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When processing repeated stimuli, the neural response is attenuated (i.e., neural adaptation) and performance seems to be facilitated; however, this neural adaptation negatively influences the subsequent processing of novel stimuli. The present study was designed to test whether and how temporal expectations reduce neural adaptation and attenuate the negative influence of neural adaptation on subsequent novel problem solving. Temporal expectations were experimentally manipulated by asking participants to solve a novel problem following three to five repeated problems, generating the expectation of repeated events in the first three serial positions as well as that of novel events in the fourth to sixth serial positions. Compared to the first occurrence, repeated problems evoked more negative deflections, including greater N1, lower P2 and greater LNC amplitudes, regardless of whether participants expected a repeated or novel event; however, the mean amplitudes of the P2 and LNC were smaller in the latter condition. These results show neural adaptation during processing of repeated stimuli and demonstrate that neural adaptation is reduced when a novel event is expected. Regarding the novel events, the conflict monitoring- and resolution-related N400, P600 and LNC amplitudes decreased with decreased neural adaptation. These results indicate that the expectation of novel events attenuate the negative influence of neural adaptation on the subsequent processing of novel events. This study provides new insight into alleviating the constraints imposed by frequently used knowledge on the processing of novel stimuli.

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Contains fulltext : 248268.pdf (Publisher’s version ) (Open Access) Although hemispheric lateralization of creativity has been a longstanding topic of debate, the underlying neurocognitive mechanism remains poorly understood. Here we designed 2 types of novel stimuli - "novel useful and novel useless," adapted from "familiar useful" designs taken from daily life - to demonstrate how the left and right medial temporal lobe (MTL) respond to novel designs of different usefulness. Taking the "familiar useful" design as a baseline, we found that the right MTL showed increased activation in response to "novel useful" designs, followed by "novel useless” ones, while the left MTL only showed increased activation in response to "novel useful" designs. Calculating an asymmetry index suggests that usefulness processing is predominant in the left MTL, whereas the right MTL is predominantly involved in novelty processing. Moreover, the left parahippocampal gyrus (PHG) showed stronger functional connectivity with the anterior cingulate cortex when responding to "novel useless" designs. In contrast, the right PHG showed stronger connectivity with the amygdala, midbrain, and hippocampus. Critically, multivoxel representational similarity analyses revealed that the left MTL was more effective than the right MTL at distinguishing the usefulness differences in novel stimuli, while representational patterns in the left PHG positively predicted the post-behavior evaluation of "truly creative" products. These findings suggest an apparent dissociation of the left and right MTL in integrating the novelty and usefulness information and novel associative processing during creativity evaluation, respectively. Our results provide novel insights into a longstanding and controversial question in creativity research by demonstrating functional lateralization of the MTL in processing novel associations. 21 p.

The process of creative discovery refers to discovering additional values of existing objects by identifying novel associations between seemingly unrelated things; however, this process is not always successful. To reveal the dynamic process of creative discovery, particularly when and why people made right or wrong judgments, the daily life scenario was described, and a possible tool was presented for judging whether it is usable to solve problems. Electrophysiological activity was recorded when people identified novel tools and then retrospectively analyzed the differences among three responses: correctly identified novel and usable (C-NU) options, falsely identified novel and usable (F-NU) options, and correctly identified novel but unusable (C-NUU) options. The results showed that, compared with ordinary tools, novel tools evoked greater N2, N400 and LSP amplitudes; the differences in these components were likely associated with the monitoring and resolution of cognitive conflicts in the process of discovering novel associations. Regarding novel tools, smaller N400 and greater LSP amplitudes were evoked by the C-NU option than by the F-NU option, and no differences in these components were found between the F-NU and C-NUU options. The findings revealed that the success or failure of discovering novel associations depended on reactive control in resolving conflicts. Only when sufficient cognitive effort is used to resolve a conflict to a great degree can the appropriately novel association be successfully discovered; otherwise, the novel and appropriate association is lost.

Predominant ordinary ideas are insufficient for solving insight-like problems; they interfere with subordinate original ideas and can produce a mental impasse. However, how people monitor and control invalid predominant ideas remains largely unknown. In the current study, participants were asked to solve a sequence of several similar practice problems that had the same solution to strengthen a predominant idea; the participants were then presented with an insight-like test problem that could not be solved by the predominant idea. The results showed that if the test problem was similar to the practice problems in which the predominant idea could typically be applied, it elicited greater late sustained potential (LSP) over the whole brain but no conflict-related N2 or N400 components, which suggests that the participants did not experience cognitive conflict and continued to verify the predominant but currently invalid idea. When the test problem differed from the practice problems, the items that participants reported trying to solve elicited greater N2-N400 and LSP over the whole brain, which suggests that the participants experienced cognitive conflict and exerted more reactive control over the invalid predominant idea; in contrast, the items that participants reported thinking about how to solve did not evoke greater conflict-related N2-N400 components and evoked even lower LSP, which likely indicates an ineffective state. These findings demonstrate three kinds of cognitive control toward invalid predominant ideas in situations where they are typically and not typically applied and provide empirical evidence of a mental impasse in insight-like problem-solving behaviors.

Although the innovative designs deliver, superior customer value has long been noted. However, the emotional experience of innovative products brings remains mostly unknown. This work focuses on two kinds of innovative products: function innovation (FI) and design innovation (DI), to uncover the mystery of the emotional experience, these two types of innovative designs bring. Participants in Study 1 were required to subjectively report their practical, emotional experience of the two kinds of innovative designs. The result showed that the emotional experience of innovation products might be a mixture of emotionality. Also, FI and DI products may cause different emotional experiences performance. Multidimensional scaling was employed in Study 2 to simplify the dimensions of these reported emotions to investigate the difference of emotion dimensions distribution that FI and DI brings. The results showed that DI products mainly reflected strong arouse than FI in positive emotions. However, DI product brings more negative emotions than positive emotions. Whereas, FI product did not show the quantitative differences between positive and negative emotions. In Study 3, the difference between FI and DI in emotion intensity was investigated, and the result indicates that both FI and DI products can bring high-intensity positive emotion. However, the DI brings higher intensity negative emotion and lower intensity positive emotion than FI. These studies demonstrate the first direct evidence of the essence of the difference between FI and DI emotion experience and suggest possible guidance for consumers to avoid the effect of the emotions when choosing innovative products.

Novelty and appropriateness have been considered two necessary criteria to distinguish creative ideas, but little is known about what kind of reactive control people will make when they evaluate appropriately or inappropriately novel ideas. To study this issue, high-density technology was used to record electroencephalography (EEG) signals when participants were evaluating ideas in novelappropriate, novelinappropriate, ordinaryappropriate, and ordinaryinappropriate conditions. An analysis of event-related potentials (ERPs) revealed that greater conflict detection-related N2 and N400-like components over the anterior scalp appeared in novel conditions than in ordinary conditions, suggesting that people are able to rapidly monitor novel ideas. Afterward, the mean amplitudes of the LPC over the left anterior scalp were greater in novelappropriate condition than ordinaryappropriate condition, but no difference was found between novelappropriate and novelinappropriate conditions, which likely displayed much more reactive control was recruited to handle novel ideas and no additional control was recruited when the novel ideas were inappropriate. In addition, the mean amplitudes of the LPC/LNC over the posterior scalp were greater in novel than ordinary conditions and were also greater in inappropriate than appropriate conditions, which likely reflected the processing difficulties of conceptual understanding. These findings revealed the early rise monitoring, conceptual understanding, and reactive control mechanism underlying the evaluation of novel ideas.

Antimicrobial resistance is considered an important threat to global health and has recently attracted significant attention from the public. In this study, the concentrations and size distribution characteristics of culturable airborne total bacteria (TB) and four antibiotic-resistant bacteria (tetracycline-resistant bacteria (TRB), ciprofloxacin-resistant bacteria (CRB), erythromycin-resistant bacteria (ERB), and ampicillin-resistant bacteria (ARB)) were investigated for approximately one year to explore their variations under different seasons, diurnal periods, and air quality levels. The concentrations of TB and four antibiotic-resistant bacteria in winter and night were higher than during other seasons and diurnal periods. Their maximum concentrations were detected from air under moderate pollution or heavy pollution. PM2.5, PM10, SO2, and NO2 were positively related to TB and four antibiotic-resistant bacteria (p &lt, 0.01), whereas O3 and wind speed were negatively related to them (p &lt, 0.05). The particle size of TB and four antibiotic-resistant bacteria were mainly distributed in stage V (1.1–2.2 µm). Bacillus was the dominant genus of ARB (75.97%) and CRB (25.67%). Staphylococcus and Macrococcus were the dominant genera of TRB (46.05%) and ERB (47.67%), respectively. The opportunistic pathogens of Micrococcus, Sphingomonas, Enterococcus, Rhodococcus, and Stenotrophomonas were also identified. This study provides important references for understanding the threat of bioaerosols to human health.

Although both originality and value are considered necessary criteria to identify creative ideas, little is known about how original and valuable ideas are generated in the human brain. To reveal how people monitor and control ongoing processing in the pursuit of original and valuable ideas, high-density electroencephalography (EEG) was used to record electrophysiological signals when participants were performing chunk decomposition tasks via novel-appropriate, novel-inappropriate, ordinary-appropriate and ordinary-inappropriate pathways. The results showed that approximately 100 ms after the problem was presented, novel pathways showed increased theta synchronization in the frontal sites compared to ordinary pathways. Novel pathways were associated with increased alpha desynchronization over the entire brain scale. These theta and alpha oscillations likely indicated rapid monitoring and effective control of novel processing in thinking. In the latter stages of problem solving, particularly during the 2000–2600-ms intervals, increased theta synchronization with decreased alpha desynchronization was found between novel-inappropriate and novel-appropriate pathways, which likely indicated slow monitoring and less control of inappropriate processing in novel thinking. The findings demonstrated the dynamic monitoring and control mechanism in the pursuit of original and valuable ideas.

Contains fulltext : 226588.pdf (Publisher’s version ) (Open Access) Creative thought relies on the reorganization of existing knowledge to generate novel and useful concepts. However, how these new concepts are formed, especially through the processing of novelty and usefulness (which are usually regarded as the key properties of creativity), is not clear. Taking familiar and useful (FU) objects/designs as the starting point or fundamental baseline, we modified them into novel and useless (NS) objects/designs or novel and useful (NU) ones (i.e., truly creative ones) to investigate how the features of novelty and usefulness are processed (processing of novelty: NU minus FU; processing of usefulness: NU minus NS). Specifically, we predicted that the creative integration of novelty and usefulness entails not only the formation of new associations, which could be critically mediated by the hippocampus and adjacent medial temporal lobe (MTL) areas, but also the formation of new concepts or categories, which is supported by the middle temporal gyrus (MTG). We found that both the MTL and the MTG were involved in the processing of novelty and usefulness. The MTG showed distinctive patterns of information processing, reflected by strengthened functional connectivity with the hippocampus to construct new concepts and strengthened functional connectivity with the executive control system to break the boundaries of old concepts. Additionally, participants’ subjective evaluations of concept distance showed that the distance between the familiar concept (FU) and the successfully constructed concept (NU) was larger than that between the FU and the unsuccessfully constructed concept (NS), and this pattern was found to correspond to the patterns of their neural representations in the MTG. These findings demonstrate the critical mechanism by which new associations and concepts are formed during novelty and usefulness processing in creative design; this mechanism may be critically mediated by the hippocampus-MTG connection. 17 p.

Inflammation has emerged as a critical biological process contributing to hypertensive cardiac remodeling. Effective pharmacological treatments targeting the cardiac inflammatory response, however, are still lacking. Prior studies suggested that the serum- and glucocorticoid-inducible kinase (SGK1) plays a key role in inflammation and cardiac remodeling. Recently, a highly selective SGK1 inhibitor, EMD638683, was developed, though whether EMD638683 can prevent hypertension-induced cardiac fibrosis and the mechanisms by which this inhibitor may alter the disease process remain unknown. Using a murine Angiotension II (Ang II) infusion-induced hypertension model we found that EMD638683 treatment inhibited cardiac fibrosis and remodeling, with significant abatement of cardiac inflammation. EMD638683 was shown to suppress Ang II infusion-induced interleukin (IL)-1β release, and substantially reduce nucleotide-binding oligomerization domain-like receptor with pyrin domain 3 (NLRP3) expression and caspase-1 activation in cardiac tissues. In vitro experiments revealed that EMD638683 ameliorated Ang II-stimulated IL-1β secretion in macrophages by blocking NLRP3 inflammasome activation. By reducing IL-1β production in macrophages, the transformation of fibroblasts to myofibroblasts was inhibited. The effects of EMD638683 on cardiac fibrosis were abolished by supplementation with exogenous IL-1β. Administration of the NLRP3 inflammasome inhibitor MCC950 indicated that EMD638683 attenuated Ang II-induced cardiac inflammation and fibrosis by inhibiting the NLRP3 inflammasome/IL-1β secretion axis. These findings indicate that the SGK1 inhibitor EMD638683 can negatively regulate NLRP3 inflammasome activation, and may represent a promising approach to the treatment of hypertensive cardiac damage.

Regulatory T cells (Tregs) are immune suppressive cells, but their roles in tumor growth have been elusive, depending on tumor type or site. Our prior study demonstrated a role of cathepsin S (CatS) in reducing Treg immunosuppressive activity. Therefore, CatS inhibition in Tregs may exacerbate tumor growth. Using mouse bladder carcinoma MB49 cell subcutaneous implant tumor model, we detected no difference in tumor growth, whether mice were given saline- or CatS inhibitor-treated Tregs. However, mice that received inhibitor-treated Tregs had fewer splenic and tumor Tregs, and lower levels of tumor and splenic cell proliferation than mice that received saline-treated Tregs. In vitro, inhibitor-treated Tregs showed lower proliferation and higher apoptosis than saline-treated Tregs when cells were exposed to MB49. In contrast, both types of Tregs showed no difference in proliferation when they were co-cultured with normal splenocytes. Inhibitor-treated Tregs had less apoptosis in splenocytes, but more apoptosis in splenocytes with MB49 conditioned media than saline-treated Tregs. In turn, we detected less proliferation and more apoptosis of MB94 cells after co-culture with inhibitor-treated Tregs, compared with saline-treated Tregs. B220+ B-cell, CD4+ T-cell, and CD8+ T-cell proliferation and apoptosis were also lower in splenocytes co-cultured with inhibitor-treated Tregs than with saline-treated Tregs. Under the same conditions, the addition of cancer cell-conditioned media greatly increased CD8+ T-cell proliferation and reduced CD8+ T-cell apoptosis. These observations suggest that CatS inhibition of Tregs may reduce overall T-cell immunity under normal conditions, but enhance CD8+ T-cell immunity in the presence of cancer cells.

Previous research has produced contradictory findings about the impact of regulatory focus on individual creativity, particularly for a prevention focus. These studies focused on how regulatory focus affects creativity in combination with evaluative stress. We hypothesized that these effects would depend on what type of stress was situationally induced. Study 1 comprised 209 undergraduate students (138 females) with a mean age of 20.13 years ( SD = 1.22) from Beijing, China. Study 2 comprised 221 high school students (133 females) with a mean age of 16.21 years ( SD = 1.01) from Beijing, China. Results indicated that under social-evaluative stress (Study 1), promotion-focused cues produced more original ideas than did prevention-focused cues. Moreover, under self-evaluative stress (Study 2), the effects of regulatory focus on creativity were moderated by self-evaluative stress. Specifically, in the higher self-evaluative stress condition, participants with a chronic prevention focus enhanced in fluency in prevention-focused states relative to promotion-focused states. In contrast, in the lower self-evaluative stress condition, participants with chronic promotion focus increased in originality in promotion-focused states relative to prevention-focused states.

Aims Obesity is a risk factor of abdominal aortic aneurysm (AAA). Inflammatory cytokine interleukin-18 (IL18) has two receptors: IL18 receptor (IL18r) and Na-Cl co-transporter (NCC). In human and mouse AAA lesions, IL18 colocalizes to its receptors at regions rich in adipocytes, suggesting a role of adipocytes in promoting IL18 actions in AAA development. Methods and results We localized both IL18r and NCC in human and mouse AAA lesions. Murine AAA development required both receptors. In mouse AAA lesions, IL18 binding to these receptors increased at regions enriched in adipocytes or adjacent to perivascular adipose tissue. 3T3-L1 adipocytes enhanced IL18 binding to macrophages, aortic smooth muscle cells (SMCs), and endothelial cells by inducing the expression of both IL18 receptors on these cells. Adipocytes also enhanced IL18r and IL18 expression from T cells and macrophages, AAA-pertinent protease expression from macrophages, and SMC apoptosis. Perivascular implantation of adipose tissue from either diet-induced obese mice or lean mice but not that from leptin-deficient ob/ob mice exacerbated AAA development in recipient mice. Further experiments established an essential role of adipocyte leptin and fatty acid-binding protein 4 (FABP4) in promoting IL18 binding to macrophages and possibly other inflammatory and vascular cells by inducing their expression of IL18, IL18r, and NCC. Conclusion Interleukin-18 uses both IL18r and NCC to promote AAA formation. Lesion adipocyte and perivascular adipose tissue contribute to AAA pathogenesis by releasing leptin and FABP4 that induce IL18, IL18r, and NCC expression and promote IL18 actions.

// Tianyi Wu 1, * , Lingmei Qu 2, * , Guoqing He 1, * , Linli Tian 1, * , Liang Li 1 , Han Zhou 1 , Qian Jin 1 , Jingyuan Ren 3 , Yu Wang 1 , Jingting Wang 1 , Xuan Kan 1 , Ming Liu 1 , Jia Shen 4 , Mian Guo 5 , Yanan Sun 1 1 Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China 2 Department of Otorhinolaryngology, Head and Neck Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, China 3 Department of Head and Neck Surgery, The Oncology Hospital of Jilin province, Changchun, China 4 Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, California, USA 5 Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China * These authors contributed equally to this work Correspondence to: Yanan Sun, e-mail: 76202920@qq.com Mian Guo, e-mail: guomian_hyd@163.com Keywords: laryngeal squamous cell cancer, lncRNA H19, miR-148a-3p, DNMT1 Received: July 07, 2015 Accepted: December 05, 2015 Published: February 08, 2016 ABSTRACT Laryngeal squamous cell carcinoma (LSCC) is a highly aggressive malignant cancer. The regulation of LSCC progression by long non-coding RNA (lncRNA) was not well understood. In this study, we reported that the lncRNA H19 was upregulated in LSCC. The expression levels of H19 were inversely correlated with the survival rate of LSCC patients. Knockdown of H19 expression inhibited LSCC cell migration, invasion and proliferation. We identified microRNA miR-148a-3p as an inhibitory target for H19. Overexpression of miR-148a-3p reduced LSCC migration, invasion and proliferation cell, while inhibition of miR-148a-3p did the opposite. The inhibition of LSCC progression induced by H19 knockdown required the activity of miR-148a-3p. We also identified DNA methyltransferase enzyme DNMT1 as a target of miR-148a-3p. Cellular DNA methylation levels were inhibited by both miR-148a-3p overexpression and H19 knockdown. In summary, our study demonstrated that the lncRNA H19 promoted LSCC progression via miR-148a-3p and DNMT1.

Objective— Asthma and abdominal aortic aneurysms (AAA) both involve inflammation. Patients with asthma have an increased risk of developing AAA or experiencing aortic rupture. This study tests the development of one disease on the progression of the other. Approach and Results— Ovalbumin sensitization and challenge in mice led to the development of allergic lung inflammation (ALI). Subcutaneous infusion of angiotensin II into mice produced AAA. Simultaneous production of ALI in AAA mice doubled abdominal aortic diameter and increased macrophage and mast cell content, arterial media smooth muscle cell loss, cell proliferation, and angiogenesis in AAA lesions. ALI also increased plasma IgE, reduced plasma interleukin-5, and increased bronchioalveolar total inflammatory cell and eosinophil accumulation. Intraperitoneal administration of an anti-IgE antibody suppressed AAA lesion formation and reduced lesion inflammation, plasma IgE, and bronchioalveolar inflammation. Pre-establishment of ALI also increased AAA lesion size, lesion accumulation of macrophages and mast cells, media smooth muscle cell loss, and plasma IgE, reduced plasma interleukin-5, interleukin-13, and transforming growth factor-β, and increased bronchioalveolar inflammation. Consequent production of ALI also doubled lesion size of pre-established AAA and increased lesion mast cell and T-cell accumulation, media smooth muscle cell loss, lesion cell proliferation and apoptosis, plasma IgE, and bronchioalveolar inflammation. In periaortic CaCl 2 injury–induced AAA in mice, production of ALI also increased AAA formation, lesion inflammation, plasma IgE, and bronchioalveolar inflammatory cell accumulation. Conclusions— This study suggests a pathological link between airway allergic disease and AAA. Production of one disease aggravates the progression of the other.

Cervical cancer is a kind of female malignant tumor with increasing incidence recently. Macrophage migration inhibitory factor (MIF) is a major tumor facilitating factor. The previous study suggests that there was a correlation between MIF and migration or invasion of tumors. Epithelial mesenchymal transition (EMT) is the basis for tumor invasion and migration. Therefore, this study utilized MFI to treat cervical carcinoma Hela cells, and the mechanism of EMT was also further analyzed. Cervical carcinoma Hela cells were transfected with pFenesil MIF siRNA plasmids, following by real-time fluorescent quantitative PCR to detect MIF levels. MTT assay was then utilized for evaluate the proliferative activity of Hela cells after transfection. The cell invasion and migration were examined. The expression of E-cadherin and Vimentin were also detected. The results indicated that the MIF was positively expressed in Hela cells, whose MIF mRNA level was increased after the transfection (P

Excessive mechanical stretch induces production of proinflammatory mediators in cardiac fibroblasts, which could act as inflammatory supporter cells in heart failure. Accumulation evidence and our previous studies suggest that serum-glucocorticoid-regulated kinase 1 (SGK1) contributes to cardiac remodeling and fibrosis, development of heart failure. However, the role and mechanism of SGK1 in mechanical stretch-induced inflammation of cardiac fibroblasts remain unclear. Here, cardiac fibroblasts isolated from wild-type (WT) and SGK1 knockout (SGK1-/-) mice were stimulated by 18% cyclic stretch, under static condition as the control. The results showed that mechanical stretch increased SGK1 expression and activation in WT cardiac fibroblasts but not its isoform, SGK2 or SGK3 expression. Bio-Plex array revealed hyperstretch could enhance chemokines release in WT cardiac fibroblasts, but SGK1 knockout significantly attenuated chemokines production through blocking activation of nuclear factor-kappa B (NF-κB). Moreover, supernatants from WT cardiac fibroblasts subjected to hyperstretch promoted macrophage migration, enhanced expression of macrophage-derived profibrotic mediators, whereas supernatants from SGK1 deficiency suppressed these effects. Although SGK1 did not directly affect mechanical stretch-induced myofibroblast differentiation, SGK1 activation of cardiac fibroblasts facilitated myofibroblast differentiation through the upregulation of the profibrotic mediators secreted by macrophages. These results suggest that SGK1 may play a critical role in the inflammatory cascade of cardiac fibroblasts triggered by mechanical stretch; SGK1 could be used as a potential target for treatment of cardiac fibrosis and heart failure.

Homeobox (HOX) transcript antisense RNA (HOTAIR) is a long intergenic noncoding RNA (lincRNA) that is significantly overexpressed in breast and hepatocellular cancers. It remains unclear, however, whether HOTAIR plays an oncogenic role in human laryngeal squamous cell cancer (LSCC). We therefore investigated the expression and functional role of HOTAIR in LSCC. HOTAIR levels were significantly higher in LSCC than in corresponding adjacent non-neoplastic tissues, and patients with poor histological grade or advanced clinical stage had higher HOTAIR expression. Log-rank test showed a significant association between high levels of HOTAIR and poor prognosis in LSCC patients. Multivariate Cox analysis suggested that HOTAIR is an independent prognostic factor of LSCC. siRNA-mediated knockdown of HOTAIR led to reduced invasion and increased apoptosis of Hep-2 cells in vitro and significantly reduced growth of LSCC xenograft tumors in mice. Moreover, PTEN methylation was significantly reduced in Hep-2 cells depleted of HOTAIR. Taken together, these results suggest that the oncogenic role of HOTAIR in LSCC is related to promotion of PTEN methylation. HOTAIR could serve as a marker for LSCC prognosis and a potential target for therapeutic intervention.

A case of a papillary thyroid carcinoma in a patient with situs inversus with associated bronchiectasis and chronic sinusitis (Kartagener's syndrome) is reported. A 61-year-old male patient has the symptoms of nasal obstruction. nasal purulent discharge and headache for 2 years. Physical examination: right nasal purulent in right nasal cavity and multiple lychee-like opaque mass in right middle meatus. A nodule, one centimeter in diameter, locates in the upper pole of right thyroid. Evidence of full situs inversus viscerum can be confirmmed by chest radiographs and ultrasound doppler. Pathology: right nasal polyps, the right small papillary thyroid cancer. TEM Tip primary ciliary dyskinesia. Clinical diagnosis: Kartagener syndrome, papillary thyroid carcinoma (T1a N0 M0, I period), chronic sinusitis-nasal polyps.

Angiotensin II (Ang II)-induced cardiac remodeling with the underlying mechanisms involving inflammation and fibrosis has been well documented. Cytosolic adaptor caspase recruitment domain 9 (CARD9) has been implicated in the innate immune response. We aimed to examine the role of CARD9 in inflammation and cardiac fibrosis induced by Ang II.Two-month-old CARD9-deficient (CARD9(-/-)) and wild-type (WT) male mice were infused with Ang II (1,500 ng/kg/min) or saline for 7 days. Heart sections were stained with hematoxylin and eosin and Masson trichrome and examined by immunohistochemistry; and activity and protein levels were measured in macrophages obtained from mice.WT mice with Ang II infusion showed a marked increase in CARD9(+) macrophages in the heart, but CARD9(-/-) mice showed significantly suppressed macrophage infiltration and expression of proinflammatory cytokines, including interleukin-1β (IL-1β) and connective tissue growth factor (CTGF). Importantly, Ang II-induced cardiac fibrosis (extracellular matrix and collagen I deposition) was diminished in CARD9(-/-) hearts, as was the expression of transforming growth factor-β (TGF-β) and level of myofibroblasts positive for α-smooth muscle actin (α-SMA). Furthermore, Ang II activation of nuclear factor-κB (NF-κB), JNK and p38 mitogen-activated protein kinases (MAPKs) in WT macrophages was reduced in CARD9(-/-) macrophages.CARD9 plays an important role in regulating cardiac inflammation and fibrosis in response to elevated Ang II.

MiRNAs are small, noncoding RNA molecules that emerge as important regulators of cancer-related processes. The miR-21 microRNA is overexpressed in a wide variety of cancers and has been causally related to cellular proliferation and apoptosis. In this study, we found that miR-21 is overexpressed in Laryngeal squamous cell carcinoma (LSCC) and correlated with advanced stage. Inhibition of miR-21 by antisense oligonucleotides (ASO) led to decreased protein level of Ras and profound suppression of cell proliferation and invasion. Hep-2 cells exposed to miR-21 ASO exhibited cell cycle arrest at G1 phase and increased apoptosis. Furthermore, growth of LSCC xenograft tumours was significantly suppressed by repeated injection of ASO-miR-21 lentivirus and the Ras protein expression in LSCC xenograft tumours was also downregulate by ASO-miR-21. Taken together, our data suggest that miR-21 may play an oncogenic role in the cellular processes of LSCC and represent a novel target for effective therapies.

This study explored the inhibitory role of the adenoviral-mediated-interleukin (IL)-12 (Ad.mIL-12) gene in the growth of laryngeal squamous cell carcinoma (LSCC). Human epithelial type 2 (Hep-2) cells were transfected with Ad.mIL-12, and IL-12 gene expression of the cells was evaluated. The proliferation and apoptosis of Hep-2 cells in vitro were detected by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay and flow cytometry. Experimental tumours in mice were injected intratumourally with the same recombinant adenoviruses and inhibition of tumour growth observed. Apoptosis in Hep-2 xenotransplants was detected using TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labelling) assay and transmission electron microscopy. The expression of IL-12 in Ad.mIL-12 transfected Hep-2 cells was significantly increased. In vitro, Ad.mIL-12 decreased the viability of and increased apoptosis in Hep-2 cells. Increased apoptosis was also seen in vivo. The mean weight and volume of tumours in Ad.mIL-12 treated mice were significantly lower than in the control group. It is concluded that Ad.mIL-12 can suppress LSCC growth and induce apoptosis.

The proteome-wide characterization and analysis of protein ligand-binding sites and their interactions with ligands can provide pivotal information in understanding the structure, function and evolution of proteins and for designing safe and efficient therapeutics. The SMAP web service (SMAP-WS) meets this need through parallel computations designed for 3D ligand-binding site comparison and similarity searching on a structural proteome scale. SMAP-WS implements a shape descriptor (the Geometric Potential) that characterizes both local and global topological properties of the protein structure and which can be used to predict the likely ligand-binding pocket [Xie,L. and Bourne,P.E. (2007) A robust and efficient algorithm for the shape description of protein structures and its application in predicting ligand-binding sites. BMC bioinformatics, 8 (Suppl. 4.), S9.]. Subsequently a sequence order independent profile–profile alignment (SOIPPA) algorithm is used to detect and align similar pockets thereby finding protein functional and evolutionary relationships across fold space [Xie, L. and Bourne, P.E. (2008) Detecting evolutionary relationships across existing fold space, using sequence order-independent profile-profile alignments. Proc. Natl Acad. Sci. USA, 105, 5441–5446]. An extreme value distribution model estimates the statistical significance of the match [Xie, L., Xie, L. and Bourne, P.E. (2009) A unified statistical model to support local sequence order independent similarity searching for ligand-binding sites and its application to genome-based drug discovery. Bioinformatics, 25, i305–i312.]. These algorithms have been extensively benchmarked and shown to outperform most existing algorithms. Moreover, several predictions resulting from SMAP-WS have been validated experimentally. Thus far SMAP-WS has been applied to predict drug side effects, and to repurpose existing drugs for new indications. SMAP-WS provides both a user-friendly web interface and programming API for scientists to address a wide range of compute intense questions in biology and drug discovery. AVAILABILITY SMAP-WS is available from the URL http://smap.nbcr.net.

The MEME Suite web server provides a unified portal for online discovery and analysis of sequence motifs representing features such as DNA binding sites and protein interaction domains. The popular MEME motif discovery algorithm is now complemented by the GLAM2 algorithm which allows discovery of motifs containing gaps. Three sequence scanning algorithms--MAST, FIMO and GLAM2SCAN--allow scanning numerous DNA and protein sequence databases for motifs discovered by MEME and GLAM2. Transcription factor motifs (including those discovered using MEME) can be compared with motifs in many popular motif databases using the motif database scanning algorithm TOMTOM. Transcription factor motifs can be further analyzed for putative function by association with Gene Ontology (GO) terms using the motif-GO term association tool GOMO. MEME output now contains sequence LOGOS for each discovered motif, as well as buttons to allow motifs to be conveniently submitted to the sequence and motif database scanning algorithms (MAST, FIMO and TOMTOM), or to GOMO, for further analysis. GLAM2 output similarly contains buttons for further analysis using GLAM2SCAN and for rerunning GLAM2 with different parameters. All of the motif-based tools are now implemented as web services via Opal. Source code, binaries and a web server are freely available for noncommercial use at http://meme.nbcr.net.

Meta-scheduling is proven to be an essential tool for resource management in cross-domain environments like Grids. This paper takes one step further in combining meta-scheduling with application management tool to present a novel multi-domain cloud environment for biological research. With the scalable architecture and stable performance, Community Scheduler Framework (CSF) is a mature meta-scheduler for traditional Grids. However, as a scheduler, CSF does not support flexible application management. In this paper, we integrate CSF with another useful tool OPAL, which is a toolkit for wrapping scientific application as web services, to take advantage of both grid and cloud resources. We first talk about the integration of CSF4 with Opal to form a user-transparent and configurable scientific cloud platform. Next, some enhancements of CSF4 are presented to improve the usability of the OPAL-CSF system. In addition, we will describe a virtual screening web service in OPAL-CSF system. The virtual screening service compares multiple receptor/ligand protein pairs using Autodock. Performance analysis of this service shows that the integration of Opal and CSF can efficiently facilitate large-scale scientific applications.

Biomedical applications have become increasingly complex, and they often require large-scale high-performance computing resources with a large number of processors and memory. The complexity of application deployment and the advances in cluster, grid and cloud computing require new modes of support for biomedical research. Scientific Software as a Service (sSaaS) enables scalable and transparent access to biomedical applications through simple standards-based Web interfaces. Towards this end, we built a production web server (http://ws.nbcr.net) in August 2007 to support the bioinformatics application called MEME. The server has grown since to include docking analysis with AutoDock and AutoDock Vina, electrostatic calculations using PDB2PQR and APBS, and off-target analysis using SMAP. All the applications on the servers are powered by Opal, a toolkit that allows users to wrap scientific applications easily as web services without any modification to the scientific codes, by writing simple XML configuration files. Opal allows both web forms-based access and programmatic access of all our applications. The Opal toolkit currently supports SOAP-based Web service access to a number of popular applications from the National Biomedical Computation Resource (NBCR) and affiliated collaborative and service projects. In addition, Opal’s programmatic access capability allows our applications to be accessed through many workflow tools, including Vision, Kepler, Nimrod/K and VisTrails. From mid-August 2007 to the end of 2009, we have successfully executed 239 814 jobs. The number of successfully executed jobs more than doubled from 205 to 411 per day between 2008 and 2009. The Opal-enabled service model is useful for a wide range of applications. It provides for interoperation with other applications with Web Service interfaces, and allows application developers to focus on the scientific tool and workflow development. Web server availability: http://ws.nbcr.net.

Grid computing provides mechanisms for making large-scale computing environments available to the masses. In recent times, with the advent of Cloud computing, the concepts of Software as a Service (SaaS), where vendors provide key software products as services over the internet that can be accessed by users to perform complex tasks, and Service as Software (SaS), where customizable and repeatable services are packaged as software products that dynamically meet the demands of individual users, have become increasingly popular. Both SaaS and SaS models are highly applicable to scientific software and users alike. Opal2 is a toolkit for wrapping scientific applications as Web services on Grid and cloud computing resources. It provides a mechanism for scientific application developers to expose the functionality of their codes via simple Web service APIs, abstracting out the details of the back-end infrastructure. Services may be combined via customized workflows for specific research areas and distributed as virtual machine images. In this paper, we describe the overall philosophy and architecture of the Opal2 framework, including its new plug-in architecture and data handling capabilities. We analyze its performance in typical cluster and Grid settings, and in a cloud computing environment within virtual machines, using Amazon's Elastic Computing Cloud (EC2).

The avian flu grid is a virtual organization dedicated to the discovery of novel inhibitors for the pandemic avian flu threat, leveraging grid technologies and computational resources provided by PRAGMA and its partners. In this context it is essential to adopt tools which increase the productivity of the computational scientists without advanced training on grid technologies. To reduce the learning curve, we have augmented tools that most domain scientists are already familiar with, and hidden the complexity of the underlaying infrastructure, through automatic user interface generation and workflow support, beyond the standard command line based approach. Here we describe the current state of the infrastructure deployed and how it has facilitated the training of new researchers in the drug discovery area. We provide details on Vision, a visual programming environment used to define scientific workflows, and Opal, an automatic Web service wrappers for scientific applications on Grid resources, and how they are integrated with other established back-end technologies.