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Background and ObjectiveAlcohol consumption is one of the important modifiable risk factors for stroke in young adults. The association between the cumulative burden of alcohol consumption and its impact on incident stroke in young adults is unknown. We aimed to investigate the association between cumulative alcohol burden and the risk for stroke among young adults.MethodsUsing data from the Korean National Health Insurance Service database, patients age between 20 and 39 years, who underwent 4 consecutive annual health examinations between 2009 and 2012, were included. The cumulative alcohol burden score of moderate-to-heavy drinking was evaluated by assigning a score of 1 for alcohol consumption ≥105 g/wk at the health examination each year and calculating the sum of 4 years (0–4). The main outcome was incident stroke and its subtypes, ischemic stroke, and hemorrhagic stroke during the follow-up period.ResultsOf 1 536 668 patients (mean age of 29.5 years, 71.5% male, and median follow-up of 6-year), 3 153 experienced an incident stroke (incidence rate, 0.37 per 1,000 person-years). After multivariable adjustment, patients with alcohol burden scores of 2, 3, and 4, who consumed more than 105 g/wk of alcohol for 2, 3, and 4 years, demonstrated significantly higher risks for stroke (hazard ratio [HR] 1.19, 95% CI 1.05–1.34 for 2; HR 1.22, 95% CI 1.09–1.38 for 3; HR 1.23, 95% CI 1.10–1.38 for 4) compared with those with a burden score of 0. This positive dose-response relationship was primarily driven by hemorrhagic rather than ischemic stroke. High alcohol burden scores (i.e., 2, 3, and 4) were significantly associated with higher risks for hemorrhagic stroke (HR 1.30, 95% CI 1.10–1.54 for 2; HR 1.42, 95% CI 1.21–1.67 for 3; HR 1.36, 95% CI 1.16–1.59 for 4) compared with a burden score of 0.DiscussionYoung adults who engaged in moderate-to-heavy drinking demonstrated a higher risk for incident stroke, especially hemorrhagic stroke. Reducing alcohol consumption should be emphasized in young adults with heavy drinking habits as part of any stroke prevention strategy.

ObjectiveOptimal antithrombotic therapy in patients with atrial fibrillation (AF) beyond 1 year after coronary stent implantation has not been well established in the era of direct oral anticoagulant (DOAC).MethodsUsing Korean National Health Insurance Service data, we analysed 4294 patients with AF who were prescribed DOAC beyond 1 year after coronary stent implantation. Subjects were classified into the monotherapy group (DOAC single therapy, n=1221) or the combination therapy group (DOAC with an antiplatelet agent, n=3073). The primary ischaemic endpoint was defined as a composite of cardiovascular death, myocardial infarction, stroke or systemic thromboembolism. The secondary endpoints were all-cause death, major bleeding defined as a bleeding event requiring hospitalisation and net adverse clinical events. Propensity score matching was performed to balance baseline covariates.ResultsAmong included patients, 94% had drug-eluting coronary stents. During a median follow-up of 19 (7–32) months, the monotherapy group had a similar risk of the primary ischaemic endpoint (HR 0.828, 95% CI 0.660 to 1.038) and all-cause death (HR 1.076, 95% CI 0.895 to 1.294) compared with the combination therapy group. Risk of major bleeding was lower in the monotherapy group (HR 0.690, 95% CI 0.481 to 0.989), which was mostly driven by reduced gastrointestinal bleeding (HR 0.562, 95% CI 0.358 to 0.883). There was no significant difference in net adverse clinical events between the two groups.ConclusionsDOAC monotherapy showed similar efficacy in preventing ischaemic events and was associated with lower major bleeding events compared with combination therapy in patients with AF beyond 1 year after coronary stent implantation.

Background and Objectives The efficacy of radiofrequency catheter ablation (RFCA) in atrial fibrillation (AF) is well established. The standard approach to RFCA in AF is pulmonary vein isolation (PVI). However, a large proportion of patients experiences recurrence of atrial tachyarrhythmia. The purpose of this study is to find out whether the AI model can assess AF recurrence in patients who underwent PVI. Materials and methods This study was a retrospective cohort study that enrolled consecutive patients who underwent catheter ablation for symptomatic, drug-refractory AF and PVI. We developed an AI algorithm to predict recurrence of AF after PVI using patient demographics and three-dimensional (3D) reconstructed left atrium (LA) images. Results We included 527 consecutive patients in the study. The overall mean LA diameter was 42.0 ± 6.8 mm, and the mean LA volume calculated using 3D reconstructed images was 151.1 ± 46.7 ml. During the follow-up period, atrial tachyarrhythmia recurred in 158 patients. The area under the curve (AUC) of the AI model based on a convolutional neural network (including 3D reconstruction images) was 0.61 (95% confidence interval [CI] 0.53–0.74) using the test dataset. The total test accuracy was 66.3% (57.0–75.6), and the sensitivity was 53.3% (34.8–71.9). The specificity was 73.2% (51.8–75.0), and the F1 score was 52.5% 34.5–66.7). Conclusion In this study, we developed an AI algorithm to predict recurrence of AF after catheter ablation of PVI using individual reconstructed LA images. This AI model was unable to predict recurrence of AF overwhelmingly; therefore, further large-scale study is needed.

Background The left lateral ridge (LLR) is an important structure for ablation of atrial fibrillation (AF). This study assessed how the LLR shape is associated with the long-term outcomes of AF ablation and investigated the relationship with radiofrequency (RF) lesion formation. Methods and results Clinical study - we assessed multi-detector computed tomography (MDCT) images in 247 patients who underwent AF ablation. Patients were classified into two groups according to the shape of the LLR: Narrow LLR group (n = 116; 47%) and Wide LLR group (n = 131; 53%). After a follow-up period 475 ± 245 days, the AF-free rate was significantly higher in the wide LLR than Narrow LLR group (83.2% vs. 62.9%, p = 0.0004). A multivariate analysis showed that the shape of the LLR was an independent predictor of AF recurrence after ablation (hazard ratio 2.58; 95% confidential interval = 1.48–4.51, p = 0.001). Experimental study - Two types of the ridge models were made with porcine atrial tissues: “Narrow ridge(4.2 ± 0.9 mm)” and “Wide ridge(9.7 ± 1.8 mm)” RF ablation was performed on each ridge model using a contact force (CF)-sensing catheter. The mean CF and the RF lesion volume of the narrow ridge were significantly less than those of the wide ridge model (5.42 ± 3.13 g vs. 10.37 ± 3.98 g, p = 0.001; 19.8 ± 9.9 mm3 vs. 44.2 ± 13.6 mm3, p Conclusions AF recurrence after ablation was more frequent in patients with a narrow LLR. LLR shape as assessed using MDCT is associated with long-term outcomes after AF ablation. CF and lesion formation data using the porcine atrial tissue model support our clinical results.

Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive fibrotic lung disease. Advanced IPF patients often demonstrate pulmonary hypertension, which severely impairs patients’ quality of life. The critical physiological roles of soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway have been well characterized in vasodilation and the corresponding therapies and pathway agonists have shown clinical benefits in treating hypertension. In recent years, many preclinical studies have demonstrated anti-fibrotic efficacy of sGC-cGMP activation in various experimental fibrosis models but the molecular basis of the efficacy in these models are not well understood. Also, sGC pathway agonism has demonstrated encouraging clinical benefits in advanced IPF patients (NCT00517933). Here, we have revealed the novel phosphorylation events downstream of sGC activation in human lung fibroblasts using phosphoproteomics. sGCact A, a potent and selective sGC activator, significantly attenuated more than 2,000 phosphorylation sites. About 20% of phosphorylation events, attenuated by transforming growth factor β (TGFβ), a master regulator of fibrosis, were further dysregulated in the sGCact A co-treated lung fibroblasts. The overall magnitude and diversity of the sGCact A phosphoproteome was extensive. Further investigation would be required to understand how these newly identified changes facilitate human pulmonary fibrosis.

Organized atrial tachycardia (AT) accounts for a substantial proportion of recurrence after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). We sought to analyze the characteristics and long-term outcome of redo RFCA for recurrent AT compared with those for recurrent AF. We analyzed 133 patients who underwent prior AF ablation and presented for redo RFCA procedure. Documented rhythm at recurrence was AT in 50 patients (37.6%) and AF in 83 patients (62.4%). Redo ablation was conducted using a stepwise approach in all subjects. Recurrent arrhythmia was more frequently a persistent type in the AT group (70.0% vs. 36.1% in the AT and AF group, respectively, p

The aim of this chapter is to describe and analyze the historical context, current situation, and governance issues of consumer cooperatives in Korea, and to explore conceptual models for consumer cooperatives. This will enable conclusions to be drawn as to the factors leading to success, the identification of difficulties, and how these difficulties can be overcome. From the macro perspective, we investigate the relationship between the state and consumer cooperatives, highlighting the roles of the state in the emergence and development of consumer cooperatives. For the microlevel analysis, organizational design and governance structure are examined to grasp the key characteristics and performance of consumer cooperatives in Korea. As the social movements of labor, gender, and the environment have been growing, Korea’s consumer cooperatives have emerged along with civil society. As consumer cooperatives developed in the 1990s, they were required to be institutionalized in the emergent legal system. The governance of Korea’s consumer cooperatives is designed for working with producers and consumers, emphasizing more on democratic participation than on management professionalism. In conclusion, Korea’s consumer cooperatives have emerged from the grassroots movement of civil society. This research is based on the case study of iCOOP and Hansalim, which are the two of the largest consumer cooperatives in Korea.

Published: 21 February 2017 Pride occurs in every known culture, appears early in development, is reliably triggered by achievements and formidability, and causes a characteristic display that is recognized everywhere. Here, we evaluate the theory that pride evolved to guide decisions relevant to pursuing actions that enhance valuation and respect for a person in the minds of others. By hypothesis, pride is a neurocomputational program tailored by selection to orchestrate cognition and behavior in the service of: (i) motivating the cost-effective pursuit of courses of action that would increase others' valuations and respect of the individual, (ii) motivating the advertisement of acts or characteristics whose recognition by others would lead them to enhance their evaluations of the individual, and (iii) mobilizing the individual to take advantage of the resulting enhanced social landscape. To modulate how much to invest in actions that might lead to enhanced evaluations by others, the pride system must forecast the magnitude of the evaluations the action would evoke in the audience and calibrate its activation proportionally. We tested this prediction in 16 countries across 4 continents (n = 2,085), for 25 acts and traits. As predicted, the pride intensity for a given act or trait closely tracks the valuations of audiences, local (mean r = + 0.82) and foreign (mean r = + 0.75). This relationship is specific to pride and does not generalize to other positive emotions that coactivate with pride but lack its audience-recalibrating function.

Ballast water is water that is filled into the ballast tank of the ship. Ballast water may be injected from the sea or be discharged into the sea in the process of loading and unloading the ship in...

Aim The purpose of this study was to verify the validity and reliability of the resilience scale for nurses (RSN). Methods 27 preliminary items were extracted from previous research. The subjects were 339 nurses who worked at 2 hospitals in South Korea in 2016. Collected data were analyzed using explanatory factor analysis (EFA). EFA was performed with principal axis factoring with oblimin rotation and confirmatory factor analysis (CFA) with SPSS 25.0 and AMOS 25.0 version program. Also, data were examined by construct, discriminant, and convergent validity, and internal consistency reliability. Results Resilience scale for nurses showed CFA supported the four-factor structure (Philosophical pattern, Relational pattern, Dispositional pattern, and Situational pattern) of the measure. The 19 items for 4 factors identified that explained 67.329% of the total variance in RSN. A total the internal consistency reliability (Cronbach's α = 0.938) was stable. Conclusion Psychometric properties of RSN show that it is a useful and reliable scale to assess Resilience in Korean nurses. Based on these results, effective resilience intervention programs for nurses can be developed.

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments.

Hematopoietic growth factors are often given for prevention of febrile neutropenia (FN), infections, and other complications by hastening neutrophil recovery in the treatment of malignancies after high dose chemotherapy (HDCT). Although several meta-analyses have already demonstrated beneficial effects of prophylactic granulocyte colony-stimulating factors (G-CSF) administration, the effects of G-CSF have not been confirmed in cancer patients receiving stem cell transplantation (SCT) after HDCT. Therefore, we performed a statistical combination of controlled clinical trials to investigate the efficacy of prophylactic use of G-CSF in preventing the neutropenic complications associated with SCT following HDCT in cancer patients. We searched PubMed to identify potentially relevant references and finally selected seven randomized controlled trials that met all of the eligibility criteria. Our meta-analysis demonstrated that prophylactic G-CSF reduced the risk of documented infections and time to hematologic recovery manifested by days to absolute neutrophil count (ANC) ≥ 0.5 × 10(9)/L, days to ANC ≥ 1.0 × 10(9)/L, and days to platelets ≥ 20 × 10(9)/L in SCT patients with cancer following HDCT. The G-CSF treated group also showed a decrease in the length of hospital stay. However, there was no difference between G-CSF treatment group and placebo group in regard to all-cause mortality, infection-related mortality, grade 2∼4 acute graft-versus-host-disease, and episode of fever.

The purpose of the ensemble methods is to increase the accuracy of predictionthrough combining many classi ers. According to recent studies, it is proved thatrandom forests and forward stagewise regression have good accuracies in classi cationproblems. However they have great prediction error in separation boundary pointsbecause they used decision tree as a base learner. In this study, we use the kernel ridgeregression instead of the decision trees in random forests and boosting. The usefulnessof our proposed ensemble methods was shown by the simulation results of the prostatecancer and the Boston housing data.Keywords: Boosting, ensemble method, forward stagewise regression, kernel ridge re-gression, random forest. 1. Introduction Ensemble methods are learning algorithms using a set of classi ers to predict a new data’sresponse value by taking a (weighted) vote or averaging of their predictions in the set ofclassi ers. The rst ensemble method is the one using Bayesian averaging. Also there areanother three famous ensemble methods such as bagging (Breiman, 1996), boosting (Freundand Schapire, 1997) and random forests (RF) (Breiman, 2001), which are based on thedecision trees. Especially, boosting and random forests are well known to be excellent in theaccuracy of prediction in classi cation problems.Bagging is a technique reducing the variance of an estimated prediction function and seemsto work well expecially for high-variance and low-bias procedures, such as in the decisiontree. For regression, we simply t the same regression trees many times to bootstrap sampledversions of the training data, to average the results. For classi cation, we cast a vote for thepredicted class in a set of trees.

Inflammation is a part of the host defense system, which provides protection against invading pathogens. However, it has become increasingly clear that inflammation can be evoked by endogenous mediators through Toll-like receptors (TLRs) to enhance tumor progression and metastasis. Here, we discuss the roles of TLR-mediated inflammation in tumor progression and the mechanisms through which it accomplishes this pathogenic function.

Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases in serum interleukin-6 (IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice. We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings may be used to prevent HCC in males.

Signal transducer and activator of transcription 1 (Stat1) is a critical mediator of gene transcription in type I interferon (IFN-alpha/beta) signaling that is essential for host defense against viruses. In the skeletal system, type I IFNs (IFN-alpha/beta) also play an important physiological role in the inhibition of receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation and bone resorption: mice deficient in IFN signaling exhibit decreased bone mass accompanied by the activation of osteoclastogenesis. On the other hand, an unexpected increase in bone mass was observed in Stat1-deficient mice, indicating that Stat1 has a hitherto unknown function in the regulation of bone formation. Indeed, Stat1 was found to have a unique, non-canonical function as a cytoplasmic attenuator of Runx2, a key transcription factor for osteoblast differentiation. Thus, the loss of Stat1 results in excessive activation of Runx2 and osteoblast differentiation, thereby tipping the balance in favor of bone formation over bone resorption. This is an interesting example in which a latent transcription factor attenuates the activity of another transcription factor in the cytoplasm, and reveals a novel regulatory mechanism of bone remodeling by immunomodulatory molecules. Here, we summarize recent advances in the study of Stat1 and IFNs in the context of osteoimmunology, including latest reports that question whether the inhibitory function of Stat1 in chondrocytes is responsible for dwarfism in achondroplasia.

Objective Suppression of bone destruction is required as part of an effective therapeutic strategy for autoimmune arthritis. Although numerous antirheumatic drugs are in clinical use, little is known about whether they inhibit bone destruction by acting on activated T cells or other cell types, such as bone-resorbing osteoclasts. This study was undertaken to determine whether leflunomide has a direct action on the osteoclast lineage and to gain insights into the molecular basis for the bone-protective effect of leflunomide. Methods The direct effect of leflunomide on osteoclast differentiation was investigated using an in vitro culture system of bone marrow monocyte/macrophages stimulated with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor. The molecular mechanism of the inhibition was analyzed by genome-wide screening. The T cell–independent effect of leflunomide was examined in rag-2−/− mice. Results Leflunomide blocked de novo pyrimidine synthesis and RANKL-induced calcium signaling in osteoclast precursor cells in vitro; hence, the induction of nuclear factor of activated T cells c1 (NF-ATc1) was strongly inhibited. The inhibition of this pathway is central to the action of leflunomide, since the inhibition was overcome by ectopic expression of NF-ATc1 in the precursor cells. Leflunomide suppressed endotoxin-induced inflammatory bone destruction even in rag-2−/− mice. Conclusion Leflunomide has a direct inhibitory effect on RANKL-mediated osteoclast differentiation by inhibiting the induction of NF-ATc1, the master switch regulator for osteoclast differentiation. Our study suggests that the direct inhibitory action of leflunomide on osteoclast differentiation constitutes an important aspect in the amelioration of bone destruction, and that the RANKL-dependent NF-ATc1 induction pathway is a promising target for pharmacologic intervention in arthritic bone destruction.

Bone remodeling is central to maintaining the integrity of the skeletal system, wherein the developed bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption. In the present study, we demonstrate a novel function of the Stat1 transcription factor in the regulation of bone remodeling. In the bone of theStat1-deficient mice, excessive osteoclastogenesis is observed, presumably caused by a loss of negative regulation of osteoclast differentiation by interferon (IFN)-β. However, the bone mass is unexpectedly increased in these mice. This increase is caused by excessive osteoblast differentiation, wherein Stat1 function is independent of IFN signaling. Actually, Stat1 interacts with Runx2 in its latent form in the cytoplasm, thereby inhibiting the nuclear localization of Runx2, an essential transcription factor for osteoblast differentiation. The new function of Stat1 does not require the Tyr 701 that is phosphorylated when Stat1 becomes a transcriptional activator. Our study provides a unique example in which a latent transcription factor attenuates the activity of another transcription factor in the cytoplasm, and reveals a new regulatory mechanism in bone remodeling.

Signaling by RANKL is essential for terminal differentiation of monocytes/macrophages into osteoclasts. The TRAF6 and c-Fos signaling pathways both play important roles downstream of RANKL. We show here that RANKL selectively induces NFATc1 expression via these two pathways. RANKL also evokes Ca2+ oscillations that lead to calcineurin-mediated activation of NFATc1, and therefore triggers a sustained NFATc1-dependent transcriptional program during osteoclast differentiation. We also show that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL.

Osteoclasts are cells of monocyte/macrophage origin that erode bone matrix: regulation of their differentiation is central to the understanding of the pathogenesis and treatment of bone diseases such as osteoporosis. Signalling by RANKL (receptor activator of NF-kappaB ligand), also known as Tnfsf11, is essential for the induction of osteoclast differentiation, and it must be strictly regulated to maintain bone homeostasis. But it is not known whether RANKL signalling to the cell interior is linked to any regulatory mechanisms. Here we show that RANKL induces the interferon-beta (IFN-beta) gene in osteoclast precursor cells, and that IFN-beta inhibits the differentiation by interfering with the RANKL-induced expression of c-Fos, an essential transcription factor for the formation of osteoclasts. This IFN-beta gene induction mechanism is distinct from that induced by virus, and is dependent on c-Fos itself. Thus an autoregulatory mechanism operates-the RANKL-induced c-Fos induces its own inhibitor. The importance of this regulatory mechanism for bone homeostasis is emphasized by the observation that mice deficient in IFN-beta signalling exhibit severe osteopenia (loss of bone mass) accompanied by enhanced osteoclastogenesis. Our study places the IFN-beta system in a new context, and may offer a molecular basis for the treatment of bone diseases.

We isolated a beta-N-acetylglucosaminidase encoding gene and its cDNA from the filamentous fungus Aspergillus nidulans, and designated it nagA. The nagA gene contained no intron and encoded a polypeptide of 603 amino acids with a putative 19-amino acid signal sequence. The deduced amino acid sequence was very similar to the sequence of Candida albicans Hex1 and Trichoderma harzianum Nag1. Yeast cells containing the nagA cDNA under the control of the GAL1 promoter expressed beta-N-acetylglucosaminidase activity. The chromosomal nagA gene of A. nidulans was disrupted by replacement with the argB marker gene. The disruptant strains expressed low levels of beta-N-acetylglucosaminidase activity and showed poor growth on a medium containing chitobiose as a carbon source. Aspergillus oryzae strain carrying the nagA gene under the control of the improved glaA promoter produced large amounts of beta-N-acetylglucosaminidase in a wheat bran solid culture.

Background Signalling cross talk provides a molecular basis for modulating a given signalling pathway by another, and it is often critical for regulating cellular responses elicited by cytokines. Previously, we reported on the critical role of the IFN-α/β signalling complex, generated by spontaneously produced IFN-α/β, in efficient IFN-γ signalling. Results In the present study, we have demonstrated that the IFN-α/β signalling complex also contributes to efficient IL-6 signalling. In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-α/β signalling complex. The induction of several target genes for these factors is also diminished, both in vitro and in vivo. We provide evidence that the cytoplasmic tyrosine residues of IFNAR-1, which remains phosphorylated by a weak IFN-α/β stimulation, provide docking sites for Stat1 and Stat3 to form homo- or heterodimers following IL-6 stimulation. Furthermore, a chemical cross-linking experiment revealed that IFNAR-1 and gp130, a common signal transducer for the IL-6 family of cytokines, exist in close proximity. Conclusions The constitutive weak IFN-α/β signal provides a foundation for strong cellular responses to IL-6, IFN-γ, and possibly other cytokines. Our results also suggest the assembly of cytokine receptor subunits, which may represent a ‘receptosome’-like structure, allowing the unique signalling cross talks to occur.