Quantum cryptography holds the promise to establish an information-theoretically secure global network. All field tests of metropolitan-scale quantum networks to date are based on trusted relays. The security critically relies on the accountability of the trusted relays, which will break down if the relay is dishonest or compromised. Here, we construct a measurement-device-independent quantum key distribution (MDIQKD) network in a star topology over a 200-square-kilometer metropolitan area, which is secure against untrustful relays and against all detection attacks. In the field test, our system continuously runs through one week with a secure key rate 10 times larger than previous results. Our results demonstrate that the MDIQKD network, combining the best of both worlds-security and practicality, constitutes an appealing solution to secure metropolitan communications.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stresslevel glucocorticoids are correlated with dementia progression in patients with AD. In this study, 12-month male mice were chronically treated with stress-level dexamethasone (DEX, 5 mg/kg) and extract of Astragalus (EA, 10, 20, and 40 mg/kg) or Ginsenoside Rg1 (Rg1, 6.5 mg/kg) for 21 days. We investigated the protective effect of EA against DEX injury in mice and its action mechanism. Our results indicate that DEX can induce learning and memory impairments and neuronal cell apoptosis. The mRNA levels of caspase-3 are selectively increased after DEX administration. The results of immunohistochemistry demonstrate that caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex are significantly increased. Furthermore, DEX treatment increased the activity of caspase-9 and caspase-3. Treatment groups with EA (20 and 40 mg/kg) or Rg1 (6.5 mg/kg) significantly improve learning and memory, downregulate the mRNA level of caspase-3, decrease expression of caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex, and inhibit activity of caspase-9 and caspase-3. The present findings highlight a possible mechanism by which stress level of DEX accelerates learning and memory impairments and increases neuronal apoptosis and the potential neuronal protection of EA.

Brucellosis is a worldwide zoonotic disease caused by Brucella spp. In China, brucellosis is recognized as a reemerging disease mainly caused by Brucella melitensis specie. To better understand the currently endemic B. melitensis strains in China, three Brucella genotyping methods were applied to 110 B. melitensis strains obtained in past several years. By MLVA genotyping, five MLVA-8 genotypes were identified, among which genotypes 42 (1-5-3-13-2-2-3-2) was recognized as the predominant genotype, while genotype 63 (1-5-3-13-2-3-3-2) and a novel genotype of 1-5-3-13-2-4-3-2 were second frequently observed. MLVA-16 discerned a total of 57 MLVA-16 genotypes among these Brucella strains, with 41 genotypes being firstly detected and the other 16 genotypes being previously reported. By BruMLSA21 typing, six sequence types (STs) were identified, among them ST8 is the most frequently seen in China while the other five STs were firstly detected and designated as ST137, ST138, ST139, ST140, and ST141 by international multilocus sequence typing database. Whole-genome sequence (WGS)-single-nucleotide polymorphism (SNP)-based typing and phylogenetic analysis resolved Chinese B. melitensis strains into five clusters, reflecting the existence of multiple lineages among these Chinese B. melitensis strains. In phylogeny, Chinese lineages are more closely related to strains collected from East Mediterranean and Middle East countries, such as Turkey, Kuwait, and Iraq. In the next few years, MLVA typing will certainly remain an important epidemiological tool for Brucella infection analysis, as it displays a high discriminatory ability and achieves result largely in agreement with WGS-SNP-based typing. However, WGS-SNP-based typing is found to be the most powerful and reliable method in discerning Brucella strains and will be popular used in the future.

Osteoarthritis (OA) is a common type of arthritis. Chronic inflammation is an important contributor to the pathogenesis of OA. The maturation and secretion of proinflammatory cytokines are controlled by inflammasomes, especially NLRP1 (NLR Family Pyrin Domain Containing 1) and NLRP3. In this study, we identified a transactivation mechanism of NLRP3 mediated by CtBPs (C-terminal-binding proteins). We found that both the mRNA and protein levels of CtBPs were significantly increased in OA biopsies. Analyzing the profiles of differentially expressed genes in CtBP-knockdown and overexpression cells, we found that the expression of NLRP3 was dependent on CtBP levels. By the knockdown or overexpression of transcription factors that potentially bind to the promoter of NLRP3, we found that only AP1 could specifically regulate the expression of NLRP3. Using immunoprecipitation (IP) and Co-IP assays, we found that AP1 formed a transcriptional complex with a histone acetyltransferase p300 and CtBPs. The knockdown of any member of this transcriptional complex resulted in a decrease in the expression of NLRP3. To explore the underlying mechanism of CtBP overexpression, we analyzed their promoters and found that they were abundant in CpG islands. Treatment with the DNA methylation inhibitor 5-aza-2′deoxycytidine (AZA) or knockdown of DNMTs (DNA methyltransferases) resulted in the overexpression of CtBPs, while overexpression of DNMTs caused the reverse effects on CtBP expression. Collectively, our results suggest that the decreased DNA methylation levels in the promoters of CtBPs upregulate their expression. Increased CtBPs associated with p300 and AP1 to form a transcriptional complex and activate the expression of NLRP3 and its downstream signaling, eventually aggravating the inflammatory response and leading to the pathogenesis of OA.

The activation of TNF-α/NF-кB signaling is involved in the regulation of a wide range of biological processes, such as cell proliferation, differentiation and apoptosis, eventually causing a number of diseases, such as cancer and inflammation. Here, we found that TNF-α/NF-кB signaling was activated in a large number of blood samples taken from foot and ankle rheumatoid arthritis (RA) patients. By applying a microarray assay to the human synovial sarcoma cell line SW982 and the human fibroblast-like synoviocyte cell line HFLS-RA, as well as in their corresponding p65 knockdown and -overexpressing cells, we identified and verified the activation of many p65 targets, including cytokines (e.g., TNF-α and IL-6), chemokines (e.g., MCP-1 and PANTES), protein receptors (e.g., CD-40 and MHC-1), and inducible enzymes (e.g., COX2). In addition, we subjected microRNAs from foot and ankle RA patients to a microRNA-specific microarray and found that miR-7-5p targeted the 3'-UTR of p65, negatively regulating its expression. By applying an in vitro screen to identify small molecules that specifically inhibited the interaction between TRADD and TNFR2, we found that NSM00191 strongly inhibited the activation of TNF-α/NF-кB signaling in vitro and in vivo, causing the downregulation of NF-кB targets and the decrease of arthritis scores. Collectively, our findings shed new light on the regulation of the TNF-α/NF-кB axis and might provide a new avenue for RA treatment.

IntroductionCancer progression is determined not only by the malignant behavior of tumors but also by the immune microenvironment. The tumor immune microenvironment also plays a pivotal role in determining the clinical response of non-small-cell lung cancer (NSCLC) to immunotherapies. To understand the possible mechanisms and explore new targets in lung cancer immunotherapy, we characterized the immune profiles in NSCLC patients.MethodsSeventy-one NSCLC patients who underwent radical resection were selected. The immune cell composition in paired tumor and adjacent normal lung tissues was tested by flow cytometry. The associations of tumor immune microenvironment characteristics with clinicopathological factors and overall survival were analyzed. Kaplan–Meier curves and Cox proportional hazards models were used to determine differences in survival.ResultsCompared with adjacent normal lung tissues, an increased proportion of CD45+ hematopoietic-derived cells, CD4+ T cell subtypes, Tregs and B cells was observed in tumor samples with a reduced frequency of myeloid cell populations. There was no significant increase in total CD8+ T cells, but both PD1+ and CD38+ CD8+ T cells were significantly enriched in tumor samples and statistically significantly associated with tumor size. In addition, positive CD38 expression was highly correlated with PD1 positivity. A high proportion of CD8+ T cells and a low percentage of PD1+ CD8+ T cells were statistically significantly associated with better survival in stage II and III patients, whereas a low frequency of CD38+ CD8+ T cells was statistically significantly associated with better survival in all patients and identified as an independent prognostic factor (p=0.049).ConclusionWe profiled the immune cells in the tumor tissues of NSCLC patients using flow cytometry. The results revealed significant enrichment of infiltrating immune cells. A strong correlation was identified between CD38 and PD-1 expression on CD8+ T cells in tumors. CD8+ T cells and their subtypes play a critical role in the prediction of prognosis.

BackgroundTo investigate the regulatory mechanism behind miR‐34a‐altered Axl levels in non‐small‐cell lung cancer (NSCLC) with gefitinib‐acquired resistance.MethodsThe expression of miR‐34a, Axl, Gas6 and related downstream signaling proteins in the EGFR mutant NSCLC cell lines were determined by qRT‐PCR and Western blot; PC9‐Gef‐miR‐34a and HCC827‐Gef‐miR‐34a cells were established by transfecting the parent cells with a miR‐34a overexpressing virus, then the expression of Axl, Gas6 and the downstream channel‐related proteins were also compared in PC9‐Gef‐miR‐34a and HCC827‐Gef‐miR‐34a and drug‐resistant strains. The survival rate of the cells were measured by CCK8 assay. A luciferase reporter detected whether Axl was the target of miR‐34a. Finally, a tumor‐bearing nude mouse model was established to verify the relationship between the expression of miR‐34a, Axl and Gas6 mRNA in vivo.ResultsThe expression levels of Axl mRNA and protein, Gas6 mRNA and protein, and related downstream proteins in PC9‐Gef and HCC827‐Gef cell lines were higher than those in PC9 and HCC827 parental cell lines, while the expression of miR‐34a was lower than it was in the parental cell lines (P < 0.05). The expression of Axl mRNA and protein, Gas6 mRNA and protein, and related downstream signaling proteins in PC9‐Gef and HCC827‐Gef cell lines was higher than the expression in PC9‐Gef‐miR‐34a and HCC827‐Gef‐miR‐34a cells, which overexpressed miR‐34a (P < 0.05).ConclusionThe miR‐34a regulation of Axl plays an important role in NSCLC‐acquired gefitinib resistance, and their expression is inversely correlated, which suggests that they can be used as prognostic markers or potential therapeutic targets for NSCLC.

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