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Background/purpose Clostridium difficile infection (CDI) leads to a significant cause of hospital-acquired morbidity and mortality. Fecal microbiota transplantation (FMT) is effective to treat recurrent or refractory CDI (rCDI). However, the change of microbial composition contributed by FMT and its association with treatment outcomes is not well determined in Taiwan. We aimed to investigate the efficacy of FMT and the association with microbial alteration endemically. Methods Twelve patients who received FMT for rCDI in Taipei Veterans General Hospital were prospectively enrolled from April 2019 to July 2020. The clinical assessments and fecal microbial analyses in comparison with fecal materials of unrelated donors were conducted before and after FMT. Results The overall success rate of FMT for rCDI was 91.7%. A prominence of Proteobacteria, Gammaproteobacteria and Enterobacteriales were observed in the feces of patients with rCDI. Increased fecal phylogenetic diversities and a significant microbial dissimilarity were provided by successful FMT compared to patients before treatment. However, the distinctness was not obvious between patients’ feces at baseline and after unsuccessful FMT. Moreover, dynamic change of fecal microbial composition after FMT was observed during follow-up but did not interrupt the treatment effects of FMT. Conclusion Gut dysbiosis commonly co-exists in patients with rCDI. Restoration of gut microbial communities by FMT provides a promising strategy to treat antibiotic-failed CDI, and the extent of microbial change would be related to the treatment outcomes of FMT. Besides, the effectiveness of FMT for CDI could be maintained even the gut microbiota has diverged over time.

BACKGROUND We aimed to investigate the long-term effects of metabolic profiles and microbiota status in patients after upper gastrointestinal (GI) surgery and lower GI surgery and compared them with a control group. METHODS In this cross-sectional study, we analyzed the occurrence of metabolic syndrome (MS) in 10 patients who underwent curative total gastrectomy with Roux-en-Y esophagojejunostomy (RYEJ) anastomosis, 11 patients who underwent curative partial colectomy with right hemicolectomy (RH), and 33 age- and sex-matched controls. Fecal samples were also analyzed by a next-generation sequencing method. RESULTS Compared with the control group, the occurrence of MS was significantly lower among patients who underwent total gastrectomy with RYEJ than the controls over the long-term follow-up (>8 years; p < 0.05). Patients who received RH only had a trend of higher serum fasting glucose (p = 0.10). The diversity of the gut microbiota significantly decreased after RH in comparison with the control group and RYEJ group, respectively (p < 0.05). Principal component analysis revealed significant differences between the control, RYEJ, and RH groups (p < 0.001). At the genus level, the ratio of Prevotella to Bacteroides (P/B) was significantly higher in the RYEJ group than in the control group, whereas the P/B ratio was significantly lower in the RH group than in the control group (p < 0.05). CONCLUSION Early gastric cancer patients who received total gastrectomy with RYEJ had a lower occurrence of MS than the controls, while early colorectal cancer patients who received RH were associated with a higher serum fasting glucose than the controls during long-term follow-up. In parallel with the metabolic differences, the P/B ratio was also significantly altered in patients after upper and lower GI surgery.

Pathological bacterial translocation from the disrupted intestinal barrier leads to substantial complications and mortality in liver cirrhosis. Vitamin D is reported as beneficial to gut barriers in some animal models. However, its effect on cirrhotic bacterial translocation is unknown. The authors aim to investigate the effects of calcitriol on bacterial translocation in cirrhotic rats.Cirrhotic rats are administrated with a 2-week course of active vitamin DCalcitriol treatment attenuates intestinal permeability, reduces bacterial translocation, and enriches potentially beneficial gut microbiota in cirrhotic rats that may enable it as a potential therapeutic agent to prevent cirrhotic complications.

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disease that associated with complicated interaction between immune, gut microbiota and environmental factors in a genetically vulnerable host. Dysbiosis is often seen in patients with IBD. Our aim is to investigate the fecal microbiota in patients with IBD and compared to healthy controls in Taiwan. Methods In this cross-sectional study, we investigated fecal microbiota in 20 patients with IBD and 48 healthy controls. Fecal samples from both IBD patients and controls were analyzed by next-generation sequencing method and relevant software. Results The IBD group showed lower bacterial richness and diversity compared to the control group. The principal coordinate analysis also revealed significant structural difference between the IBD group and the control group. These findings were consistent whether the analysis was based on operational taxonomic unit or amplicon sequence variant. However, no significant difference was found when comparing the composition of fecal microbiota between ulcerative colitis (UC) and Crohn’s disease (CD). Further analysis showed that Lactobacillus, Enterococcus, Bifidobacterium and Veillonella were dominant in the IBD group, while Faecalibacterium and Subdoligranulum were dominant in the control group at genus level. When comparing UC, CD and control group, Lactobacillus, Bifidobacterium and Enterococcus were identified as dominant genera in the UC group. Fusobacterium and Escherichia_Shigella were dominant in the CD group. Faecalibacterium and Subdoligranulum were dominant in the control group. Conclusions Compared to the healthy control, the IBD group showed dysbiosis with a significant decreased in both richness and diversity of gut microbiota.

In this study, we found a mosquito antimicrobial peptide (AMP), Aedes aegypti cecropin B (Aacec B), was expressed constitutively in pupae. Knockdown in the pupae of Aacec B using double-stranded RNA (dsRNA) resulted in high mortality, the emergence of deformed adults and an impairment of pharate adult cuticle formation with fewer lamellae being deposited and the helicoidal pattern of the chitin microfibrils being disorganized. Simultaneous injection of Aacec B dsRNA and Aacec B peptide into pupae significantly reduced this mortality and no deformed adults then emerged. The expression levels of Ae. aegypti prophenoloxidase (AaPPO) 3 and AaPPO 4 were significantly reduced in the Aacec B knockdown pupae. Exogenous Aacec B peptide significantly enhanced the transcription of AaPPO 3 in pupae. Knockdown of AaPPO 3 in pupae caused effects similar to Aacec B-knockdown. The Aacec B peptide could be detected in both the cytoplasm and nuclei of pupal cells and was able to bind to the TTGG(A/C)A motif in AaPPO 3 DNA both in vitro and in vivo. These findings suggest that Aacec B plays a crucial role in pharate adult cuticle formation via the regulation of AaPPO 3 gene expression in pupae.

Background This study applied a new strategy, termed high-turnover utility bed intervention , to offer early admission chances for emergency department (ED) patients and alleviate ED crowding. Methods This before-and-after observational cohort study was conducted at the ED of an urban tertiary hospital. On January 1, 2012, 14 utility beds were prepared exclusively for ED patient use. A strict 48-hour course limit for each patient was formulated to govern these high-turnover beds. The primary outcome measure for this study was ED length of stay. Secondary outcome measures were the number of ED admissions, patients who left without being seen, and revisits within 72 hours of discharge, as well as the outcomes of cardiac arrest management and ambulance diversion hours. Results There were 70,515 adult ED visits enrolled during the preintervention period (January–December 2011), and 69,706 during the postintervention period (July 2012–June 2013). In the postintervention period, this new strategy offered 1401 early admission opportunities. The ambulance diversion hours decreased prominently from 5.4 hours to 1.6 hours per day. A shortening in ED length of stay from 9.7 hours to 8.0 hours was achieved, mainly in cases of nontrauma. More patients (31.2% vs. 29.7%) were admitted to the wards with a lower discharge rate in the postintervention period. Additionally, there was no difference in ED revisit within 72 hours and cardiac arrest management. Conclusion The high-turnover ED utility bed intervention offered improved admission chance and alleviated ED crowding output. ED efficiency improved, with shortened ED length of stay and fewer ambulance diversion hours.

Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3′-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.

Background and aims Pathological bacterial translocation from the disrupted intestinal barrier leads to substantial complications and mortality in liver cirrhosis. Vitamin D was reported beneficial to gut barriers in some animal models. However, its effect on cirrhotic bacterial translocation is unknown. We aimed to investigate the effects of active vitamin D3 on bacterial translocation in cirrhotic rats. Methods Cirrhotic rats were administrated with a 2-week course of active vitamin D3 (calcitriol, 0.1μg/kg/day) or vehicle by oral gavage after thioacetamide (TAA) injection for 16 weeks. Bacterial translocation, gut permeability, gut microbiota and associated mechanisms were investigated. Result Calcitriol treatment significantly attenuated bacterial translocation and reduced intestinal permeability in TAA-induced cirrhotic rats. It upregulated the expressions of occludin in the small intestine and claudin-1 in the colon of cirrhotic rats directly independent of intrahepatic status. Even when a short period of calcitriol treatment did not reduce intestinal bacterial overgrowth, it induced a remarkable change of bacterial diversities and enrichment of Muribaculaceae, Bacteroidales, Allobaculum, Anaerovorax, and Ruminococcaceae. Conclusion Calcitriol treatment attenuated intestinal permeability, reduced bacterial translocation and enriched potentially beneficial gut microbiota in cirrhotic rats that may enable it as a potential therapeutic agent to prevent cirrhotic complications. This article is protected by copyright. All rights reserved.

Whether there are subsequent changes of metabolic profiles and microbiota status after partial colectomy remains unknown. We evaluated and compared long-term effects of microbiota status and metabolic profiles in early colorectal cancer (CRC) patients after curative colectomy to the controls. In this cross-sectional study, we analyzed metabolic syndrome occurrence in 165 patients after curative partial colectomy with right hemicolectomy (RH) or low anterior resection (LAR) and 333 age-sex matched controls. Fecal samples from some of those with RH, LAR, and controls were analyzed by next-generation sequencing method. The occurrences of metabolic syndrome were significantly higher in patients after RH, but not LAR, when compared with the controls over the long term (> 5 years) follow-up (P = 0.020). Compared with control group, RH group showed lower bacterial diversity (P = 0.007), whereas LAR group showed significantly higher bacterial diversity at the genera level (P = 0.016). Compared with the control group, the principal component analysis revealed significant differences in bacterial genera abundance after RH and LAR (P < 0.001). Furthermore, the Firmicutes to Bacteroidetes ratio was significantly lower in the RH group than the control group (22.0% versus 49.4%, P < 0.05). In conclusion, early CRC patients after RH but not LAR were associated with a higher occurrence of metabolic syndrome than the controls during long-term follow-up. In parallel with metabolic change, patients with RH showed dysbiosis with a tendency to decreased richness and a significant decrease in the diversity of gut microbiota.

Objective Using standards is not only useful for data interchange during the process of a clinical trial, but also useful for analyzing data in a review process. Any step, which speeds up approval of new drugs, may benefit patients. As a result, adopting standards for regulatory submission becomes mandatory in some countries. However, preparing standard-compliant documents, such as annotated case report form (aCRF), needs a great deal of knowledge and experience. The process is complex and labor-intensive. Therefore, there is a need to use information technology to facilitate this process. Materials and methods Instead of standardizing data after the completion of a clinical trial, this study proposed a standard-driven approach. This approach was achieved by implementing a computer-assisted “standard-driven pipeline (SDP)” in an existing clinical data management system. SDP used CDISC standards to drive all processes of a clinical trial, such as the design, data acquisition, tabulation, etc. Results A completed phase I/II trial was used to prove the concept and to evaluate the effects of this approach. By using the CDISC-compliant question library, aCRFs were generated automatically when the eCRFs were completed. For comparison purpose, the data collection process was simulated and the collected data was transformed by the SDP. This new approach reduced the missing data fields from sixty-two to eight and the controlled term mismatch field reduced from eight to zero during data tabulation. Conclusion This standard-driven approach accelerated CRF annotation and assured data tabulation integrity. The benefits of this approach include an improvement in the use of standards during the clinical trial and a reduction in missing and unexpected data during tabulation. The standard-driven approach is an advanced design idea that can be used for future clinical information system development.

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A4G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that cosegregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.

Summary Background Whether sequential treatment can replace triple therapy as the standard treatment for Helicobacter pylori infection is unknown. We compared the efficacy of sequential treatment for 10 days and 14 days with triple therapy for 14 days in first-line treatment. Methods For this multicentre, open-label, randomised trial, we recruited patients (≥20 years of age) with H pylori infection from six centres in Taiwan. Using a computer-generated randomisation sequence, we randomly allocated patients (1:1:1; block sizes of six) to either sequential treatment (lansoprazole 30 mg and amoxicillin 1 g for the first 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 500 mg for another 7 days; with all drugs given twice daily) for either 10 days (S-10) or 14 days (S-14), of 14 days of triple therapy (T-14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg for 14 days; with all drugs given twice daily). Investigators were masked to treatment allocation. Our primary outcome was the eradication rate in first-line treatment by intention-to-treat (ITT) and per-protocol (PP) analyses. This trial is registered with ClinicalTrials.gov, number NCT01042184. Findings Between Dec 28, 2009, and Sept 24, 2011, we enrolled 900 patients: 300 to each group. The eradication rate was 90·7% (95% CI 87·4–94·0; 272 of 300 patients) in the S-14 group, 87·0% (83·2–90·8; 261 of 300 patients) in the S-10 group, and 82·3% (78·0–86·6; 247 of 300 patients) in the T-14 group. Treatment efficacy was better in the S-14 group than it was in the T-14 group in both the ITT analysis (number needed to treat of 12·0 [95% CI 7·2–34·5]; p=0·003) and PP analyses (13·7 [8·3–40], p=0·003). We recorded no significant difference in the occurrence of adverse effects or in compliance between the three groups. Interpretation Our findings lend support to the use of sequential treatment as the standard first-line treatment for H pylori infection. Funding National Taiwan University Hospital and National Science Council.

Background The association between genetic polymorphisms of ADRβ2, IL-4, and ADAM3 and asthma remains undetermined. Furthermore, it is not clear as to whether these three gene polymorphisms combined produce a correlative increase in asthmatic risk. Methods A total of 476 asthmatic patients and 115 healthy volunteers were enrolled. Single nucleotide polymorphisms (SNPs) of the C-589T IL-4 promoter (rs2243250), the ADRβ2 gene [at nucleic acid 46 (rs1042713) and 79 (rs1042714)] and the ADAM33 gene [at rs2280091 (T1), rs3918396 (S1), rs3918391 (D1), and rs615436] were analyzed. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE for inhalant allergens and total eosinophil counts were assessed. Results The T allele for the IL-4 gene promoter (C-589T locus), the C allele frequency for ADRβ2 (Gln27Glu locus), and the A allele for the ADAM33 gene (rs2280091, T1) were higher in asthma patients than in normal individuals. In asthmatic patients, the A allele of ADAM33 (rs2280091) was associated with higher eosinophil count and increased hyperresponsiveness compared to the C allele. Combination of the three risk genes SNP had an additive effect on the risk of asthma (OR: 3.46; CI: 1.51–7.93) and increased the diagnostic sensitivity and specificity of asthma. Conclusion Genetic polymorphism in the IL-4 promoter, ADRβ2, and ADAM33 is associated with asthma. Furthermore, ADAM33 genetic polymorphism modifies the phenotype of asthma in atopy and hyperresponsiveness. Asthma is a complex polygenic disease, and combinations of polymorphisms of various genes have an additive effect on the risk of asthma.

Introduction Precision medicine is an important milestone toward the attainment of personalized medicine. A learning health system (LHS) may facilitate the evidence collection and knowledge generation process for disease‐based research and for the diagnosis, classification, or treatment of each disease subtype to improve patient care. Methods The LHS design and implementation used by Taichung Veterans General Hospital (TCVGH) in Taiwan for their newly funded precision medicine research, a dementia registry study, was modeled from an LHS developed at the National Institutes of Health in the United States. This Clinical Informatics and Management System (CIMS), including its subsystems, facilitates and enhances operations associated with the institutional review board, clinical research data collection and study management, the hospital biobank, and the participating health research centers to support their precision medicine research aimed at improving patient care. Results The implementation of a shared‐design, full‐cycle LHS with an enhanced CIMS, combined with hospital‐based real‐world data marts, has made the TCVGH dementia registry study a reality. The research data, including clinical assessment and genomics analysis information collected in CIMS, combined with data marts, are the foundation of the TCVGH dementia registry for outcome analyses. These high‐quality datasets are useful for clinical validation, new hypotheses, and knowledge generation, leading to new clinical recommendations or guidelines for better patient treatment and care. The cyclic data flow supports the full‐cycle LHS for TCVGH's dementia research to improve the care of elderly patients. Conclusions Knowledge generation requires high‐quality research and health care datasets. While the details of LHS implementation methods in the United States and Taiwan may differ slightly, the LHS concept design and basic system architecture, with improved CIMSs, were proven feasible. As a result, learning health processes in support of translational research and the potential for improvement in patient care were significantly facilitated.

D-amino acid oxidase (DAO) has been reported to be associated with schizophrenia. This study aimed to search for genetic variants associated with this gene. The genomic regions of all exons, highly conserved regions of introns, and promoters of this gene were sequenced. Potentially meaningful single-nucleotide polymorphisms (SNPs) obtained from direct sequencing were selected for genotyping in 600 controls and 912 patients with schizophrenia and in a replicated sample consisting of 388 patients with schizophrenia. Genetic associations were examined using single-locus and haplotype association analyses. In single-locus analyses, the frequency of the C allele of a novel SNP rs55944529 located at intron 8 was found to be significantly higher in the original large patient sample (p = 0.016). This allele was associated with a higher level of DAO mRNA expression in the Epstein-Barr virus-transformed lymphocytes. The haplotype distribution of a haplotype block composed of rs11114083-rs2070586-rs2070587-rs55944529 across intron 1 and intron 8 was significantly different between the patients and controls and the haplotype frequencies of AAGC were significantly higher in patients, in both the original (corrected p < 0.0001) and replicated samples (corrected p = 0.0003). The CGTC haplotype was specifically associated with the subgroup with deficits in sustained attention and executive function and the AAGC haplotype was associated with the subgroup without such deficits. The DAO gene was a susceptibility gene for schizophrenia and the genomic region between intron 1 and intron 8 may harbor functional genetic variants, which may influence the mRNA expression of DAO and neurocognitive functions in schizophrenia.

DNA microarray technology provides tools for studying the expression profiles of a large number of distinct genes simultaneously. This technology has been applied to sample clustering and sample prediction. Because of a large number of genes measured, many of the genes in the original data set are irrelevant to the analysis. Selection of discriminatory genes is critical to the accuracy of clustering and prediction. This paper considers statistical significance testing approach to selecting discriminatory gene sets for multi-class clustering and prediction of experimental samples. A toxicogenomic data set with nine treatments (a control and eight metals, As, Cd, Ni, Cr, Sb, Pb, Cu, and AsV with a total of 55 samples) is used to illustrate a general framework of the approach. Among four selected gene sets, a gene set Ω I formed by the intersection of the F -test and the set of the union of one-versus-all t -tests performs the best in terms of clustering as well as prediction. Hierarchical and two modified partition ( k -means) methods all show that the set Ω I is able to group the 55 samples into seven clusters reasonably well, in which the As and AsV samples are considered as one cluster (the same group) as are the Cd and Cu samples. With respect to prediction, the overall accuracy for the gene set Ω I using the nearest neighbors algorithm to predict 55 samples into one of the nine treatments is 85%.

DNA microarray technology provides useful tools for profiling global gene expression patterns in different cell/tissue samples. One major challenge is the large number of genes relative to the number of samples. The use of all genes can suppress or reduce the performance of a classification rule due to the noise of nondiscriminatory genes. Selection of an optimal subset from the original gene set becomes an important prestep in sample classification. In this study, we propose a family-wise error (FWE) rate approach to selection of discriminatory genes for two-sample or multiple-sample classification. The FWE approach controls the probability of the number of one or more false positives at a prespecified level. A public colon cancer data set is used to evaluate the performance of the proposed approach for the two classification methods: k nearest neighbors (k-NN) and support vector machine (SVM). The selected gene sets from the proposed procedure appears to perform better than or comparable to several results reported in the literature using the univariate analysis without performing multivariate search. In addition, we apply the FWE approach to a toxicogenomic data set with nine treatments (a control and eight metals, As, Cd, Ni, Cr, Sb, Pb, Cu, and AsV) for a total of 55 samples for a multisample classification. Two gene sets are considered: the gene set omegaF formed by the ANOVA F-test, and a gene set omegaT formed by the union of one-versus-all t-tests. The predicted accuracies are evaluated using the internal and external crossvalidation. Using the SVM classification, the overall accuracies to predict 55 samples into one of the nine treatments are above 80% for internal crossvalidation. OmegaF has slightly higher accuracy rates than omegaT. The overall predicted accuracies are above 70% for the external crossvalidation; the two gene sets omegaT and omegaF performed equally well.

Heterosexual contact is one of the common routes of transmission for hepatitis B virus (HBV) among adults in Taiwan, but only a few studies have provided direct evidence at the level of the HBV genome of infected couples with acute non-fulminant hepatitis to document a common source. By cloning and sequencing polymerase chain reaction-amplified HBV-DNA, we analysed the sequences of the conserved region of the surface gene (nucleotide (n.t.) 305-513, representing 6.5% of the viral genome) of HBV in five HBV-infected index patients, their spouses and four randomly selected HBV carriers as controls. Risk factors associated with acute HBV infection in index cases were sexual contact with their spouses within 3 months before the onset of hepatitis. For all five couples, the HBV-infected index patient and the spouse shared a 100% sequence homology of HBV-DNA. In contrast, there was significantly more variation (mean heterogeneity 6.1%, range 1-13.9%) in the amplified region between the five couples and between each couple and the controls (P

Genomic DNAs containing the gene encoding apolipoprotein A-I (apoA-I) from four strains of mice and three strains of rats have been sequenced. Some peculiar repetitive sequences were found in the third intron of apoA-I of the murine species. The striking features include regular tandem repeats of C(A)4 and C(A)6 in mice and long A-tracts in rats. Not completely identical but very similar motifs were found in mice or rats belonging to the same species while repetitive elements from different species show some variation from their species-specific consensus sequences. These repetitive motifs are very similar to the sequences flanking human Alu and rodent B 1 repetitive elements, although no evidence for the existence of Alu or B 1 was found near the peculiar repetitive DNA sequences in apoA-I gene.

As assayed by both in vivo and in vitro UV-crosslinking techniques, four RNA binding proteins, with apparent molecular weight of 56, 54, 42, and 40 kilodaltons, associated specifically with the Xenopus Vg1 mRNA localization signal (LS) RNA. The 56 and 54 kD proteins were assigned as the masking proteins described previously, on the basis of their thermal stability and the effect of phosphorylation on RNA binding activity. The 42 and 40 kD proteins associated with the LS RNA at a lower extract concentration than the masking proteins did in vitro. Dephosphorylation will eliminate the RNA binding activities of all four proteins. However, either raising the extract concentration or phosphorylating the extract by the catalytic domain of protein kinase A had opposite effects on the crosslinking efficiencies of these two sets of RNA binding proteins. Phosphorylation might regulate this protein exchange process in vitro.

It is very important to select a small set of relevant features from a high dimensional data set and useful to design either an effective classification or prediction model. This procedure involves a series of estimations of the relationship between each pair of variables and between each variable and class labels. Mutual information is widely used to estimate these relationships. However, alternative strategies may be useful to estimate the mutual information with continuous or hybrid data. In this study, we attempt to evaluate the difference between the selection strategies involved with mutual information and fuzzy mutual information. The results indicate that using fuzzy mutual information is more helpful to obtain more stable feature sets and more accurate estimations of the relationship between two variables.

Background Schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment. Methods We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia. Results We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely A-T-C of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the DAO gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including DAO*DISC1, DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of DAO and the between-gene interaction of DAO and PTK2B were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of CACNG2, all of the identified risk haplotypes and interactions involved SNPs from DAO. Conclusions These results suggest that DAO, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between DAO and RASD2 has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.

Background In biological systems, pathways coordinate or interact with one another to achieve a complex biological process. Studying how they influence each other is essential for understanding the intricacies of a biological system. However, current methods rely on statistical tests to determine pathway relations, and may lose numerous biologically significant relations. Results This study proposes a method that identifies the pathway relations by measuring the functional relations between pathways based on the Gene Ontology (GO) annotations. This approach identified 4,661 pathway relations among 166 pathways from Pathway Interaction Database (PID). Using 143 pathway interactions from PID as testing data, the function-based approach (FBA) is able to identify 93% of pathway interactions, better than the existing methods based on the shared components and protein-protein interactions. Many well-known pathway cross-talks are only identified by FBA. In addition, the false positive rate of FBA is significantly lower than others via pathway co-expression analysis. Conclusions This function-based approach appears to be more sensitive and able to infer more biologically significant and explainable pathway relations.

Background Ras is frequently mutated in a variety of human cancers, including lung cancer, leading to constitutive activation of MAPK signaling. Despite decades of research focused on the Ras oncogene, Ras-targeted phosphorylation events and signaling pathways have not been described on a proteome-wide scale. Methodology/Principal Findings By functional phosphoproteomics, we studied the molecular mechanics of oncogenic Ras signaling using a pathway-based approach. We identified Ras-regulated phosphorylation events (n = 77) using label-free comparative proteomics analysis of immortalized human bronchial epithelial cells with and without the expression of oncogenic Ras. Many were newly identified as potential targets of the Ras signaling pathway. A majority (∼60%) of the Ras-targeted events consisted of a [pSer/Thr]-Pro motif, indicating the involvement of proline-directed kinases. By integrating the phosphorylated signatures into the Pathway Interaction Database, we further inferred Ras-regulated pathways, including MAPK signaling and other novel cascades, in governing diverse functions such as gene expression, apoptosis, cell growth, and RNA processing. Comparisons of Ras-regulated phosphorylation events, pathways, and related kinases in lung cancer-derived cells supported a role of oncogenic Ras signaling in lung adenocarcinoma A549 and H322 cells, but not in large cell carcinoma H1299 cells. Conclusions/Significance This study reveals phosphorylation events, signaling networks, and molecular functions that are regulated by oncogenic Ras. The results observed in this study may aid to extend our knowledge on Ras signaling in lung cancer.