Enhanced protein-metabolite correlation analysis: To investigate the association between Staphylococcus aureus mastitis and metabolic immune pathways.

Mastitis is a disease characterized by congestion, swelling, and inflammation of the mammary gland and usually caused by infection with pathogenic microorganisms. Furthermore, the development of mastitis is closely linked to the exogenous pathway of the gastrointestinal tract. However, the regulatory mechanisms governing the gut-metabolism-mammary axis remain incompletely understood. The present study revealed alterations in the gut microbiota of mastitis rats characterized by an increased abundance of the Proteobacteria phylum. Plasma analysis revealed significantly higher levels of L-isoleucine and cholic acid along with 7-ketodeoxycholic acid. Mammary tissue showed elevated levels of arachidonic acid metabolites and norlithocholic acid. Proteomic analysis showed increased levels of IFIH1, Tnfaip8l2, IRGM, and IRF5 in mastitis rats, which suggests that mastitis triggers an inflammatory response and immune stress. Follistatin (Fst) and progesterone receptor (Pgr) were significantly downregulated, raising the risk of breast cancer. Extracellular matrix (ECM) receptors and focal adhesion signaling pathways were downregulated, while blood-milk barrier integrity was disrupted. Analysis of protein-metabolic network regulation revealed that necroptosis, protein digestion and absorption, and arachidonic acid metabolism were the principal regulatory pathways involved in the development of mastitis. In short, the onset of mastitis leads to changes in the microbiota and alterations in the metabolic profiles of various biological samples, including colonic contents, plasma, and mammary tissue. Key manifestations include disturbances in bile acid metabolism, amino acid metabolism, and arachidonic acid metabolism. At the same time, the integrity of the blood-milk barrier is compromised while inflammation is promoted, thereby reducing cell adhesion in the mammary glands. These findings contribute to a more comprehensive understanding of the metabolic status of mastitis and provide new insights into its impact on the immune system.

Evaluation standards regulate the generation and selection of novel ideas in creative behaviors: insights from individual differences in event-related potentials.

Evaluation is generally considered to occur after the generation of novel ideas to select truly creative ideas; however, evaluation may occur concurrently with the generation and regulate its efficiency. To test this hypothesis, 120 participants who held strict, moderate, or loose evaluation standards were grouped, and neural responses related to novel idea generation were compared retrospectively. The results showed that lower N400 amplitudes and greater LSP amplitudes were simultaneously elicited by objectively defined novel and usable options than by novel but unusable options among participants with moderate standards but not among participants with strict or loose standards. Evaluation standards influence the efficiency of novel idea generation; neither strict nor loose evaluation standards are conducive to fully resolving cognitive conflicts and generating novel ideas. Moreover, lower N400 amplitudes and greater LSP amplitudes were simultaneously elicited by the subjectively rated novel and usable option than by the novel but unusable option among participants with strict and moderate standards but not among participants with loose standards. Evaluation standards influence the selection among the generated ideas; participants in the strict and moderate groups made a wise choice based on the degree of conflict resolution, whereas participants in the loose group did not.

Divergent thinking benefits from functional antagonism of the left IFG and right TPJ: a transcranial direct current stimulation study.

Divergent thinking is assumed to benefit from releasing the constraint of existing knowledge (i.e. top-down control) and enriching free association (i.e. bottom-up processing). However, whether functional antagonism between top-down control-related and bottom-up processing-related brain structures is conducive to generating original ideas is largely unknown. This study was designed to investigate the effect of functional antagonism between the left inferior frontal gyrus and the right temporoparietal junction on divergent thinking performance. A within-subjects design was adopted for three experiments. A total of 114 participants performed divergent thinking tasks after receiving transcranial direct current stimulation over target regions. In particular, cathodal stimulation over the left inferior frontal gyrus and anodal stimulation over the right inferior frontal gyrus (Experiment 1), anodal stimulation over the right temporoparietal junction (Experiment 2), and both cathodal stimulation over the left inferior frontal gyrus and anodal stimulation over the right temporoparietal junction (Experiment 3) were manipulated. Compared with sham stimulation, the combination of hyperpolarization of the left inferior frontal gyrus and depolarization of the right temporoparietal junction comprehensively promoted the fluency, flexibility, and originality of divergent thinking without decreasing the rationality of generated ideas. Functional antagonism between the left inferior frontal gyrus (hyperpolarization) and right temporoparietal junction (depolarization) has a "1 + 1 > 2" superposition effect on divergent thinking.

Functional lateralization of the medial temporal lobe in novel associative processing during creativity evaluation.

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.

Adipocytes promote interleukin-18 binding to its receptors during abdominal aortic aneurysm formation in mice.

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.

The function of the hippocampus and middle temporal gyrus in forming new associations and concepts during the processing of novelty and usefulness features in creative designs.

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.

The SGK1 inhibitor EMD638683, prevents Angiotensin II-induced cardiac inflammation and fibrosis by blocking NLRP3 inflammasome activation.

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)-1ß 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-1ß secretion in macrophages by blocking NLRP3 inflammasome activation. By reducing IL-1ß 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-1ß. Administration of the NLRP3 inflammasome inhibitor MCC950 indicated that EMD638683 attenuated Ang II-induced cardiac inflammation and fibrosis by inhibiting the NLRP3 inflammasome/IL-1ß 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.

Serum-glucocorticoid-regulated kinase 1 contributes to mechanical stretch-induced inflammatory responses in cardiac fibroblasts.

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.

The Neural Basis of Fear Promotes Anger and Sadness Counteracts Anger.

In contrast to cognitive emotion regulation theories that emphasize top-down control of prefrontal-mediated regulation of emotion, in traditional Chinese philosophy and medicine, different emotions are considered to have mutual promotion and counteraction relationships. Our previous studies have provided behavioral evidence supporting the hypotheses that "fear promotes anger" and "sadness counteracts anger"; this study further investigated the corresponding neural correlates. A basic hypothesis we made is the "internal versus external orientation" assumption proposing that fear could promote anger as its external orientation associated with motivated action, whereas sadness could counteract anger as its internal or homeostatic orientation to somatic or visceral experience. A way to test this assumption is to examine the selective involvement of the posterior insula (PI) and the anterior insula (AI) in sadness and fear because the posterior-to-anterior progression theory of insular function suggests that the role of the PI is to encode primary body feeling and that of the AI is to represent the integrative feeling that incorporates the internal and external input together. The results showed increased activation in the AI, parahippocampal gyrus (PHG), posterior cingulate (PCC), and precuneus during the fear induction phase, and the activation level in these areas could positively predict subsequent aggressive behavior; meanwhile, the PI, superior temporal gyrus (STG), superior frontal gyrus (SFG), and medial prefrontal cortex (mPFC) were more significantly activated during the sadness induction phase, and the activation level in these areas could negatively predict subsequent feelings of subjective anger in a provocation situation. These results revealed a possible cognitive brain mechanism underlying "fear promotes anger" and "sadness counteracts anger." In particular, the finding that the AI and PI selectively participated in fear and sadness emotions was consistent with our "internal versus external orientation" assumption about the different regulatory effects of fear and sadness on anger and aggressive behavior.

Allergic Lung Inflammation Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice.

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-ß, 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 CaCl2 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.

Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma.

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.

Memory enhancement for emotional words is attributed to both valence and arousal.

We do not memorize items in our surroundings with equal priority. Previous literature has widely shown that emotional stimuli are better remembered than neutral stimuli. However, given emotional stimuli and neutral stimuli often differ in both valence and arousal dimensions, it remains unclear whether the enhancement effects can be attributed to valence, or just to arousal. Importantly, most prior studies relied on a relatively small number of stimuli and non-emotional factors such as word length, imageability and other confounds were hard to control. To address these challenges, we analyzed multiple large databases of recognition memory and free recall tasks from previous research by items with many lexical and semantic covariates included, examining the effects of valence or arousal when controlling for each other. Our results showed a U-shaped relationship between valence and memory performance for both recognition and free recall, and a linear relationship between arousal and memory performance for both tasks. These findings showed that the memory enhancement effects can be attributed to both valence and arousal. We demonstrated these effects with generalizability across many stimuli and controlled for non-emotional factors. Together, these findings disentangle the contribution of valence and arousal in emotional memory enhancement effects and provide insights for current major theories of emotional memory.

Structural analysis of polysaccharide from Inonotus obliquus and investigate combined impact on the sex hormones, intestinal microbiota and metabolism in SPF male mice.

The dysregulation of sex hormone levels is associated with metabolic disorders such as obesity. Inonotus obliquus polysaccharide (IOP) exhibits a promising therapeutic effect on conditions like obesity and diabetes, potentially linked to its influence on intestinal microbiota and metabolism. The exact cause and mechanisms that link sex hormones, gut microbiota and metabolism are still unknown. In this research, we examined the molecular weight, monosaccharide composition, and glycosidic bond type of IOP. We found that IOP mostly consists of alpha-structured 6­carbon glucopyranose, with a predominant (1 â†’ 4) linkage to monosaccharides and a uniform distribution. Following this, we administered two different concentrations of IOP to mice through gavage. The results of the enzyme-linked immunosorbent assay (ELISA) demonstrated a significant increase in testosterone (T) levels in the IOP group as compared to the control group. Additionally, the results of tissue immunofluorescence indicated that increased IOP led to a decrease in adiponectin content and an increase in SET protein expression. The study also revealed changes in the intestinal microbiota and metabolic changes in mice through 16S rRNA data and non-targeted LC-MS data, respectively. The study also found that IOP mainly affects pathways linked to glycerophospholipid metabolism. In addition, it has been observed that there is an increase in the number of beneficial bacteria, such as the Eubacterium coprostanoligenes group and g.Lachnospiraceae NK4A136 group, while the levels of metabolites that are linked to obesity or diabetes, such as 1,5-anhydrosorbitol, are reduced. Furthermore, biomarker screening has revealed that the main microorganism responsible for the differences between the three groups is g.Erysipelatoclostridiaceae. In summary, these findings suggest that IOP exerts its therapeutic effects through a synergistic interplay between sex hormones, gut microbiome composition, and metabolic processes.

Promoting the healing of diabetic wounds with an antimicrobial gel containing AgNPs with anti-infective and anti-inflammatory properties.

Diabetic wounds are prone to develop chronic wounds due to bacterial infection and persistent inflammatory response. However, traditional dressings are monofunctional, lack bioactive substances, have limited bacterial inhibition as well as difficulties in adhesion and retention. These limit the therapeutic efficacy of traditional dressings on diabetic wounds. Therefore, finding and developing efficient and safe wound dressings is currently an urgent clinical need. In this study, an antimicrobial gel loaded with silver nanoparticles (AgNPs) (referred to as AgNPs@QAC-CBM) was prepared by crosslinking quaternary ammonium chitosan (QAC) with carbomer (CBM) as a gel matrix. AgNPs@QAC-CBM exhibited a reticulated structure, strong adhesion, good stability, and remarkable bactericidal properties, killing 99.9% of Escherichia coli, Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa within 1 min. Furthermore, AgNPs@QAC-CBM improved the wound microenvironment and accelerated wound healing in diabetic mice by promoting tissue production and collagen deposition, inducing M2 macrophages, reducing pro-inflammatory factor secretion and increasing anti-inflammatory factor levels. Moreover, AgNPs@QAC-CBM was proven to be safe for use through skin irritation and cytotoxicity tests, as they did not cause any irritation or toxicity. To summarize, AgNPs@QAC-CBM showed promising potential in enhancing the diabetic wound healing process.

Cognitive control in creative discovery: The gap between ideal and reality.

Creative discovery involves discovering the additional values of existing things in the environment by identifying the novel associations between seemingly unrelated things; the judgment made in this process is expected to be accurate but not entirely correct. From the perspective of cognitive processing, what is the difference between the ideal and real states of creative discovery? This is largely unknown. In this study, a daily life scenario was presented, and a great number of seemingly unrelated tools were presented for participants to discover valuable tools. Electrophysiological activity was recorded when participants identified tools, and we then retrospectively analyzed the differences between responses. Compared with usual tools, unusual tools evoked greater N2, N400 and late sustained potential (LSP) amplitudes, which was likely associated with the monitoring and resolution of cognitive conflicts. Moreover, unusual tools evoked smaller N400 and greater LSP amplitudes when correctly identified as usable than when identified as unusable; this result suggested that creative discovery in the ideal state should depend on the cognitive control involved in resolving conflicts. However, in the comparison between subjectively rated usable and unusable tools, smaller N400 and greater LSP amplitudes were observed only when unusual tools could be identified by expanding the application scope but not by releasing functional fixedness; this outcome suggested that creative discovery in the real state was not always influenced by the cognitive control involved in resolving conflicts. The difference in cognitive control that should be exerted and that was actually exerted to identify novel associations was discussed.

When and why will creative discovery succeed or fail? The role of reactive control in resolving conflicts.

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.

IGF2BP3 Regulates TMA7-mediated Autophagy and Cisplatin Resistance in Laryngeal Cancer via m6A RNA Methylation.

Translation machinery associated 7 homolog (TMA7) is closely related to proliferation-related diseases. However, the function and regulatory mechanism of TMA7 in laryngeal squamous cell carcinoma (LSCC) remain unclear. The present study aimed to investigate the effect of TMA7 on the occurrence and development of LSCC and to study the mechanism of TMA7. TMA7 is upregulated in LSCC tissues and associated with poor prognosis. After TMA7 downregulation, the autophagy level was increased, and the proliferation, migration, and invasion of LSCC cells were inhibited. The m6A methylated reader IGF2BP3 enhanced the stability of TMA7 and reduced the level of autophagy. TMA7 interacted directly with UBA2. Furthermore, the activation of the IGF2BP3-regulated TMA7-UBA2-PI3K pathway is the primary mechanism by which TMA7 inhibits autophagy and promotes the progression of LSCC. The current study revealed that IGF2BP3-mediated TMA7 m6A modification promotes LSCC progression and cisplatin-resistance through UBA2-PI3K pathway, providing new insights into the autophagy-related mechanism, potential biomarkers, and therapeutic targets for LSCC.

SMAP-WS: a parallel web service for structural proteome-wide ligand-binding site comparison.

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. SMAP-WS is available from the URL http://smap.nbcr.net.

Opal web services for biomedical 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.