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Search Results: 1 - 10 of 210270 matches for " Mitchell L. Drumm "
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Modifier genes and variation in cystic fibrosis
Mitchell L Drumm
Respiratory Research , 2001, DOI: 10.1186/rr47
Abstract: Rozmahel et al [1] reported, in 1996, that the lethality associated with a knockout allele of the murine cystic fibrosis transmembrane conductance regulator (CFTR) could be modified by different strain backgrounds. They genetically mapped a locus conferring the modifying effect to chromosome 7. Because the predominant manifestation of disrupting CFTR in the mouse is intestinal obstruction, a feature of cystic fibrosis (CF) in humans, a region of the human genome on chromosome 19 corresponding to the mouse locus was tracked in siblings with CF. Zielenski et al [2] thus found the occurrence or absence of meconium ileus, a perinatal form of intestinal obstruction, coincided with haplotypes of chromosome 19 inherited by the siblings. This coincidence implied that the gene conferring resistance or susceptibility to intestinal obstruction in mice is also polymorphic in humans, and that those polymorphisms have a similar effect on CF patients to that which strain variants of these genes have on CF mice.Whereas the identity of the gene, or genes, responsible for this phenomenon has not yet been determined, this study illustrates several important points. Firstly, it demonstrates that some of the clinical variation between CF patients is genetic, but conferred by genes other than that for CFTR. It importantly also indicates that relatively common genetic variation, with little or no overt phenotypic effect on the general population, can have a significant effect in the context of CF.This is an important precedent for CF, but the effect of this particular locus seems restricted to the gut. CF, however, involves multiple organs whose common feature is epithelium expressing CFTR, and most morbidity and mortality is due to the complications in the respiratory tract. Decreased mucociliary clearance, viscous secretions and glandular plugging by these secretions, and altered ion transport are all thought to contribute to the milieu that allows colonization by opportunistic species
Genetic Influences on Cystic Fibrosis Lung Disease Severity
Colleen A. Weiler,Mitchell L. Drumm
Frontiers in Pharmacology , 2013, DOI: 10.3389/fphar.2013.00040
Abstract: Understanding the causes of variation in clinical manifestations of disease should allow for design of new or improved therapeutic strategies to treat the disease. If variation is caused by genetic differences between individuals, identifying the genes involved should present therapeutic targets, either in the proteins encoded by those genes or the pathways in which they function. The technology to identify and genotype the millions of variants present in the human genome has evolved rapidly over the past two decades. Originally only a small number of polymorphisms in a small number of subjects could be studied realistically, but speed and scope have increased nearly as dramatically as cost has decreased, making it feasible to determine genotypes of hundreds of thousands of polymorphisms in thousands of subjects. The use of such genetic technology has been applied to cystic fibrosis (CF) to identify genetic variation that alters the outcome of this single gene disorder. Candidate gene strategies to identify these variants, referred to as “modifier genes,” has yielded several genes that act in pathways known to be important in CF and for these the clinical implications are relatively clear. More recently, whole-genome surveys that probe hundreds of thousands of variants have been carried out and have identified genes and chromosomal regions for which a role in CF is not at all clear. Identification of these genes is exciting, as it provides the possibility for new areas of therapeutic development.
ADEMA: An Algorithm to Determine Expected Metabolite Level Alterations Using Mutual Information
A. Ercument Cicek ,Ilya Bederman,Leigh Henderson,Mitchell L. Drumm,Gultekin Ozsoyoglu
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1002859
Abstract: Metabolomics is a relatively new “omics” platform, which analyzes a discrete set of metabolites detected in bio-fluids or tissue samples of organisms. It has been used in a diverse array of studies to detect biomarkers and to determine activity rates for pathways based on changes due to disease or drugs. Recent improvements in analytical methodology and large sample throughput allow for creation of large datasets of metabolites that reflect changes in metabolic dynamics due to disease or a perturbation in the metabolic network. However, current methods of comprehensive analyses of large metabolic datasets (metabolomics) are limited, unlike other “omics” approaches where complex techniques for analyzing coexpression/coregulation of multiple variables are applied. This paper discusses the shortcomings of current metabolomics data analysis techniques, and proposes a new multivariate technique (ADEMA) based on mutual information to identify expected metabolite level changes with respect to a specific condition. We show that ADEMA better predicts De Novo Lipogenesis pathway metabolite level changes in samples with Cystic Fibrosis (CF) than prediction based on the significance of individual metabolite level changes. We also applied ADEMA's classification scheme on three different cohorts of CF and wildtype mice. ADEMA was able to predict whether an unknown mouse has a CF or a wildtype genotype with 1.0, 0.84, and 0.9 accuracy for each respective dataset. ADEMA results had up to 31% higher accuracy as compared to other classification algorithms. In conclusion, ADEMA advances the state-of-the-art in metabolomics analysis, by providing accurate and interpretable classification results.
Histo-Blood Group Gene Polymorphisms as Potential Genetic Modifiers of Infection and Cystic Fibrosis Lung Disease Severity
Jennifer L. Taylor-Cousar, Maimoona A. Zariwala, Lauranell H. Burch, Rhonda G. Pace, Mitchell L. Drumm, Hollin Calloway, Haiying Fan, Brent W. Weston, Fred A. Wright, Michael R. Knowles, for the Gene Modifier Study Group
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004270
Abstract: Background The pulmonary phenotype in cystic fibrosis (CF) is variable; thus, environmental and genetic factors likely contribute to clinical heterogeneity. We hypothesized that genetically determined ABO histo-blood group antigen (ABH) differences in glycosylation may lead to differences in microbial binding by airway mucus, and thus predispose to early lung infection and more severe lung disease in a subset of patients with CF. Methods and Principal Findings Clinical information and DNA was collected on >800 patients with the ΔF508/ΔF508 genotype. Patients in the most severe and mildest quartiles for lung phenotype were enrolled. Blood samples underwent lymphocyte transformation and DNA extraction using standard methods. PCR and sequencing were performed using standard techniques to identify the 9 SNPs required to determine ABO blood type, and to identify the four SNPs that account for 90–95% of Lewis status in Caucasians. Allele identification of the one nonsynonymous SNP in FUT2 that accounts for >95% of the incidence of nonsecretor phenotype in Caucasians was completed using an ABI Taqman assay. The overall prevalence of ABO types, and of FUT2 (secretor) and FUT 3 (Lewis) alleles was consistent with that found in the Caucasian population. There was no difference in distribution of ABH type in the severe versus mild patients, or the age of onset of Pseudomonas aeruginosa infection in the severe or mild groups. Multivariate analyses of other clinical phenotypes, including gender, asthma, and meconium ileus demonstrated no differences between groups based on ABH type. Conclusions and Significance Polymorphisms in the genes encoding ABO blood type, secretor or Lewis genotypes were not shown to associate with severity of CF lung disease, or age of onset of P. aeruginosa infection, nor was there any association with other clinical phenotypes in a group of 808 patients homozygous for the ΔF508 mutation.
Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis
Lindsay B. Henderson,Vishal K. Doshi,Scott M. Blackman,Kathleen M. Naughton,Rhonda G. Pace,Jackob Moskovitz,Michael R. Knowles,Peter R. Durie,Mitchell L. Drumm,Garry R. Cutting
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002580
Abstract: Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI (P = 1.99×10?5 to 1.08×10?6; Bonferroni P = 0.057 to 3.1×10?3). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2×10?4). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr?/? and Cftr?/?Msra?/? mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.
Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC
XueLiang Guo, Rhonda G. Pace, Jaclyn R. Stonebraker, Clayton W. Commander, Anthony T. Dang, Mitchell L. Drumm, Ann Harris, Fei Zou, Dallas M. Swallow, Fred A. Wright, Wanda K. O'Neal, Michael R. Knowles
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025452
Abstract: Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2×10?4 after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.
Mice: The International Muon Ionisation Cooling Experiment
P. Drumm
Physics , 2005,
Abstract: Muon storage rings have been proposed for use as sources of intense high-energy neutrino beams and as the basis for muon colliders. Phase-space compression (cooling) of the muon beam prior to acceleration and storage is needed to optimise performance and cost. Traditional techniques cannot be employed to cool the beam because of decay during the short muon lifetime. Ionisation cooling, a process in which the muon beam is passed through an alternating series of liquid-hydrogen absorbers and accelerating RF-cavities, is the technique proposed to cool the muon beam. An international collaboration has been formed to carry out the Muon Ionisation Cooling Experiment (MICE), and its proposal to Rutherford Appleton Laboratory (RAL) has been approved. The status of the MICE cooling channel, the instrumentation, and the implementation at RAL are described, together with the predicted performance of the channel and the measurements that will be made.
Thermodynamic stability of neutral Xe defects in diamond
D. W. Drumm,M. C. Per,S. P. Russo,L. C. L. Hollenberg
Physics , 2012, DOI: 10.1103/PhysRevB.82.054102
Abstract: Optically active defect centers in diamond are of considerable interest, and ab initio calculations have provided valuable insight into the physics of these systems. Candidate structures for the Xe center in diamond, for which little structural information is known, are modeled using density functional theory. The relative thermodynamic stabilities were calculated for two likely structural arrangements. The split-vacancy structure is found to be the most stable for all temperatures up to 1500 K. A vibrational analysis was also carried out, predicting Raman- and IR-active modes which may aid in distinguishing between center structures.
Ab initio calculation of valley splitting in monolayer delta-doped phosphorus in silicon
Daniel W Drumm, Akin Budi, Manolo C Per, Salvy P Russo and Lloyd C L Hollenberg
Nanoscale Research Letters , 2013, DOI: 10.1186/1556-276X-8-111
Abstract: The differences in energy between electronic bands due to valley splitting are of paramount importance in interpreting transport spectroscopy experiments on state-of-the-art quantum devices defined by scanning tunnelling microscope lithography. Using VASP, we develop a plane-wave density functional theory description of systems which is size limited due to computational tractability. Nonetheless, we provide valuable data for the benchmarking of empirical modelling techniques more capable of extending this discussion to confined disordered systems or actual devices. We then develop a less resource-intensive alternative via localised basis functions in SIESTA, retaining the physics of the plane-wave description, and extend this model beyond the capability of plane-wave methods to determine the ab initio valley splitting of well-isolated delta-layers. In obtaining an agreement between plane-wave and localised methods, we show that valley splitting has been overestimated in previous ab initio calculations by more than 50%.
Effective mass theory of monolayer δ-doping in the high-density limit
Daniel W. Drumm,Lloyd C. L. Hollenberg,Michelle Y. Simmons,Mark Friesen
Physics , 2012, DOI: 10.1103/PhysRevB.85.155419
Abstract: Monolayer \delta-doped structures in silicon have attracted renewed interest with their recent incorporation into atomic-scale device fabrication strategies as source and drain electrodes and in-plane gates. Modeling the physics of \delta-doping at this scale proves challenging, however, due to the large computational overhead associated with ab initio and atomistic methods. Here, we develop an analytical theory based on an effective mass approximation. We specifically consider the Si:P materials system, and the limit of high donor density, which has been the subject of recent experiments. In this case, metallic behavior including screening tends to smooth out the local disorder potential associated with random dopant placement. While smooth potentials may be difficult to incorporate into microscopic, single-electron analyses, the problem is easily treated in the effective mass theory by means of a jellium approximation for the ionic charge. We then go beyond the analytic model, incorporating exchange and correlation effects within a simple numerical model. We argue that such an approach is appropriate for describing realistic, high-density, highly disordered devices, providing results comparable to density functional theory, but with greater intuitive appeal, and lower computational effort. We investigate valley coupling in these structures, finding that valley splitting in the low-lying \Gamma band grows much more quickly than the \Gamma-\Delta band splitting at high densities. We also find that many-body exchange and correlation corrections affect the valley splitting more strongly than they affect the band splitting.
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