Crosstalk between the Notch and wingless-type MMTV integration site (WNT) signaling pathways has been investigated for many developmental processes. However, this negative correlation between Notch and WNT/ β-catenin signaling activity has been studied primarily in normal developmental and physiological processes in which negative feedback loops for both signaling pathways are intact. We found that Notch1 signaling retained the capability of suppressing the expression of WNT target genes in colorectal cancers even when β-catenin destruction by the adenomatous polyposis coli (APC) complex was disabled. Activation of Notch1 converted high-grade adenoma into low-grade adenoma in an Apc min mouse colon cancer model and suppressed the expression of WNT target genes in human colorectal cancer cells through epigenetic modification recruiting histone methyltransferase SET domain bifurcated 1 (SETDB1). Extensive microarray analysis of human colorectal cancers also showed a negative correlation between the Notch1 target gene, Notch-regulated ankyrin repeat protein 1 (NRARP), and WNT target genes. Notch is known to be a strong promoter of tumor initiation, but here we uncovered an unexpected suppressive role of Notch1 on WNT/β-catenin target genes involved in colorectal cancer.

Mitochondria play key roles in cellular immunity. How mitochondria contribute to organismal immunity remains poorly understood. Here, we show that HSP-60/HSPD1, a major mitochondrial chaperone, boosts anti-bacterial immunity through the up-regulation of p38 MAP kinase signaling. We first identify 16 evolutionarily conserved mitochondrial components that affect the immunity of against pathogenic (PA14). Among them, the mitochondrial chaperone HSP-60 is necessary and sufficient to increase resistance to PA14. We show that HSP-60 in the intestine and neurons is crucial for the resistance to PA14. We then find that p38 MAP kinase signaling, an evolutionarily conserved anti-bacterial immune pathway, is down-regulated by genetic inhibition of , and up-regulated by increased expression of Overexpression of , the mammalian ortholog of, increases p38 MAP kinase activity in human cells, suggesting an evolutionarily conserved mechanism. Further, cytosol-localized HSP-60 physically binds and stabilizes SEK-1/MAP kinase kinase 3, which in turn up-regulates p38 MAP kinase and increases immunity. Our study suggests that mitochondrial chaperones protect host eukaryotes from pathogenic bacteria by up-regulating cytosolic p38 MAPK signaling.

The GVL was not used frequently by EPs during the initial two years after its introduction. Although the GVL provides a better glottic view, the overall success rates were similar to a CL. The GVL may be useful in patients with difficult airway.

We found that topical calcitriol restored both the epidermal permeability and antimicrobial barrier that had been impaired by corticosteroids. This restoration was mediated by both an activation of the cutaneous vitamin D pathway and an increase of epidermal lipids and antimicrobial peptides, promoted by the formation of the LB and the activity of epidermal lipid synthesis-related enzymes.

The comprehensive identification of functional transcription factor binding sites (TFBSs) is an important step in understanding complex transcriptional regulatory networks. This study presents a motif-based comparative approach, STAT-Finder, for identifying functional DNA binding sites of STAT3 transcription factor. STAT-Finder combines STAT-Scanner, which was designed to predict functional STAT TFBSs with improved sensitivity, and a motif-based alignment to minimize false positive prediction rates. Using two reference sets containing promoter sequences of known STAT3 target genes, STAT-Finder identified functional STAT3 TFBSs with enhanced prediction efficiency and sensitivity relative to other conventional TFBS prediction tools. In addition, STAT-Finder identified novel STAT3 target genes among a group of genes that are over-expressed in human cancer cells. The binding of STAT3 to the predicted TFBSs was also experimentally confirmed through chromatin immunoprecipitation. Our proposed method provides a systematic approach to the prediction of functional TFBSs that can be applied to other TFs.

ObjectiveTo evaluate whether the use of a GlideScope video laryngoscope (GVL) improves first-attempt intubation success compared with the Macintosh laryngoscope (MAC) in the emergency department (ED).DesignA propensity score-matched analysis of data from a prospective multicentre ED airway registry—the Korean Emergency Airway Management Registry (KEAMR).Setting4 academic EDs located in a metropolitan city and a province in South Korea.ParticipantsA total of 4041 adult patients without cardiac arrest who underwent emergency intubation from January 2007 to December 2010.Outcome measuresThe primary and secondary outcomes were successful first intubation attempt and intubation failure, respectively. To reduce the selection bias and potential confounding effects, we rigorously adjusted for the baseline differences between two groups using a propensity score matching.ResultsOf the 4041 eligible patients, a GVL was initially used in 540 patients (13.4%). Using 1:2 propensity score matching, 363 and 726 patients were assigned to the GVL and MAC groups, respectively. The adjusted relative risks (95% CIs) for the first-attempt success rates with a GVL compared with a MAC were 0.76 (0.56 to 1.04; p=0.084) and the respective intubation failure rates 1.03(0.99 to 1.07; p=0.157). Regarding the subgroups, the first-attempt success of the senior residents and attending physicians was lower with the GVL (0.47 (0.23 to 0.98), p=0.043). In the patients with slight intubation difficulty, the first-attempt success was lower (0.60 (0.41 to 0.88), p=0.008) and the intubation failure was higher with the GVL (1.07 (1.02 to 1.13), p=0.008).ConclusionsIn this propensity score-matched analysis of data from a prospective multicentre ED airway registry, the overall first-attempt intubation success and failure rates did not differ significantly between GVL and MAC in the ED setting. Further randomised controlled trials are needed to confirm our findings.

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It is known that the behavior of a drug released from a supporting carrier is influenced by the surrounding environment and the carrier. In this study, we investigated the drug behavior of a swellable electrospun nanofibrous membrane. Nanofibrous mats with different swelling ratios were prepared by mixing cellulose acetate (CA) and polyurethane (PU). CA has excellent biocompatibility and is capable of high water uptake, while PU has excellent mechanical properties. Paclitaxel (PTX) was the drug of choice for observing drug release behavior, which was characterized by UV-spectroscopy. FE-SEM was used to confirm the morphology of the nanofibrous mats and to measure the average fiber diameters. We observed a noticeable increase in the total volume of the nanofibrous membrane when it was immersed in water. Also, the drug release behavior increased proportionally with increasing swelling rate of the composite nanofibrous mat. Biocompatibility testing of nanofiber materials was confirmed by CCK-8 assay and cell morphology was observed. Based on these results, we propose nanofibrous mats as promising candidates in wound dressing and other drug carrier applications.