.g., TNF-a, IL-1, IL-6, IL-17 and IFN-γ,) also increased significantly, indicating immune-related adverse events. Subsequently, the doctors adjusted immunotherapy to single-agent chemotherapy with additional anti-fungal and anti-bacterial infection treatment. The infection was well under control after these adjustments. 18F-FDG PET/ CT recorded the series of changes in the course of the patient from the start of immunotherapy.

The immunosuppressive function of mesenchymal stem cells (MSCs) is well known. Aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, is widely expressed in several cells and is involved in various physiological and pathological processes. Previously, we found that the expression of AhR was downregulated in MSCs isolated from mice with neutrophilic asthma and that the activation of AhR enhanced the function of MSCs to alleviate neutrophilic asthma. We hypothesized that AhR activation enhanced MSCs for their immunosuppressive function. We aimed to investigate whether AhR activation can augment the suppressive function of MSCs against splenocyte proliferation. We co-cultured MSCs or AhR-activated MSCs with splenocytes at different ratios. The results showed that AhR activation in MSCs upregulated the expression of inducible nitric oxide (iNOS), which promoted the production of nitric oxide (NO), thus enhancing the inhibitory effect on splenocyte proliferation. The NO donor S-nitroso-N-acetylpenicillamine also inhibited the proliferation of splenocytes, and the iNOS inhibitor N(G)-nitro L-arginine methyl ester and NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide partially reversed the immunosuppressive function. Our study indicates that the AhR activation of MSCs might have an important role in the regulation of splenocyte proliferation and might serve as a potential strategy for treating immune-related diseases.

Aims The relationship between TRIM59 and drug resistance is elusive despite of its multiple uncovered roles in human cancers. Here we aimed to characterize the expression status of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells and elucidate its mechanism underlying the drug resistance. Main methods Gefitinib-resistant cell lines were established by progressive dosage. Relative expression of TRIM59 was determined by both real-time PCR and Western blot. Target gene knockdown was achieved by specific shRNAs. Cell viability was measured by MTT assay. Cell apoptosis was analyzed by flow cytometry with Annexin V/7-AAD double staining. Cell proliferation was determined by clonogenic formation assay. Migration and invasion capacities were detected using transwell chamber assay. Direct interaction between TRIM59 and STAT3 was analyzed by co-immunoprecipitation assay. Key findings We first observed overexpression of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells. ShRNA-mediated knockdown of TRIM59 significantly inhibited cell viability and stimulated apoptosis. Meanwhile, TRIM59-deficiency suppressed cell migration and invasion. We further identified the interaction between TRIM59 and STAT3. TRIM59-deficiency remarkably impaired the activation of STAT3 signaling. STAT3-specific shRNAs significantly re-sensitized TRIM59-proficient EGFR mutant lung adenocarcinoma cells to gefitinib. Significance Our data characterized aberrant TRIM59 overexpression in gefitinib-resistance EGFR mutant lung adenocarcinoma cells, and indicated the potential involvement of TRIM59-STAT3 signaling in the occurrence of gefitinib-resistance.

Whole genome sequencing (WGS) is one of the most reliable methods for detection of drug resistance, genetic diversity in other virulence factor and also evolutionary dynamics of Mycobacterium tuberculosis complex (MTBC). First-line anti-tuberculosis drugs are the major weapons against Mycobacterium tuberculosis (MTB). However, the emergence of drug resistance remained a major obstacle towards global tuberculosis (TB) control program 2030, especially in high burden countries including Pakistan. To overcome the resistance and design potent drugs, genomic variations in drugs targets as well as in the virulence and evolutionary factors might be useful for better understanding and designing potential inhibitors. Here we aimed to find genomic variations in the first-line drugs targets, along with other virulence and evolutionary factors among the circulating isolates in Khyber Pakhtunkhwa, Pakistan. Samples were collected and drug susceptibility testing (DST) was performed as per WHO standard. The resistance samples were subjected to WGS. Among the five whole genome sequences, three samples (NCBI BioProject Accession: PRJNA629298, PRJNA629388) harbored 1997, 1162, and 2053 mutations. Some novel mutations have been detected in drugs targets. Similarly, numerous novel variants have also been detected in virulency and evolutionary factors, PE, PPE, and secretory system of MTB isolates. Exploring the genomic variations among the circulating isolates in geographical specific locations might be useful for future drug designing. To the best of our knowledge, this is the first study that provides useful data regarding the insight genomic variations in virulency, evolutionary factors including ESX and PE/PPE as well as drug targets, for better understanding and management of TB in a WHO declared high burden country.

Cisplatin (CDDP) is the first generation of platinum-based drug and is widely used to treat many cancers due to its potency. The present study aims to explore the effects of CDDP on lung carcinoma and its relationship with macrophage phagocytosis. In in vitro study, murine and human lung cancer cell lines were applied and treated with CDDP, CD47 antibody (aCD47), or CDDP plus aCD47. In in vivo study, a tumor xenograft animal model was treated with CDDP, aCD47, or CDDP plus aCD47. Real-time PCR was applied to determine the mRNA expressions. Enzyme-linked immunosorbent assay (ELISA), Western blotting, and Immunofluorescent staining were applied to determine the protein expressions. Flow cytometry was applied to analyze cell apoptosis, phagocytosis, and specific cell populations. CDDP enhanced the expressions of CD47 in lung cancer cells. Interestingly, the blockage of CD47 enhanced the macrophages' phagocytic activity on the CDDP-treated tumor cells. The treatment of CDDP and aCD47 exhibited anti-tumor effects and prolonged the LLC tumor-bearing mice survival time. Mechanistic studies revealed that the treatment of CDDP and aCD47 regulated the phagocytic activity of macrophage, percentage of CD8+ T cells, and cytokines (tumor growth factor (TGF)-β, interleukin (IL)12p70, and interferon (IFN)-γ) in the tumor-bearing model. CD47 blockade enhanced therapeutic efficacy of cisplatin against lung carcinoma in vivo and in vitro.

Experimental teaching is an important link of cultivating students’ innovation ability and practice ability, and is also a good platform for applying the abstract theoretical knowledge to practice. However, the deficiency of teachers and experimental equipment has been the bottleneck for experimental teaching to further develop. In order to solve this problem, a kind of intelligent experimental teaching platform based on Internet technology is proposed in this paper; the structure and the basic composition of the system as well as the key technology for the software development are also discussed. Based on this teaching platform, students can do experiments at any time where they are as long as a computer internet can be available, and there is no restriction on time and site. It optimizes the experimental management and improves the effect of the experimental teaching.

To identify asthma clinical phenotypes using cluster analysis and improve our understanding of heterogeneity in asthma.Clustering approaches were applied to 203 patients who were diagnosed with asthma in XinHua Hospital (January 2012 to December 2015). One hundred and twenty patients underwent multi-slice spiral computed tomography (MSCT) examination and 30 underwent bronchial mucosal biopsy for evaluation of airway remodeling and airway inflammation among the phenotypes.Four groups were identified. Patients in cluster 1 (n=52) had early onset atopic asthma and patients in cluster 2 (n=65) had small airway obstruction and atopic asthma. Cluster 3 (n=52) was a unique group of patients with late-onset and non-atopic asthma. Patients in cluster 4 (n=34) had severe airflow obstruction and obvious airway remodeling as observed on MSCT (P0.05). According to the immunohistochemistry of IL-5 and IL-17 (P0.05), the results of clusters 1 and 2 may be attributable to the Th2 immune response, whereas those of clusters 3 and 4 to the Th17 immune response.Four distinct clinical phenotypes of asthma were identified by cluster analysis. The results of the MSCT and pathological examinations may suggest specific pathogeneses among the phenotypes.

Cigarette smoke (CS)-induced inflammation is critical in chronic obstructive pulmonary disease (COPD). However, the role of acetylation at histone 3 lysine 9 (H3K9) in COPD inflammation remains unclear. The present study assessed the effect of acetylation of H3K9 on transcription both in rat lungs and in macrophages.Sprague-Dawley rats were exposed to CS for either 6 or 12 weeks and rat lungs were collected. Rat macrophages were subjected to 20 % cigarette smoke extract (CSE) for 48 h.CS increased MCP-1 and IL-8 expressions at both mRNA and protein levels in rat lungs after 6 and 12 weeks; increased TNF-α and MMP9 expressions at both levels were noted only after 12 weeks. CSE increased these genes expression in macrophages after 48 h exposure. Increased abundance of acetylated H3K9 protein in rat lungs and in macrophages were associated with decreased expression of histone deacetylase-1(HDAC1). Chromatin immunoprecipitation demonstrated increased level of acetylated H3K9 on promoter regions of these genes both in vivo and in vitro. Knockdown of HDAC1 increased these genes mRNA expression.CS increased H3K9 acetylation and subsequently altered the expression of pro-inflammatory mediators and protease genes through HDAC1 depression in CS-induced rat lungs and in macrophages.

Notch is a single-pass transmembrane receptor protein expressed by T cells, which contributes to the pathogenesis of asthma through regulation of the development and differentiation of T cells. γ-Secretase inhibitor (GSI) acts as an effective blocker of Notch signalling. The present study aimed to investigate the role of GSI MW167 in T cell differentiation and antigen-induced airway inflammation. An OVA-induced airway inflammation mouse model was established. Blockade of Notch signalling was achieved using MW167. The expression of IL-4, IL-5, IFN-γ, Notch1 signalling and pro-inflammatory transcription factors in activated lung T cells was evaluated. Finally, the therapeutic effect of MW167 was investigated by haematoxylin and eosin staining, real-time PCR and ELISA. The expression of IL-4 and IL-5 decreased and that of IFN-γ increased significantly, and the protein expression levels of pro-inflammatory transcription factors reduced in active lung T cells after administration of MW167, compared to the control group. MW167 treatment prevented OVA-induced airway inflammation and histological changes. The serum and bronchoalveolar lavage fluid (BALF) levels of IL-4 and IL-5 in MW167-treated mice decreased significantly, whereas those of IFN-γ increased, relative to the levels in OVA-challenged animals treated with PBS. Our findings indicate that Notch signalling plays an important role in the pathogenesis of asthma and that MW167 may be a potential therapeutic target for allergen-induced airway inflammation.

Cigarette smoke has been shown to cause chronic inflammation of the lungs, eventually leading to chronic obstructive pulmonary disease (COPD). Additionally, recent studies have suggested that mesenchymal stem cells (MSCs) can mediate local inflammatory responses in the lungs. Thus, the aim of the present study was to test the effects of rat MSCs (rMSCs) on inflammation of the lungs and destructive pulmonary function induced by cigarette smoke in rats. Rats were exposed to cigarette smoke for 7 weeks. rMSCs were cultured in vitro and infused intratracheally into cigarette smoke-exposed rats. The total and differential cell counts in the bronchoalveolar lavage fluid (BALF), histological changes, pro-inflammatory cytokines, transforming growth factor-β1 (TGF-β1) expression, and pulmonary function were evaluated. Additionally, human peripheral blood mononuclear cells and human MSCs were cocultured in vitro to detect cytokines and TGF-β1 levels. We found that rMSC administration resulted in downregulation of pro-inflammatory cytokines in the lungs while increasing TGF-β1 expression, reducing total inflammatory cell numbers in the BALF, and improving pulmonary histopathology and airflow obstruction. Coculture revealed that human MSCs mediated an anti-inflammatory effect partly via upregulation of TGF-β1. These findings suggested that MSCs may have therapeutic potential in cigarette smoke-induced inflammation and airflow obstruction, partly via upregulation of TGF-β1.

Progressive pulmonary inflammation and emphysema have been implicated in the progression of chronic obstructive pulmonary disease (COPD), while current pharmacological treatments are not effective. Transplantation of bone marrow mesenchymal stem cells (MSCs) has been identified as one such possible strategy for treatment of lung diseases including acute lung injury (ALI) and pulmonary fibrosis. However, their role in COPD still requires further investigation. The aim of this study is to test the effect of administration of rat MSCs (rMSCs) on emphysema and pulmonary function. To accomplish this study, the rats were exposed to cigarette smoke (CS) for 11 weeks, followed by administration of rMSCs into the lungs. Here we show that rMSCs infusion mediates a down-regulation of pro-inflammatory mediators (TNF-α, IL-1β, MCP-1, and IL-6) and proteases (MMP9 and MMP12) in lung, an up-regulation of vascular endothelial growth factor (VEGF), VEGF receptor 2, and transforming growth factor (TGFβ-1), while reducing pulmonary cell apoptosis. More importantly, rMSCs administration improves emphysema and destructive pulmonary function induced by CS exposure. In vitro co-culture system study of human umbilical endothelial vein cells (EA.hy926) and human MSCs (hMSCs) provides the evidence that hMSCs mediates an anti-apoptosis effect, which partly depends on an up-regulation of VEGF. These findings suggest that MSCs have a therapeutic potential in emphysematous rats by suppressing the inflammatory response, excessive protease expression, and cell apoptosis, as well as up-regulating VEGF, VEGF receptor 2, and TGFβ-1.

Asthma is an inflammatory disease of the airways, and the current treatment in managing asthma is the control of inflammation. Notch signaling pathway has been linked to T-cell imbalance. The present study aimed to explore the histone modifications of Notch1 promoter in normal and asthmatic lung CD4+ T cells. Chromatin immunoprecipitation analysis showed that the acetylation levels of total H3, H4, site-specific H3K9, H3K14, H3K27, H3K18, H4K16, and the trimethylation levels of H3K4, H3K79 of Notchl gene promoter were increased significantly in asthmatic lung CD4+ T cells compared to the control group, which correlated with increased P300, PCAF activity and decreased HDAC1, HDAC2 activity. After intervention of garcinol, a potent inhibitor of histone acetyltransferases, in asthmatic lung CD4+ T cells, HAT activity decreased significantly and the increased Notch1 and hes-1 expression was reversed. The total H3ac, H4ac, site-specific H3K9ac, H3K14ac, H3K27ac, H3K18ac, H4K16ac and H3K79me3 levels of Notch1 gene promoter decreased significantly, and the H3K4me3, H3K9me3, H4K20me3 levels had no significant difference. We further investigated the suppressive effects of GAR on asthmatic parameters. Results showed that the levels of IL-4, 1L-5 and IL-13 were significantly reduced and a small reverse trend was found in the level of IFN-g after GAR treatment. Furthermore, the expression of NF-κB and AP-1 reduced significantly. These results suggest that asthma is associated with changes in the epigenetic status of Notchl promoter, including abnormal histone acetylation and methylation, and GAR may have applications in the treatment of asthma.

Yes-associated protein 1 (YAP1), a nuclear effector of the Hippo pathway, plays an important role in tumorigenesis and progression of multiple cancers. The present study aimed to investigate the clinical significance of YAP1 and receptor tyrosine kinase Axl expression in human lung adenocarcinomas (LAC). We further explored possible molecular mechanisms mediated by YAP1 in LAC and gastric adenocarcinoma (GAC) cells. Forty-nine cases of human LAC and normal lung tissue (NLT) were collected. The expression of YAP1 and Axl was assessed by immunohistochemical assay through tissue microarray procedure and the clinicopathologic characteristics of all patients were analyzed. Using a loss of function approach, we investigated the effects of small hairpin RNA (shRNA)-mediated knockdown of YAP1 on the expression of Axl, proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-9 (MMP-9), and the proliferative activities and invasive potential in LAC A549 and GAC SGC-7901 cell lines. As a result, the expression of YAP1 and Axl was found in LAC tissues with higher strong reactivity rate compared to the NLT (87.8 percent vs.60.8 percent, P=0.000; 77.6 percent vs 0.0 percent, P=0.000), but they did not associate with the age, gender, tumor size, TNM staging or lymph node metastases of LAC patients (each P#62;0.05). Spearman rank correlation analysis showed a positive correlation between YAP1 and Axl expression. Furthermore, knockdown of YAP in vitro markedly down-regulated the expression of Axl, PCNA and MMP-9, and inhibited the proliferation and invasion of LAC and GAC cells. Taken together, YAP1 and Axl are highly expressed in LAC compared to the NLT, and knockdown of YAP1 may inhibit the proliferation and invasion of adenocarcinoma cells through downregulation of the Axl pathway, representing a potential therapeutic target for the treatment of cancer.

In this paper, a new ARM controller-based distributed intelligent control system, combining the process the features of the injection molding machine, is proposed. Embedded technology and fieldbus technology are utilized. The basic components of the hardware and the design scheme of the software are also discussed. The innovative application of the artificial intelligence technology in the control system of the injection molding machine enables the simple processing procedure self-learning, fault diagnosing and process parameters optimizing. The ARM controller as the slave computer of this control system can not only realize the on-site control for the injection molding machines but also can provide distributed remote control services for the host computer. The closed-loop control system, composed of the ARM controller and sensors, realizes the prompt adjustment of the processing parameters, such as flow, injection pressure and the control of multi-stage injection pressure in the molding process etc. This can meet the requirements of different plastic products.

A new idea for studying the ability for computer to bear and process viruses after suffering from the intrusion of the viruses was discussed in this paper. This ability was named intrusion tolerance. Starting from the intrusions, capturing the behavioral characteristics and dynamically adopting different strategies enable the system to continue to provide security services. In the mean time, applying artificial intelligence to intrusion tolerant system can adaptively adjust and learn according to the extent of damage caused by attack. Establishing behavioral database was proposed for the first time. This method can avoid updating a large number of virus database frequently, realize the coordinative detection and early warning among the different servers and further improves the ability for computer to prevent and process the viruses.