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Yang X.,Merck And Co. | Zhang B.,Merck And Co. | Molony C.,Merck And Co. | Chudin E.,Merck And Co. | And 17 more authors.
Genome Research | Year: 2010

Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s. © 2010 by Cold Spring Harbor Laboratory Press.


Jane Tseng Y.,National Taiwan University | Martin E.,Novartis | Bologa C.G.,University of New Mexico | Shelat A.A.,Saint Jude Childrens Research Hospital
Journal of Computer-Aided Molecular Design | Year: 2013

The "Cheminformatics aspects of high throughput screening (HTS): from robots to models" symposium was part of the computers in chemistry technical program at the American Chemical Society National Meeting in Denver, Colorado during the fall of 2011. This symposium brought together researchers from high throughput screening centers and molecular modelers from academia and industry to discuss the integration of currently available high throughput screening data and assays with computational analysis. The topics discussed at this symposium covered the data-infrastructure at various academic, hospital, and National Institutes of Health-funded high throughput screening centers, the cheminformatics and molecular modeling methods used in real world examples to guide screening and hit-finding, and how academic and non-profit organizations can benefit from current high throughput screening cheminformatics resources. Specifically, this article also covers the remarks and discussions in the open panel discussion of the symposium and summarizes the following talks on "Accurate Kinase virtual screening: biochemical, cellular and selectivity", "Selective, privileged and promiscuous chemical patterns in high-throughput screening" and "Visualizing and exploring relationships among HTS hits using network graphs". © 2013 Springer Science+Business Media Dordrecht.


Henry J.,University of Florida | Smeyne R.J.,Saint Jude Childrens Research Hospital | Jang H.,Saint Jude Childrens Research Hospital | Miller B.,University of Florida | Okun M.S.,University of Florida
Parkinsonism and Related Disorders | Year: 2010

Purpose: Given the recent paper by Jang et al. on "A Highly Pathogenic H5N1 Influenza Virus" which reported a novel animal model of parkinsonism, we aimed to perform a complete historical review of the 20th and 21st century literature on parkinsonism and neurological manifestations of influenza. Scope: There were at least twelve major flu pandemics reported in the literature in the 20th and 21st century. Neurological manifestations most prevalent during the pandemics included delirium, encephalitis, ocular abnormalities, amyotrophy, myelopathy, radiculopathy, ataxia and seizures. Very little parkinsonism was reported with the exception of the 1917 cases originally described by von Economo. Conclusions: To date there have been surprisingly few cases of neurological issues inclusive of parkinsonism associated with influenza pandemics. Given the recent animal model of H5N1 influenza associated parkinsonism, the medical establishment should be prepared to evaluate for the re-emergence of parkinsonism during future outbreaks. © 2010 Elsevier Ltd.


Gadd S.,Northwestern University | Huff V.,University of Houston | Huang C.-C.,Northwestern University | Cristy Ruteshouser E.,University of Houston | And 7 more authors.
Neoplasia (United States) | Year: 2012

Wilms tumors (WT) have provided broad insights into the interface between development and tumorigenesis. Further understanding is confounded by their genetic, histologic, and clinical heterogeneity, the basis of which remains largely unknown. We evaluated 224 WT for global gene expression patterns; WT1, CTNNB1, and WTX mutation; and 11p15 copy number and methylation patterns. Five subsets were identified showing distinct differences in their pathologic and clinical features: these findings were validated in 100 additional WT. The gene expression pattern of each subset was compared with published gene expression profiles during normal renal development. A novel subset of epithelial WT in infants lacked WT1, CTNNB1, and WTX mutations and nephrogenic rests and displayed a gene expression pattern of the postinduction nephron, and none recurred. Three subsets were characterized by a low expression of WT1 and intralobar nephrogenic rests. These differed in their frequency of WT1 and CTNNB1 mutations, in their age, in their relapse rate, and in their expression similarities with the intermediate mesoderm versus the metanephric mesenchyme. The largest subset was characterized by biallelic methylation of the imprint control region 1, a gene expression profile of the metanephric mesenchyme, and both interlunar and perilobar. © 2012 Neoplasia Press, Inc. All rights reserved.


Green D.M.,Saint Jude Childrens Research Hospital | Nolan V.G.,Saint Jude Childrens Research Hospital | Kawashima T.,Fred Hutchinson Cancer Research Center | Stovall M.,University of Texas M. D. Anderson Cancer Center | And 5 more authors.
Fertility and Sterility | Year: 2011

Objective: To evaluate the effect of hypothalamic/pituitary radiation (HPT RT) dose on the occurrence of first pregnancy. Design: Retrospective cohort study of childhood cancer 5-year survivors (CCS) diagnosed between 1970 and 1986 before 21 years of age at one of 26 North American pediatric cancer treatment centers. Setting: Self-administered questionnaire. Patient(s): A total of 3,619 female CCS who participated in the Childhood Cancer Survivor Study and received no or scatter (≤0.1 Gy) radiation to the ovaries and 2,081 female siblings (Sibs) of the participants. Intervention(s): None. Main Outcome Measure(s): Self-reported pregnancy events. Result(s): As a group, CCS were as likely to report being pregnant as Sibs (hazard ratio 1.07, 95% confidence interval 0.97-1.19). Multivariable models showed a significant decrease in the risk of pregnancy with HPT RT doses ≥22 Gy compared with those CCS receiving no HPT RT. Conclusion(s): These results support the hypothesis that exposures of 22-27 Gy HPT RT may be a contributing factor to infertility among female CCS. © 2011 by American Society for Reproductive Medicine.


Ramahi J.S.,Saint Jude Childrens Research Hospital | Solecki D.J.,Saint Jude Childrens Research Hospital
Advances in Experimental Medicine and Biology | Year: 2014

Proper migration of neurons is one of the most important aspects of early brain development. After neuronal progenitors are born in their respective germinal niches, they must migrate to their final locations to form precise neural circuits. A majority of migrating neurons move by associating and disassociating with glial fibers, which serve as scaffolding for the developing brain. Cerebellar granule neurons provide a model system for examination of the mechanisms of neuronal migration in dissociated and slice culture systems; the ability to purify these cells allows migration assays to be paired with genetic, molecular, and biochemical findings. CGNs migrate in a highly polarized fashion along radial glial fibers, using a two-stroke nucleokinesis cycle. The PAR polarity complex of PARD3, PARD6, and an atypical protein kinase C (aPKC) regulate several aspects of neuronal migration. The PAR polarity complex regulates the coordinated movements of the centrosome and soma during nucleokinesis, and also the stability of the microtubule cytoskeleton during migration. PAR proteins coordinate actomyosin dynamics in the leading process of migrating neurons, which are required for migration. The PAR complex also controls the cell-cell adhesions made by migrating neurons along glial cells, and through this mechanism regulates germinal zone exit during prenatal brain development. These findings suggest that the PAR complex coordinates the movement of multiple cellular elements as neurons migrate and that further examination of PAR complex effectors will not only provide novel insights to address fundamental challenges to the field but also expand our understanding of how the PAR complex functions at the molecular level. © Springer Science+Business Media Dordrecht 2014.


Jiao Y.,Saint Jude Childrens Research Hospital | Lu L.,University of Tennessee Health Science Center | Williams R.W.,University of Tennessee Health Science Center | Smeyne R.J.,Saint Jude Childrens Research Hospital
PLoS ONE | Year: 2012

The etiology of the vast majority of Parkinson's disease (PD) cases is unknown. It is generally accepted that there is an interaction between exposures to environmental agents with underlying genetic sensitivity. Recent epidemiological studies have shown that people living in agricultural communities have an increased risk of PD. Within these communities, paraquat (PQ) is one of the most utilized herbicides. PQ acts as a direct redox cycling agent to induce formation of free radicals and when administered to mice induces the cardinal symptoms of parkinsonism, including loss of TH+-positive dopaminergic (DA) neurons in the ventral midbrain's substantia nigra pars compacta (SNpc). Here we show that PQ-induced SNpc neuron loss is highly dependent on genetic background: C57BL/6J mice rapidly lose ~50% of their SNpc DA neurons, whereas inbred Swiss-Webster (SWR/J) mice do not show any significant loss. We intercrossed these two strains to map quantitative trait loci (QTLs) that underlie PQ-induced SNpc neuron loss. Using genome-wide linkage analysis we detected two significant QTLs. The first is located on chromosome 5 (Chr 5) centered near D5Mit338, whereas the second is on Chr 14 centered near D14Mit206. These two QTLs map to different loci than a previously identified QTL (Mptp1) that controls a significant portion of strain sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), suggesting that the mechanism of action of these two parkinsonian neurotoxins are different. © 2012 Jiao et al.


Bharatham N.,Saint Jude Childrens Research Hospital | Bharatham K.,Saint Jude Childrens Research Hospital | Shelat A.A.,Saint Jude Childrens Research Hospital | Bashford D.,Saint Jude Childrens Research Hospital
Journal of Chemical Information and Modeling | Year: 2014

The p53-binding domains of Mdm2 and Mdmx, two negative regulators of the tumor suppressor p53, are validated targets for cancer therapeutics, but correct binding poses of some proven inhibitors, particularly the nutlins, have been difficult to obtain with standard docking procedures. Virtual screening pipelines typically draw from a database of compounds represented with 1D or 2D structural information from which one or more 3D conformations must be generated. These conformations are then passed to a docking algorithm that searches for optimal binding poses on the target protein. This work tests alternative pipelines using several commonly used conformation generation programs (LigPrep, ConfGen, MacroModel, and Corina/Rotate) and docking programs (GOLD, Glide, MOE-dock, and AutoDock Vina) for their ability to reproduce known poses for a series of Mdmx and/or Mdm2 inhibitors, including several nutlins. Most combinations of these programs using default settings fail to find correct poses for the nutlins but succeed for all other compounds. Docking success for the nutlin class requires either computationally intensive conformational exploration or an "anchoring" procedure that incorporates knowledge of the orientation of the central imidazoline ring. © 2013 American Chemical Society.


Sadasivan S.,Saint Jude Childrens Research Hospital | Zanin M.,Saint Jude Childrens Research Hospital | O'Brien K.,Saint Jude Childrens Research Hospital | Schultz-Cherry S.,Saint Jude Childrens Research Hospital | Smeyne R.J.,Saint Jude Childrens Research Hospital
PLoS ONE | Year: 2015

Although influenza is primarily a respiratory disease, it has been shown, in some cases, to induce encephalitis, including people acutely infected with the pandemic A/California/04/ 2009 (CA/09) H1N1 virus. Based on previous studies showing that the highly pathogenic avian influenza (HPAI) A/Vietnam/1203/2004 H5N1 virus was neurotropic, induced CNS inflammation and a transient parkinsonism, we examined the neurotropic and inflammatory potential of the CA/09 H1N1 virus in mice. Following intranasal inoculation, we found no evidence for CA/09 H1N1 virus neurotropism in the enteric, peripheral or central nervous systems.We did, however, observe a robust increase in microglial activity in the brain characterized by an increase in the number of activated Iba-1-positive microglia in the substantia nigra (SN) and the hippocampus, despite the absence of virus in the brain. qPCR analysis in SN tissue showed that the induction of microgliosis was preceded by reduced gene expression of the neurotrophic factors bdnf, and gdnf and increases in the immune modulatory chemokine chemokine (C-C motif) ligand 4 (ccl4 ). We also noted changes in the expression of transforming growth factor-1 (tgfβ1) in the SN starting at 7 days post-infection (dpi) that was sustained through 21 dpi, coupled with increases in arginase-1 (arg1) and csf1, M2 markers for microglia. Given that neuroinflammation contributes to generation and progression of a number of neurodegenerative disorders, these findings have significant implications as they highlight the possibility that influenza and perhaps other non-neurotropic viruses can initiate inflammatory signals via microglia activation in the brain and contribute to, but not necessarily be the primary cause of, neurodegenerative disorders. © 2015 Sadasivan et al.


Feige M.J.,TU Munich | Hendershot L.M.,Saint Jude Childrens Research Hospital | Buchner J.,TU Munich
Trends in Biochemical Sciences | Year: 2010

B cells use unconventional strategies for the production of a seemingly unlimited number of antibodies from a very limited amount of DNA. These methods dramatically increase the likelihood of producing proteins that cannot fold or assemble appropriately. B cells are therefore particularly dependent on 'quality control' mechanisms to oversee antibody production. Recent in vitro experiments demonstrate that Ig domains have evolved diverse folding strategies ranging from robust spontaneous folding to intrinsically disordered domains that require assembly with their partner domains to fold; in vivo experiments reveal that these different folding characteristics form the basis for cellular checkpoints in Ig transport. Taken together, these reports provide a detailed understanding of how B cells monitor and ensure the functional fidelity of Ig proteins. © 2009 Elsevier Ltd.

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