Highly Efficient Synthesis of an Emerging Lipophilic Antioxidant: 2-Ethylhexyl Ferulate.

Ferulic acid in ester form has shown a stronger ability in ameliorating certain pathological conditions and inhibiting lipid oxidation. In present study, a solvent-free and reduced pressure evaporation system was developed for lipase-catalyzed synthesis of 2-ethylhexyl ferulate (2-EF) from ferulic acid and 2-ethylhexanol. A Box-Behnken design with response surface methodology (RSM) and artificial neural network (ANN) was selected to model and optimize the process. Based on the yields of 2-EF, reaction temperature was shown to be the most important process factor on the molar conversion among all variables. The residual values and the coefficient of determination (R²) calculated from the design data indicated that ANN was better than RSM in data fitting. Overall, the present lipase-catalyzed approach for 2-EF synthesis at low reaction temperature in a reduced pressure evaporation system shows high 2-EF production efficiency. Notably, this approach can reduce the enzyme denaturation and ferulic acid oxidation that usually occur during long-term biosynthetic operations at high temperature.

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia.

BACKGROUND: Epigenetics of schizophrenia provides important information on how the environmental factors affect the genetic architecture of the disease. DNA methylation plays a pivotal role in etiology for schizophrenia. Previous studies have focused mostly on the discovery of schizophrenia-associated SNPs or genetic variants. As postmortem brain samples became available, more and more recent studies surveyed transcriptomics of the diseases. In this study, we constructed protein-protein interaction (PPI) network using the disease associated SNP (or genetic variants), differentially expressed disease genes and differentially methylated disease genes (or promoters). By combining the different datasets and topological analyses of the PPI network, we established a more comprehensive understanding of the development and genetics of this devastating mental illness. RESULTS: We analyzed the previously published DNA methylation profiles of prefrontal cortex from 335 healthy controls and 191 schizophrenic patients. These datasets revealed 2014 CpGs identified as GWAS risk loci with the differential methylation profile in schizophrenia, and 1689 schizophrenic differential methylated genes (SDMGs) identified with predominant hypomethylation. These SDMGs, combined with the PPIs of these genes, were constructed into the schizophrenic differential methylation network (SDMN). On the SDMN, there are 10 hypermethylated SDMGs, including GNA13, CAPNS1, GABPB2, GIT2, LEFTY1, NDUFA10, MIOS, MPHOSPH6, PRDM14 and RFWD2. The hypermethylation to differential expression network (HyDEN) were constructed to determine how the hypermethylated promoters regulate gene expression. The enrichment analyses of biochemical pathways in HyDEN, including TNF alpha, PDGFR-beta signaling, TGF beta Receptor, VEGFR1 and VEGFR2 signaling, regulation of telomerase, hepatocyte growth factor receptor signaling, ErbB1 downstream signaling and mTOR signaling pathway, suggested that the malfunctioning of these pathways contribute to the symptoms of schizophrenia. CONCLUSIONS: The epigenetic profiles of DNA differential methylation from schizophrenic brain samples were investigated to understand the regulatory roles of SDMGs. The SDMGs interplays with SCZCGs in a coordinated fashion in the disease mechanism of schizophrenia. The protein complexes and pathways involved in SDMN may be responsible for the etiology and potential treatment targets. The SDMG promoters are predominantly hypomethylated. Increasing methylation on these promoters is proposed as a novel therapeutic approach for schizophrenia.

Transcriptome alterations of mitochondrial and coagulation function in schizophrenia by cortical sequencing analysis.

BACKGROUND: Transcriptome sequencing of brain samples provides detailed enrichment analysis of differential expression and genetic interactions for evaluation of mitochondrial and coagulation function of schizophrenia. It is implicated that schizophrenia genetic and protein interactions may give rise to biological dysfunction of energy metabolism and hemostasis. These findings may explain the biological mechanisms responsible for negative and withdraw symptoms of schizophrenia and antipsychotic-induced venous thromboembolism. RESULTS: Published BA22 RNA-Seq brain data of 9 schizophrenic patients and 9 controls samples were analyzed. The differentially expressed genes in the BA22 brain samples of schizophrenia are proposed as schizophrenia candidate marker genes (SCZCGs). The genetic interactions between mitochondrial genes and many under-expressed SCZCGs indicate the genetic predisposition of mitochondria dysfunction in schizophrenia. The biological functions of SCZCGs, as listed in the Pathway Interaction Database (PID), indicate that these genes have roles in DNA binding transcription factor, signal and cancer-related pathways, coagulation and cell cycle regulation and differentiation pathways. CONCLUSIONS: It is implicated that the energy metabolism and hemostatic process have important roles in the pathogenesis for schizophrenia. The cross-talk of genetic interaction by these co-expressed genes and reached candidate genes may address the key network in disease pathology. The accuracy of candidate genes evaluated from different quantification tools could be improved by crosstalk analysis of overlapping genes in genetic networks.

Functional ginger extracts from supercritical fluid carbon dioxide extraction via in vitro and in vivo assays: antioxidation, antimicroorganism, and mice xenografts models.

Supercritical fluid carbon dioxide extraction technology was developed to gain the active components from a Taiwan native plant, Zingiber officinale (ginger). We studied the biological effects of ginger extracts via multiple assays and demonstrated the biofunctions in each platform. Investigations of ginger extracts indicated antioxidative properties in dose-dependant manners on radical scavenging activities, reducing powers and metal chelating powers. We found that ginger extracts processed moderate scavenging values, middle metal chelating levels, and slight ferric reducing powers. The antibacterial susceptibility of ginger extracts on Staphylococcus aureus, Streptococcus sobrinus, S. mutans, and Escherichia coli was determined with the broth microdilution method technique. The ginger extracts had operative antimicroorganism potentials against both Gram-positive and Gram-negative bacteria. We further discovered the strong inhibitions of ginger extracts on lethal carcinogenic melanoma through in vivo xenograft model. To sum up, the data confirmed the possible applications as medical cosmetology agents, pharmaceutical antibiotics, and food supplements.

Analysis of schizophrenia and hepatocellular carcinoma genetic network with corresponding modularity and pathways: novel insights to the immune system.

BACKGROUND: Schizophrenic patients show lower incidences of cancer, implicating schizophrenia may be a protective factor against cancer. To study the genetic correlation between the two diseases, a specific PPI network was constructed with candidate genes of both schizophrenia and hepatocellular carcinoma. The network, designated schizophrenia-hepatocellular carcinoma network (SHCN), was analysed and cliques were identified as potential functional modules or complexes. The findings were compared with information from pathway databases such as KEGG, Reactome, PID and ConsensusPathDB. RESULTS: The functions of mediator genes from SHCN show immune system and cell cycle regulation have important roles in the eitology mechanism of schizophrenia. For example, the over-expressing schizophrenia candidate genes, SIRPB1, SYK and LCK, are responsible for signal transduction in cytokine production; immune responses involving IL-2 and TREM-1/DAP12 pathways are relevant for the etiology mechanism of schizophrenia. Novel treatments were proposed by searching the target genes of FDA approved drugs with genes in potential protein complexes and pathways. It was found that Vitamin A, retinoid acid and a few other immune response agents modulated by RARA and LCK genes may be potential treatments for both schizophrenia and hepatocellular carcinoma. CONCLUSIONS: This is the first study showing specific mediator genes in the SHCN which may suppress tumors. We also show that the schizophrenic protein interactions and modulation with cancer implicates the importance of immune system for etiology of schizophrenia.

Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature.

Headaches and nausea are the 2 most common adverse effects of electroconvulsive therapy (ECT). These adverse effects have been frequently reported in the postictal period and make it difficult for the patient to continue with the following ECTs. Mirtazapine is an antidepressant with a mechanism that involves activating serotonin (5-HT1) receptors. This mechanism has been hypothesized to be the underlying therapeutic effects for depression and anxiety. In addition, mirtazapine possesses antagonistic effects on the postsynaptic serotonin 5-HT2 and 5-HT3 receptors. The pharmacological actions are hypothesized to be related to its treatment effects of headaches and nausea. Here, we report a case series of patients developing post-ECT headaches and nausea, and the concomitant administration of mirtazapine successfully relieved the ECT-associated adverse effects. This case series suggest that mirtazapine may be an optional treatment for ECT-induced headaches and nausea.

Construction and analysis of the protein-protein interaction networks for schizophrenia, bipolar disorder, and major depression.

BACKGROUND: Schizophrenia, bipolar disorder, and major depression are devastating mental diseases, each with distinctive yet overlapping epidemiologic characteristics. Microarray and proteomics data have revealed genes which expressed abnormally in patients. Several single nucleotide polymorphisms (SNPs) and mutations are associated with one or more of the three diseases. Nevertheless, there are few studies on the interactions among the disease-associated genes and proteins. RESULTS: This study, for the first time, incorporated microarray and protein-protein interaction (PPI) databases to construct the PPI network of abnormally expressed genes in postmortem brain samples of schizophrenia, bipolar disorder, and major depression patients. The samples were collected from Brodmann area (BA) 10 of the prefrontal cortex. Abnormally expressed disease genes were selected by t-tests comparing the disease and control samples. These genes were involved in housekeeping functions (e.g. translation, transcription, energy conversion, and metabolism), in brain specific functions (e.g. signal transduction, neuron cell differentiation, and cytoskeleton), or in stress responses (e.g. heat shocks and biotic stress).The diseases were interconnected through several "switchboard"-like nodes in the PPI network or shared abnormally expressed genes. A "core" functional module which consisted of a tightly knitted sub-network of clique-5 and -4s was also observed. These cliques were formed by 12 genes highly expressed in both disease and control samples. CONCLUSIONS: Several previously unidentified disease marker genes and drug targets, such as SBNO2 (schizophrenia), SEC24C (bipolar disorder), and SRRT (major depression), were identified based on statistical and topological analyses of the PPI network. The shared or interconnecting marker genes may explain the shared symptoms of the studied diseases. Furthermore, the "switchboard" genes, such as APP, UBC, and YWHAZ, are proposed as potential targets for developing new treatments due to their functional and topological significance.

Source authenticity in the UMLS--a case study of the Minimal Standard Terminology.

As the UMLS integrates multiple source vocabularies, the integration process requires that certain adaptation be applied to the source. Our interest is in examining the relationship between the UMLS representation of a source vocabulary and the source vocabulary itself. We investigated the integration of the Minimal Standard Terminology (MST) into the UMLS in order to examine how close its UMLS representation is to the source MST. The MST was conceived as a "minimal" list of terms and structure intended for use within computer systems to facilitate standardized reporting of gastrointestinal endoscopic examinations. Although the MST has an overall schema and implied relationship structure, many of the UMLS integrated MST terms were found to be hierarchically orphaned, and with lateral relationships that do not closely adhere to the source MST. Thus, the MST representation within the UMLS significantly differs from that of the source MST. These representation discrepancies may affect the usability of the MST representation in the UMLS for knowledge acquisition. Furthermore, they pose a problem from the perspective of application developers. While these findings may not necessarily apply to other source terminologies, they highlight the conflict between preservation of authentic concept orientation and the UMLS overall desire to provide fully specified names for all source terms.

Auditing SNOMED Integration into the UMLS for Duplicate Concepts.

The UMLS contains terms from many sources. Every update of a source requires reintegration. Each new term needs to be assigned to a preexisting UMLS concept, or a new concept must be created. Whenever the integration process unnecessarily creates a new concept, this is undesirable. We report on a method to detect such undesirable duplicate concepts. Terms are removed from the UMLS and reintegrated using "piecewise synonym generation." The concept of the reintegrated term is programmatically compared to the initial concept of the term (before removal). If they are different, this indicates an error, either in the integration process or in the initial concept. Thus, such a term-concept pair is deemed suspicious. A study of five hierarchies of the SNOMED found 7.7% suspicious matches. A human expert needs to evaluate the correctness of suspicious concepts. In a sample of 149 of those, 19% of concepts were found to be duplicates.

POINeT: protein interactome with sub-network analysis and hub prioritization.

BACKGROUND: Protein-protein interactions (PPIs) are critical to every aspect of biological processes. Expansion of all PPIs from a set of given queries often results in a complex PPI network lacking spatiotemporal consideration. Moreover, the reliability of available PPI resources, which consist of low- and high-throughput data, for network construction remains a significant challenge. Even though a number of software tools are available to facilitate PPI network analysis, an integrated tool is crucial to alleviate the burden on querying across multiple web servers and software tools. RESULTS: We have constructed an integrated web service, POINeT, to simplify the process of PPI searching, analysis, and visualization. POINeT merges PPI and tissue-specific expression data from multiple resources. The tissue-specific PPIs and the numbers of research papers supporting the PPIs can be filtered with user-adjustable threshold values and are dynamically updated in the viewer. The network constructed in POINeT can be readily analyzed with, for example, the built-in centrality calculation module and an integrated network viewer. Nodes in global networks can also be ranked and filtered using various network analysis formulas, i.e., centralities. To prioritize the sub-network, we developed a ranking filtered method (S3) to uncover potential novel mediators in the midbody network. Several examples are provided to illustrate the functionality of POINeT. The network constructed from four schizophrenia risk markers suggests that EXOC4 might be a novel marker for this disease. Finally, a liver-specific PPI network has been filtered with adult and fetal liver expression profiles. CONCLUSION: The functionalities provided by POINeT are highly improved compared to previous version of POINT. POINeT enables the identification and ranking of potential novel genes involved in a sub-network. Combining with tissue-specific gene expression profiles, PPIs specific to selected tissues can be revealed. The straightforward interface of POINeT makes PPI search and analysis just a few clicks away. The modular design permits further functional enhancement without hampering the simplicity. POINeT is available at (http://poinet.bioinformatics.tw/).

Using WordNet synonym substitution to enhance UMLS source integration.

OBJECTIVE: Synonym-substitution algorithms have been developed for the purpose of matching source vocabulary terms with existing Unified Medical Language System (UMLS) terms during the integration process. A drawback is the possible explosion in the number of newly generated (potential) synonyms, which can tax computational and expert review resources. Experiments are run using a synonym-substitution approach based on WordNet to see how constraining two methodological parameters, namely, "maximum number of substitutions per term" and "maximum term length," affects performance. Our hypothesis is that these values can be constrained rather tightly--thus greatly speeding up the methodology--without a marked decline in the additional matches produced. Furthermore, we investigate whether a limitation on only the first of the two parameters is sufficient to achieve the same results. METHODS: A four-stage synonym-substitution methodology using WordNet is presented. A group of experiments is carried out in which the two methodological parameters "maximum number of substitutions per term" and "maximum term length" are varied. The purpose is to examine their effect on the growth in the number of potential synonyms generated and the associated loss of results. The experiments are based on the re-integration of the "Minimal Standard Terminology" (MST) into the UMLS. Synonym-substitution matches found to be inconsistent with the current content of the UMLS and thus deemed to be incorrect are further manually scrutinized as an audit of the original integration of the MST. RESULTS: An increase of 11% in the number of "MST term/UMLS term" matches was achieved using the synonym-substitution methodology. Importantly, this result prevailed when tight threshold values (such as a maximum of two synonym substitutions per term) were imposed on the parameters. Furthermore, it was found that limiting only the "maximum number of substitutions per term" parameter was sufficient to obtain the performance enhancement. During the additional audit phase, a number of the reported mismatches were actually seen to be correct, representing an additional 10% increase in the number of matches obtained. CONCLUSION: A synonym-substitution methodology that utilizes WordNet is a useful automated aide in UMLS source integration. Experiments showed that there was a significant speed-up but no degradation in match results when the methodology's "maximum number of substitutions per term" parameter was relatively tightly constrained. The methodology also helped to discover errors in the MST's original integration, and improve the quality of the UMLS's conceptual content.

Piecewise synonyms for enhanced UMLS source terminology integration.

The UMLS contains more than 100 source vocabularies and is growing via the integration of others. When integrating a new source, the source terms already in the UMLS must first be found. The easiest approach to this is simple string matching. However, string matching usually does not find all concepts that should be found. A new methodology, based on the notion of piecewise synonyms, for enhancing the process of concept discovery in the UMLS is presented. This methodology is supported by first creating a general synonym dictionary based on the UMLS. Each multi-word source term is decomposed into its component words, allowing for the generation of separate synonyms for each word from the general synonym dictionary. The recombination of these synonyms into new terms creates an expanded pool of matching candidates for terms from the source. The methodology is demonstrated with respect to an existing UMLS source. It shows a 34% improvement over simple string matching.