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Search Results: 1 - 10 of 168502 matches for " Curtis E. Gumbs "
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Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene
Nara L. M. Sobreira equal contributor,Elizabeth T. Cirulli equal contributor,Dimitrios Avramopoulos equal contributor,Elizabeth Wohler,Gretchen L. Oswald,Eric L. Stevens,Dongliang Ge,Kevin V. Shianna,Jason P. Smith,Jessica M. Maia,Curtis E. Gumbs,Jonathan Pevsner,George Thomas,David Valle ?,Julie E. Hoover-Fong ?,David B. Goldstein ?
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000991
Abstract: Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.
The Characterization of Twenty Sequenced Human Genomes
Kimberly Pelak equal contributor,Kevin V. Shianna equal contributor,Dongliang Ge equal contributor,Jessica M. Maia,Mingfu Zhu,Jason P. Smith,Elizabeth T. Cirulli,Jacques Fellay,Samuel P. Dickson,Curtis E. Gumbs,Erin L. Heinzen,Anna C. Need,Elizabeth K. Ruzzo,Abanish Singh,C. Ryan Campbell,Linda K. Hong,Katharina A. Lornsen,Alexander M. McKenzie,Nara L. M. Sobreira,Julie E. Hoover-Fong,Joshua D. Milner,Ruth Ottman,Barton F. Haynes,James J. Goedert,David B. Goldstein
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001111
Abstract: We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten “case” genomes from individuals with severe hemophilia A and ten “control” genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.
A New Role for Clathrin Adaptor Proteins 1 and 3 in Lipoplex Trafficking
Justine E. Alford, Jade Gumbs, Emma C. Anderson
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091429
Abstract: Intracellular protein trafficking through secretory and endocytic pathways depends on the function of adaptor proteins that bind motifs on cargo proteins. The adaptor proteins then recruit coat proteins such as clathrin, enabling the formation of a transport vesicle. While studying the role of the clathrin adaptor proteins, AP-1, AP-2 and AP-3 in viral protein trafficking, we discovered that AP-1 and AP-3 potentially have a role in successful transfection of mammalian cells with DNA-liposome complexes (lipoplexes). We showed that AP-1, -2 and -3 are not required for lipoplexes to enter cells, but that lipoplexes and/or released DNA are unable to reach the nucleus in the absence of AP-1 or AP-3, leading to minimal exogenous gene expression. In contrast, gene expression from liposome-delivered mRNA, which does not require nuclear entry, was not impaired by the absence of AP-1 or AP-3. Despite the use of lipoplexes to mediate gene delivery being so widely used in cell biology and, more recently, gene therapy, the mechanism by which lipoplexes or DNA reach the nucleus is poorly characterised. This work sheds light on the components involved in this process, and demonstrates a novel role for AP-1 and AP-3 in trafficking lipoplexes.
Magnetoplasmons in layered graphene structures
Oleg L. Berman,Godfrey Gumbs,Yurii E. Lozovik
Physics , 2008, DOI: 10.1103/PhysRevB.78.085401
Abstract: We calculate the dispersion equations for magnetoplasmons in a single layer, a pair of parallel layers, a graphite bilayer and a superlattice of graphene layers in a perpendicular magnetic field. We demonstrate the feasibility of a drift-induced instability of magnetoplasmons. The magnetoplasmon instability in a superlattice is enhanced compared to a single graphene layer. The energies of the unstable magnetoplasmons could be in the terahertz (THz) part of the electromagnetic spectrum. The enhanced instability makes superlattice graphene a potential source of THz radiation.
Bose-Einstein condensation and Superfluidity of magnetoexcitons in Graphene
Oleg L. Berman,Yurii E. Lozovik,Godfrey Gumbs
Physics , 2007, DOI: 10.1103/PhysRevB.77.155433
Abstract: We propose experiments to observe Bose-Einstein condensation (BEC) and superfluidity of quasi-two-dimensional (2D) spatially indirect magnetoexcitons in bilayer graphene. The magnetic field $B$ is assumed strong. The energy spectrum of collective excitations, the sound spectrum as well as the effective magnetic mass of magnetoexcitons are presented in the strong magnetic field regime. The superfluid density $n_S$ and the temperature of the Kosterlitz-Thouless phase transition $T_c$ are shown to be increasing functions of the excitonic density $n$ but decreasing functions of $B$ and the interlayer separation $D$. Numerical results are presented from these calculations.
Common Genetic Variation and the Control of HIV-1 in Humans
Jacques Fellay equal contributor,Dongliang Ge equal contributor,Kevin V. Shianna,Sara Colombo,Bruno Ledergerber,Elizabeth T. Cirulli,Thomas J. Urban,Kunlin Zhang,Curtis E. Gumbs,Jason P. Smith,Antonella Castagna,Alessandro Cozzi-Lepri,Andrea De Luca,Philippa Easterbrook,Huldrych F. Günthard,Simon Mallal,Cristina Mussini,Judith Dalmau,Javier Martinez-Picado,José M. Miro,Niels Obel,Steven M. Wolinsky,Jeremy J. Martinson,Roger Detels,Joseph B. Margolick,Lisa P. Jacobson,Patrick Descombes,Stylianos E. Antonarakis,Jacques S. Beckmann,Stephen J. O'Brien,Norman L. Letvin,Andrew J. McMichael,Barton F. Haynes,Mary Carrington,Sheng Feng,Amalio Telenti ,David B. Goldstein ,NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000791
Abstract: To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.
Markers typed in genome-wide analysis identify regions showing deviation from Hardy-Weinberg equilibrium
Anna E Vine, David Curtis
BMC Research Notes , 2009, DOI: 10.1186/1756-0500-2-29
Abstract: We investigated genotypes from 463842 autosomal markers from 1504 British subjects. We identified regions in which several neighbouring markers exhibited deviation from HWE in the same direction by considering "heterozygosity scores" in windows of 10 markers. The heterozygosity score for each marker was defined as -log(p) or log(p) according to whether the marker demonstrated increased heterozygosity or homozygosity. In each window the marker with the highest absolute score was ignored and the positive and negative scores were summed for the other nine markers. Windows were selected on the basis of this sum exceeding a given threshold, for which we used values of 50 or 15.For the threshold of 50, we identified 7 regions with increased heterozygosity and for the threshold of 15 we identified 22 regions with increased heterozygosity, 23 with increased homozygosity and 2 containing both kinds of window. The most impressive of these results came from a group of 6 markers at 17q21, each of which showed increased heterozygosity significant at p < 10-190.The human genome contains regions which deviate markedly from HWE and these might harbour genes influencing embryonic survival.When marker allele frequencies in controls deviate markedly from Hardy-Weinberg equilibrium (HWE) this is commonly taken as an indicator that the genotyping is unreliable or that there is marked population stratification and the marker is discarded [1]. However if common polymorphisms influence embryonic survival then it is expected that these may also lead to such deviations. The existence of such loci is supported by a genome-wide tendency for siblings to share alleles more than would be expected by chance [2].As previously suggested, we reasoned that if groups of nearby markers all showed deviation from HWE then this could not result purely from genotyping errors since there would be no reason for the same kind of error to be replicated in each marker [3]. Hence we used the control data from the
Primal-Dual Active-Set Methods for Isotonic Regression and Trend Filtering
Zheng Han,Frank E. Curtis
Mathematics , 2015,
Abstract: Isotonic regression (IR) is a non-parametric calibration method used in supervised learning. For performing large-scale IR, we propose a primal-dual active-set (PDAS) algorithm which, in contrast to the state-of-the-art Pool Adjacent Violators (PAV) algorithm, can be parallized and is easily warm-started thus well-suited in the online settings. We prove that, like the PAV algorithm, our PDAS algorithm for IR is convergent and has a work complexity of O(n), though our numerical experiments suggest that our PDAS algorithm is often faster than PAV. In addition, we propose PDAS variants (with safeguarding to ensure convergence) for solving related trend filtering (TF) problems, providing the results of experiments to illustrate their effectiveness.
Epidural Analgesia Following Component Separation Hernia Repair: Is It Beneficial?  [PDF]
Emily L. Albright, Curtis E. Bower, Daniel L. Davenport, John S. Roth
Surgical Science (SS) , 2013, DOI: 10.4236/ss.2013.47062

Purpose: Optimal pain management strategies for patients undergoing component separation hernia repair are not defined. Epidural analgesia (EA) has been shown to decrease pulmonary complications and duration of ileus and to improve pain control in other patient populations. In this study we examined outcomes of patients receiving EA after separation of components (SOC). Methods: After obtaining IRB approval, a retrospective review was performed of patients undergoing ventral hernia repair with SOC from January 2006 to October 2010 at the University of Kentucky. Patients were identified from hospital operative records. Pre-operative patient characteristics and operative data were obtained from the medical record. Information was collected relating to use of EA, complications, and length of hospitalization (LOS). Post-operative outcomes were compared between those that had epidurals and those that did not. Results: One hundred seventeen patients were identified that underwent SOC, 34 of whom had EA. These two groups were similar in relation to age, BMI, and co-morbidities. Three patients in the epidural group had complications limiting epidural durationtwo with hypotension and one with refractory pruritus. There was no difference in pneumonia, deep vein thrombosis (DVT), wound infection, urinary tract infection (UTI), recurrence, or mortality (Table 1). There was an increase in LOS (6.68 vs. 6.06 days, p < 0.01) in patients with EA. Conclusions: The use of EA results in increased LOS in patients undergoing SOC. EA associated morbidity occurs infrequently. The incidence of post-operative complications is unaffected by EA. Further studies are needed to delineate the benefit of EA in this patient population.

Immune response to sympatric and allopatric parasites in a snail-trematode interaction
Erik E Osnas, Curtis M Lively
Frontiers in Zoology , 2005, DOI: 10.1186/1742-9994-2-8
Abstract: We found that infection was greater in sympatric host-parasite combinations. We also found that the host-defense response (hemocyte concentration) was induced by parasite exposure, but the response did not increase with increased parasite dose nor did it depend on parasite source, host source, or host-parasite combination.The results are consistent with a genetically specific host-parasite interaction, but inconsistent with a general arms-race type interaction where allocation to defense is the main determinant of host resistance.Studies of host-parasite interactions can be seen as split between two different approaches [1,2]. One approach tends to emphasize the induction and cost of defense against parasites, while the other approach tends to emphasize the genetic basis and specificity required for successful infection. Both avenues have been productive, but they need not be seen as mutually exclusive [1-3]. The induction of an immune defense, for example, might be required to eliminate parasites once detected by the host [4]. On the other hand, the relative effectiveness of host defense is expected to decline as the diversity of parasite genotypes increases, provided these genotypes show a high degree of host specificity [1]. Understanding the relative importance and possible interactions between immune defense and genotypic specificity requires that both aspects are studied simultaneously in the same system. For example, Kurtz et al. [5] showed that the immune response of grasshoppers was reduced in foreign environments, even though body mass, a measure of general condition, was not reduced. They interpreted this to mean that the grasshoppers require less immune defense in the face of foreign, and presumably locally adapted, parasites. In order to more fully address the interaction between genetic specificity and immune defense, one could first test for local adaptation, and then measure the immune response in both sympatric and allopatric host-parasite combinati
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