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1.  MICO: A meta-tool for prediction of the effects of non-synonymous mutations 
Bioinformation  2014;10(7):469-471.
The Next Generation Sequencing (NGS) is a state-of-the-art technology that produces high throughput data with high resolution mutation information in the genome. Numerous methods with different efficiencies have been developed to predict mutational effects in the genome. The challenge is to present the results in a balanced manner for better biological insights and interpretation. Hence, we describe a meta-tool named Mutation Information Collector (MICO) for automatically querying and collecting related information from multiple biology/bioinformatics enabled web servers with prediction capabilities. The predicted mutational results for the proteins of interest are returned and presented as an easy-to-read summary table in this service. MICO also allows for navigating the result from each website for further analysis.
http: // /MICO
PMCID: PMC4135298  PMID: 25187690
2.  A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation 
Human Molecular Genetics  2013;23(2):418-433.
‘Salt & Pepper’ syndrome is an autosomal recessive condition characterized by severe intellectual disability, epilepsy, scoliosis, choreoathetosis, dysmorphic facial features and altered dermal pigmentation. High-density SNP array analysis performed on siblings first described with this syndrome detected four shared regions of loss of heterozygosity (LOH). Whole-exome sequencing narrowed the candidate region to chromosome 2p11.2. Sanger sequencing confirmed a homozygous c.994G>A transition (p.E332K) in the ST3GAL5 gene, which encodes for a sialyltransferase also known as GM3 synthase. A different homozygous mutation of this gene has been previously associated with infantile-onset epilepsy syndromes in two other cohorts. The ST3GAL5 enzyme synthesizes ganglioside GM3, a glycosophingolipid enriched in neural tissue, by adding sialic acid to lactosylceramide. Unlike disorders of glycosphingolipid (GSL) degradation, very little is known regarding the molecular and pathophysiologic consequences of altered GSL biosynthesis. Glycolipid analysis confirmed a complete lack of GM3 ganglioside in patient fibroblasts, while microarray analysis of glycosyltransferase mRNAs detected modestly increased expression of ST3GAL5 and greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other GSL biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked and GSL glycans revealed collateral alterations in response to loss of complex gangliosides in patient fibroblasts and in zebrafish embryos injected with antisense morpholinos that targeted zebrafish st3gal5 expression. Morphant zebrafish embryos also exhibited increased apoptotic cell death in multiple brain regions, emphasizing the importance of GSL expression in normal neural development and function.
PMCID: PMC3869362  PMID: 24026681
3.  Regulation of Cellular Metabolism and Cytokines by the Medicinal Herb Feverfew in the Human Monocytic THP-1 Cells 
The herb feverfew is a folk remedy for various symptoms including inflammation. Inflammation has recently been implicated in the genesis of many diseases including cancers, atherosclerosis and rheumatoid arthritis. The mechanisms of action of feverfew in the human body are largely unknown. To determine the cellular targets of feverfew extracts, we have utilized oligo microarrays to study the gene expression profiles elicited by feverfew extracts in human monocytic THP-1 cells. We have identified 400 genes that are consistently regulated by feverfew extracts. Most of the genes are involved in cellular metabolism. However, the genes undergoing the highest degree of change by feverfew treatment are involved in other pathways including chemokine function, water homeostasis and heme-mediated signaling. Our results also suggest that feverfew extracts effectively reduce Lipopolysaccharides (LPS)-mediated TNF-α and CCL2 (MCP-1) releases by THP-1 cells. We hypothesize that feverfew components mediate metabolism, cell migration and cytokine production in human monocytes/macrophages.
PMCID: PMC2644270  PMID: 18955216
feverfew; herbal medicine; immune response; microarray; monocyte
4.  Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation 
Oncology Reports  2014;33(2):935-941.
Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the ‘period’ (PER) clock genes, which have tumor suppressor properties. A variable number tandem repeat (VNTR) in the PERIOD3 (PER3) gene has been associated with sleep disorders, differences in diurnal hormone secretion, and increased premenopausal breast cancer risk. Susceptibility related to PER3 has not been examined in conjunction with adenomatous polyps. This exploratory case-control study was the first to test the hypothesis that the 5-repeat PER3 VNTR sequence is associated with increased odds of adenoma formation. Information on demographics, medical history, occupation and lifestyle was collected prior to colonoscopy. Cases (n=49) were individuals with at least one histopathologically confirmed adenoma. Controls (n=97) included patients with normal findings or hyperplastic polyps not requiring enhanced surveillance. Unconditional multiple logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), after adjusting for potential confounding. Adenomas were detected in 34% of participants. Cases were more likely to possess the 5-repeat PER3 genotype relative to controls (4/5 OR, 2.1; 95% CI, 0.9–4.8; 5/5 OR, 5.1; 95% CI, 1.4–18.1; 4/5+5/5 OR, 2.5; 95% CI, 1.7–5.4). Examination of the Oncomine microarray database indicated lower PERIOD gene expression in adenomas relative to adjacent normal tissue. Results suggest a need for follow-up in a larger sample.
PMCID: PMC4306271  PMID: 25501848
adenoma; clock gene; circadian rhythm; colorectal cancer; variable number tandem repeat
5.  Genome sequence and transcriptome analyses of the thermophilic zygomycete fungus Rhizomucor miehei 
BMC Genomics  2014;15:294.
The zygomycete fungi like Rhizomucor miehei have been extensively exploited for the production of various enzymes. As a thermophilic fungus, R. miehei is capable of growing at temperatures that approach the upper limits for all eukaryotes. To date, over hundreds of fungal genomes are publicly available. However, Zygomycetes have been rarely investigated both genetically and genomically.
Here, we report the genome of R. miehei CAU432 to explore the thermostable enzymatic repertoire of this fungus. The assembled genome size is 27.6-million-base (Mb) with 10,345 predicted protein-coding genes. Even being thermophilic, the G + C contents of fungal whole genome (43.8%) and coding genes (47.4%) are less than 50%. Phylogenetically, R. miehei is more closerly related to Phycomyces blakesleeanus than to Mucor circinelloides and Rhizopus oryzae. The genome of R. miehei harbors a large number of genes encoding secreted proteases, which is consistent with the characteristics of R. miehei being a rich producer of proteases. The transcriptome profile of R. miehei showed that the genes responsible for degrading starch, glucan, protein and lipid were highly expressed.
The genome information of R. miehei will facilitate future studies to better understand the mechanisms of fungal thermophilic adaptation and the exploring of the potential of R. miehei in industrial-scale production of thermostable enzymes. Based on the existence of a large repertoire of amylolytic, proteolytic and lipolytic genes in the genome, R. miehei has potential in the production of a variety of such enzymes.
PMCID: PMC4023604  PMID: 24746234
Rhizomucor miehei; Genome; Transcriptome; Thermophilic fungus; Thermostable enzymes
6.  Decreased tryptophan metabolism in patients with autism spectrum disorders 
Molecular Autism  2013;4:16.
Autism spectrum disorders (ASDs) are relatively common neurodevelopmental conditions whose biological basis has been incompletely determined. Several biochemical markers have been associated with ASDs, but there is still no laboratory test for these conditions.
We analyzed the metabolic profile of lymphoblastoid cell lines from 137 patients with neurodevelopmental disorders with or without ASDs and 78 normal individuals, using Biolog Phenotype MicroArrays.
Metabolic profiling of lymphoblastoid cells revealed that the 87 patients with ASD as a clinical feature, as compared to the 78 controls, exhibited on average reduced generation of NADH when tryptophan was the sole energy source. The results correlated with the behavioral traits associated with either syndromal or non-syndromal autism, independent of the genetic background of the individual. The low level of NADH generation in the presence of tryptophan was not observed in cell lines from non-ASD patients with intellectual disability, schizophrenia or conditions exhibiting several similarities with syndromal autism except for the behavioral traits. Analysis of a previous small gene expression study found abnormal levels for some genes involved in tryptophan metabolic pathways in 10 patients.
Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.
PMCID: PMC3680090  PMID: 23731516
Autism; Biomarker; Tryptophan; Metabolism; Screening
7.  Expression of a Novel Antimicrobial Peptide Penaeidin4-1 in Creeping Bentgrass (Agrostis stolonifera L.) Enhances Plant Fungal Disease Resistance 
PLoS ONE  2011;6(9):e24677.
Turfgrass species are agriculturally and economically important perennial crops. Turfgrass species are highly susceptible to a wide range of fungal pathogens. Dollar spot and brown patch, two important diseases caused by fungal pathogens Sclerotinia homoecarpa and Rhizoctonia solani, respectively, are among the most severe turfgrass diseases. Currently, turf fungal disease control mainly relies on fungicide treatments, which raises many concerns for human health and the environment. Antimicrobial peptides found in various organisms play an important role in innate immune response.
Methodology/Principal Findings
The antimicrobial peptide - Penaeidin4-1 (Pen4-1) from the shrimp, Litopenaeus setiferus has been reported to possess in vitro antifungal and antibacterial activities against various economically important fungal and bacterial pathogens. In this study, we have studied the feasibility of using this novel peptide for engineering enhanced disease resistance into creeping bentgrass plants (Agrostis stolonifera L., cv. Penn A-4). Two DNA constructs were prepared containing either the coding sequence of a single peptide, Pen4-1 or the DNA sequence coding for the transit signal peptide of the secreted tobacco AP24 protein translationally fused to the Pen4-1 coding sequence. A maize ubiquitin promoter was used in both constructs to drive gene expression. Transgenic turfgrass plants containing different DNA constructs were generated by Agrobacterium-mediated transformation and analyzed for transgene insertion and expression. In replicated in vitro and in vivo experiments under controlled environments, transgenic plants exhibited significantly enhanced resistance to dollar spot and brown patch, the two major fungal diseases in turfgrass. The targeting of Pen4-1 to endoplasmic reticulum by the transit peptide of AP24 protein did not significantly impact disease resistance in transgenic plants.
Our results demonstrate the effectiveness of Pen4-1 in a perennial species against fungal pathogens and suggest a potential strategy for engineering broad-spectrum fungal disease resistance in crop species.
PMCID: PMC3171467  PMID: 21931807
8.  Candidate Agtr2 influenced genes and pathways identified by expression profiling in the developing brain of Agtr2−/y mice 
Genomics  2009;94(3):188-195.
Intellectual disability (ID) is a common developmental disability observed in one to three percent of the human population. A possible role for the Angiotensin II type 2 receptor (AGTR2) in brain function, affecting learning, memory, and behavior, has been suggested in humans and rodents. Mice lacking the Agtr2 gene (Agtr2−/y) showed significant impairment in their spatial memory and exhibited abnormal dendritic spine morphology. To identify Agtr2 influenced genes and pathways, we performed whole genome microarray analysis on RNA isolated from brains of Agtr2−/y and control male mice at embryonic day 15 (E15) and postnatal day one (P1). The gene expression profiles of the Agtr2−/y brain samples were significantly different when compared to profiles of the age-matched control brains. We identified 62 differently expressed genes (p ≤ 0.005) at E15 and in P1 brains of the Agtr2−/y mice. We verified the differential expression of several of these genes in brain samples using quantitative RT-PCR. Differentially expressed genes encode molecules involved in multiple cellular processes including microtubule functions associated with dendritic spine morphology. This study provides insight into Agtr2 influenced candidate genes and suggests that expression dysregulation of these genes may modulate Agtr2 actions in the brain that influences learning and memory.
PMCID: PMC3164574  PMID: 19501643
Learning and memory; Intellectual Disability; Dendritic spine; Expression profiling; Agtr2
9.  G-SESAME: web tools for GO-term-based gene similarity analysis and knowledge discovery 
Nucleic Acids Research  2009;37(Web Server issue):W345-W349.
We have developed a set of online tools for measuring the semantic similarities of Gene Ontology (GO) terms and the functional similarities of gene products, and for further discovering biomedical knowledge from the GO database. The tools have been used for about 6.9 million times by 417 institutions from 43 countries since October 2006. The online tools are available at:
PMCID: PMC2703883  PMID: 19491312
10.  Expressed sequence tags from Peromyscus testis and placenta tissue: Analysis, annotation, and utility for mapping 
BMC Genomics  2008;9:300.
Mice of the genus Peromyscus are found in nearly every habitat from Alaska to Central America and from the Atlantic to the Pacific. They provide an evolutionary outgroup to the Mus/Rattus lineage and serve as an intermediary between that lineage and humans. Although Peromyscus has been studied extensively under both field and laboratory conditions, research has been limited by the lack of molecular resources. Genes associated with reproduction typically evolve rapidly and thus are excellent sources of evolutionary information. In this study we describe the generation of two cDNA libraries, one from placenta and one from testis, characterize the resulting ESTs, and describe their utility for mapping the Peromyscus genome.
The 5' ends of 1,510 placenta and 4,798 testis clones were sequenced. Low quality sequences were removed and after clustering and contig assembly, 904 unique placenta and 2,002 unique testis sequences remained. Average lengths of placenta and testis ESTs were 711 bp and 826 bp, respectively. Approximately 82% of all ESTs were identified using the BLASTX algorithm to Mus and Rattus, and 34 – 54% of all ESTs could be assigned to a biological process gene ontology category in either Mus or Rattus. Because the Peromyscus genome organization resembles the Rattus genome more closely than Mus we examined the distribution of the Peromyscus ESTs across the rat genome finding markers on all rat chromosomes except the Y. Approximately 40% of all ESTs were specific to only one location in the Mus genome and spanned introns of an appropriate size for sequencing and SNP detection. Of the primers that were tried 54% provided useful assays for genotyping on interspecific backcross and whole-genome radiation hybrid cell panels.
The 2,906 Peromyscus placenta and testis ESTs described here significantly expands the molecular resources available for the genus. These ESTs allow for specific PCR amplification and broad coverage across the genome, creating an excellent genetic marker resource for the generation of a medium-density genomic map. Thus, this resource will significantly aid research of a genus that is uniquely well-suited to both laboratory and field research.
PMCID: PMC2443383  PMID: 18577228
11.  Rat Genome Database (RGD): mapping disease onto the genome 
Nucleic Acids Research  2002;30(1):125-128.
The Rat Genome Database (RGD, is an NIH-funded project whose stated mission is ‘to collect, consolidate and integrate data generated from ongoing rat genetic and genomic research efforts and make these data widely available to the scientific community’. In a collaboration between the Bioinformatics Research Center at the Medical College of Wisconsin, the Jackson Laboratory and the National Center for Biotechnology Information, RGD has been created to meet these stated aims. The rat is uniquely suited to its role as a model of human disease and the primary focus of RGD is to aid researchers in their study of the rat and in applying their results to studies in a wider context. In support of this we have integrated a large amount of rat genetic and genomic resources in RGD and these are constantly being expanded through ongoing literature and bulk dataset curation. RGD version 2.0, released in June 2001, includes curated data on rat genes, quantitative trait loci (QTL), microsatellite markers and rat strains used in genetic and genomic research. VCMap, a dynamic sequence-based homology tool was introduced, and allows researchers of rat, mouse and human to view mapped genes and sequences and their locations in the other two organisms, an essential tool for comparative genomics. In addition, RGD provides tools for gene prediction, radiation hybrid mapping, polymorphic marker selection and more. Future developments will include the introduction of disease-based curation expanding the curated information to cover popular disease systems studied in the rat. This will be integrated with the emerging rat genomic sequence and annotation pipelines to provide a high-quality disease-centric resource, applicable to human and mouse via comparative tools such as VCMap. RGD has a defined community outreach focus with a Visiting Scientist program and the Rat Community Forum, a web-based forum for rat researchers and others interested in using the rat as an experimental model. Thus, RGD is not only a valuable resource for those working with the rat but also for researchers in other model organisms wishing to harness the existing genetic and physiological data available in the rat to complement their own work.
PMCID: PMC99132  PMID: 11752273

Results 1-11 (11)