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In regions where the development of formal finance is relatively lagging behind, commercial credit has partially replaced the role of formal finance and facilitated the development of the private economy and even the country, thus making commercial credit an important entry point for understanding and promoting sustainable economic development. Taking the Hangzhou Bay Greater Bay Area as a case study, based on the City Business Credit Environment Index (CEI) from 2015 to 2019, we examine the characteristics of business credit networks using social network analysis and discuss the impact of business credit on urban green economy efficiency heterogeneity by drawing on spatial econometrics. The study confirms that the structure of business credit networks in the Hangzhou Bay Greater Bay Area tends to be dense, the network density and number of connections show growth, the spatial network structure is taking shape, and the strength of spatial connections among cities has increased. Hangzhou, Shaoxing, Jiaxing and Shanghai are at the centre of the network and play a radiation-driven role. The business credit network in the Hangzhou Bay Greater Bay Area is characterised by self-stability and has evolved from a multi-centre to a single centre. Business credit is negatively correlated with the efficiency of the green economy in the Hangzhou Bay Area, which is a departure from the Chinese "financial development paradox". In terms of heterogeneity, the relationship remains consistent for port cities and open coastal cities in general, while the effect is less pronounced for cities above sub-provincial level. The study concludes that, with the high-quality economic development of the Hangzhou Bay Greater Bay Area, the Chinese "financial development paradox" does not exist in the region at this stage, which also highlights the need to accelerate the construction of a Chinese-style modernisation theory and practice system. [ABSTRACT FROM AUTHOR]

The mitotic exit is a key step in cell cycle, but the mechanism of mitotic exit network in the wheat head blight fungus Fusarium graminearum remains unclear. F. graminearum infects wheat spikelets and colonizes the entire head by growing through the rachis node at the bottom of each spikelet. In this study, we found that a small GTPase FgTem1 plays an important role in F. graminearum pathogenicity and functions in regulating the formation of infection structures and invasive hyphal growth on wheat spikelets and wheat coleoptiles, but plays only little roles in vegetative growth and conidiation of the phytopathogen. FgTem1 localizes to both the inner nuclear periphery and the spindle pole bodies, and negatively regulates mitotic exit in F. graminearum. Furthermore, the regulatory mechanisms of FgTem1 have been further investigated by high-throughput co-immunoprecipitation and genetic strategies. The septins FgCdc10 and FgCdc11 were demonstrated to interact with the dominant negative form of FgTem1, and FgCdc11 was found to regulate the localization of FgTem1. The cell cycle arrest protein FgBub2-FgBfa1 complex was shown to act as the GTPase-activating protein (GAP) for FgTem1. We further demonstrated that a direct interaction exists between FgBub2 and FgBfa1 which crucially promotes conidiation, pathogenicity and DON production, and negatively regulates septum formation and nuclear division in F. graminearum. Deletions of FgBUB2 and FgBFA1 genes caused fewer perithecia and immature asci formations, and dramatically down-regulated trichothecene biosynthesis (TRI) gene expressions. Double deletion of FgBUB2/FgBFA1 genes showed that FgBUB2 and FgBFA1 have little functional redundancy in F. graminearum. In summary, we systemically demonstrated that FgTem1 and its GAP FgBub2-FgBfa1 complex are required for fungal development and pathogenicity in F. graminearum. Author summary: Cell cycle is controlled by numerous mechanisms ensuring correct cell division. One fundamental question in the cell cycle is the mitotic exit and entry into the next cycle, but the mechanism of mitotic exit network in the wheat head blight fungus Fusarium graminearum remains unclear. In this study, we identified a small GTPase FgTem1 to be involved in mitotic exit in this fungus and demonstrated that this protein is required for the fungal pathogenicity and functions in regulating the infection structures formation and invasive hyphal growth on wheat spikelets and wheat coleoptiles. Furthermore, the regulatory mechanisms of FgTem1 have been further investigated. To the best of our knowledge, this work is the most comprehensive genetic dissection of Tem1 in filamentous fungal pathogens. Our results unveil a key link between mitotic exit network and the pathogenicity of the phytopathogen. These findings provide a novel molecular basis for the design and development of chemicals that prevent phytopathogen infection. [ABSTRACT FROM AUTHOR]

Purpose: Poor sleep quality is closed related with driving accidents. However, due to the lack of a valid instrument for assessing drivers' sleep quality, few studies have examined drivers' sleep quality and its associations with driving behaviours and traffic accidents in China. The aim of this paper is to revise the Sleep Quality Scale (SQS) and assess its reliability and validity in Chinese drivers. Methods: 522 Chinese drivers aged from 18 to 56 years old agreed to complete the SQS, Daytime Sleepiness Perception Scale version 4 (DSPS-4), Self-report of Risky Driving Behavior (RD-SR) and Self-assessment of the Likelihood of Being Involved in a Risky Driving Situation (RD-SA). Results: The final Chinese version of the SQS contained 23 items across four factors: difficulty in getting up, difficulty in falling asleep, sleep recovery and daytime dysfunction. Second, man scored lower on the difficulty in falling asleep factor but higher on the sleep recovery factor than women. Third, low to moderate correlations were found between the SQS factors and the DSPS-4, RD-SA and RD-SR, indicating that the validity of the revised scale was satisfactory. More importantly, daytime dysfunction factor is an effective predictor of violation involvement and accident involvement. Conclusion: The revised SQS has acceptable reliability and validity and can be used as a tool to measure the sleep quality of Chinese drivers. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effects of age and refractive status on anterior segment anatomical structures, including the ciliary body, using a new swept-source anterior segment optical coherence tomography (AS-OCT) device. Methods: This prospective observational study included 63 healthy volunteers (mean age: 44.2 years). Images of the anterior segment were obtained using a new swept-source AS-OCT (ANTERION, Heidelberg Engineering GmbH, Heidelberg, Germany) with tracking and image averaging from the right eye of all participants. Repeatability as well as inter- and intra-observer reliability of biometric measurements were evaluated. The impact of image tracking and averaging on ciliary muscle measurements was tested. Univariate and multivariable statistical models were developed to evaluate the relationship of age and refractive status on anterior segment biometric measurements. Results: For all test-retest repeatability and inter- and intra-observer reproducibility of swept-source AS-OCT measurements, high intraclass correlation (ICC) was noted (0.88–1.00). The nasal maximum ciliary muscle thickness (CMTMAX) and distance between scleral spur to the thickest point of the ciliary muscle (SSMAX) were larger than those on the temporal side (p<0.001 and p = 0.006, respectively). Nasal and temporal CMTMAX (p = 0.004 and p<0.001, respectively) and lens thickness (p<0.01) increased with age. Nasal and temporal SSMAX decreased with older age and increasing hyperopia (p = 0.01 and p<0.001, respectively). Image averaging resulted in improved ciliary muscle measurements (p = 0.008 to 0.02). Lens vault increased with older age and increased hyperopia (p<0.01). OCT measurements of the angle decreased with older age and increased hyperopia (p<0.001 to 0.03). Aqueous depth decreased with older age and increased hyperopia (p<0.01). Pupil diameter decreased with older age (p<0.01). Conclusions: Repeatability and reproducibility of biometric measurements using the ANTERION AS-OCT were excellent. Image averaging improved the accuracy of ciliary muscle measurements. The device produced measurements of biometric parameters that described superficial and deep structures including the ciliary body and full lens thickness from a single image. [ABSTRACT FROM AUTHOR]

Deficits in cognitive control have been found in depression, but how they contribute to depressive symptoms remains unknown. The present study investigated whether the regulatory efficacy of cognitive control on negative emotion varies with depression level and whether the regulatory efficacy affects depressive symptoms via the mediation of rumination. Fifty participants screened by the Zung Self-Rating Depressive Scale (SDS) with high and low depression levels were selected. They were instructed to controlled-process different semantic representations of aversive pictures, and the amplitude of the late positive potential (LPP) evoked by the pictures was used as the measure of electrocortical response. We found that controlled-processing neutral representations of aversive pictures significantly decreased the amplitude of LPP relative to that under controlled-processing unpleasant ones in an early window in the low depression group and that this regulatory effect was impaired in the high depression group. Furthermore, a mediation analyses indicated that the regulatory efficacy of controlled-processing different semantic representations was associated with SDS score via the mediation of rumination. These findings shed light on the mechanisms underlying the association between the function of cognitive control in emotion generation and depressive symptoms and indicated a pathway from the regulatory efficacy of cognitive control to depression via rumination. [ABSTRACT FROM AUTHOR]

We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice. [ABSTRACT FROM AUTHOR]

Background: Chongqing is the largest municipality and located in Southwestern of China, with over 30 million registered inhabitants. There are few reports regarding the epidemiology of influenza in Chongqing. The objective of the paper is to explore the epidemiology of influenza in Chongqing, in order to provide scientific basis for prevention and control of influenza. Methodology /Principal Findings: From 2011 to 2015, we collected information on influenza-like illness (ILI) patients fulfilling the case definition, and took nasalpharyngeal or throat swabs specimens from ILI cases per week at the 7 sentinel hospitals. Specimens were tested by reverse transcription-polymerase chain reaction(RT-PCR) for influenza. Descriptive epidemiology was applied to analyze the epidemiology and etiology of influenza. A total of 9,696,212 cases were enrolled, of which 111,589 were ILI. Of those 24,868 samples from ILI cases, 13.3% (3,314/24,868) tested positive for influenza virus (65.7% influenza A, 34.1% influenza B, and 0.2% influenza A and B co-infection). Among the influenza A viruses, 71.3% were seasonal influenza A(H3N2) and 28.7% were influenza A(H1N1)pdm09. No cases of seasonal A(H1N1) were detected. The isolation rate was highest in children aged 5–14 years old. Influenza activity consistently peaked during January-March in 2011–2015, and June-July in 2012, 2014 and 2015. Conclusions: Influenza is an important public health problem among ILI patients in Chongqing, especially among school-aged children. It might be beneficial to prioritize influenza vaccination for school-aged children and implement the school-based intervention to prevent and mitigating influenza outbreaks in Chongqing, particularly during the seasonal peaks. [ABSTRACT FROM AUTHOR]

Event-related potentials were used to investigate whether semantic integration in discourse is influenced by the number of intervening sentences between the endpoints of integration. Readers read discourses in which the last sentence contained a critical word that was either congruent or incongruent with the information introduced in the first sentence. Furthermore, for the short discourses, the first and last sentence were intervened by only one sentence while for the long discourses, they were intervened by three sentences. We found that the incongruent words elicited an N400 effect for both the short and long discourses. However, a P600 effect was only observed for the long discourses, but not for the short ones. These results suggest that although readers can successfully integrate upcoming words into the existing discourse representation, the effort required for this integration process is modulated by the number of intervening sentences. Thus, discourse distance as measured by the number of intervening sentences should be taken as an important factor for semantic integration in discourse. [ABSTRACT FROM AUTHOR]

Plasticity of vascular smooth muscle cells (VSMCs) plays a central role in the onset and progression of proliferative vascular diseases. In adult tissue, VSMCs exist in a physiological contractile-quiescent phenotype, which is defined by lack of the ability of proliferation and migration, while high expression of contractile marker proteins. After injury to the vessel, VSMC shifts from a contractile phenotype to a pathological synthetic phenotype, associated with increased proliferation, migration and matrix secretion. It has been demonstrated that PDGF-BB is a critical mediator of VSMCs phenotypic switch. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methyl-glutaryl l coenzyme A (HMG-CoA) reductase, exhibits various protective effects against VSMCs. In this study, we investigated the effects of atorvastatin calcium on phenotype modulation of PDGF-BB-induced VSMCs and the related intracellular signal transduction pathways. Treatment of VSMCs with atorvastatin calcium showed dose-dependent inhibition of PDGF-BB-induced proliferation. Atorvastatin calcium co-treatment inhibited the phenotype modulation and cytoskeleton rearrangements and improved the expression of contractile phenotype marker proteins such as α-SM actin, SM22α and calponin in comparison with PDGF-BB alone stimulated VSMCs. Although Akt phosphorylation was strongly elicited by PDGF-BB, Akt activation was attenuated when PDGF-BB was co-administrated with atorvastatin calcium. In conclusion, atorvastatin calcium inhibits phenotype modulation of PDGF-BB-induced VSMCs and activation of the Akt signaling pathway, indicating that Akt might play a vital role in the modulation of phenotype. [ABSTRACT FROM AUTHOR]

Carbon reduction at the household level is an integral part of carbon mitigation. This study analyses the characteristics, effects, contributing factors and policies for urban household carbon emissions in the Yangtze River Delta of China. Primary data was collected through structured questionnaire surveys in three cities in the region – Nanjing, Ningbo, and Changzhou in 2011. The survey data was first used to estimate the magnitude of household carbon emissions in different urban contexts. It then examined how, and to what extent, each set of demographic, economic, behavioral/cognitive and spatial factors influence carbon emissions at the household level. The average of urban household carbon emissions in the region was estimated to be 5.96 tonnes CO2 in 2010. Energy consumption, daily commuting, garbage disposal and long-distance travel accounted for 51.2%, 21.3%, 16.0% and 11.5% of the total emission, respectively. Regulating rapidly growing car-holdings of urban households, stabilizing population growth, and transiting residents’ low-carbon awareness to household behavior in energy saving and other spheres of consumption in the context of rapid population aging and the growing middle income class are suggested as critical measures for carbon mitigation among urban households in the Yangtze River Delta. [ABSTRACT FROM AUTHOR]

Shiraia bambusicola P. Henn. is a pathogenic fungus of bamboo, and its fruiting bodies are regarded as folk medicine. We determined and analyzed its complete mitochondrial DNA sequence (circular DNA molecule of 39,030 bp, G + C content of 25.19%). It contains the typical genes encoding proteins involved in electron transport and coupled oxidative phosphorylation (nad1-6 and nad4L, cob and cox1-3), one ATP synthase subunit (atp6), 4 hypothetical proteins, and two genes for large and small rRNAs (rnl and rns). There is a set of 32 tRNA genes comprising all 20 amino acids, and these genes are evenly distributed on the two strands. Phylogenetic analyses based on concatenated mitochondrial proteins indicated that S. bambusicola clustered with members of the order Pleosporales, which is in agreement with previous results. The gene arrangements of Dothideomycetes species contained three regions of gene orders partitioned in their mitochondrial genomes, including block 1 (nad6-atp6), block 2 (nad1-cox3) and block 3 (genes around rns). S. bambusicola displayed unique special features that differed from the other Pleosporales species, especially in the coding regions around rns (trnR-trnY). Moreover, a comparison of gene orders in mitochondrial genomes from Pezizomycotina revealed that although all encoded regions are located on the same strand in most Pezizomycotina mtDNAs, genes from Dothideomycetes species had different orientations, as well as diverse positions and colocalization of genes (such as cox3, cox1-cox2 and nad2–nad3); these distinctions were regarded as class-specific features. Interestingly, two incomplete copies of the atp6 gene were found on different strands of the mitogenomic DNA, a finding that has not been observed in the other analyzed fungal species. In our study, mitochondrial genomes from Dothideomycetes species were comprehensively analyzed for the first time, including many species that have not appeared in previous reports. [ABSTRACT FROM AUTHOR]

Background: The interaction of tumor necrosis factor-α (TNF-α) with its receptors: TNFRSF1A and TNFRSF1B is critical for the promotion of tumor growth, invasion and metastasis. To better understand the roles of single nucleotide polymorphisms (SNPs) in the TNF-α, TNFRSF1A and TNFRSF1B genes in the development of breast cancer, we explored the associations between SNPs in these three genes and breast cancer susceptibility in northeast Chinese Han women. Methodology/Principal Findings: This case-control study was conducted among 1016 breast cancer patients and 806 age-matched healthy controls. Seven SNPs in the TNF-α (rs1800629, rs361525), TNFRSF1A (rs767455, rs4149577 and rs1800693) and TNFRSF1B (rs1061622 and rs1061624) genes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In TNFRSF1B, the rs1061622 GT genotype and the G allele conferred a reduced susceptibility to breast cancer (P = 0.000662, OR = 0.706, 95% CI: 0.578–0.863; P = 0.002, OR = 0.769, 95% CI; 0.654–0.905, respectively). Moreover, the AG genotype, the AA genotype and the A allele in rs1061624 conferred an increased risk of breast cancer (P = 0.007, OR = 1.470, 95% CI:1.112–1.943; P = 0.00109, OR = 1.405 95% CI:1.145–1.724; P = 0.001, OR = 1.248 95% CI:1.092–1.426, respectively). These two SNPs also had associations with breast cancer risk under the dominant model. In haplotype analysis, the CTA (rs767455 C-rs4149577 T-rs1800693 A) haplotype in TNFRSF1A and the TA (rs1061622 T-rs1061624 A) haplotype in TNFRSF1B had higher frequencies in breast cancer patients (P = 0.00324; P = 0.000370, respectively), but the frequency of GG (rs1061622 G-rs1061624 G) haplotype in TNFRSF1B was lower in breast cancer patients (P = 0.000251). The associations of the three haplotypes remained significant after correcting for multiple testing. In addition, significant associations were also observed between TNFRSF1A polymorphisms and lymph node metastasis, P53, estrogen receptor (ER) and progesterone receptor (PR) statuses. Conclusions: Our results suggest that rs1061622 and rs1061624 in TNFRSF1B may affect breast cancer risk, and SNPs in TNFRSF1A are associated with the clinical features of breast cancer. [ABSTRACT FROM AUTHOR]

The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM. [ABSTRACT FROM AUTHOR]

The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. C/EBPε is expressed only in myeloid cells including monocytes/macrophages. Atherosclerosis is an inflammatory disorder of the vascular wall and circulating immune cells such as monocytes/macrophages. Mice deficient in the low density lipoprotein (LDL) receptor (Ldlr−/−) fed on a high cholesterol diet (HCD) show elevated blood cholesterol levels and are widely used as models to study human atherosclerosis. In this study, we generated Ldlr and Cebpe double-knockout (llee) mice and compared their atherogenic phenotypes to Ldlr single deficient (llEE) mice after HCD. Macrophages from llee mice have reduced lipid uptake by foam cells and impaired phagokinetic motility in vitro compared to macrophages from llEE mice. Also, compared to llEE mice, llee mice have alterations of lipid metabolism, and reduced atheroma and obesity, particularly the males. Peritoneal macrophages of llee male mice have reduced mRNA expression of FABP4, a fatty acid binding protein implicated in atherosclerosis. Overall, our study suggests that the myeloid specific factor C/EBPε is involved in systemic lipid metabolism and that silencing of C/EBPε could decrease the development of atherosclerosis. [ABSTRACT FROM AUTHOR]

This study investigated whether semantic integration in discourse context could be influenced by topic structure using event-related brain potentials. Participants read discourses in which the last sentence contained a critical word that was either congruent or incongruent with the topic established in the first sentence. The intervening sentences between the first and the last sentence of the discourse either maintained or shifted the original topic. Results showed that incongruent words in topic-maintained discourses elicited an N400 effect that was broadly distributed over the scalp while those in topic-shifted discourses elicited an N400 effect that was lateralized to the right hemisphere and localized over central and posterior areas. Moreover, a late positivity effect was only elicited by incongruent words in topic-shifted discourses, but not in topic-maintained discourses. This suggests an important role for discourse structure in semantic integration, such that compared with topic-maintained discourses, the complexity of discourse structure in topic-shifted condition reduces the initial stage of semantic integration and enhances the later stage in which a mental representation is updated. [ABSTRACT FROM AUTHOR]

Chlamydia pneumoniae (CP) lung infection can induce chronic lung inflammation and is associated with not only acute asthma but also COPD exacerbations. However, in mouse models of CP infection, most studies have investigated specifically the acute phase of the infection and not the longer-term chronic changes in the lungs. We infected C57BL/6 mice with 5×105 CP intratracheally and monitored inflammation, cellular infiltrates and cytokine levels over time to investigate the chronic inflammatory lung changes. While bacteria numbers declined by day 28, macrophage numbers remained high through day 35. Immune cell clusters were detected as early as day 14 and persisted through day 35, and stained positive for B, T, and follicular dendritic cells, indicating these clusters were inducible bronchus associated lymphoid tissues (iBALTs). Classically activated inflammatory M1 macrophages were the predominant subtype early on while alternatively activated M2 macrophages increased later during infection. Adoptive transfer of M1 but not M2 macrophages intratracheally 1 week after infection resulted in greater lung inflammation, severe fibrosis, and increased numbers of iBALTS 35 days after infection. In summary, we show that CP lung infection in mice induces chronic inflammatory changes including iBALT formations as well as fibrosis. These observations suggest that the M1 macrophages, which are part of the normal response to clear acute C. pneumoniae lung infection, result in an enhanced acute response when present in excess numbers, with greater inflammation, tissue injury, and severe fibrosis. [ABSTRACT FROM AUTHOR]

As a costimulatory molecule, Herpesvirus entry mediator (HVEM) can bind with several costimulatory members, thus HVEM plays different roles in T cell immunity. HVEM and its ligands have been involved in the pathogenesis of various autoimmune, inflammatory diseases and tumors. In the current study, we conducted a case-control study comparing polymorphisms of HVEM and breast cancer. Subjects included 575 females with breast cancer and 604 age-matched healthy controls. Six HVEM SNPs (rs2281852, rs1886730, rs2234163, rs11573979, rs2234165, and rs2234167) were genotyped by PCR-RFLP. The results showed significant differences in genotypes and alleles between rs1886730 and rs2234167 (P<0.05). One haplotype (CTGCGG) that was associated with breast cancer was found via haplotype analysis. Our research also indicated an association between polymorphisms of HVEM and clinicopathologic features, including lymph node metastasis, estrogen receptor, progesterone receptor and P53. Our results primarily indicate that polymorphisms of the HVEM gene were associated with the risk of sporadic breast cancer in northeast Chinese females. [ABSTRACT FROM AUTHOR]

OX40L is an important costimulatory molecule that plays a crucial role in the regulation of T-cell-mediated immunity. The interaction of OX40-OX40L is involved in the pathogenesis of multiple autoimmune and inflammatory diseases such as systemic lupus erythematosus (SLE), carotid artery disease and cancer. The genetic variants of OX40L can increase the risk of SLE, atherosclerosis, systemic sclerosis and show gender-specific effects in some studies. Accordingly, we performed a case-control study including 557 breast cancer patients and 580 age- and sex-matched healthy controls to investigate whether single nucleotide polymorphisms (SNPs) in the OX40L gene are associated with sporadic breast cancer susceptibility and progression in Chinese Han women. Seven SNPs of OX40L (rs6661173, rs1234313, rs3850641, rs1234315, rs12039904, rs844648 and rs1 0912580) were genotyped with the method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results indicated that rs3850641G allele could increase the susceptibility to breast cancer (P = 0.009662), even in the validation study (P = 0.0001515). A significant association between rs3850641 and breast cancer risk was observed under the additive model and dominant model (P = 0.01042 and 0.01942, respectively). The haplotype analysis showed that haplotype Ars844648Ars10912580 was significantly associated with breast cancer, even after 10,000 permutations for haplotypes in block only (P = 0.0003). In clinicopathologic features analysis, the association between rs1234315 and C-erbB2 status was significant (P = 0.02541). Our data primarily indicates that rs3850641 of OX40L gene contributes to sporadic breast carcinogenesis in a northeast Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a polygenetic disorder with a complex inheritance pattern. Single nucleotide polymorphisms (SNPs), the most common genetic variations, influence not only phenotypic traits, but also interindividual predisposition to disease, treatment outcomes with drugs and disease prognosis. The co-stimulatory molecule CD40 plays a prominent role in immune regulation and homeostasis. Accumulating evidence suggests that CD40 contributes to the pathogenesis of cancer. Here, we set out to test the association between polymorphisms in the CD40 gene and breast carcinogenesis and tumor pathology. Methodology and Principal Findings: Four SNPs (rs1800686, rs1883832, rs4810485 and rs3765459) were genotyped by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method in a case-control study including 591 breast cancer patients and 600 age-matched healthy controls. Differences in the genotypic distribution between breast cancer patients and healthy controls were analyzed by the Chi-square test for trends. Our preliminary data showed a statistically significant association between the four CD40 gene SNPs and sporadic breast cancer risk (additive P = 0.0223, 0.0012, 0.0013 and 0.0279, respectively). A strong association was also found using the dominant, recessive and homozygote comparison genetic models. In the clinical features analysis, significant associations were observed between CD40 SNPs and lymph node metastasis, human epidermal growth factor receptor 2 (C-erbB2), estrogen receptor (ER), progesterone receptor (PR) and tumor protein 53 (P53) statuses. In addition, our haplotype analysis indicated that the haplotype Crs1883832Grs4810485, which was located within the only linkage disequilibrium (LD) block identified, was a protective haplotype for breast cancer, whereas Trs1883832Trs4810485 increased the risk in the studied population, even after correcting the P value for multiple testing (P = 0.0337 and 0.0430, respectively). Conclusions and Significance: Our findings primarily show that CD40 gene polymorphisms contribute to sporadic breast cancer risk and have a significant association with clinicopathological features among Chinese Han women from the Heilongjiang Province. [ABSTRACT FROM AUTHOR]

Chlamydia pneumoniae (CP) is an important human pathogen that causes atypical pneumonia and is associated with various chronic inflammatory disorders. Caspase-1 is a key component of the 'inflammasome', and is required to cleave pro-IL-1&bgr; to bioactive IL-1&bgr;. Here we demonstrate for the first time a critical requirement for IL-1&bgr; in response to CP infection. Caspase- 1-/-mice exhibit delayed cytokine production, defective clearance of pulmonary bacteria and higher mortality in response to CP infection. Alveolar macrophages harbored increased bacterial numbers due to reduced iNOS levels in Caspase-12/2 mice. Pharmacological blockade of the IL-1 receptor in CP infected wild-type mice phenocopies Caspase-1-deficient mice, and administration of recombinant IL-1&bgr; rescues CP infected Caspase-1-/-mice from mortality, indicating that IL-1&bgr; secretion is crucial for host immune defense against CP lung infection. In vitro investigation reveals that CP-induced IL-1&bgr; secretion by macrophages requires TLR2/MyD88 and NLRP3/ASC/Caspase-1 signaling. Entry into the cell by CP and new protein synthesis by CP are required for inflammasome activation. Neither ROS nor cathepsin was required for CP infection induced inflammasome activation. Interestingly, Caspase-1 activation during CP infection occurs with mitochondrial dysfunction indicating a possible mechanism involving the mitochondria for CP-induced inflammasome activation. [ABSTRACT FROM AUTHOR]

To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS) in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2ra) do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8+ and CD4+ T cells contribute to HSV-IL-2-induced CNS demyelination with CD8+ T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs) have opposing but complementary functions in directing bone growth, repair, and turnover. Both are found in the bone matrix. Proteins that bind to and affect the activity of these growth factors will determine the relative abundance of the growth factors and, therefore, regulate bone formation. Secreted phosphoprotein 24 kD (Spp24) is a bone matrix protein that has been demonstrated to bind to and affect the activity of BMPs. The arginine-rich carboxy terminus of Spp24 is proteolytically processed to produce three other predictable truncation products (Spp18.1, Spp16.0, and Spp14.5). In this work, we report that kinetic data obtained by surface plasmon resonance demonstrate that Spp24 and the three C-terminal truncation products all bind to TGF-β1 and TGF-β2 with a similar but somewhat less affinity than they bind BMP-2; that, as in the case of BMP-2, the full-length (FL) form of Spp24 binds TGF-β with greater affinity than do the truncation products; that FL-Spp24 inhibits TGF-β2 induced bone formation in vivo, but Spp14.5 does not; and that co-administration of FL-Spp24 or Spp14.5 with TGF-β2 in vivo is associated with a reduction in the amount of cartilage, relative to new bone, present at the site of injection. This finding is consistent with the observation that low-dose TGF-β administration in vivo is associated with greater bone formation than high-dose TGF-β administration, and suggests that one function of Spp24 and its truncation products is to down-regulate local TGF-β activity or availability during bone growth and development. The similarities and differences of the interactions between Spp24 proteins and TGF-β compared to the interaction of the Spp24 proteins and BMPs have significant implications with respect to the regulation of bone metabolism and with respect to engineering therapeutic proteins for skeletal disorders. [ABSTRACT FROM AUTHOR]

Chlamydia pneumoniae (CP) lung infection can induce chronic lung inflammation and is associated with not only acute asthma but also COPD exacerbations. However, in mouse models of CP infection, most studies have investigated specifically the acute phase of the infection and not the longer-term chronic changes in the lungs. We infected C57BL/6 mice with 5 × 10(5) CP intratracheally and monitored inflammation, cellular infiltrates and cytokine levels over time to investigate the chronic inflammatory lung changes. While bacteria numbers declined by day 28, macrophage numbers remained high through day 35. Immune cell clusters were detected as early as day 14 and persisted through day 35, and stained positive for B, T, and follicular dendritic cells, indicating these clusters were inducible bronchus associated lymphoid tissues (iBALTs). Classically activated inflammatory M1 macrophages were the predominant subtype early on while alternatively activated M2 macrophages increased later during infection. Adoptive transfer of M1 but not M2 macrophages intratracheally 1 week after infection resulted in greater lung inflammation, severe fibrosis, and increased numbers of iBALTS 35 days after infection. In summary, we show that CP lung infection in mice induces chronic inflammatory changes including iBALT formations as well as fibrosis. These observations suggest that the M1 macrophages, which are part of the normal response to clear acute C. pneumoniae lung infection, result in an enhanced acute response when present in excess numbers, with greater inflammation, tissue injury, and severe fibrosis.

Background: CD28 is one of a number of costimulatory molecules that play crucial roles in immune regulation and homeostasis. Accumulating evidence indicates that immune factors influence breast carcinogenesis. To clarify the relationships between polymorphisms in the CD28 gene and breast carcinogenesis, a case-control study was conducted in women from Heilongjiang Province in northeast of China., Methodology/principal Findings: Our research subjects consisted of 565 female patients with sporadic breast cancer and 605 age- and sex-matched healthy controls. In total, 12 single nucleotide polymorphisms (SNPs) in the CD28 gene were successfully determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relationship between the CD28 variants and clinical features, including histological grade, tumor size, lymph node metastasis, human epidermal growth factor receptor 2 (C-erbB2), estrogen receptor (ER), progesterone receptor (PR), and tumor protein 53 (P53) status were analyzed. A statistically significant association was observed between rs3116496 and breast cancer risk under different genetic models (additive P = 0.0164, dominant P = 0.0042). Different distributions of the rs3116496 'T' allele were found in patients and controls, which remained significant after correcting the P value for multiple testing using Haploview with 10,000 permutations (corrected P = 0.0384). In addition, significant associations were observed between rs3116487/rs3116494 (D' = 1, r(2) = 0.99) and clinicopathological features such as C-erbB2 and ER status, in breast cancer patients., Conclusions/significance: Our findings indicate that CD28 gene polymorphisms contribute to sporadic breast cancer risk and have a significant association with clinicopathological features in a northeast Chinese Han population.

Plasmacytoid dendritic cells (pDCs) are known for their robust antiviral response and their pro-tolerance effects towards allergic diseases and tissue engraftments. However, little is known about the role pDCs may play during a bacterial infection, including pulmonary Chlamydia pneumoniae (CP). In this study, we investigated the role of pDCs during pulmonary CP infection. Our results revealed that depletion of pDCs during acute CP infection in mice results in delayed and reduced lung inflammation, with an early delay in cellular recruitment and significant reduction in early cytokine production in the lungs. This was followed by impaired and delayed bacterial clearance from the lungs which then resulted in a severe and prolonged chronic inflammation and iBALT like structures containing large numbers of B and T cells in these animals. We also observed that increasing the pDC numbers in the lung by FLT3L treatment experimentally results in greater lung inflammation during acute CP infection. In contrast to these results, restimulation of T-cells in the draining lymph nodes of pDC-depleted mice induced greater amounts of proinflammatory cytokines than we observed in control mice. These results suggest that pDCs in the lung may provide critical proinflammatory innate immune responses in response to CP infection, but are suppressive towards adaptive immune responses in the lymph node. Thus pDCs in the lung and the draining lymph node appear to have different roles and phenotypes during acute CP infection and may play a role in host immune responses.

Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs.

Locusts exhibit remarkable density-dependent phenotype (phase) changes from the solitary to the gregarious, making them one of the most destructive agricultural pests. This phenotype polyphenism arises from a single genome and diverse transcriptomes in different conditions. Here we report a de novo transcriptome for the migratory locust and a comprehensive, representative core gene set. We carried out assembly of 21.5 Gb Illumina reads, generated 72,977 transcripts with N50 2,275 bp and identified 11,490 locust protein-coding genes. Comparative genomics analysis with eight other sequenced insects was carried out to identify the genomic divergence between hemimetabolous and holometabolous insects for the first time and 18 genes relevant to development was found. We further utilized the quantitative feature of RNA-seq to measure and compare gene expression among libraries. We first discovered how divergence in gene expression between two phases progresses as locusts develop and identified 242 transcripts as candidates for phase marker genes. Together with the detailed analysis of deep sequencing data of the 4(th) instar, we discovered a phase-dependent divergence of biological investment in the molecular level. Solitary locusts have higher activity in biosynthetic pathways while gregarious locusts show higher activity in environmental interaction, in which genes and pathways associated with regulation of neurotransmitter activities, such as neurotransmitter receptors, synthetase, transporters, and GPCR signaling pathways, are strongly involved. Our study, as the largest de novo transcriptome to date, with optimization of sequencing and assembly strategy, can further facilitate the application of de novo transcriptome. The locust transcriptome enriches genetic resources for hemimetabolous insects and our understanding of the origin of insect metamorphosis. Most importantly, we identified genes and pathways that might be involved in locust development and phase change, and may thus benefit pest management.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in neonatal intensive care units, however its pathogenesis is not completely understood. We have previously shown that platelet activating factor (PAF), bacteria and TLR4 are all important factors in the development of NEC. Given that Toll-like receptors (TLRs) are expressed at low levels in enterocytes of the mature gastrointestinal tract, but were shown to be aberrantly over-expressed in enterocytes in experimental NEC, we examined the regulation of TLR4 expression and signaling by PAF in intestinal epithelial cells using human and mouse in vitro cell lines, and the ex vivo rat intestinal loop model. In intestinal epithelial cell (IEC) lines, PAF stimulation yielded upregulation of both TLR4 mRNA and protein expression and led to increased IL-8 secretion following stimulation with LPS (in an otherwise LPS minimally responsive cell line). PAF stimulation resulted in increased human TLR4 promoter activation in a dose dependent manner. Western blotting and immunohistochemical analysis showed PAF induced STAT3 phosphorylation and nuclear translocation in IEC, and PAF-induced TLR4 expression was inhibited by STAT3 and NFκB Inhibitors. Our findings provide evidence for a mechanism by which PAF augments inflammation in the intestinal epithelium through abnormal TLR4 upregulation, thereby contributing to the intestinal injury of NEC.

Inflammatory bowel disease (IBD) is a disorder of chronic inflammation with increased susceptibility to colorectal cancer. The etiology of IBD is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host. Toll-like receptor (TLR) signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis, innate immunity and the enhancement of intestinal epithelial cell (IEC) integrity. However, the role of TLR2 in the development of colorectal cancer has not been studied. We utilized the AOM-DSS model for colitis-associated colorectal cancer (CAC) in wild type (WT) and TLR2(-/-) mice. Colons harvested from WT and TLR2(-/-) mice were used for histopathology, immunohistochemistry, immunofluorescence and cytokine analysis. Mice deficient in TLR2 developed significantly more and larger colorectal tumors than their WT controls. We provide evidence that colonic epithelium of TLR2(-/-) mice have altered immune responses and dysregulated proliferation under steady-state conditions and during colitis, which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth. At the earliest time-points assessed, TLR2(-/-) colons exhibited a significant increase in aberrant crypt foci (ACF), resulting in tumors that developed earlier and grew larger. In addition, the intestinal microenvironment revealed significantly higher levels of IL-6 and IL-17A concomitant with increased phospho-STAT3 within ACF. These observations indicate that in colitis, TLR2 plays a protective role against the development of CAC.

Here we investigated the role of the Nod/Rip2 pathway in host responses to Chlamydophila pneumoniae-induced pneumonia in mice. Rip2(-/-) mice infected with C. pneumoniae exhibited impaired iNOS expression and NO production, and delayed neutrophil recruitment to the lungs. Levels of IL-6 and IFN-gamma levels as well as KC and MIP-2 levels in bronchoalveolar lavage fluid (BALF) were significantly decreased in Rip2(-/-) mice compared to wild-type (WT) mice at day 3. Rip2(-/-) mice showed significant delay in bacterial clearance from the lungs and developed more severe and chronic lung inflammation that continued even on day 35 and led to increased mortality, whereas WT mice cleared the bacterial load, recovered from acute pneumonia, and survived. Both Nod1(-/-) and Nod2(-/-) mice also showed delayed bacterial clearance, suggesting that C. pneumoniae is recognized by both of these intracellular receptors. Bone marrow chimera experiments demonstrated that Rip2 in BM-derived cells rather than non-hematopoietic stromal cells played a key role in host responses in the lungs and clearance of C. pneumoniae. Furthermore, adoptive transfer of WT macrophages intratracheally was able to rescue the bacterial clearance defect in Rip2(-/-) mice. These results demonstrate that in addition to the TLR/MyD88 pathway, the Nod/Rip2 signaling pathway also plays a significant role in intracellular recognition, innate immune host responses, and ultimately has a decisive impact on clearance of C. pneumoniae from the lungs and survival of the infectious challenge.