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BACKGROUND: Patients with (versus without) diabetes mellitus who develop colon cancer are at increased risk of dying within 30 days after surgery. OBJECTIVE: The purpose of this study was to identify potential mediators of the effect of... more
BACKGROUND: Patients with (versus without) diabetes mellitus who develop colon cancer are at increased risk of dying within 30 days after surgery. OBJECTIVE: The purpose of this study was to identify potential mediators of the effect of diabetes mellitus on all-cause 30-day mortality risk after surgery for colon cancer. DESIGN: A retrospective cohort study was conducted using the 2013–2015 National Surgical Quality Improvement Program data. SETTING: The study was conducted at various hospitals across the United States (from 435 to 603 hospitals). PATIENTS: Patients who underwent resection for colon cancer with or without obstruction based on the National Surgical Quality Improvement Program colectomy module were included. Patients who had ASA physical status classification V or metastatic disease and those who presented emergently were excluded. Patients were classified as “no diabetes,” “diabetes not requiring insulin,” or “diabetes requiring insulin.” Potential reasons for increas...
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We utilized a mouse model of maternal obesogenic diet exposure to evaluate the effect on offspring microbiome and bile acid homeostasis. We identified shifts in the offspring microbiome associated with changes in cecal bile acid levels.... more
We utilized a mouse model of maternal obesogenic diet exposure to evaluate the effect on offspring microbiome and bile acid homeostasis. We identified shifts in the offspring microbiome associated with changes in cecal bile acid levels. Transfer of the microbiome from maternal obesogenic diet-exposed offspring to microbiome-depleted mice altered bile acid homeostasis and increased fructose-induced hepatic steatosis.
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Research Interests: Chemistry, Biology, Immunohistochemistry, Biological Chemistry, Medicine, and 15 moreWestern blotting, Biological Sciences, Xenopus, Humans, Animals, Male, Biological, Fructose, tESTIS, CHEMICAL SCIENCES, Substrate Specificity, Transporter, Spermatozoa, Small Intestine, and Medical and Health Sciences
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The presence of advanced adenomas in younger individuals is a criterion for Lynch syndrome (LS). However, the utility of screening advanced adenomas for loss of mismatch repair (MMR) protein expression to identify suspected LS remains... more
The presence of advanced adenomas in younger individuals is a criterion for Lynch syndrome (LS). However, the utility of screening advanced adenomas for loss of mismatch repair (MMR) protein expression to identify suspected LS remains unclear. Determine the prevalence of MMR defects to understand whether these patients harbor a defined genetic risk for CRC. The study cohort included adult patients ≤45 years of age with advanced adenomas (villous histology, ≥1 cm in diameter, ≥3 polyps of any size) endoscopically removed between 2001 and 2011. Clinical records were reviewed along with detailed pathological review and immunohistochemical MMR analysis. A total of 76 (40.1 % male, age 40.6 ± 5.4 years) patients met inclusion and exclusion criteria. Indications for colonoscopy were gastrointestinal (GI) bleeding 39 (51.3 %), CRC in a first-degree relative 17 (22.4 %) and somatic GI symptoms 20 (26.3 %). Index colonoscopy revealed a median of 1 adenoma (range 1-4), mean diameter of 12.9 ±...
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AimBile acid synthesis is regulated by nuclear receptors including farnesoid X receptor (FXR) and small heterodimer partner (SHP), and by fibroblast growth factor 15/19 (FGF15/19). We hypothesized that hepatic cysteine sulfinic acid... more
AimBile acid synthesis is regulated by nuclear receptors including farnesoid X receptor (FXR) and small heterodimer partner (SHP), and by fibroblast growth factor 15/19 (FGF15/19). We hypothesized that hepatic cysteine sulfinic acid decarboxylase (CSAD) (a key enzyme in taurine synthesis) is regulated by bile acids (BA). The aim of this study was to investigate CSAD regulation by BA dependent regulatory mechanisms.MethodsMice were fed a control diet or a diet supplemented with either 0.5% cholate or 2% cholestyramine. To study BA dependent pathways, we utilized GW4064 (FXR agonist), FGF19 or T‐0901317 (liver X receptor [LXR] agonist) and Shp−/− mice. Tissue mRNA was determined by quantitative reverse transcription polymerase chain reaction. Amino acids were measured by high‐performance liquid chromatography.ResultsMice supplemented with dietary cholate exhibited reduced hepatic CSAD mRNA while those receiving cholestyramine exhibited increased mRNA. Activation of FXR suppressed CSAD...
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Background Calmodulin (CaM) is a major calcium sensor in all eukaryotes. It binds calcium and modulates the activity of a wide range of downstream proteins in response to calcium signals. However, little is known about the CaM gene family... more
Background Calmodulin (CaM) is a major calcium sensor in all eukaryotes. It binds calcium and modulates the activity of a wide range of downstream proteins in response to calcium signals. However, little is known about the CaM gene family in Solanaceous species, including the economically important species, tomato (Solanum lycopersicum), and the gene silencing model plant, Nicotiana benthamiana. Moreover, the potential function of CaM in plant disease resistance remains largely unclear. Results We performed genome-wide identification of CaM gene families in Solanaceous species. Employing bioinformatics approaches, multiple full-length CaM genes were identified from tomato, N. benthamiana and potato (S. tuberosum) genomes, with tomato having 6 CaM genes, N. benthamiana having 7 CaM genes, and potato having 4 CaM genes. Sequence comparison analyses showed that three tomato genes, SlCaM3/4/5, two potato genes StCaM2/3, and two sets of N. benthamiana genes, NbCaM1/2/3/4 and NbCaM5/6, en...
Research Interests: Genetics, Microbiology, Molecular Evolution, Plant Biology, Biology, and 15 moreTobacco, Medicine, Phylogeny, Sequence alignment, Genome, Gene, Calmodulin, Intron, Solanum Tuberosum, Amino Acid Sequence, Gene Family, PLANT PROTEINS, Lycopersicon esculentum, Molecular Sequence Data, and Nicotiana benthamiana
Sphingolipids are present in cell membranes and in plasma lipoproteins. Mechanisms of sphingolipid transport to plasma lipoproteins are unknown. We found that plasma levels of ceramide and sphingomyelin were significantly lower in... more
Sphingolipids are present in cell membranes and in plasma lipoproteins. Mechanisms of sphingolipid transport to plasma lipoproteins are unknown. We found that plasma levels of ceramide and sphingomyelin were significantly lower in homozygous abetalipoproteinemia subjects defective in microsomal triglyceride transfer protein (MTP) function compared with heterozygotes, and in mice deficient in both intestinal and hepatic MTP compared with control mice. In contrast, plasma concentrations of hexosylceramide, lactosylceramide and different sphingosines were not affected by MTP deficiency. MTP deficiency had no effect on ceramide and sphingomyelin synthesis, but reduced their secretion. MTP was found to transfer ceramide and sphingomyelin. These studies suggest that MTP is a critical determinant of plasma ceramide and sphingomyelins, but not of glycosylceramide and sphingosine. The MTP-dependent transport processes to carry ceramide and sphingomyelin might have evolved to protect against toxicity associated with cellular ceramide accretions and to supply sphingomyelin to other tissues to maintain membrane integrity and to control cellular differentiation and proliferation.
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... Celiac sprue. N Engl J Med.2002 ;364:180– 188. ↵ Bai J, Moran C, Martinez C, et al. Celiac sprue after surgery of the upper gastrointestinal tract. Report of 10 patients with special attention to diagnosis, clinical behavior and... more
... Celiac sprue. N Engl J Med.2002 ;364:180– 188. ↵ Bai J, Moran C, Martinez C, et al. Celiac sprue after surgery of the upper gastrointestinal tract. Report of 10 patients with special attention to diagnosis, clinical behavior and follow-up. J Clin Gastroenterol. 1991;13:521– 524. ...
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Currently available bisulfite sequencing tools frequently suffer from low mapping rates and low methylation calls, especially for data generated from the Illumina sequencer, NextSeq. Here we introduce a sequential trimming-and-retrieving... more
Currently available bisulfite sequencing tools frequently suffer from low mapping rates and low methylation calls, especially for data generated from the Illumina sequencer, NextSeq. Here we introduce a sequential trimming-and-retrieving alignment approach for investigating DNA methylation patterns, which significantly improves the number of mapped reads and covered CpG sites. The method is implemented in an automated analysis toolkit for processing bisulfite sequencing reads. Availability: http://mysbfiles.stonybrook.edu/~xuefenwang/software.html https://github.com/xfwang/BStools CONTACT: xuefeng.wang@stonybrook.edu SUPPLEMENTARY INFORMATION: Supplementary materials are available at Bioinformatics online.
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Mammalian C-to-U RNA editing was described more than 30 yr ago as a single nucleotide modification in small intestinal Apob RNA, later shown to be mediated by the RNA-specific cytidine deaminase APOBEC1. Reports of other examples of... more
Mammalian C-to-U RNA editing was described more than 30 yr ago as a single nucleotide modification in small intestinal Apob RNA, later shown to be mediated by the RNA-specific cytidine deaminase APOBEC1. Reports of other examples of C-to-U RNA editing, coupled with the advent of genome-wide transcriptome sequencing, identified an expanded range of APOBEC1 targets. Here we analyze the cis-acting regulatory components of verified murine C-to-U RNA editing targets, including nearest neighbor as well as flanking sequence requirements and folding predictions. RNA secondary structure of the editing cassette was associated with editing frequency and exhibited minimal free energy values comparable to small nuclear RNAs. We summarize findings demonstrating the relative importance of trans-acting factors (A1CF, RBM47) acting in concert with APOBEC1. Cofactor dominance was associated with editing frequency, with RNAs targeted by both RBM47 and A1CF edited at a lower frequency than RBM47-domina...
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Mammalian apolipoprotein B (apoB) C to U RNA editing is catalyzed by a multicomponent holoenzyme containing a single catalytic subunit, apobec-1. We have characterized an apobec-1 homologue, ARCD-1, located on chromosome 6p21.1, and... more
Mammalian apolipoprotein B (apoB) C to U RNA editing is catalyzed by a multicomponent holoenzyme containing a single catalytic subunit, apobec-1. We have characterized an apobec-1 homologue, ARCD-1, located on chromosome 6p21.1, and determined its role in apoB mRNA editing. ARCD-1 mRNA is ubiquitously expressed; phylogenetic analysis reveals it to be a distant member of the RNA editing family. Recombinant ARCD-1 demonstrates cytidine deaminase and apoB RNA binding activity but does not catalyze C to U RNA editing, either in vitro or in vivo. Although not competent itself to mediate deamination of apoB mRNA, ARCD-1 inhibits apobec-1-mediated C to U RNA editing. ARCD-1 interacts and heterodimerizes with both apobec-1 and apobec-1 complementation factor (ACF) and localizes to both the nucleus and cytoplasm of transfected cells. Together, the data suggest that ARCD-1 is a novel cytidine deaminase that interacts with apobec-1 and ACF to inhibit apoB mRNA editing, possibly through interac...
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Apobec-1, the catalytic subunit of the mammalian apolipoprotein B (apoB) mRNA-editing enzyme, is a cytidine deaminase with RNA binding activity for AU-rich sequences. This RNA binding activity is required for Apobec-1 to mediate C-to-U... more
Apobec-1, the catalytic subunit of the mammalian apolipoprotein B (apoB) mRNA-editing enzyme, is a cytidine deaminase with RNA binding activity for AU-rich sequences. This RNA binding activity is required for Apobec-1 to mediate C-to-U RNA editing. Filter binding assays, using immobilized Apobec-1, demonstrate saturable binding to a 105-nt apoB RNA with a K d of ∼435 nM. A series of AU-rich templates was used to identify a high-affinity (∼50 nM) binding site of consensus sequence UUUN[A/U]U, with multiple copies of this sequence constituting the high-affinity binding site. In order to determine whether this consensus site could be functionally demonstrated from within an apoB RNA, circular-permutation analysis was performed, revealing one major (UUUGAU) and one minor (UU) site located 3 and 16 nucleotides, respectively, downstream of the edited base. Secondary-structure predictions reveal a stem-loop flanking the edited base with Apobec-1 binding to the consensus site(s) at an open ...
Research Interests: Biology, Medicine, RNA Editing, Biological Sciences, Molecular and cellular biology, and 14 moreSequence alignment, Animals, mRNA stability, Apolipoprotein B, Enzyme, RNA-binding proteins, Base Sequence, Protein Binding, Binding Site, Nucleotides, Molecular Sequence Data, Secondary structure prediction, binding sites, and Medical and Health Sciences
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Phenotypic divergence in diet induced obesity (DIO) and hepatic steatosis has been reported in two independently generated lines of L-Fabp(-/-) mice (NJ L-Fabp (-/-) vs. WU L-Fabp(-/-) mice). We performed side-by-side studies to examine... more
Phenotypic divergence in diet induced obesity (DIO) and hepatic steatosis has been reported in two independently generated lines of L-Fabp(-/-) mice (NJ L-Fabp (-/-) vs. WU L-Fabp(-/-) mice). We performed side-by-side studies to examine differences between the lines and investigate the role of genetic background, intestinal microbiota, gender and diet in the divergent phenotypes. Fasting-induced steatosis was attenuated in both L-Fabp(-/-) lines compared to C57BL/6J controls, with restoration of hepatic triglyceride levels following adenoviral L-Fabp rescue. Both lines were protected against DIO after high saturated fat diet feeding. Hepatic steatosis was attenuated in WU but not NJ L-Fabp(-/-) mice, though this difference between the lines disappeared upon antibiotic treatment and cohousing. In contrast, there was phenotypic divergence in L-Fabp(-/-) mice fed a high cocoa butter fat diet, with WU L-Fabp(-/-) mice but not NJ L-Fabp(-/-) mice, showing protection against both DIO and ...
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HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth... more
HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur (IKO) mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of Apc(min/+) mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a three-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis, and decreased expression of transcripts encoding antiapoptotic HuR target RNAs. Similarly, Hur(IKO) mice subjected to an inflammatory colon carcinogenesis protocol [azoxymethane and dextran sodium sulfate (AOM-DSS)...
Research Interests: Cancer, Biology, Apoptosis, Medicine, Intestinal Mucosa, and 3 moreMice, Animals, and Colonic Neoplasms
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Mammalian apolipoprotein B (apoB) mRNA editing is mediated by a multicomponent holoenzyme containing apobec-1 and ACF. We have now identified CUGBP2, a 54-kDa RNA-binding protein, as a component of this holoenzyme. CUGBP2 and ACF... more
Mammalian apolipoprotein B (apoB) mRNA editing is mediated by a multicomponent holoenzyme containing apobec-1 and ACF. We have now identified CUGBP2, a 54-kDa RNA-binding protein, as a component of this holoenzyme. CUGBP2 and ACF co-fractionate in bovine liver S-100 extracts, and addition of recombinant apobec-1 leads to assembly of a holoenzyme. Immunodepletion of CUGBP2 co-precipitates ACF, and these proteins co-localize the nucleus of transfected cells, suggesting that CUGBP2 and ACF are boundin vivo. CUGBP2 binds apoB RNA, specifically an AU-rich sequence located immediately upstream of the edited cytidine. ApoB RNA from McA cells, bound to CUGBP2, was more extensively edited than the unbound fraction. However, addition of recombinant CUGBP2 to a reconstituted system demonstrated a dose-dependent inhibition of C to U RNA editing, which was rescued with either apobec-1 or ACF. Antisense CUGBP2 knockout increased endogenous apoB RNA editing, whereas antisense knockout of either ap...
Research Interests: Fluorescence Microscopy, Biological Chemistry, Biological Sciences, Cell line, Liver, and 15 moreAnimals, Biological, Apolipoprotein B, CHEMICAL SCIENCES, Cattle, Molecular cloning, Cell nucleus, Rats, Glutathione Transferase, Base Sequence, Recombinant Proteins, Protein Binding, Cytoplasm, Molecular Sequence Data, and Medical and Health Sciences
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Previous European studies suggest NOD2/CARD15 and interleukin-23 receptor (IL-23R) donor or recipient variants are associated with adverse clinical outcomes in allogeneic hematopoietic stem cell transplantation. We reexamined these... more
Previous European studies suggest NOD2/CARD15 and interleukin-23 receptor (IL-23R) donor or recipient variants are associated with adverse clinical outcomes in allogeneic hematopoietic stem cell transplantation. We reexamined these findings as well as the role of another inflammatory bowel disease (IBD) susceptibility gene (immunity-related GTPase family, M [IRGM]) on transplantation outcomes in 390 US patients and their matched unrelated donors, accrued between 1995 and 2004. Patients received T-replete grafts with mostly myeloablative conditioning regimens. Multivariate analyses were performed for overall survival, disease-free survival, transplantation-related mortality, relapse, and acute and chronic graft-versus-host disease. Of 390 pairs, NOD2/CARD15 variant single nucleotide polymorphisms (SNPs) were found in 14% of donors and 17% of recipients. In 3% both donor and recipient had a mutant SNP. Thirteen percent of donors and 16% of recipients had variant IL23R SNPs, with 3% ha...
Research Interests: Adolescent, Inflammatory Bowel Disease, Humans, Child, Internal Medicine, and 15 moreChronic Disease, Female, Blood, Infant, Clinical Sciences, Adult, Biological markers, Gtp Binding Proteins, Inflammatory Bowel Diseases, Hematopoietic Stem Cell Transplantation, Acute Disease, Child preschool, Disease Free Survival, Cardiovascular medicine and haematology, and Hematologic neoplasms
Background High throughput parallel sequencing, RNA-Seq, has recently emerged as an appealing alternative to microarray in identifying differentially expressed genes (DEG) between biological groups. However, there still exists... more
Background High throughput parallel sequencing, RNA-Seq, has recently emerged as an appealing alternative to microarray in identifying differentially expressed genes (DEG) between biological groups. However, there still exists considerable discrepancy on gene expression measurements and DEG results between the two platforms. The objective of this study was to compare parallel paired-end RNA-Seq and microarray data generated on 5-azadeoxy-cytidine (5-Aza) treated HT-29 colon cancer cells with an additional simulation study. Methods We first performed general correlation analysis comparing gene expression profiles on both platforms. An Errors-In-Variables (EIV) regression model was subsequently applied to assess proportional and fixed biases between the two technologies. Then several existing algorithms, designed for DEG identification in RNA-Seq and microarray data, were applied to compare the cross-platform overlaps with respect to DEG lists, which were further validated using qRT-P...
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Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in vitro... more
Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in vitro RNA editing, A1cf–/– mice exhibited no change in apolipoproteinB (apoB) RNA editing, while Rbm47 mutant mice exhibited impaired intestinal RNA editing of apoB as well as other targets. Here we examined the role of A1CF and RBM47 in adult mouse liver and intestine, following deletion of either one or both gene products and also following forced (liver or intestinal) transgenic A1CF expression. There were minimal changes in hepatic and intestinal apoB RNA editing in A1cf–/– mice and no changes in either liver- or intestine-specific A1CF transgenic mice. Rbm47 liver-specific knockout (Rbm47LKO) mice demonstrated reduced editing in a subset (11 of 20) of RNA targets, including apoB. By contrast, apoB RNA editing was virtually eliminated (<6% activity...
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J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 0021-9738/96/08/1010/11 $2.00 Volume 98, Number 4, August 1996, 1010–1020 ... Enterocolitis and Colon Cancer in Interleukin-10–deficient Mice Are ...
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Pediatric short bowel syndrome (SBS) is a malabsorptive state placing patients at risk for malnutrition, dehydration, and bacterial overgrowth. These patients are often dependent on parenteral nutrition (PN) while intestinal adaptation is... more
Pediatric short bowel syndrome (SBS) is a malabsorptive state placing patients at risk for malnutrition, dehydration, and bacterial overgrowth. These patients are often dependent on parenteral nutrition (PN) while intestinal adaptation is underway. The aim of this study was to characterize the effect of remnant small bowel length on the gut microbiome. Further, we sought to examine the contribution of clinical and nutritional variables to the gut microbiota and anthropometric growth. Clinical data, anthropometrics, and fecal samples were collected from 14 SBS patients and 10 age- and sex-matched controls. Fecal bacterial DNA composition was analyzed using 16s ribosomal RNA gene sequencing. Statistical analysis was completed using the Mann-Whitney or Fisher's exact tests when applicable and linear mixed effect modeling. Distinct microbiota changes were found among those with the least remaining small bowel (<35 cm) compared with those with longer remaining bowel and controls. ...
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Hepatic stellate cell (HSC) activation occurs along with decreased Perilipin5 (Plin5) and liver fatty acid-binding protein (L-Fabp) expression and coincident lipid droplet (LD) depletion. Conversely, the activated phenotype is reversible... more
Hepatic stellate cell (HSC) activation occurs along with decreased Perilipin5 (Plin5) and liver fatty acid-binding protein (L-Fabp) expression and coincident lipid droplet (LD) depletion. Conversely, the activated phenotype is reversible in WT HSCs upon forced expression of Plin5. Here, we asked if L-Fabp expression is required for Plin5-mediated rescue of the quiescent phenotype. Lentiviral Plin5 transduction of passaged HSCs failed to reverse activation markers or restore lipogenic gene expression and LD formation. However, adenoviral L-Fabp infection of lentiviral Plin5 transduced HSCs restored both the quiescent phenotype and LD formation, an effect also mediated by adenoviral intestine-Fabp or adipocyte-Fabp. Expression of exogenous Plin5 in activated WT HSCs induced a transcriptional program of lipogenic gene expression including endogenous L-Fabp, but none of the other FABPs. We further demonstrated that selective, small molecule inhibition of endogenous L-Fabp also eliminate...