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1

HERG1 channelopathies  

PubMed Central

Human ether a go-go-related gene type 1 (hERG1) K+ channels conduct the rapid delayed rectifier K+ current and mediate action potential repolarization in the heart. Mutations in KCNH2 (the gene that encodes hERG1) causes LQT2, one of the most common forms of long QT syndrome, a disorder of cardiac repolarization that predisposes affected subjects to ventricular arrhythmia and increases the risk of sudden cardiac death. Hundreds of LQT2-associated mutations have been described, and most cause a loss of function by disrupting subunit folding, assembly, or trafficking of the channel to the cell surface. Loss-of-function mutations in hERG1 channels have also recently been implicated in epilepsy. A single gain-of-function mutation has been described that causes short QT syndrome and cardiac arrhythmia. In addition, up-regulation of hERG1 channel expression has been demonstrated in specific tumors and has been associated with skeletal muscle atrophy in mice. PMID:20544339

2009-01-01

2

Molecular Determinants of Human ether-à-go-go-Related Gene 1 (hERG1) K+ Channel Activation by NS1643  

PubMed Central

Human ether-à-go-go-related gene 1 (hERG1) channels conduct the rapid delayed rectifier K+ current, IKr, an important determinant of action potential repolarization in mammals, including humans. Reduced IKr function caused by mutations in KCNH2 or drug block of hERG1 channels prolongs the QT interval of the electrocardiogram and increases the risk of ventricular fibrillation and sudden cardiac death. Several activators of hERG1 channels have been discovered in recent years. These compounds shorten the duration of cardiac action potentials and have been proposed as a new therapeutic approach for the treatment of acquired or congenital long QT syndrome. We defined previously the mechanism of action of 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643), a compound that increases hERG1 currents by shifting the voltage-dependence of inactivation to more positive potentials. Here, we use scanning mutagenesis of hERG1 and functional characterization of 56 mutant channels heterologously expressed in Xenopus laevis oocytes to define the molecular determinants of the binding site for NS1643. Most point mutations did not alter response to the drug; however, 10 mutant channels had reduced sensitivity, and F619A and I567A exhibited enhanced activation by the drug. Some of these residues form a cluster and, together with molecular modeling, suggest that NS1643 binds to a pocket near the extracellular ends of the S5/S6 segments of two adjacent hERG1 channel subunits. This putative binding site differs from the sites described previously for two other hERG1 activators, (3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) and 2-(4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino)-benzoic acid (PD-118057). PMID:20876384

Abbruzzese, Jennifer; Sachse, Frank B.; Sanguinetti, Michael C.

2011-01-01

3

Long-term channel block is required to inhibit cellular transformation by human ether-à-go-go-related gene (hERG1) potassium channels.  

PubMed

Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (hEAG1) channel are aberrantly expressed in a large proportion of human cancers. In the present study, we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malignant transformation. An important finding of this work is that this transformation could be reversed by chronic incubation (for 2-3 weeks) with the hERG channel blocker dofetilide (100 nM), whereas more acute applications (for 1-2 days) were ineffective. The hERG1 expression resulted in a profound loss of cell contact inhibition, multiple layers of overgrowing cells, and high saturation densities. Cells also changed from fibroblast-like to a more spindle-shaped morphology, which was associated with a smaller cell size, a dramatic increase in cell polarization, a reduction in the number of actin stress fibers, and less punctate labeling of focal adhesions. Analysis of single-cell migration and scratch-wound closure clearly demonstrated that hERG1-expressing cells migrated more rapidly than vector-transfected control cells. In contrast to previous studies on hEAG1, there were no increases in rates of proliferation, or loss of growth factor dependency; however, hERG1-expressing cells were capable of substrate-independent growth. Allogeneic transplantation of hERG1-expressing cells into nude mice resulted in an increased incidence of tumors. In contrast to hEAG1, the mechanism of cellular transformation is dependent on ion conduction. Trafficking-deficient and conduction-deficient hERG1 mutants also prevented cellular transformation. These results provide evidence that hERG1 expression is sufficient to induce cellular transformation by a mechanism distinct from hEAG1. The most important conclusion of this study is that selective hERG1 channel blockers have therapeutic potential in the treatment of hERG1-expressing cancers. PMID:24830940

Pier, David M; Shehatou, George S G; Giblett, Susan; Pullar, Christine E; Trezise, Derek J; Pritchard, Catrin A; Challiss, R A John; Mitcheson, John S

2014-08-01

4

Long-Term Channel Block Is Required to Inhibit Cellular Transformation by Human Ether-à-Go-Go–Related Gene (hERG1) Potassium Channels  

PubMed Central

Both human ether-à-go-go–related gene (hERG1) and the closely related human ether-à-go-go (hEAG1) channel are aberrantly expressed in a large proportion of human cancers. In the present study, we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malignant transformation. An important finding of this work is that this transformation could be reversed by chronic incubation (for 2–3 weeks) with the hERG channel blocker dofetilide (100 nM), whereas more acute applications (for 1–2 days) were ineffective. The hERG1 expression resulted in a profound loss of cell contact inhibition, multiple layers of overgrowing cells, and high saturation densities. Cells also changed from fibroblast-like to a more spindle-shaped morphology, which was associated with a smaller cell size, a dramatic increase in cell polarization, a reduction in the number of actin stress fibers, and less punctate labeling of focal adhesions. Analysis of single-cell migration and scratch-wound closure clearly demonstrated that hERG1-expressing cells migrated more rapidly than vector-transfected control cells. In contrast to previous studies on hEAG1, there were no increases in rates of proliferation, or loss of growth factor dependency; however, hERG1-expressing cells were capable of substrate-independent growth. Allogeneic transplantation of hERG1-expressing cells into nude mice resulted in an increased incidence of tumors. In contrast to hEAG1, the mechanism of cellular transformation is dependent on ion conduction. Trafficking-deficient and conduction-deficient hERG1 mutants also prevented cellular transformation. These results provide evidence that hERG1 expression is sufficient to induce cellular transformation by a mechanism distinct from hEAG1. The most important conclusion of this study is that selective hERG1 channel blockers have therapeutic potential in the treatment of hERG1-expressing cancers. PMID:24830940

Pier, David M.; Shehatou, George S. G.; Giblett, Susan; Pullar, Christine E.; Trezise, Derek J.; Pritchard, Catrin A.; Challiss, R. A. John

2014-01-01

5

Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators  

PubMed Central

One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K+, Ca2+ and Na+ currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4–S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs. PMID:25191697

Perissinotti, Laura L.; Hargreaves, Jason M.; Back, Thomas G.; Noskov, Sergei Y.; Duff, Henry J.

2014-01-01

6

The amiodarone derivative KB130015 activates hERG1 potassium channels via a novel mechanism.  

PubMed

Human ether à go-go related gene (hERG1) potassium channels underlie the repolarizing I(Kr) current in the heart. Since they are targets of various drugs with cardiac side effects we tested whether the amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) blocks hERG1 channels like its parent compound. Using patch-clamp and two-electrode voltage-clamp techniques we found that KB130015 blocks native and recombinant hERG1 channels at high voltages, but it activates them at low voltages. The activating effect has an apparent EC(50) value of 12microM and is brought about by an about 4-fold acceleration of activation kinetics and a shift in voltage-dependent activation by -16mV. Channel activation was not use-dependent and was independent of inactivation gating. KB130015 presumably binds to the hERG1 pore from the cytosolic side and functionally competes with hERG1 block by amiodarone, E4031 (N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl] carbonyl] phenyl] methanesulfonamide dihydrochloride), and sertindole. Vice versa, amiodarone attenuates hERG1 activation by KB130015. Based on synergic channel activation by mallotoxin and KB130015 we conclude that the hERG1 pore contains at least two sites for activators that are functionally coupled among each other and to the cavity-blocker site. KB130015 and amiodarone may serve as lead structures for the identification of hERG1 pore-interacting drugs favoring channel activation vs. block. PMID:20097192

Gessner, Guido; Macianskiene, Regina; Starkus, John G; Schönherr, Roland; Heinemann, Stefan H

2010-04-25

7

A novel, primate-specific, brain isoform of KCNH2 impacts cortical physiology, cognition, neuronal repolarization and risk for schizophrenia  

PubMed Central

Organized neuronal firing is critical for cortical processing and is disrupted in schizophrenia. Using 5’ RACE in human brain, we identified a primate-specific isoform (3.1) of the K+-channel KCNH2 that modulates neuronal firing. KCNH2-3.1 mRNA levels are comparable to KCNH2-1A in brain, but 1000-fold lower in heart. In schizophrenic hippocampus, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A. A meta-analysis of 5 clinical samples (367 families, 1158 unrelated cases, 1704 controls) shows association of SNPs in KCNH2 with schizophrenia. Risk-associated alleles predict lower IQ scores and speed of cognitive processing, altered memory-linked fMRI signals, and increased KCNH2-3.1 expression in post-mortem hippocampus. KCNH2-3.1 lacks a domain critical for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, non-adapting firing pattern. These results identify a novel KCNH2 channel involved in cortical physiology, cognition, and psychosis, providing a potential new psychotherapeutic drug target. PMID:19412172

Huffaker, Stephen J.; Chen, Jingshan; Nicodemus, Kristin K.; Sambataro, Fabio; Yang, Feng; Mattay, Venkata; Lipska, Barbara K.; Hyde, Thomas M.; Song, Jian; Rujescu, Daniel; Giegling, Ina; Mayilyan, Karine; Proust, Morgan J.; Soghoyan, Armen; Caforio, Grazia; Callicott, Joseph H.; Bertolino, Alessandro; Meyer-Lindenberg, Andreas; Chang, Jay; Ji, Yuanyuan; Egan, Michael F.; Goldberg, Terry E.; Kleinman, Joel E.; Lu, Bai; Weinberger, Daniel R.

2009-01-01

8

Inhibition of HERG1 K+ channels by the novel second-generation antihistamine mizolastine  

PubMed Central

Ventricular arrhythmias are rare but life-threatening side effects of therapy with the second-generation H1 receptor antagonists terfenadine and astemizole. Blockade of the K+ channels encoded by the Human Ether-à-go-go-Related Gene 1 (HERG1) K+ channels, which is the molecular basis of the cardiac repolarizing current IKr, by prolonging cardiac repolarization, has been recognized as the mechanism underlying the cardiac toxicity of these compounds.In the present study, the potential blocking ability of the novel second-generation H1 receptor antagonist mizolastine of the HERG1 K+ channels heterologously expressed in Xenopus oocytes and in HEK 293 cells or constitutively present in SH-SY5Y human neuroblastoma cells has been examined and compared to that of astemizole.Mizolastine blocked HERG1 K+ channels expressed in Xenopus oocytes with an estimated IC50 of 3.4??M. Mizolastine blockade was characterized by a fast dissociation rate when compared to that of astemizole; when fitted to a monoexponential function, the time constants for drug dissociation from the K+ channel were 72.4±11.9?s for 3??M mizolastine, and 1361±306?s for 1??M astemizole.In human embryonic kidney 293 cells (HEK 293 cells) stably transfected with HERG1 cDNA, extracellular application of mizolastine exerted a dose-related inhibitory action on IHERG1, with an IC50 of 350±76?nM. Furthermore, mizolastine dose-dependently inhibited HERG1 K+ channels constitutively expressed in SH-SY5Y human neuroblastoma clonal cells.The results of the present study suggest that the novel second-generation H1 receptor antagonist mizolastine, in concentrations higher than those achieved in vivo during standard therapy, is able to block in some degree both constitutively and heterologously expressed HERG1 K+ channels, and confirm the heterogeneity of molecules belonging to this therapeutical class with respect to their HERG1-inhibitory action. PMID:11082114

Taglialatela, Maurizio; Pannaccione, Anna; Castaldo, Pasqualina; Giorgio, Giovanna; Annunziato, Lucio

2000-01-01

9

Stoichiometry of altered hERG1 channel gating by small molecule activators  

PubMed Central

Voltage-gated K+ channels are tetramers formed by coassembly of four identical or highly related subunits. All four subunits contribute to formation of the selectivity filter, the narrowest region of the channel pore which determines K+ selective conductance. In some K+ channels, the selectivity filter can undergo a conformational change to reduce K+ flux by a mechanism called C-type inactivation. In human ether-a-go-go–related gene 1 (hERG1) K+ channels, C-type inactivation is allosterically inhibited by ICA-105574, a substituted benzamide. PD-118057, a 2-(phenylamino) benzoic acid, alters selectivity filter gating to enhance open probability of channels. Both compounds bind to a hydrophobic pocket located between adjacent hERG1 subunits. Accordingly, a homotetrameric channel contains four identical activator binding sites. Here we determine the number of binding sites required for maximal drug effect and determine the role of subunit interactions in the modulation of hERG1 gating by these compounds. Concatenated tetramers were constructed to contain a variable number (zero to four) of wild-type and mutant hERG1 subunits, either L646E to inhibit PD-118057 binding or F557L to inhibit ICA-105574 binding. Enhancement of hERG1 channel current magnitude by PD-118057 and attenuated inactivation by ICA-105574 were mediated by cooperative subunit interactions. Maximal effects of the both compounds required the presence of all four binding sites. Understanding how hERG1 agonists allosterically modify channel gating may facilitate mechanism-based drug design of novel agents for treatment of long QT syndrome. PMID:24638994

Wu, Wei; Sachse, Frank B.; Gardner, Alison

2014-01-01

10

Concatenated hERG1 Tetramers Reveal Stoichiometry of Altered Channel Gating by RPR-260243.  

PubMed

Activation of human ether-a-go-go-related gene 1 (hERG1) K(+) channels mediates repolarization of action potentials in cardiomyocytes. RPR-260243 [(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid] (RPR) slows deactivation and attenuates inactivation of hERG1 channels. A detailed understanding of the molecular mechanism of hERG1 agonists such as RPR may facilitate the design of more selective and potent compounds for prevention of arrhythmia associated with abnormally prolonged ventricular repolarization. RPR binds to a hydrophobic pocket located between two adjacent hERG1 subunits, and, hence, a homotetrameric channel has four identical RPR binding sites. To investigate the stoichiometry of altered channel gating induced by RPR, we constructed and characterized tetrameric hERG1 concatemers containing a variable number of wild-type subunits and subunits containing a point mutation (L553A) that rendered the channel insensitive to RPR, ostensibly by preventing ligand binding. The slowing of deactivation by RPR was proportional to the number of wild-type subunits incorporated into a concatenated tetrameric channel, and four wild-type subunits were required to achieve maximal slowing of deactivation. In contrast, a single wild-type subunit within a concatenated tetramer was sufficient to achieve half of the maximal RPR-induced shift in the voltage dependence of hERG1 inactivation, and maximal effect was achieved in channels containing three or four wild-type subunits. Together our findings suggest that the allosteric modulation of channel gating involves distinct mechanisms of coupling between drug binding and altered deactivation and inactivation. PMID:25519838

Wu, Wei; Gardner, Alison; Sanguinetti, Michael C

2015-03-01

11

PD-118057 contacts the pore helix of hERG1 channels to attenuate inactivation and enhance K+ conductance  

PubMed Central

Human ether-a-go-go-related gene 1 (hERG1) K+ channels mediate repolarization of cardiac action potentials. Unintended block of hERG1 channels by some drugs can prolong the QT interval and induce arrhythmia. Recently, hERG1 channel agonists were discovered and, based on their mechanisms of action can be classified into two types. RPR260243 [(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5 trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid], a type 1 agonist, binds to residues located near the intracellular end of S5 and S6 transmembrane segments and activates hERG1 channels by a dual mechanism of slowed deactivation and attenuated P-type inactivation. As defined here, type 2 agonists such as PD-118057 [2-(4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino)-benzoic acid] attenuate inactivation but do not slow deactivation. At 10 ?M, PD-118057 shifted the half-point for inactivation of wild-type hERG1 channels by +19 mV and increased peak outward current by 136%. Scanning mutagenesis and functional characterization of 44 mutant channels expressed in Xenopus oocytes was used to identify the major structural determinants of the binding site for PD-118057. Single mutations of residues in the pore helix (F619) or the S6 segment (L646) of hERG1 eliminated agonist activity. Mutation of a nearby residues in the S6 segment (C643, M645) enhanced drug activity, presumably by reducing steric hindrance for drug binding. Molecular modeling indicates that PD-118057 binds to a hydrophobic pocket formed by L646 of one hERG1 subunit and F619 of an adjacent subunit. We conclude that direct interaction of PD-118057 with the pore helix attenuates fast P-type inactivation and increases open probability of hERG1 channels. PMID:19892732

Perry, Matthew; Sachse, Frank B.; Abbruzzese, Jennifer; Sanguinetti, Michael C.

2009-01-01

12

Elevated Heart Rate Triggers Action Potential Alternans and Sudden Death. Translational Study of a Homozygous KCNH2 Mutation  

PubMed Central

Background Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed “human HERG knockout” and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. Methods and Results Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ?506 ms with notched T waves). Parents were I° cousins – both heterozygous for the mutation and clinically unremarkable (QTc ?447 ms, father and ?396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. Conclusion Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates. PMID:25140878

Marschall, Christoph; Takac, Ina; Brandes, Ralf P.; Kotzot, Dieter; Girmatsion, Zenawit; Hohnloser, Stefan H.; Ehrlich, Joachim R.

2014-01-01

13

Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome  

PubMed Central

Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype. PMID:24213244

Bellin, Milena; Casini, Simona; Davis, Richard P; D'Aniello, Cristina; Haas, Jessica; Ward-van Oostwaard, Dorien; Tertoolen, Leon G J; Jung, Christian B; Elliott, David A; Welling, Andrea; Laugwitz, Karl-Ludwig; Moretti, Alessandra; Mummery, Christine L

2013-01-01

14

Modification of hERG1 channel gating by Cd2+  

PubMed Central

Each of the four subunits in a voltage-gated potassium channel has a voltage sensor domain (VSD) that is formed by four transmembrane helical segments (S1–S4). In response to changes in membrane potential, intramembrane displacement of basic residues in S4 produces a gating current. As S4 moves through the membrane, its basic residues also form sequential electrostatic interactions with acidic residues in immobile regions of the S2 and S3 segments. Transition metal cations interact with these same acidic residues and modify channel gating. In human ether-á-go-go–related gene type 1 (hERG1) channels, Cd2+ coordinated by D456 and D460 in S2 and D509 in S3 induces a positive shift in the voltage dependence of activation of ionic currents. Here, we characterize the effects of Cd2+ on hERG1 gating currents in Xenopus oocytes using the cut-open Vaseline gap technique. Cd2+ shifted the half-point (V1/2) for the voltage dependence of the OFF gating charge–voltage (QOFF-V) relationship with an EC50 of 171 µM; at 0.3 mM, V1/2 was shifted by +50 mV. Cd2+ also induced an as of yet unrecognized small outward current (ICd-out) upon repolarization in a concentration- and voltage-dependent manner. We propose that Cd2+ and Arg residues in the S4 segment compete for interaction with acidic residues in S2 and S3 segments, and that the initial inward movement of S4 associated with membrane repolarization displaces Cd2+ in an outward direction to produce ICd-out. Co2+, Zn2+, and La3+ at concentrations that caused ?+35-mV shifts in the QOFF-V relationship did not induce a current similar to ICd-out, suggesting that the binding site for these cations or their competition with basic residues in S4 differs from Cd2+. New Markov models of hERG1 channels were developed that describe gating currents as a noncooperative two-phase process of the VSD and can account for changes in these currents caused by extracellular Cd2+. PMID:20660661

Abbruzzese, Jennifer; Sachse, Frank B.; Tristani-Firouzi, Martin

2010-01-01

15

Interacting sites of scorpion toxin ErgTx1 with hERG1 K+ channels.  

PubMed

Peptides purified from scorpion venoms were shown to interact with specific amino acid residues present in the outer vestibule of various sub-types of potassium channels, occluding the pore and causing a decrement of K(+) permeability through the membrane of excitable and non excitable cells. This communication describes the identification of several interacting sites of toxin ErgTx1, a toxin purified from the venom of the scorpion Centruroides noxius, with the human ERG1 K(+) channels, by means of site-directed mutagenesis of specific residues of the toxin. Recombinant mutants of the gene coding for ErgTx1 were expressed heterologously in Escherichia coli, properly folded and their affinities and interactions with hERG1 channels were determined by patch-clamp techniques. Residues in position Y14, Y17 and F37 of the solvent exposed hydrophobic surface, and charged residues at the position K13 and K38 of ErgTx1 were shown to cause a decrement of the affinity from 20 folds to 3 orders of magnitude, thus suggesting that they are certainly participating on the binding surface of this toxin towards the hERG1 channels. Double mutants at positions K13 and F37, Y14 and F37, Y17 and F37 and K13 and K38 were also prepared and assayed, but the results obtained are not much different from the single point mutants of ErgTx1. The results of the present work indicate the most probable surface area of ErgTx1 that makes contact with the hERG channels. PMID:22366117

Jimenez-Vargas, J M; Restano-Cassulini, R; Possani, L D

2012-05-01

16

Cooperative subunit interactions mediate fast C-type inactivation of hERG1 K+ channels.  

PubMed

At depolarized membrane potentials, the conductance of some voltage-gated K(+) channels is reduced by C-type inactivation. This gating process is voltage independent in Kv1 and involves a conformational change in the selectivity filter that is mediated by cooperative subunit interactions. C-type inactivation in hERG1 K(+) channels is voltage-dependent, much faster in onset and greatly attenuates currents at positive potentials. Here we investigate the potential role of subunit interactions in C-type inactivation of hERG1 channels. Point mutations in hERG1 known to eliminate (G628C/S631C), inhibit (S620T or S631A) or enhance (T618A or M645C) C-type inactivation were introduced into subunits that were combined with wild-type subunits to form concatenated tetrameric channels with defined subunit composition and stoichiometry. Channels were heterologously expressed in Xenopus oocytes and the two-microelectrode voltage clamp was used to measure the kinetics and steady-state properties of inactivation of whole cell currents. The effect of S631A or T618A mutations on inactivation was a graded function of the number of mutant subunits within a concatenated tetramer as predicted by a sequential model of cooperative subunit interactions, whereas M645C subunits increased the rate of inactivation of concatemers, as predicted for subunits that act independently of one another. For mutations located within the inactivation gate proper (S620T or G628C/S631C), the presence of a single subunit in a concatenated hERG1 tetramer disrupted gating to the same extent as that observed for mutant homotetramers. Together, our findings indicate that the final step of C-type inactivation of hERG1 channels involves a concerted, all-or-none cooperative interaction between all four subunits, and that probing the mechanisms of channel gating with concatenated heterotypic channels should be interpreted with care, as conclusions regarding the nature of subunit interactions may depend on the specific mutation used to probe the gating process. PMID:25063820

Wu, Wei; Gardner, Alison; Sanguinetti, Michael C

2014-10-15

17

Molecular Determinants for Activation of Human Ether-à-go-go-related Gene 1 Potassium Channels by 3-Nitro-N-(4-phenoxyphenyl) BenzamideS?  

PubMed Central

Human ether-à-go-go-related gene 1 (hERG1) channels mediate repolarization of cardiac action potentials. Inherited long QT syndrome (LQTS) caused by loss-of-function mutations, or unintended blockade of hERG1 channels by many drugs, can lead to severe arrhythmia and sudden death. Drugs that activate hERG1 are a novel pharmacological approach to treat LQTS. 3-Nitro-n-(4-phenoxyphenyl) benzamide [ICA-105574 (ICA)] has been discovered to activate hERG1 by strong attenuation of pore-type inactivation. Here, we used scanning mutagenesis of hERG1 to identify the molecular determinants of ICA action. Three mutations abolished the activator effects of 30 ?M ICA, including L622C in the pore helix, F557L in the S5 segment, and Y652A in the S6 segment. One mutation in S6 (A653M) switched the activity of ICA from an activator to an inhibitor, revealing its partial agonist activity. This was confirmed by showing that the noninactivating mutant hERG1 channel (G628C/S631C) was inhibited by ICA and that the addition of the F557L mutation rendered the channel drug-insensitive. Simulated molecular docking of ICA to homology models of hERG1 corroborated the scanning mutagenesis findings. Together, our findings indicate that ICA is a mixed agonist of hERG1 channels. Activation or inhibition of currents is mediated by the same or overlapping binding site located in the pore module between two adjacent subunits of the homotetrameric channel. PMID:21743002

Garg, Vivek; Stary-Weinzinger, Anna; Sachse, Frank

2011-01-01

18

A Single Amino Acid Difference between Ether-a-go-go-Related Gene Channel Subtypes Determines Differential Sensitivity to a Small Molecule Activator  

PubMed Central

Activators of human ether-a-go-go-related gene 1 (hERG1) channels, such as (3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243), reverse the effect of hERG1 blockers and shorten the duration of cardiac action potentials. RPR260243 (RPR) slows the rate of deactivation and shifts the voltage dependence of channel inactivation to more positive potentials. We recently mapped the binding site for RPR to several residues located near the cytoplasmic ends of the S5 and S6 helices of the hERG1 subunit. These residues are conserved in the highly homologous ether-a-go-go-related gene 3 (ERG3) subunit; however, RPR blocks ERG3 channels. Here, we compare hERG1 and rat ERG3 (rERG3) channels to explore the molecular basis for differential channel sensitivity to RPR. Channels were heterologously expressed in Xenopus laevis oocytes, and currents were recorded using the two-electrode voltage-clamp technique. Site-directed mutagenesis was used to swap the two residues within the putative binding domain that differed between hERG1 and rERG3. The differential sensitivity of hERG1 and rERG3 channels to the agonist effect of RPR could be accounted for by a single S5 residue (Thr556 in hERG1, Ile558 in rERG3). A Thr in this position favors agonist activity, whereas an Ile reveals a secondary blocking effect of RPR. PMID:18162604

Perry, Matthew; Sanguinetti, Michael C.

2008-01-01

19

RELATIONSHIP OF COMMON CANDIDATE GENE VARIANTS TO ELECTROCARDIOGRAPHIC T-WAVE PEAK TO T-WAVE END INTERVAL AND T-WAVE MORPHOLOGY PARAMETERS  

PubMed Central

BACKGROUND Single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels and nitric oxide synthase 1 adaptor protein (NOS1AP) are associated with electrocardiographic (ECG) QT-interval duration, but the association of these SNPs with new prognostically important ECG measures of ventricular repolarization has been unknown. OBJECTIVE Our aim was to examine the relationship of SNPs to ECG T-wave peak to T-wave end (TPE) interval and T-wave morphology parameters. METHODS We studied 5,890 adults attending the Health 2000 Study, a Finnish epidemiological survey. TPE interval and four T-wave morphology parameters were measured from digital 12-lead ECGs and related to those seven SNPs showing a phenotypic effect on QT-interval duration in the Health 2000 Study population. RESULTS In multivariable analyses, the KCNH2 K897T minor allele was associated with a 1.2 ms TPE-interval shortening (P=.00005) and the KCNH2 intronic rs3807375 minor allele was associated with a 0.8 ms TPE-interval prolongation (P=.001), whereas the KCNE1 D85N variant had no TPE-interval effect (P=.20). NOS1AP minor alleles (rs2880058, rs4657139, rs10918594, rs10494366) were associated with shorter TPE interval (effects from 0.5 to 0.8 ms, P from .032 to .002), which resulted from their stronger effects on QTpeak than QTend interval. None of the SNPs showed a consistent association with T-wave morphology parameters. CONCLUSIONS KCNH2 K897T and rs3807375 as well as the four studied NOS1AP variants have modest effects on ECG TPE interval but are not related to T-wave morphology measures. The previously observed prognostic value of T-wave morphology parameters is unlikely to be based on these SNPs. PMID:20215044

Porthan, Kimmo; Marjamaa, Annukka; Viitasalo, Matti; Väänänen, Heikki; Jula, Antti; Toivonen, Lauri; Nieminen, Markku S; Newton-Cheh, Christopher; Salomaa, Veikko; Kontula, Kimmo; Oikarinen, Lasse

2010-01-01

20

Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator  

PubMed Central

Activation of human ether-a-go-go-related gene 1 (hERG1) K+ channels mediates cardiac action potential repolarization. Drugs that activate hERG1 channels represent a mechanism-based approach for the treatment of long QT syndrome, a disorder of cardiac repolarization associated with ventricular arrhythmia and sudden death. Here, we characterize the mechanisms of action and the molecular determinants for binding of RPR260243 [(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid] (RPR), a recently discovered hERG1 channel activator. Channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured by using the two-microelectrode voltage-clamp technique. RPR induced a concentration-dependent slowing in the rate of channel deactivation and enhanced current magnitude by shifting the voltage dependence of inactivation to more positive potentials. This mechanism was confirmed by demonstrating that RPR slowed the rate of deactivation, but did not increase current magnitude of inactivation-deficient mutant channels. The effects of RPR on hERG1 kinetics and magnitude could be simulated by reducing three rate constants in a Markov model of channel gating. Point mutations of specific residues located in the S4–S5 linker or cytoplasmic ends of the S5 and S6 domains greatly attenuated or ablated the effects of 3 ?M RPR on deactivation (five residues), inactivation (one residue), or both gating mechanisms (four residues). These findings define a putative binding site for RPR and confirm the importance of an interaction between the S4–S5 linker and the S6 domain in electromechanical coupling of voltage-gated K+ channels. PMID:17693551

Perry, Matthew; Sachse, Frank B.; Sanguinetti, Michael C.

2007-01-01

21

Common candidate gene variants are associated with QT interval duration in the general population  

PubMed Central

Marjamaa A, Newton-Cheh C, Porthan K, Reunanen A, Lahermo P, Väänänen H, Jula A, Karanko H, Swan H, Toivonen L, Nieminen MS, Viitasalo M, Peltonen L, Oikarinen L, Palotie A, Kontula K, Salomaa V (Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MA, USA; University of Helsinki, Helsinki, Finland; National Public Health Institute, Helsinki, Finland; Finnish Genome Center, University of Helsinki, Helsinki, Finland; Laboratory of Biomedical Engineering, Helsinki University of Technology, Espoo, Finland; and University of Helsinki, Helsinki, Finland). Common candidate gene variants are associated with QT interval duration in the general population. Objectives QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30–40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. Methods We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. Results The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QTNc interval (P = 3.6 × 10?11) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QTNc interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P = 4.7 × 10?5], KCNH2 K897T [?2.6 ms (SE 0.5) or ?0.14 SD, P = 2.1 × 10?7] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P = 3.2 × 10?24] under additive models. Conclusions We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval. PMID:19019189

Marjamaa, A.; Newton-Cheh, C.; Porthan, K.; Reunanen, A.; Lahermo, P.; Väänänen, H.; Jula, A.; Karanko, H.; Swan, H.; Toivonen, L.; Nieminen, M. S.; Viitasalo, M.; Peltonen, L.; Oikarinen, L.; Palotie, A.; Kontula, K.; Salomaa, V.

2009-01-01

22

Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes: Assessment by Real-Time PCR Arrays  

PubMed Central

Chronic arsenic exposure results in higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array (TLDA). We found that expression of tumor necrosis factor-? (TNF-?), which activates both inflammation and NF-?B-dependent survival pathways, was strongly associated with water and urinary arsenic levels. Expression of KCNA5, which encodes a potassium ion channel protein, was positively associated with water and toe nail arsenic levels. Expression of 2 and 11 genes were positively associated with nail and urinary arsenic, respectively. Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans, we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro. Expression of the ion-channel genes CACNA1, KCNH2, KCNQ1 and KCNE1 were down-regulated by 1-?M arsenic. Alteration of some common pathways, including those involved in oxidative stress, inflammatory signaling, and ion-channel function, may underlay the seemingly disparate array of arsenic-associated diseases, such as cancer, cardiovascular disease, and diabetes. PMID:21776218

Mo, Jinyao; Xia, Yajuan; Wade, Timothy J.; DeMarini, David M.; Davidson, Mercy; Mumford, Judy

2011-01-01

23

Altered gene expression by low-dose arsenic exposure in humans and cultured cardiomyocytes: assessment by real-time PCR arrays.  

PubMed

Chronic arsenic exposure results in higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array (TLDA). We found that expression of tumor necrosis factor-? (TNF-?), which activates both inflammation and NF-?B-dependent survival pathways, was strongly associated with water and urinary arsenic levels. Expression of KCNA5, which encodes a potassium ion channel protein, was positively associated with water and toe nail arsenic levels. Expression of 2 and 11 genes were positively associated with nail and urinary arsenic, respectively. Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans, we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro. Expression of the ion-channel genes CACNA1, KCNH2, KCNQ1 and KCNE1 were down-regulated by 1-?M arsenic. Alteration of some common pathways, including those involved in oxidative stress, inflammatory signaling, and ion-channel function, may underlay the seemingly disparate array of arsenic-associated diseases, such as cancer, cardiovascular disease, and diabetes. PMID:21776218

Mo, Jinyao; Xia, Yajuan; Wade, Timothy J; DeMarini, David M; Davidson, Mercy; Mumford, Judy

2011-06-01

24

Comparative gene expression profiling in human-induced pluripotent stem cell--derived cardiocytes and human and cynomolgus heart tissue.  

PubMed

Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity, and there is a need for alternative physiologically relevant models. Here we describe the gene expression profile of human-induced pluripotent stem cell-derived cardiocytes (iCC) postthaw over a period of 42 days in culture and compare this profile to human fetal and adult as well as adult cynomolgus nonhuman primate (NHP, Macaca fascicularis) heart tissue. Our results indicate that iCC express relevant cardiac markers such as ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1, and KCNH2), tissue-specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2, and TNNI3), and transcription factors (NKX2.5, GATA4, and GATA6) and lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42). Furthermore, we performed a functional evaluation of contractility of the iCC and showed functional and pharmacological correlations with myocytes isolated from adult NHP hearts. These results suggest that stem cell-derived cardiocytes may represent a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation. PMID:22982684

Puppala, Dinesh; Collis, Leon P; Sun, Sunny Z; Bonato, Vinicius; Chen, Xian; Anson, Blake; Pletcher, Mathew; Fermini, Bernard; Engle, Sandra J

2013-01-01

25

Genes  

NSDL National Science Digital Library

Illustration of the placement of genes in a chromosome. A gene can be defined as a region of DNA that controls a hereditary characteristic. It usually corresponds to a sequence used in the production of a specific protein or RNA. A gene carries biological information in a form that must be copied and transmitted from each cell to all its progeny. This includes the entire functional unit: coding DNA sequences, non-coding regulatory DNA sequences, and introns. Genes can be as short as 1000 base pairs or as long as several hundred thousand base pairs. It can even be carried by more than one chromosome. The estimate for the number of genes in humans has decreased as our knowledge has increased. As of 2001, humans are thought to have between 30,000 and 40,000 genes.

Access Excellence

2005-03-12

26

Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death  

PubMed Central

Importance Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. Objective To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. Design, Setting, and Patients In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. Main Outcomes and Measures Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. Results The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases) that conferred in vitro electrophysiological characteristics consistent with potentially proarrhythmic phenotypes. Conclusions and Relevance In this molecular genetic evaluation of 91 cases of intrauterine fetal death, missense mutations associated with LQTS susceptibility were discovered in 3 cases (3.3%) and overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%). These preliminary findings may provide insights into mechanisms of some cases of stillbirth. PMID:23571586

Crotti, Lia; Tester, David J.; White, Wendy M.; Bartos, Daniel C.; Insolia, Roberto; Besana, Alessandra; Kunic, Jennifer D.; Will, Melissa L.; Velasco, Ellyn J.; Bair, Jennifer J.; Ghidoni, Alice; Cetin, Irene; Van Dyke, Daniel L.; Wick, Myra J.; Brost, Brian; Delisle, Brian P.; Facchinetti, Fabio; George, Alfred L.; Schwartz, Peter J.; Ackerman, Michael J.

2013-01-01

27

Genes and Gene Therapy  

MedlinePLUS

... a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

28

Role of ERG1 isoforms in modulation of ERG1 channel trafficking and function  

Microsoft Academic Search

The ‘ether-a-go-go-related’ gene type 1 (ERG1 or Kv11.1) protein is the product of the KCNH2 gene. Currents generated by ERG1 channels are important in a range of tissues including neuronal, smooth muscle, and cardiac\\u000a tissues, as well as in cancer cells. There are five known isoforms of the ERG1 protein. Overlapping patterns of endogenous\\u000a expression of ERG1 isoforms have been

Anders Peter Larsen; Pflugers Arch; Eur J Physiol

2010-01-01

29

Common variants at ten loci modulate the QT interval duration in the QTSCD Study  

E-print Network

Steinbeck7, Fabio Marroni9, Andrew A Hicks9, Edward Lakatta16, Bertram Mu¨ller-Myhsok13, Peter P Pramstaller additional loci at P o 5 � 10�8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A as in the general population4. Furthermore, mutations in genes associated with long- and short-QT syndromes (LQTS

Abecasis, Goncalo

30

Rehabilitating drug-induced long-QT promoters: In-silico design of hERG-neutral cisapride analogues with retained pharmacological activity  

PubMed Central

Background The human ether-a-go-go related gene 1 (hERG1), which codes for a potassium ion channel, is a key element in the cardiac delayed rectified potassium current, IKr, and plays an important role in the normal repolarization of the heart’s action potential. Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval. Most of these drugs have high potencies for their principal targets and are often irreplaceable, thus “rehabilitation” studies for decreasing their high hERG1 blocking affinities, while keeping them active at the binding sites of their targets, have been proposed to enable these drugs to re-enter the market. Methods In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity. Here we tested an a priori strategy to predict a compound’s cardiotoxicity using de novo drug design with molecular docking and Molecular Dynamics (MD) simulations to generate a strategy for the rehabilitation of cisapride. Results We focused on two key receptors, a target interaction with the (adenosine) receptor and an off-target interaction with hERG1 channels. An analysis of the fragment interactions of cisapride at human A2A adenosine receptors and hERG1 central cavities helped us to identify the key chemical groups responsible for the drug activity and hERG1 blockade. A set of cisapride derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier approach. This set was compared against a large dataset of commercially available cisapride analogs and derivatives. Conclusions An interaction decomposition of cisapride and cisapride derivatives allowed for the identification of key active scaffolds and functional groups that may be responsible for the unwanted blockade of hERG1. PMID:24606761

2014-01-01

31

Genes and gene regulation  

SciTech Connect

Genetics has long been a central topic for biologists, and recent progress has captured the public imagination as well. This book addresses questions that are at the leading edge of this continually advancing discipline. In tune with the increasing emphasis on molecular biology and genetic engineering, this text emphasizes the molecular aspects of gene expression, and the evolution of gene sequence organization and control. It reviews the genetic material of viruses, bacteria, and of higher organisms. Cells and organisms are compared in terms of gene numbers, their arrangements within a cell, and the control mechanisms which regulate the activity of genes.

MacLean, N.

1988-01-01

32

Studying Genes  

MedlinePLUS

NIGMS Home > Science Education > Studying Genes Studying Genes Tagline (Optional) Middle/Main Content Area What are genes? Genes are sections of DNA that contain instructions for making the molecules—many of ...

33

Gene Cloning  

NSDL National Science Digital Library

This lesson covers the utilization of gene cloning to isolate and copy a specific gene of interest. The transformation of bacteria with plasmids containing antibiotic resistance genes to make gene libraries and the selection of bacteria colonies that contain the specific gene of interest are described.

34

Gene Concepts, Gene Talk, and Gene Patents  

E-print Network

Since the existence of a discrete unit of heredity was first proposed by Gregor Mendel, scientific concepts of the “gene” have undergone rapid evolution. Beyond obvious epistemic and operational importance to the scientific community, changing gene...

Torrance, Andrew W.

2010-01-01

35

Gene Regions  

NSDL National Science Digital Library

This animation shows the three gene coding regions. This is the fourth of a series of seven animations that detail the process of crop genetic engineering. To begin at the beginning, see Overview of Crop Genetic Engineering. (To return to the animation previous to this, go to Gene Cloning. To go to the next animation, go to Gene Modification.)

36

Gene Modifications  

NSDL National Science Digital Library

This animation shows how a gene is constructed to eventually produce a protein in a Bt corn plant. This is the fifth of a series of seven animations that detail the process of crop genetic engineering. To begin at the beginning, see Overview of Crop Genetic Engineering. (To return to the animation previous to this, go to Gene Regions. To go to the next animation, go to Gene Gun.)

37

Gene Gun  

NSDL National Science Digital Library

How the gene gun works to transform cells with new DNA. This is thesixth of a series of seven animations that detail the process of cropgenetic engineering. To begin at the beginning, see Overview of Crop Genetic Engineering. (To return to the animation previous to this, go to Gene Modification. To go to the next animation, go to Backcross Breeding.)

38

Gene Cloning  

NSDL National Science Digital Library

A basic depiction of the steps in gene cloning. This is the third of a series of seven animations that detail the process of crop genetic engineering. To begin at the beginning, see Overview of Crop Genetic Engineering. (To return to the animation previous to this, go to DNA and DNA Extraction. To go to the next animation, go to Gene Regions.)

39

Trichoderma genes  

DOEpatents

Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

Foreman, Pamela (Los Altos, CA); Goedegebuur, Frits (Vlaardingen, NL); Van Solingen, Pieter (Naaldwijk, NL); Ward, Michael (San Francisco, CA)

2012-06-19

40

Gene Puzzles  

NSDL National Science Digital Library

In this Science NetLinks lesson, students will examine a fictional pedigree and determine which gene is responsible for a given trait. The genetic information for individuals is depicted as a jigsaw puzzle. Without delving into a complicated explanation of the process, the activity in this lesson will help students build an understanding of how offspring inherit genes from their parents.

Science Netlinks

2001-10-20

41

[Gene therapy].  

PubMed

In the last years there has been much progress in our understanding of molecular mechanisms in the pathogenesis of disease. In this review we provide an overview of gene therapy, its most actualized techniques for gene delivery, and we give specific examples of laboratory and clinical achievements to date. The development of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. As a result, concepts and methods that would have been considered purely science fiction 50 years ago are now used in the treatment of diseases. The widespread application of gene therapy technology to many diseases is already breaking down the traditional boundaries of modern medicine. However, despite its progress, several key technical drawbacks need to be overcome before gene therapy can be used safely and effectively in clinical settings. Technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy. PMID:9527700

Rodríguez-Fragoso, L

1997-01-01

42

Gene Cloning  

NSDL National Science Digital Library

This interactive activity adapted from the University of Nebraska's Library of Crop Technologies details the steps involved in producing clones of genes that can then be used to transform the characteristics of an organism.

WGBH Educational Foundation

2009-12-07

43

Analysis of Gene-Gene Interactions  

PubMed Central

The goal of this unit is to introduce gene-gene interactions (epistasis) as a significant complicating factor in the search for disease susceptibility genes. This unit begins with an overview of gene-gene interactions and why they are likely to be common. Then, it reviews several statistical and computational methods for detecting and characterizing genes with effects that are dependent on other genes. The focus of this unit is genetic association studies of discrete and quantitative traits because most of the methods for detecting gene-gene interactions have been developed specifically for these study designs. PMID:21735376

Gilbert-Diamond, Diane; Moore, Jason H.

2014-01-01

44

Attention Genes  

ERIC Educational Resources Information Center

A major problem for developmental science is understanding how the cognitive and emotional networks important in carrying out mental processes can be related to individual differences. The last five years have seen major advances in establishing links between alleles of specific genes and the neural networks underlying aspects of attention. These…

Posner, Michael I.; Rothbart, Mary K.; Sheese, Brad E.

2007-01-01

45

Genes and Hearing Loss  

MedlinePLUS

Genes and Hearing Loss Genes and Hearing Loss Patient Health Information News media interested in covering the ... mutation may only have dystopia canthorum. How Do Genes Work? Genes are a road map for the ...

46

Genetic analysis, in silico prediction, and family segregation in long QT syndrome.  

PubMed

The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc?500?ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality. PMID:24667783

Riuró, Helena; Campuzano, Oscar; Berne, Paola; Arbelo, Elena; Iglesias, Anna; Pérez-Serra, Alexandra; Coll-Vidal, Mònica; Partemi, Sara; Mademont-Soler, Irene; Picó, Ferran; Allegue, Catarina; Oliva, Antonio; Gerstenfeld, Edward; Sarquella-Brugada, Georgia; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Mont, Lluís; Brugada, Josep; Scornik, Fabiana S; Brugada, Ramon

2015-01-01

47

Gene Switches  

NSDL National Science Digital Library

In this activity, learners explore how genetic switches function and the role of genetic switches in the process of evolution. To make these concepts less abstract and more understandable, learners first view a series of video clips and animations from the HHMI DVD (or online) "Evolution: Constant Change and Common Threads." Then, learners construct a model of a gene switch using craft materials or FridgiGears (magnetic gears). This activity can be done as a demonstration, a student inquiry activity, or a combination of the two.

2013-07-30

48

Essential Bacillus subtilis genes  

Microsoft Academic Search

To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among 4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were predicted to be essential. The vast majority of essential genes were categorized in relatively

K. Kobayashi; S. D. Ehrlichb; A. Albertini; G. Amati; K. Asaig Arnaudf; M. Arnaud; K. Asai; S. Ashikaga; S. Aymerich; P. Bessieres; F. Boland; S. C. Brignell; S. Bron; K. Bunai; J. Chapuis; L. C. Christiansen; A. Danchin; M. Débarbouillé; E. Dervyn; E. Deuerling; K. Devine; S. K. Devine; O. Dreesen; J. Errington; S. Fillinger; S. J. Foster; Y. Fujita; A. Galizzi; R. Gardan; C. Eschevins; T. Fukushima; K. Haga; C. R. Harwood; M. Hecker; D. Hosoya; M. F. Hullo; H. Kakeshita; D. Karamata; Y. Kasahara; F. Kawamura; K. Koga; P. Koski; R. Kuwana; D. Imamura; M. Ishimaru; S. Ishikawa; I. Ishio; D. Le Coq; A. Masson; C. Mauël; R. Meima; R. P. Mellado; A. Moir; S. Moriya; E. Nagakawa; H. Nanamiya; S. Nakai; P. Nygaard; M. Ogura; T. Ohanan; M. O'Reilly; M. O'Rourke; Z. Pragai; H. M. Pooley; G. Rapoport; J. P. Rawlins; L. A. Rivas; C. Rivolta; A. Sadaie; Y. Sadaie; M. Sarvas; T. Sato; H. H. Saxild; E. Scanlan; W. Schumann; J. F. Seegers; J. Sekiguchi; A. Sekowska; S. J. Seror; M. Simon; P. Stragier; R. Studer; H. Takamatsu; T. Tanaka; M. Takeuchi; H. B. Thomaides; V. Vagner; J. M. van Dijl; K. Watabe; A. Wipat; H. Yamamoto; M. Yamamoto; Y. Yamamoto; K. Yamane; K. Yata; K. Yoshida; H. Yoshikawa; U. Zuber; N. Ogasawara

2003-01-01

49

Genes and Psoriasis  

MedlinePLUS

... is responsible for causing psoriatic disease. How do genes work? Genes control everything from height to eye ... disease such as psoriasis may result. How are genes different in people with psoriatic disease? Researchers are ...

50

Therapeutic genes for cancer gene therapy  

Microsoft Academic Search

Cancer still represents a disease of high incidence and is therefore one major target for gene therapy approaches. Gene therapy\\u000a for cancer implies that ideally selective tumor cell killing or inhibition of tumor cell growth can be achieved using nucleic\\u000a acids (DNA and RNA) as the therapeutic agent. Therefore, the majority of cancer gene therapy strategies introduce foreign\\u000a genes into

Wolfgang Walther; Ulrike Stein

1999-01-01

51

QT Is Longer in Drug-Free Patients with Schizophrenia Compared with Age-Matched Healthy Subjects  

PubMed Central

The potassium voltage-gated channel KCNH2 is a well-known gene in which mutations induce familial QT interval prolongation. KCNH2 is suggested to be a risk gene for schizophrenia. Additionally, the disturbance of autonomic control, which affects the QT interval, is known in schizophrenia. Therefore, we speculate that schizophrenic patients have characteristic features in terms of the QT interval in addition to the effect of antipsychotic medication. The QT interval of patients with schizophrenia not receiving antipsychotics (n?=?85) was compared with that of patients with schizophrenia receiving relatively large doses of antipsychotics (n?=?85) and healthy volunteers (n?=?85). The QT interval was corrected using four methods (Bazett, Fridericia, Framingham or Hodges method). In ANCOVA with age and heart rate as covariates, patients not receiving antipsychotic treatment had longer QT intervals than did the healthy volunteers, but antipsychotics prolonged the QT interval regardless of the correction method used (P<0.01). Schizophrenic patients with and without medication had a significantly higher mean heart rate than did the healthy volunteers, with no obvious sex-related differences in the QT interval. The QT interval prolongation may be manifestation of a certain biological feature of schizophrenia. PMID:24887423

Fujii, Kumiko; Ozeki, Yuji; Okayasu, Hiroaki; Takano, Yumiko; Shinozaki, Takahiro; Hori, Hiroaki; Orui, Masami; Horie, Minoru; Kunugi, Hiroshi; Shimoda, Kazutaka

2014-01-01

52

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome  

PubMed Central

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type ? subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death. PMID:18464931

Brunner, Michael; Peng, Xuwen; Liu, Gong Xin; Ren, Xiao-Qin; Ziv, Ohad; Choi, Bum-Rak; Mathur, Rajesh; Hajjiri, Mohammed; Odening, Katja E.; Steinberg, Eric; Folco, Eduardo J.; Pringa, Ekatherini; Centracchio, Jason; Macharzina, Roland R.; Donahay, Tammy; Schofield, Lorraine; Rana, Naveed; Kirk, Malcolm; Mitchell, Gary F.; Poppas, Athena; Zehender, Manfred; Koren, Gideon

2008-01-01

53

Gene doping: gene delivery for olympic victory  

PubMed Central

With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called ‘gene doping’. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. PMID:23082866

Gould, David

2013-01-01

54

Clustering gene expression data  

E-print Network

CG 1 Clustering gene expression data #12;CG 2 How Gene Expression Data Looks Expression levels · ... · Row = gene's expression pattern · Column = experiment/condition's profile #12;CG 3 Data Preprocessing Expression levels, "Raw Data" conditions genes ·Input: Real-valued raw data matrix. ·Compute the similarity

Shamir, Ron

55

Life with 6000 Genes  

Microsoft Academic Search

The genome of the yeast Saccharomyces cerevisiae has been completely sequenced through a worldwide collaboration. The sequence of 12,068 kilobases defines 5885 potential protein-encoding genes, approximately 140 genes specifying ribosomal RNA, 40 genes for small nuclear RNA molecules, and 275 transfer RNA genes. In addition, the complete sequence provides information about the higher order organization of yeast's 16 chromosomes and

A. Gofieau; B. G. Barrell; H. Bussey; R. W. Davis; B. Dujon; H. Feldmann; F. Galibert; J. D. Hoheisel; C. Jacq; M. Johnston; E. J. Louis; H. W. Mewes; Y. Murakami; P. Philippsen; H. Tettelin; S. G. Oliver

1996-01-01

56

Autism and Genes  

ERIC Educational Resources Information Center

This document defines and discusses autism and how genes play a role in the condition. Answers to the following questions are covered: (1) What are genes? (2) What is autism? (3) What causes autism? (4) Why study genes to learn about autism? (5) How do researchers look for the genes involved in autism? (screen the whole genome; conduct cytogenetic…

National Institutes of Health, 2005

2005-01-01

57

Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes  

PubMed Central

Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart. PMID:23470493

Matsa, Elena; Dixon, James E.; Medway, Christopher; Georgiou, Orestis; Patel, Minal J.; Morgan, Kevin; Kemp, Paul J.; Staniforth, Andrew; Mellor, Ian; Denning, Chris

2014-01-01

58

Zebrafish model for human long QT syndrome.  

PubMed

Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model of inherited LQTS does not exist. The zebrafish is a powerful vertebrate model used to dissect molecular pathways of cardiovascular development and disease. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. Here we describe the molecular, cellular, and electrophysiological basis of a zebrafish mutant characterized by ventricular asystole. Genetic mapping and direct sequencing identify the affected gene as kcnh2, which encodes the channel responsible for the rapidly activating delayed rectifier K(+) current (I(Kr)). We show that complete loss of functional I(Kr) in embryonic hearts leads to ventricular cell membrane depolarization, inability to generate action potentials (APs), and disrupted calcium release. A small hyperpolarizing current restores spontaneous APs, implying wild-type function of other ionic currents critical for AP generation. Heterozygous fish manifest overt cellular and electrocardiographic evidence for delayed ventricular repolarization. Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias. PMID:17592134

Arnaout, Rima; Ferrer, Tania; Huisken, Jan; Spitzer, Kenneth; Stainier, Didier Y R; Tristani-Firouzi, Martin; Chi, Neil C

2007-07-01

59

Human Gene Therapy: Genes without Frontiers?  

ERIC Educational Resources Information Center

Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

Simon, Eric J.

2002-01-01

60

Hox genes: from master genes to micromanagers.  

PubMed

We still have little idea how the differential expression of one 'master' gene can control the morphology of complex structures, but recent studies suggest that the Drosophila Hox gene Ultrabithorax micromanages segment development by manipulating a large number of different targets at many developmental stages. PMID:9768351

Akam, M

1998-09-24

61

Your Genes, Your Choices  

MedlinePLUS

Your Genes, Your Choices describes the Human Genome Project, the science behind it, and the ethical, legal, and social ... Nothing could be further from the truth. Your Genes, Your Choices points out how the progress of ...

62

Gene Carlson Oral History  

E-print Network

Oral history interview with Gene Carlson conducted by Clint Shriner on December 10, 2009. In this interview, Gene Carlson, lead pastor at Westlink Christian Church, discusses the formative experiences that resulted in his ...

Carlson, Gene; Shriner, Clint

2009-12-10

63

What Is a Gene?  

MedlinePLUS

... think about all the many different breeds of dogs. They all have the genes that make them dogs instead of cats, fish, or people. But those same genes that make a dog a dog also make different dog traits. So ...

64

Proto-genes and de novo gene birth  

E-print Network

Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo. Processes involving re-organization of pre-existing genes, notably after gene duplication, have been extensively described. ...

Carvunis, Anne-Ruxandra

65

Dopamine genes and ADHD  

Microsoft Academic Search

Family, twin, and adoption studies have documented a strong genetic basis for ADHD\\/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD\\/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which

J. M Swanson; Pamela Flodman; James Kennedy; M. Anne Spence; Robert Moyzis; Sabrina Schuck; Michael Murias; Joan Moriarity; Cathy Barr; Moyra Smith; Michael Posner

2000-01-01

66

Sandro Rusconi Gene transfer  

E-print Network

Sandro Rusconi UNIFR Rusconi 2003 Gene transfer: limits and potential as doping vehicle Geneva 30.09.03 AISTS 'genes & sport' workshop 1972-75 Primary school teacher (Locarno, Switzerland) 1975-79 Graduation medicine' & molecular doping: applications and problems, Gene-based doping applications, comparison

Málaga, Universidad de

67

Sandro Rusconi Gene transfer  

E-print Network

Sandro Rusconi aaaaaa UNIFR Rusconi 2003 Gene transfer: limits and potential as doping vehicle Geneva 30.09.03 AISTS 'genes & sport' workshop 1972-75 Primary school teacher (Locarno, Switzerland) 1975 on 'molecular medicine' & molecular doping: applications and problems, Gene-based doping applications

Málaga, Universidad de

68

UniGene  

NSDL National Science Digital Library

Created by the National Center for Biotechnology Information, UniGene is "an experimental system for automatically partitioning GenBank sequences into a non-redundant set of gene-oriented clusters." In addition to gene sequences, this Web site also offers thousands of novel expressed sequence tag (EST) sequences, a useful gene discovery resource. Organisms currently cataloged include human, rat, mouse, cow, zebrafish, clawed frog, fruitfly, mosquito, wheat, rice, barley, maize, and cress. Users may also access the Digital Differential Display to compare gene expression fingerprints for cancer cells and their normal counterparts. Other Web site features include query tips, FAQs, and relevant external links.

69

Cancer gene therapy  

E-print Network

Cancer gene therapy can be defined as transfer of nucleic acids into tumor or normal cells with aim to eradicate or reduce tumor mass by direct killing of cells, immunomodulation or correction of genetic errors, and reversion of malignant status. Initially started with lots of optimism and enthusiasm, cancer gene therapy has shown limited success in treatment of patients. This review highlights current limitations and almost endless possibilities of cancer gene therapy. The major difficulty in advancing gene therapy technology from the bench to the clinical practice is problem with gene delivery vehicles (so called vectors) needed to ferry genetic material into a cell. Despite few reports of therapeutic responses in some patients, there is still no proof of clinical efficacy of most cancer gene therapy approaches, primarily due to very low transduction and expression efficacy in vivo of available vectors. An ãidealÒ gene therapy vector should be administrated through a noninvasive route and should be targeted not only to primary tumor mass but also to disseminated tumor cells and micrometastases; it should also carry therapeutic gene with tumor-restricted, time-regulated, and sustained expression. Current strategies for combating the cancer with gene therapy can be divided into four basic concepts: (1) replacement of missing tumor suppressor gene and/or blocking of oncogenes or pro-inflammatory genes, (2)

Arch Oncol; Tatjana Mitroviæ

70

Cochlear Gene Therapy  

PubMed Central

The purpose of this review is to highlight recent advances in cochlear gene therapy over the past several years. Cochlear gene therapy has undergone tremendous advances over the past decade. Beginning with some groundbreaking work in 2005 documenting hair cell regeneration using virallymediated delivery of the mouse atonal 1 gene, gene therapy is now being explored as a possible treatment for a variety of causes of hearing loss. Recent advances in cochlear gene therapy include improved methods of gene delivery with a better delineation of viral vectors that are suitable for this purpose, additional improvements in hair cell regeneration, and directed research towards autoimmune hearing loss, ototoxicity, spiral ganglion survival, and genetic forms of hearing loss. If successful, cochlear gene therapy will dramatically alter our ability to treat a variety of forms of acquired and genetic hearing loss. PMID:22157110

Lustig, Lawrence R.; Akil, Omar

2013-01-01

71

Do LQTS Gene Single Nucleotide Polymorphisms Alter QTc Intervals at Rest and During Exercise Stress Testing?  

PubMed Central

Background The impact of harboring, genetic variants or single nucleotide polymorphisms (LQT-PM) on the repolarization response during exercise and recovery is unknown. Objective To assess the QTc interval adaptation during exercise stress testing (EST) in children with LQT polymorphisms compared to a group of age and gender matched normal controls. Methods One-hundred and forty-eight patients were age and gender matched into two groups: LQT-PM and control. Each patient underwent a uniform exercise protocol employing a cycle ergometer followed by a 9 minute recovery phase with continuous 12-lead electrocardiogram (ECG) monitoring. Intervals (RR, QT and QTc) at rest (supine), peak exercise and in recovery (1, 3, 5, 7, and 9 minutes) were measured. Results Forty three patients were positive for LQT-PM and the control group consisted of 105 patients. A total of 83 SNPs were identified: SCN5A n=31 (37%), KCNE1 n=29 (35%), KCNH2 n=20 (24%), KCNQ1 n=2 (2%) and KCNE2 n=1 (1%). The QTc interval measurements of the LQT-PM were longer at rest, peak exercise and all phases of recovery when compared to the control group. Neither group demonstrated abnormal QTc interval adaptation in response to exercise. Patients with homozygous SNPs had longer resting QTc intervals when compared to patients with only heterozygous SNPs (435±23 ms vs 415±20 ms respectively, P-value <0.006). Conclusions Individuals with LQT-PM may have longer QTc intervals at rest as well as at peak exercise and all phases of the recovery period compared to normal controls. Additionally, subjects with homozygous SNPs had longer resting QTc intervals when compared to those with only heterozygous SNPs. PMID:23714088

Aziz, Peter F; Wieand, Tammy S; Ganley, Jamie; Henderson, Jacqueline; McBride, Michael; Shah, Maully J

2015-01-01

72

Human HOX gene disorders.  

PubMed

The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies. PMID:24239177

Quinonez, Shane C; Innis, Jeffrey W

2014-01-01

73

The gap gene network  

PubMed Central

Gap genes are involved in segment determination during the early development of the fruit fly Drosophila melanogaster as well as in other insects. This review attempts to synthesize the current knowledge of the gap gene network through a comprehensive survey of the experimental literature. I focus on genetic and molecular evidence, which provides us with an almost-complete picture of the regulatory interactions responsible for trunk gap gene expression. I discuss the regulatory mechanisms involved, and highlight the remaining ambiguities and gaps in the evidence. This is followed by a brief discussion of molecular regulatory mechanisms for transcriptional regulation, as well as precision and size-regulation provided by the system. Finally, I discuss evidence on the evolution of gap gene expression from species other than Drosophila. My survey concludes that studies of the gap gene system continue to reveal interesting and important new insights into the role of gene regulatory networks in development and evolution. PMID:20927566

2010-01-01

74

Mammalian suppressor genes  

SciTech Connect

A method is described of suppressing a nonsense codon in a gene for production of a protein of interest in mammalian cells, the method comprising: (a) preparing an oligonucleotide primer comprising a region complementary to the nonsense codon; (b) preparing a DNA template for production of a tRNA molecule; (c) forming a suppressor gene from the template and primer by site specific mutagenesis; and (d) transforming the suppressor gene into a mammalian cell, whereby the nonsense codon will be suppressed.

Sharp, P.A.; Capecchi, M.R.; Raj Bhandary, U.L.; Laski, F.A.

1987-08-18

75

Refining discordant gene trees  

PubMed Central

Background Evolutionary studies are complicated by discordance between gene trees and the species tree in which they evolved. Dealing with discordant trees often relies on comparison costs between gene and species trees, including the well-established Robinson-Foulds, gene duplication, and deep coalescence costs. While these costs have provided credible results for binary rooted gene trees, corresponding cost definitions for non-binary unrooted gene trees, which are frequently occurring in practice, are challenged by biological realism. Result We propose a natural extension of the well-established costs for comparing unrooted and non-binary gene trees with rooted binary species trees using a binary refinement model. For the duplication cost we describe an efficient algorithm that is based on a linear time reduction and also computes an optimal rooted binary refinement of the given gene tree. Finally, we show that similar reductions lead to solutions for computing the deep coalescence and the Robinson-Foulds costs. Conclusion Our binary refinement of Robinson-Foulds, gene duplication, and deep coalescence costs for unrooted and non-binary gene trees together with the linear time reductions provided here for computing these costs significantly extends the range of trees that can be incorporated into approaches dealing with discordance. PMID:25434729

2014-01-01

76

Chapter 19: Gene: A Directory of Genes Donna Maglott  

E-print Network

Chapter 19: Gene: A Directory of Genes Donna Maglott Kim Pruitt Tatiana Tatusova Summary A major goal of genomic sequencing projects is to identify and characterize genes. Gene (1) has been genes, serving as a major node in the nexus of genomic map, sequence, expression, protein structure

Levin, Judith G.

77

4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP ...  

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP LOOKING SOUTHWEST. DAM AND SPILLWAY VISIBLE IN BOTTOM OF PHOTO. - Gene Wash Reservoir & Dam, 2 miles west of Parker Dam, Parker Dam, San Bernardino County, CA

78

Making a Gene Library  

NSDL National Science Digital Library

This animation shows how to make a colony of new DNA in order to locate a specific gene of interest. This is the third of four animations detailing the gene cloning process. To begin at the beginning, choose Making a Recombinant Plasmid. (The animation prior to this one is Bacteria Transformation. The animation just after this one is Screening a DNA Library.)

79

Genes Involved in Atherosclerosis  

Microsoft Academic Search

Atherosclerosis is a multifactorial disease that involves several genes and proteins. The purpose of this article is to focus on the arterial wall and to review lipoprotein receptors, growth factors, cytokines, chemokines, matrix metalloproteinases, adhesion molecules, and apoptosis genes and their involvement in atherogenesis.

Johanna Laukkanen; Seppo Ylä-Herttuala

2002-01-01

80

Gene Patents and Justice  

Microsoft Academic Search

heredity; they ‘‘specify the proteins that form the units of which homoeostatic devices are composed.’’ 2 New genetic diagnostics and therapies might help us prevent, reduce or possibly even cure certain diseases. By manipulating our genes we may be able to influence our propensity for certain physical, intellectual, psychological or even moral characteristics. The first officially sanctioned human somatic-cell gene-therapy

Colin Farrelly

2007-01-01

81

The Gene Ontology Consortium  

Microsoft Academic Search

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied

Michael Ashburner; Catherine A. Ball; Judith A. Blake; David Botstein; Heather Butler; J. Michael Cherry; Allan P. Davis; Kara Dolinski; Selina S. Dwight; Janan T. Eppig; Midori A. Harris; David P. Hill; Laurie Issel-Tarver; Andrew Kasarskis; Suzanna Lewis; John C. Matese; Joel E. Richardson; Martin Ringwald; Gerald M. Rubin; Gavin Sherlock

2000-01-01

82

GeneEd: Genetics, Education, Discovery  

NSDL National Science Digital Library

The GeneEd website was created by the National Library of Medicine (NLM), the National Human Genome Research Institute (NHGRI), and the National Institutes of Health (NIH) as a helpful resource for the teaching and learning of genetics. On the site, visitors can find labs and experiments, fact sheets, and teacher resources on topics including DNA forensics, genetic conditions, evolution, and biostatistics. First-time visitors will want to start their journey by looking over the Topics tab at the top of the page. There are 40 different thematic areas here consisting of articles, video clips, webcasts, and links to additional quality resources vetted by the GeneEd web team. The Labs & Experiments section includes virtual labs that explore the genetics of different organisms as well as links to resources provided by the Howard Hughes Medical Institute and Cold Spring Harbor Laboratory. Young people may also wish to take a look at the Careers in Genetics section as it features interviews with scientists that will inspire and delight.

83

Multivariate detection of gene-gene interactions  

E-print Network

for independent contributions of each gene, usually detected by univariate logistic regression methods. Using a multivariate extension of linkage disequilibrium, we have developed a novel method, based on distances between with a disease phe- notype. Since a disease-associated interacting locus will often be in linkage disequilibrium

Washington at Seattle, University of

84

Virtual Gene: Using Correlations Between Genes to Select Informative Genes on Microarray Datasets  

E-print Network

Virtual Gene: Using Correlations Between Genes to Select Informative Genes on Microarray Datasets State University of New York at Buffalo, Buffalo, NY 14260, USA Abstract. Gene Selection is one class of most used data analysis algorithms on microarray datasets. The goal of gene selection algorithms

Buffalo, State University of New York

85

The evolution of the plastid chromosome in land plants: gene content, gene order, gene function  

E-print Network

The evolution of the plastid chromosome in land plants: gene content, gene order, gene function and evolution- ary aspects of plastid chromosome architecture in land plants and their putative ancestors. We. Keywords Plastid genome Á Land plants Á Genome evolution Á Plastid gene function Á Gene retention

dePamphilis, Claude

86

Gene Testing for Hereditary Ataxia  

MedlinePLUS

... FAQ NATIONAL ATAXIA FOUNDATION FREQUENTLY ASKED QUESTIONS ABOUT... Gene Testing for Hereditary Ataxia This fact sheet provides ... onset. For which of the hereditary ataxias is gene testing available? Discovery of specific ataxia genes makes ...

87

Bispecific Antibodies and Gene Therapy  

Microsoft Academic Search

\\u000a Gene therapy is the transfer of therapeutic genes, via gene transfer vectors, into patients for therapeutic purposes. Different\\u000a gene therapy strategies are being pursued, including long-term gene correction of monogenetic diseases, eradication of tumor\\u000a cells in cancer patients, or genetic vaccination for infectious diseases. Bispecific antibodies and gene therapy are connected\\u000a in two ways. First, bispecific antibodies are tools of

Dirk M. Nettelbeck

88

Genes and Social Behavior  

PubMed Central

What specific genes and regulatory sequences contribute to the organization and functioning of brain circuits that support social behavior? How does social experience interact with information in the genome to modulate these brain circuits? Here we address these questions by highlighting progress that has been made in identifying and understanding two key “vectors of influence” that link genes, brain, and social behavior: 1) social information alters gene readout in the brain to influence behavior; and 2) genetic variation influences brain function and social behavior. We also briefly discuss how evolutionary changes in genomic elements influence social behavior and outline prospects for a systems biology of social behavior. PMID:18988841

Robinson, Gene E.; Fernald, Russell D.; Clayton, David F.

2011-01-01

89

TIGR Drosophila Gene Index  

NSDL National Science Digital Library

TIGR, The Institute for Genomic Research, has announced the release of the Drosophila Gene Index (DGI). The Drosophila Gene Index, which may be searched by Nucleotide or Protein Sequence, Identifier (TC, ET, EST, GB) Tissue, cDNA Library Name or cDNA Library Identifier(cat#), or Gene Product Name, contains some 50,500 total sequences (ET, EST, TC, and singletons). Data may be requested free of charge by "researchers at non-profit institutions using it for non-commercial purposes;" instructions are provided on-site.

1999-01-01

90

CARTaGENE Project  

Cancer.gov

Launched in October 2009, the CARTaGENE project is the largest prospective longitudinal cohort of Québec. CARTaGENE's distinguishing features are that it is a quantitative prospective cohort that has deeply phenotyped 20,000 individuals aged 40-69, the age most individuals will develop chronic disease. 37,000 individuals will be enrolled by 2014. It is an open-access infrastructure enabling researchers to investigate the genetic, environmental, and lifestyle determinants of disease in the French Canadian population. CARTaGENE has collected whole blood for DNA from 30,000 individuals.

91

Gene-gene interaction between tuberculosis candidate genes in a South African population  

Microsoft Academic Search

In a complex disease such as tuberculosis (TB) it is increasingly evident that gene-gene interactions play a far more important\\u000a role in an individual’s susceptibility to develop the disease than single polymorphisms on their own, as one gene can enhance\\u000a or hinder the expression of another gene. Gene-gene interaction analysis is a new approach to elucidate susceptibility to\\u000a TB. The

Erika de Wit; Lize van der Merwe; Paul D. van Helden; Eileen G. Hoal

2011-01-01

92

Gene Regulation: Gene Control Network in Development  

Microsoft Academic Search

Abstract Controlling the differential expression of many,thousands,of genes is the most fundamental,task of a developing organism. It requires an enormous,computational,device that has the capacity to process in parallel a vast number,of regulatory inputs in the various cells of the embryo,and,come,out with regulatory outputs that are tissue specific. The regulatory genome,constitutes this computational,de- vice, comprising many thousands of processing units in

Smadar Ben-Tabou de-Leon; Eric H. Davidson

2007-01-01

93

Positive Darwinian Selection after Gene Duplication in Primate Ribonuclease Genes  

Microsoft Academic Search

Evolutionary mechanisms of origins of new gene function have been a subject of long-standing debate. Here we report a convincing case in which positive Darwinian selection operated at the molecular level during the evolution of novel function by gene duplication. The genes for eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) in primates belong to the ribonuclease gene family, and

Jianzhi Zhang; Helene F. Rosenberg; Masatoshi Nei

1998-01-01

94

5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP ...  

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP PLANT IS AT CENTER WITH ADMINISTRATIVE COMPLEX IN FOREGROUND AND RESIDENTIAL AREA BEYOND PLANT. - Gene Pump Plant, South of Gene Wash Reservoir, 2 miles west of Whitsett Pump Plant, Parker Dam, San Bernardino County, CA

95

A Gene Scrapbook A Tribute to Gene Loh  

E-print Network

A Gene Scrapbook A Tribute to Gene Loh on the Occasion of His Retirement Feb 22, 2003 #12;The Early of Technology, 1961 #12;The Missing Years Not much is known about Gene's whereabouts between 1961 until his (probably kelp) for transport by sea. #12;Why did Gene leave Cornell? He got tired of shoveling all

96

Connectionist Approaches for Predicting Mouse Gene Function from Gene Expression  

E-print Network

Therapy. Identifying gene function based on gene expression data is much easier in prokaryotes than eukaryotes due to the relatively simple structure of prokaryotes. That is why tissue-specific expression ways, especially in Gene Therapy [5]. Identifying gene function in prokaryotes is much easier than

Bonner, Anthony

97

Using Gene Expression Noise to Understand Gene Regulation  

E-print Network

REVIEW Using Gene Expression Noise to Understand Gene Regulation Brian Munsky,1 * Gregor Neuert,2 * Alexander van Oudenaarden2,3 Phenotypic variation is ubiquitous in biology and is often traceable environments display variable phenotypes. Stochastic gene expression, or gene expression "noise," has been

Munsky, Brian

98

Immunity-Related Genes and Gene Families in Anopheles gambiae  

Microsoft Academic Search

We have identified 242 Anopheles gambiae genes from 18 gene families implicated in innate immunity and have detected marked diversification relative to Drosophila melanogaster. Immune-related gene families involved in recognition, signal modulation, and effector systems show a marked deficit of orthologs and excessive gene expansions, possibly reflecting selection pressures from different pathogens encountered in these insects' very different life-styles. In

George K. Christophides; Evgeny Zdobnov; Carolina Barillas-Mury; Ewan Birney; Stephanie Blandin; Claudia Blass; Paul T. Brey; Frank H. Collins; Alberto Danielli; George Dimopoulos; Charles Hetru; Ngo T. Hoa; Jules A. Hoffmann; Stefan M. Kanzok; Ivica Letunic; Elena A. Levashina; Thanasis G. Loukeris; Gareth Lycett; Stephan Meister; Kristin Michel; Luis F. Moita; Hans-Michael Müller; Mike A. Osta; Susan M. Paskewitz; Jean-Marc Reichhart; Andrey Rzhetsky; Laurent Troxler; Kenneth D. Vernick; Dina Vlachou; Jennifer Volz; Christian von Mering; Jiannong Xu; Liangbiao Zheng; Peer Bork; Fotis C. Kafatos

2002-01-01

99

Harnessing Gene Expression Networks to Prioritize Candidate Epileptic Encephalopathy Genes  

PubMed Central

We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets. PMID:25014031

Oliver, Karen L.; Lukic, Vesna; Thorne, Natalie P.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Bahlo, Melanie

2014-01-01

100

Reading and Generalist Genes  

PubMed Central

Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called generalist genes. This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading ability in a study of 4,258 7-year-old children that screened 100,000 SNPs. Using the same sample, we show that this early reading SNP set also correlates with other aspects of literacy, components of mathematics, and more general cognitive abilities. These results provide support for the generalist genes hypothesis. Although the effect size of the current SNP set is small, such SNP sets could eventually be used to predict genetic risk for learning disabilities as well as to prescribe genetically tailored intervention and prevention programs. PMID:20383260

Haworth, Claire M A; Meaburn, Emma L; Harlaar, Nicole; Plomin, Robert

2007-01-01

101

Genes underlying altruism  

PubMed Central

William D. Hamilton postulated the existence of ‘genes underlying altruism’, under the rubric of inclusive fitness theory, a half-century ago. Such genes are now poised for discovery. In this article, we develop a set of intuitive criteria for the recognition and analysis of genes for altruism and describe the first candidate genes affecting altruism from social insects and humans. We also provide evidence from a human population for genetically based trade-offs, underlain by oxytocin-system polymorphisms, between alleles for altruism and alleles for non-social cognition. Such trade-offs between self-oriented and altruistic behaviour may influence the evolution of phenotypic diversity across all social animals. PMID:24132092

Thompson, Graham J.; Hurd, Peter L.; Crespi, Bernard J.

2013-01-01

102

Microfluidic gene synthesis  

E-print Network

The ability to synthesize custom de novo DNA constructs rapidly, accurately, and inexpensively is highly desired by researchers, as synthetic genes and longer DNA constructs are enabling to numerous powerful applications ...

Kong, David Sun, 1979-

2008-01-01

103

Some Genes Are Dominant  

NSDL National Science Digital Library

This interactive activity, adapted from the Dolan DNA Learning Center, illustrates how Gregor Mendel used pure-bred yellow and green peas to show that some genes are dominant and others are recessive.

Foundation, Wgbh E.

2007-04-19

104

Genes, chromosomes, and rhabdomyosarcoma.  

PubMed

Rhabdomyosarcomas are a heterogeneous group of malignant tumors and are the most common soft-tissue sarcoma of childhood. Rhabdomyosarcomas resemble developing skeletal muscle, notably in their expression of the MRF family of transcription factors and the PAX3 and PAX7 genes. These PAX genes are also involved through specific translocations, t(2;13)(q35;q14) and variant t(1;13)(p36;q14) in the alveolar subtype, which result in PAX3-FKHR and PAX7-FKHR fusion genes, respectively. The fusion genes are thought critically to affect downstream targets of PAX3 and PAX7 or possibly have novel targets. Similar downstream changes may also be involved in embryonal and fusion gene negative cases. Genomic amplification of such genes as MYCN, MDM2, CDK4, and PAX7-FKHR is a feature mainly of the alveolar subtype, while specific chromosomal gains, including chromosomes 2, 8, 12, and 13, are associated with the embryonal subtype. Loss of alleles and imprinting at 11p15.5 and disruption of genes such as IGF2, ATR, PTC, P16, and TP53 have also been implicated in rhabdomyosarcoma development. Whereas there is now a realistic possibility of cure in the majority of cases, there remains a subset that is resistant to multimodality therapy, including high-dose chemotherapy. Characterization of the defining molecular features of tumors that are likely to behave aggressively represents a particular challenge. Current research is leading toward a better understanding of rhabdomyosarcoma tumorigenesis, which may ultimately result in novel therapeutic strategies that increase the overall cure. Genes Chromosomes Cancer 26:275-285, 1999. PMID:10534762

Anderson, J; Gordon, A; Pritchard-Jones, K; Shipley, J

1999-12-01

105

Stochastic Gene Expression Model Base Gene Regulatory Networks  

NASA Astrophysics Data System (ADS)

Gene regulatory networks consist of a number of genes and their interactions which regulate expressions of the genes. Along with the development of gene regulatory network studies, computer simulations have become a valuable tool to evaluate complex relationships between genes. Due to the stochastic nature of gene expressions, various stochastic approaches have attracted increasing interest. In this study, we build gene regulatory networks based on a stochastic gene expression model with delicate assumptions such as transcription, translation, DNA-protein, protein-protein associations and time delay for protein activation. Two simple in-silico gene regulatory network models are constructed and monitored their expression profiles reflecting the inhibition and activation of the gene regulations.

Kim, Haseong; Gelenbe, Erol

106

Hox genes and study of Hox genes in crustacean  

NASA Astrophysics Data System (ADS)

Homeobox genes have been discovered in many species. These genes are known to play a major role in specifying regional identity along the anterior-posterior axis of animals from a wide range of phyla. The products of the homeotic genes are a set of evolutionarily conserved transcription factors that control elaborate developmental processes and specify cell fates in metazoans. Crustacean, presenting a variety of body plans not encountered in any other class or phylum of the Metazoa, has been shown to possess a single set of homologous Hox genes like insect. The ancestral crustacean Hox gene complex comprised ten genes: eight homologous to the hometic Hox genes and two related to nonhomeotic genes presented within the insect Hox complexes. The crustacean in particular exhibits an abundant diversity segment specialization and tagmosis. This morphological diversity relates to the Hox genes. In crustacean body plan, different Hox genes control different segments and tagmosis.

Hou, Lin; Chen, Zhijuan; Xu, Mingyu; Lin, Shengguo; Wang, Lu

2004-12-01

107

GeneClinics  

PubMed Central

GeneClinics is an online genetic information resource consisting of descriptions of specific inherited disorders (“disease profiles”) as well as information on the role of genetic testing in the diagnosis, management, and genetic counseling of patients with these inherited conditions. GeneClinics is intended to promote the use of genetic services in medical care and personal decision making by providing health care practitioners and patients with information on genetic testing for specific inherited disorders. GeneClinics is implemented as an object-oriented database containing a combination of data and semistructured text that is rendered as HTML for publishing a given “disease profile” on the Web. Content is acquired from authors via templates, converted to an XML document reflecting the underlying database schema (with tagging of embedded data), and then loaded into the database and subjected to peer review. The initial implementation of a production system and the first phase of population of the GeneClinics database content are complete. Further expansion of the content to cover more disease, significant scaling up of rate of content creation, and evaluation redesign are under way. The ultimate goal is to have an entry in GeneClinics for each entry in the GeneTests directory of medical genetics laboratories—that is, for each disease for which clinical genetic testing is available. PMID:10833163

Tarczy-Hornoch, Peter; Shannon, Paul; Baskin, Patty; Espeseth, Miriam; Pagon, Roberta A.

2000-01-01

108

GeneCards Version 3: the human gene integrator.  

PubMed

GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73,000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards' unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene's functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org. PMID:20689021

Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

2010-01-01

109

Mytilus edulis Histone Gene Clusters Containing Only H1 Genes  

Microsoft Academic Search

.   We isolated five different phage clones containing histone gene clusters with up to five H1 genes per phage clone from a\\u000a Mytilus edulis genomic library. Among these H1 genes, nine gene types coding for five different H1 proteins have been identified. All H1\\u000a histone genes were located on repetitive restriction fragments with only slightly different sizes. The H1 coding

Birgit Drabent; Jae-Sun Kim; Werner Albig; Eva Prats; Luis Cornudella; Detlef Doenecke

1999-01-01

110

5____________________________________________________________________________ Gene Regulation in Spermatogenesis  

E-print Network

Nuclear Receptors C. HeatShock Factors D. Sox E. Plzf F. Dmrt1 G. CAF1 H. Homeobox Genes I. Perspective IV5____________________________________________________________________________ Gene Regulation. TestisSpecific Gene Expression and DNA Methylation A. Male Germ Cell­Specific Genes B. SomaticCell Testis

Wilkinson, Miles F.

111

Gene Therapy and Children (For Parents)  

MedlinePLUS

... that don't respond to conventional therapies. About Genes Our genes help make us unique. Inherited from ... by a "bad" gene. Continue Two Types of Gene Therapy The two forms of gene therapy are: ...

112

FunGene: the functional gene pipeline and repository  

PubMed Central

Ribosomal RNA genes have become the standard molecular markers for microbial community analysis for good reasons, including universal occurrence in cellular organisms, availability of large databases, and ease of rRNA gene region amplification and analysis. As markers, however, rRNA genes have some significant limitations. The rRNA genes are often present in multiple copies, unlike most protein-coding genes. The slow rate of change in rRNA genes means that multiple species sometimes share identical 16S rRNA gene sequences, while many more species share identical sequences in the short 16S rRNA regions commonly analyzed. In addition, the genes involved in many important processes are not distributed in a phylogenetically coherent manner, potentially due to gene loss or horizontal gene transfer. While rRNA genes remain the most commonly used markers, key genes in ecologically important pathways, e.g., those involved in carbon and nitrogen cycling, can provide important insights into community composition and function not obtainable through rRNA analysis. However, working with ecofunctional gene data requires some tools beyond those required for rRNA analysis. To address this, our Functional Gene Pipeline and Repository (FunGene; http://fungene.cme.msu.edu/) offers databases of many common ecofunctional genes and proteins, as well as integrated tools that allow researchers to browse these collections and choose subsets for further analysis, build phylogenetic trees, test primers and probes for coverage, and download aligned sequences. Additional FunGene tools are specialized to process coding gene amplicon data. For example, FrameBot produces frameshift-corrected protein and DNA sequences from raw reads while finding the most closely related protein reference sequence. These tools can help provide better insight into microbial communities by directly studying key genes involved in important ecological processes. PMID:24101916

Fish, Jordan A.; Chai, Benli; Wang, Qiong; Sun, Yanni; Brown, C. Titus; Tiedje, James M.; Cole, James R.

2013-01-01

113

Gene therapy prospects--intranasal delivery of therapeutic genes.  

PubMed

Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue. PMID:23240459

Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Ma?ecki, Maciej

2012-01-01

114

DETECTING CANCER-RELATED GENES AND GENE-GENE INTERACTIONS BY MACHINE LEARNING METHODS  

E-print Network

..........................................................................................................1 1.1 SIGNIFICANCE OF DETECTING CANCER-RELATED GENES AND GENE-GENE INTERACTIONS ...1 1.2 MY CONTRIBUTION.................................................................................................................3 CHAPTER 2 BACKGROUND... AND RELATED WORK.................................................................8 2.1 DIFFERENTIAL GENE DETECTION...................................................................................................8 2.1.1 Statistical Methods for Detecting...

Han, Bing

2011-12-31

115

Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions  

Microsoft Academic Search

Motivation: Polymorphisms in human genes are being described in remarkable numbers. Determining which polymorphisms and which environmental factors are associated with common, complex diseases has become a daunting task. This is partly because the effect of any single genetic variation will likely be dependent on other genetic variations (gene-gene interaction or epistasis) and environmental factors (gene-environment interac- tion). Detecting and

Lance W. Hahn; Marylyn D. Ritchie; Jason H. Moore

2003-01-01

116

Gene finding in metatranscriptomic sequences  

PubMed Central

Background Metatranscriptomic sequencing is a highly sensitive bioassay of functional activity in a microbial community, providing complementary information to the metagenomic sequencing of the community. The acquisition of the metatranscriptomic sequences will enable us to refine the annotations of the metagenomes, and to study the gene activities and their regulation in complex microbial communities and their dynamics. Results In this paper, we present TransGeneScan, a software tool for finding genes in assembled transcripts from metatranscriptomic sequences. By incorporating several features of metatranscriptomic sequencing, including strand-specificity, short intergenic regions, and putative antisense transcripts into a Hidden Markov Model, TranGeneScan can predict a sense transcript containing one or multiple genes (in an operon) or an antisense transcript. Conclusion We tested TransGeneScan on a mock metatranscriptomic data set containing three known bacterial genomes. The results showed that TranGeneScan performs better than metagenomic gene finders (MetaGeneMark and FragGeneScan) on predicting protein coding genes in assembled transcripts, and achieves comparable or even higher accuracy than gene finders for microbial genomes (Glimmer and GeneMark). These results imply, with the assistance of metatranscriptomic sequencing, we can obtain a broad and precise picture about the genes (and their functions) in a microbial community. Availability TransGeneScan is available as open-source software on SourceForge at https://sourceforge.net/projects/transgenescan/. PMID:25253067

2014-01-01

117

Engineered Gene Circuits  

NASA Astrophysics Data System (ADS)

Uncovering the structure and function of gene regulatory networks has become one of the central challenges of the post-genomic era. Theoretical models of protein-DNA feedback loops and gene regulatory networks have long been proposed, and recently, certain qualitative features of such models have been experimentally corroborated. This talk will focus on model and experimental results that demonstrate how a naturally occurring gene network can be used as a ``parts list'' for synthetic network design. The model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics, and the utility of such a formulation will be demonstrated through the consideration of specific design criteria for several novel genetic devices. Fluctuations originating from small molecule-number effects will be discussed in the context of model predictions, and the experimental validation of these stochastic effects underscores the importance of internal noise in gene expression. Potential biotech applications will be highlighted within the framework of cellular control schemes. Specifically, the coupling of an oscillating cellular process to a synthetic oscillator will be considered, and the resulting model behavior will be analyzed in the context of synchronization. The underlying methodology highlights the utility of engineering-based methods in the design of synthetic gene regulatory networks.

Hasty, Jeff

2003-03-01

118

Gene Network Biological Validity Based on Gene-Gene Interaction Relevance  

PubMed Central

In recent years, gene networks have become one of the most useful tools for modeling biological processes. Many inference gene network algorithms have been developed as techniques for extracting knowledge from gene expression data. Ensuring the reliability of the inferred gene relationships is a crucial task in any study in order to prove that the algorithms used are precise. Usually, this validation process can be carried out using prior biological knowledge. The metabolic pathways stored in KEGG are one of the most widely used knowledgeable sources for analyzing relationships between genes. This paper introduces a new methodology, GeneNetVal, to assess the biological validity of gene networks based on the relevance of the gene-gene interactions stored in KEGG metabolic pathways. Hence, a complete KEGG pathway conversion into a gene association network and a new matching distance based on gene-gene interaction relevance are proposed. The performance of GeneNetVal was established with three different experiments. Firstly, our proposal is tested in a comparative ROC analysis. Secondly, a randomness study is presented to show the behavior of GeneNetVal when the noise is increased in the input network. Finally, the ability of GeneNetVal to detect biological functionality of the network is shown. PMID:25295303

Gómez-Vela, Francisco; Díaz-Díaz, Norberto

2014-01-01

119

Genes and Vocal Learning  

PubMed Central

Could a mutation in a single gene be the evolutionary lynchpin supporting the development of human language? A rare mutation in the molecule known as FOXP2 discovered in a human family seemed to suggest so, and its sequence phylogeny reinforced a Chomskian view that language emerged wholesale in humans. Spurred by this discovery, research in primates, rodents and birds suggests that FoxP2 and other language-related genes are interactors in the neuromolecular networks that underlie subsystems of language, such symbolic understanding, vocal learning and theory of mind. The whole picture will only come together through comparative and integrative study into how the human language singularity evolved. PMID:19913899

White, Stephanie A.

2009-01-01

120

IBM Research: Blue Gene  

NSDL National Science Digital Library

This is the home page of an IBM research and development project that is designing a supercomputer, called Blue Gene/L, capable of 200 trillion floating point operations per second. According to the Web site, this specification "is larger than the total computing power of the top 500 supercomputers in the world today." Working in collaboration with Lawrence Livermore National Laboratories, IBM expects the project to be completed by 2005. There are a few publications and presentations given about the status of the project and its uses. There is also a fact sheet and several industry links about protein folding, which is the main application of Blue Gene/L.

1999-01-01

121

XLMR genes: Update 1994  

SciTech Connect

We provide a comprehensive list of all known forms of X-linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes. The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators. 74 refs., 2 figs., 5 tabs.

Neri, G.; Chiurazzi, P. [Universita Cattolica del Sacro Cuore, Rome (Italy); Arena, J.F.; Lubs, H.A. [Univ. of Miami School of Medicine, FL (United States)

1994-07-15

122

Gene Characterization Index: Assessing the Depth of Gene Annotation  

PubMed Central

Background We introduce the Gene Characterization Index, a bioinformatics method for scoring the extent to which a protein-encoding gene is functionally described. Inherently a reflection of human perception, the Gene Characterization Index is applied for assessing the characterization status of individual genes, thus serving the advancement of both genome annotation and applied genomics research by rapid and unbiased identification of groups of uncharacterized genes for diverse applications such as directed functional studies and delineation of novel drug targets. Methodology/Principal Findings The scoring procedure is based on a global survey of researchers, who assigned characterization scores from 1 (poor) to 10 (extensive) for a sample of genes based on major online resources. By evaluating the survey as training data, we developed a bioinformatics procedure to assign gene characterization scores to all genes in the human genome. We analyzed snapshots of functional genome annotation over a period of 6 years to assess temporal changes reflected by the increase of the average Gene Characterization Index. Applying the Gene Characterization Index to genes within pharmaceutically relevant classes, we confirmed known drug targets as high-scoring genes and revealed potentially interesting novel targets with low characterization indexes. Removing known drug targets and genes linked to sequence-related patent filings from the entirety of indexed genes, we identified sets of low-scoring genes particularly suited for further experimental investigation. Conclusions/Significance The Gene Characterization Index is intended to serve as a tool to the scientific community and granting agencies for focusing resources and efforts on unexplored areas of the genome. The Gene Characterization Index is available from http://cisreg.ca/gci/. PMID:18213364

Yusuf, Dimas; Brumm, Jochen; Cheung, Warren; Wahlestedt, Claes; Lenhard, Boris; Wasserman, Wyeth W.

2008-01-01

123

Selection of reference genes for gene expression studies in astrocytomas  

Microsoft Academic Search

This study was aimed to test a panel of six housekeeping genes (GAPDH, HPRT1, POLR2A, RPLP0, ACTB, and H3F) so as to identify and validate the most suitable reference genes for expression studies in astrocytomas. GAPDH was the most stable and HPRT1 was the least stable reference gene. The effect of reference gene selection on quantitative real-time polymerase chain reaction

Sylwia M. Gresner; Ewa Golanska; Dominika Kulczycka-Wojdala; Dariusz J. Jaskolski; Wielislaw Papierz; Pawel P. Liberski

2011-01-01

124

Reactivating Tumor Suppressor Genes  

Cancer.gov

This is the first clinical trial to test the combination of a drug called 5-fluoro-2'-deoxycytidine (FdCyd) and tetrahydrouridine (THU) in humans. Researchers are interested in establishing the maximum tolerated dose and determining how this regimen affects the activity of certain tumor suppressor genes in patients with advanced solid tumors.

125

Ultrasound mediated gene transfection  

NASA Astrophysics Data System (ADS)

Gene therapy is a promising modality for the treatment of a variety of human diseases both inherited and acquired, such as cystic fibrosis and cancer. The lack of an effective, safe method for the delivery of foreign genes into the cells, a process known as transfection, limits this effort. Ultrasound mediated gene transfection is an attractive method for gene delivery since it is a noninvasive technique, does not introduce any viral particles into the host and can offer very good temporal and spatial control. Previous investigators have shown that sonication increases transfection efficiency with and without ultrasound contrast agents. The mechanism is believed to be via a cavitation process where collapsing bubble nuclei permeabilize the cell membrane leading to increased DNA transfer. The research is focused on the use of pulsed wave high frequency focused ultrasound to transfect DNA into mammalian cells in vitro and in vivo. A better understanding of the mechanism behind the transfection process is also sought. A summary of some in vitro results to date will be presented, which includes the design of a sonication chamber that allows us to model the in vivo case more accurately.

Williamson, Rene G.; Apfel, Robert E.; Brandsma, Janet L.

2002-05-01

126

Gene-Environment Interdependence  

ERIC Educational Resources Information Center

Behavioural genetics was initially concerned with partitioning population variance into that due to genetics and that due to environmental influences. The implication was that the two were separate and it was assumed that gene-environment interactions were usually of so little importance that they could safely be ignored. Theoretical…

Rutter, Michael

2007-01-01

127

Horizontal Gene Transfer  

NSDL National Science Digital Library

This Citizendium article offers a comprehensive review of horizontal gene transfer (HGT). Topics include main features of HGT in nature, HGT in prokaryotes, HGT in eukaryotes, history and discovery of HGT, and decoding the tree of life from genomes scrambled by HGT. The image-rich text includes a list of related articles, a bibliography and external links of interest.

Citizendium

128

Genes and Vocal Learning  

ERIC Educational Resources Information Center

Could a mutation in a single gene be the evolutionary lynchpin supporting the development of human language? A rare mutation in the molecule known as FOXP2 discovered in a human family seemed to suggest so, and its sequence phylogeny reinforced a Chomskian view that language emerged wholesale in humans. Spurred by this discovery, research in…

White, Stephanie A.

2010-01-01

129

Gene Manipulation In Cereals  

Technology Transfer Automated Retrieval System (TEKTRAN)

Aluminum, the most abundant metal on earth, is detrimental to plant growth and agricultural production. There are about 2.5 billion hectares of acid soils high in aluminum around the world. Molecular markers linked to aluminum tolerance gene complexes in rye would be of value in marker-mediated ge...

130

Gene electrotransfer clinical trials.  

PubMed

Plasmid or non-viral gene therapy offers an alternative to classic viral gene delivery that negates the need for a biological vector. In this case, delivery is enhanced by a variety of approaches including lipid or polymer conjugation, particle-mediated delivery, hydrodynamic delivery, ultrasound or electroporation. Electroporation was originally used as a laboratory tool to deliver DNA to bacterial and mammalian cells in culture. Electrode development allowed this technique to be modified for in vivo use. After preclinical therapeutic studies, clinical delivery of cell impermeant chemotherapeutic agents progressed to clinical delivery of plasmid DNA. One huge benefit of this delivery technique is its malleability. The pulse protocol used for plasmid delivery can be fine-tuned to control the levels and duration of subsequent transgene expression. This fine-tuning allows transgene expression to be tailored to each therapeutic application. Effective and appropriate expression induces the desired clinical response that is a critical component for any gene therapy. This chapter focuses on clinical trials using in vivo electroporation or electrotransfer as a plasmid delivery method. The first clinical trial was initiated in 2004, and now more than fifty trials use electric fields for gene delivery. Safety and tolerability has been demonstrated by several groups, and early clinical efficacy results are promising in both cancer therapeutic and infectious disease vaccine applications. PMID:25620013

Heller, Richard; Heller, Loree C

2015-01-01

131

Resistance gene capture.  

PubMed

Integrons are the primary mechanism for antibiotic-resistance gene capture and dissemination among Gram-negative bacteria. The recent finding of super-integron structures in the genomes of several bacterial species has expanded their role in genome evolution and suggests that they are the source of mobile multi-resistant integrons. PMID:10508722

Rowe-Magnus, D A; Mazel, D

1999-10-01

132

Graphene based gene transfection.  

PubMed

Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy. PMID:21270989

Feng, Liangzhu; Zhang, Shuai; Liu, Zhuang

2011-03-01

133

UBE3A Gene  

NSDL National Science Digital Library

Fang et al. (1999) sequenced the major coding exons of the UBE3A gene in 56 index patients with a clinical diagnosis of Angelman syndrome (105830) and a normal DNA methylation pattern. Disease-causing mutations were identified in 17 of the 56 patients (30%),

2009-04-14

134

Genes in mammalian reproduction  

SciTech Connect

This is an informative book which deals mainly with genomic imprinting, the role of steroid hormones in development, the expression of a variety of genes during development and the link to hereditary diseases. It is an up-to-date review in a field that is quickly changing and provides valuable basic information and current research trends.

Gwatkin, R.B.L. [ed.

1996-11-01

135

Gene therapy in diabetes  

PubMed Central

Type 1 diabetes (T1D) is a chronic autoimmune disease, whereby auto-reactive cytotoxic T cells target and destroy insulin-secreting ?-cells in pancreatic islets leading to insulin deficiency and subsequent hyperglycemia. These individuals require multiple daily insulin injections every day of their life without which they will develop life-threatening diabetic ketoacidosis (DKA) and die. Gene therapy by viral vector and non-viral transduction may be useful techniques to treat T1D as it can be applied from many different angles; such as the suppression of autoreactive T cells to prevent islet destruction (prophylactic) or the replacement of the insulin gene (post-disease). The need for a better method for providing euglycemia arose from insufficient numbers of cadaver islets for transplantation and the immunosuppression required post-transplant. Ectopic expression of insulin or islet modification have been examined, but not perfected. This review examines the various gene transfer methods, gene therapy techniques used to date and promising novel techniques for the maintenance of euglycemia in the treatment of T1D. PMID:21487475

Wong, Mary S; Hawthorne, Wayne J

2010-01-01

136

Differentially Coexpressed Genes  

E-print Network

Fine-tuning #12;Do these pattern exist in real data ? Acute Lymphoblastic Leukemia · About 1/3 of all compared cytogenetically normal children to those with the phil+ translocation Yeoh EJ, RossMEet al. (2002) Classication, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene

Spang, Rainer

137

GENE METHYLATION CHANGES IN TUMOR SUPPRESSOR GENES INDUCED BY ARSENIC  

EPA Science Inventory

The choice of a dose-response model used for extrapolation can be influenced by knowledge of mechanism of action. We have already showed that arsenic affects methylation of the human p53 gene promoter. Evidence that genes other than the p53 tumor suppressor gene are affected woul...

138

Gene modulation in Drosophila: Dosage compensation and relocated v + genes  

Microsoft Academic Search

The v+ gene of Drosophila and its associated enzyme, tryptophan pyrrolase, were employed in a study of the relationship between dosage compensation and the location of the gene in the genome. Enzyme assays performed on various genotypes indicate that although differently positioned genes may specify different enzyme activities, they still show dosage compensation. In each rearrangement examined, the enzyme activity

Jack Tobler; James T. Bowman; John R. Simmons

1971-01-01

139

Eukaryotic Gene Prediction Using GeneMark.hmm-E and GeneMark-ES  

PubMed Central

This unit describes how to use gene finding programs GeneMark.hmm-E and GeneMark-ES for finding protein-coding genes in genomic DNA of eukaryotic genomes. These bioinformatics tools were demonstrated to have state-of-the-art accuracy for many fungal, plant and animal genomes and have been frequently used for gene annotation in novel genomic sequences. Additional advantage of GeneMark-ES is that the problem of algorithm parameterization is solved automatically, with parameters estimated by iterative self-training (unsupervised training). PMID:21901742

Borodovsky, Mark; Lomsadze, Alex

2011-01-01

140

Interactive Fly: Maternally transcribed genes  

NSDL National Science Digital Library

The maternally transcribed genes section of the award-winning and comprehensive site: Interactive fly. It thoroughly discusses genes, tissues, biochemical paths, and developmental processes in the fruit fly, Drosophila.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-11-13

141

Intervention in gene regulatory networks  

E-print Network

In recent years Boolean Networks (BN) and Probabilistic Boolean Networks (PBN) have become popular paradigms for modeling gene regulation. A PBN is a collection of BNs in which the gene state vector transitions according to the rules of one...

Choudhary, Ashish

2006-10-30

142

Using Genes to Guide Prescriptions  

MedlinePLUS

... role in how your body responds to medicines. Credit: Stock image. Your genes determine the color of ... of them, and genes might make the difference. Credit: Stock image. For people who have had a ...

143

Chapter 15: Disease Gene Prioritization  

PubMed Central

Disease-causing aberrations in the normal function of a gene define that gene as a disease gene. Proving a causal link between a gene and a disease experimentally is expensive and time-consuming. Comprehensive prioritization of candidate genes prior to experimental testing drastically reduces the associated costs. Computational gene prioritization is based on various pieces of correlative evidence that associate each gene with the given disease and suggest possible causal links. A fair amount of this evidence comes from high-throughput experimentation. Thus, well-developed methods are necessary to reliably deal with the quantity of information at hand. Existing gene prioritization techniques already significantly improve the outcomes of targeted experimental studies. Faster and more reliable techniques that account for novel data types are necessary for the development of new diagnostics, treatments, and cure for many diseases. PMID:23633938

Bromberg, Yana

2013-01-01

144

Chapter 15: disease gene prioritization.  

PubMed

Disease-causing aberrations in the normal function of a gene define that gene as a disease gene. Proving a causal link between a gene and a disease experimentally is expensive and time-consuming. Comprehensive prioritization of candidate genes prior to experimental testing drastically reduces the associated costs. Computational gene prioritization is based on various pieces of correlative evidence that associate each gene with the given disease and suggest possible causal links. A fair amount of this evidence comes from high-throughput experimentation. Thus, well-developed methods are necessary to reliably deal with the quantity of information at hand. Existing gene prioritization techniques already significantly improve the outcomes of targeted experimental studies. Faster and more reliable techniques that account for novel data types are necessary for the development of new diagnostics, treatments, and cure for many diseases. PMID:23633938

Bromberg, Yana

2013-04-01

145

Gene expression in aggressive fibromatosis  

Microsoft Academic Search

Aggressive fibromatosis represents a group of tumors with heterogeneous patterns of biologic behavior. In this study, gene expression in 12 samples of aggressive fibromatosis, as well as that in samples of normal skeletal muscle and a variety of normal tissues, was determined at Gene Logic Inc (Gaithersburg, MD), with the use of Affymetrix GeneChip U_133 arrays containing approximately 33,000 genes.

Keith M Skubitz; Amy P. N Skubitz

2004-01-01

146

Gene therapy for lung cancer.  

PubMed

Over the past three decades, the molecular biology of lung cancer has been progressively delineated. Concurrently, gene therapy techniques have been developed that allow targeting or replacement of dysfunctional genes in cancer cells, such as activated tumor-promoting oncogenes, inactivated tumor-suppressing, or apoptosis-promoting genes. This article will review the therapeutic implications of molecular changes associated with non-small cell lung cancer and the status of gene therapy. PMID:16253824

Toloza, Eric M

2005-01-01

147

Gene insertion into Hevea brasiliensis  

Microsoft Academic Search

A transformation system has been developed for Hevea brasiliensis using the particle gun method. Anther derived calluses were transformed with vectors harbouring the ß-glucuronidase (gus) gene, the neomycin phosphotransferase (nptII) gene, and the chloramphenicol acetyl transferase (cat) gene. Gene transfer was determined by histochemical staining and fluorometric assay for ß-glucuronidase activity, enzyme linked immunosorbent assay for detecting neomycin phosphotransferase II

P. Arokiaraj; H. Jones; K. F. Cheong; S. Coomber; B. V. Charlwood

1994-01-01

148

Prediction of disease genes using tissue-specified gene-gene network  

PubMed Central

Background Tissue specificity is an important aspect of many genetic diseases in the context of genetic disorders as the disorder affects only few tissues. Therefore tissue specificity is important in identifying disease-gene associations. Hence this paper seeks to discuss the impact of using tissue specificity in predicting new disease-gene associations and how to use tissue specificity along with phenotype information for a particular disease. Methods In order to find out the impact of using tissue specificity for predicting new disease-gene associations, this study proposes a novel method called tissue-specified genes to construct tissues-specific gene-gene networks for different tissue samples. Subsequently, these networks are used with phenotype details to predict disease genes by using Katz method. The proposed method was compared with three other tissue-specific network construction methods in order to check its effectiveness. Furthermore, to check the possibility of using tissue-specific gene-gene network instead of generic protein-protein network at all time, the results are compared with three other methods. Results In terms of leave-one-out cross validation, calculation of the mean enrichment and ROC curves indicate that the proposed approach outperforms existing network construction methods. Furthermore tissues-specific gene-gene networks make a more positive impact on predicting disease-gene associations than generic protein-protein interaction networks. Conclusions In conclusion by integrating tissue-specific data it enabled prediction of known and unknown disease-gene associations for a particular disease more effectively. Hence it is better to use tissue-specific gene-gene network whenever possible. In addition the proposed method is a better way of constructing tissue-specific gene-gene networks. PMID:25350876

2014-01-01

149

Eukaryotic Gene Prediction Kelli Davies  

E-print Network

Eukaryotic Gene Prediction Kelli Davies 2009 December 12 Introduction: The advent of large in 1977, that of a small bacteriophage consisting of 11 genes over 5.4kb of DNA. In the bacteriophage, coding genes comprise 95% of the genome.1 Since then, numerous prokaryotic and eukaryotic genomes have

150

Independent Gene Discovery and Testing  

ERIC Educational Resources Information Center

A clear understanding of basic gene structure is critical when teaching molecular genetics, the central dogma and the biological sciences. We sought to create a gene-based teaching project to improve students' understanding of gene structure and to integrate this into a research project that can be implemented by instructors at the secondary level…

Palsule, Vrushalee; Coric, Dijana; Delancy, Russell; Dunham, Heather; Melancon, Caleb; Thompson, Dennis; Toms, Jamie; White, Ashley; Shultz, Jeffry

2010-01-01

151

PLANT MORPHOGENESIS AND KNOX GENES  

Technology Transfer Automated Retrieval System (TEKTRAN)

KNOX genes function in plant meristems, which produce leaves and stems. Three recent studies show that the dwarf phenotype, brevipedicellus, is caused by a recessive mutation in a KNOX gene. A fourth study shows that misexpression of KNOX genes leads to novel features that may have selective value....

152

Gene Machine: The Lac Operon  

NSDL National Science Digital Library

Build a gene network! The lac operon is a set of genes which are responsible for the metabolism of lactose in some bacterial cells. Explore the effects of mutations within the lac operon by adding or removing genes from the DNA.

Simulations, Phet I.; Blanco, John; Perkins, Kathy; Podolefsky, Noah; Spiegelman, George; Taylor, Jared

2010-05-01

153

Mouse Genetics: Determining gene function  

E-print Network

Mouse Genetics: Determining gene function An International Centre for Mouse Genetics Mammalian Genetics Unit #12;Determining gene function · Mutagenesis approaches · Gene-driven, phenotype for Mouse Genetics Mammalian Genetics Unit #12;An International Centre for Mouse Genetics Mammalian Genetics

Goldschmidt, Christina

154

Simulating Gene Expression using Netlogo  

NSDL National Science Digital Library

Using a modeling environment that simulates the behavior of DNA, RNA, protein, transcription, and translation, a system can emerge that shows properties qualitatively similar to gene expression models. Two models were created: one simulates the lac operon, one of the classical models in gene expression. Another model illustrates how a gene expression system can behave like any logical gate (AND, OR, NAND, NOR).

Steven Brewer (University of Massachusetts;); Allen Koop (Grand Valley State University;); Patrick Ehrman (Institue for Systems Biology;)

2004-06-12

155

Genes, stress, and depression.  

PubMed

A relationship between genetic makeup and susceptibility to major depressive disorder (MDD) has long been suspected on the basis of family and twin studies. A metaanalysis of reports on the basis of twin studies has estimated MDD's degree of heritability to be 0.33 (confidence interval, 0.26-0.39). Among families exhibiting an increased prevalence of MDD, risk of developing the illness was enhanced in members exposed to a highly stressful environment. Aberrant genes can predispose to depression in a number of ways, for example, by diminishing production of growth factors that act during brain development. An aberrant gene could also increase or decrease a neurotransmitter's release into synapses, its actions, or its duration of activity. The gene products of greatest interest at present are those involved in the synthesis and actions of serotonin; among them, the serotonin-uptake protein localized within the terminals and dendrites of serotonin-releasing neurons. It has been found that the Vmax of platelet serotonin uptake is low in some patients with MDD; also, Vmax is highly correlated in twins. Antidepressant drugs such as the selective serotonin reuptake inhibitors act on this uptake protein. The specific genetic locus causing serotonin uptake to be lower in some patients with major depression involves a polymorphic region (5-HTTLPR) in the promoter region of the gene for the uptake protein. The gene itself exists as several alleles, the short "S" allele and the long "L" allele. The S variant is associated with less, and the L variant with more, of the uptake protein. The effect of stressful life events on depressive symptoms in young adults was found to be significantly stronger among SS or SL subjects than among LL subjects. Neuroimaging studies showed that people with the SS or SL alleles exhibited a greater activation of the amygdala in response to fearful stimuli than those with LL. It has been reported recently that mutations in the gene that controls serotonin synthesis in the human brain (tryptophan hydroxylase) also predispose to mood disturbances. It may be asked whether people who lack a psychiatric history should be advised to avoid stressful environments if they are found to carry the SS or SL alleles. PMID:15877307

Wurtman, Richard J

2005-05-01

156

Genes and Disease: Prader-Willi Syndrome  

MedlinePLUS

... MD): National Center for Biotechnology Information (US); 1998-. Genes and Disease [Internet]. Show details National Center for ... Willi syndrome. PDF version of this page (250K) Gene sequence Genome view see gene locations Entrez Gene ...

157

Genetics Home Reference: What is gene therapy?  

MedlinePLUS

... Genomic Research Next Handbook > Gene Therapy > What is gene therapy? Gene therapy is an experimental technique that ... have no other cures. For general information about gene therapy: MedlinePlus from the National Library of Medicine ...

158

Graphene based gene transfection  

NASA Astrophysics Data System (ADS)

Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy.Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy. Electronic supplementary information (ESI) available: Thickness distribution of GO and GO-PEI; IR and TGA data; and confocal images of HeLa cells treated with bare EGFP pDNA and GO + pDNA. See DOI: 10.1039/c0nr00680g

Feng, Liangzhu; Zhang, Shuai; Liu, Zhuang

2011-03-01

159

Myc Cancer Gene  

NSDL National Science Digital Library

This Web site, offered through Johns Hopkins University School of Medicine and Johns Hopkins Health System, aims to "provide a hub for the integration of information on Myc target genes, the role of Myc in human cancers, and proteins that interact with the Myc transcription factors." Users will find a well-organized collection of resources relating to Myc, such as an extensive set of links to PubMed articles, related databases, and some original data. The Web site's introduction provides a very readable explanation of Myc gene function and its role in tumor formation. Researchers working with Myc are encouraged to submit data to the site, which also offers a Myc-related listserve for convenient email updates.

160

Alginate Gene Regulation  

Microsoft Academic Search

\\u000a Alginate is an important virulence factor of Pseudomonas aeruginosa, and so our understanding of alginate gene regulation is best understood in this species. Expression of the algD operon for alginate biosynthesis is only highly expressed in mucoid clinical isolates that usually have pathoadaptive mucA mutations. The three major regulators of the algD promoter (PalgD) are AlgR, AlgB, and AmrZ. Each

Dennis E. Ohman

161

Pure genes, pure genius.  

PubMed

The 2012 Albert Lasker Special Achievement Award in Medical Science will be shared by Donald Brown and Tom Maniatis for their scientific work leading to the purification and study of single genes by physical and molecular biological methodologies. Brown and Maniatis are also recognized for their extraordinary commitment and generosity in promoting the careers of young scientists. The impact of these accomplishments has transformed biological and medical science over the past four decades. PMID:22980972

McKnight, Steven L

2012-09-14

162

Genes associated with addiction  

Microsoft Academic Search

Drug addiction is a complex disorder that has a large spectrum of causes. Vulnerability to addiction has been shown in twin\\u000a studies to have a robust genetic component. This genetic basis for addiction has general and specific components for each\\u000a drug abused. Although many genes have been implicated in drug addiction, only a handful have either been replicated to have

Mary Jeanne Kreek; David A. Nielsen; K. Steven LaForge

2004-01-01

163

Gene-Gene, Gene-Environment & Multiple Interactions in Colorectal Cancer  

Microsoft Academic Search

This review comprehensively evaluates the influence of gene-gene, gene-environment and multiple interactions on the risk of colorectal cancer (CRC). Methods of studying these interactions and their limitations have been discussed herein. There is a need to develop biomarkers of exposure and of risk that are sensitive, specific, present in the pathway of the disease, and that have been clinically tested

FARID E. AHMED

2006-01-01

164

Physical methods for gene transfer.  

PubMed

The key impediment to the successful application of gene therapy in clinics is not the paucity of therapeutic genes. It is rather the lack of nontoxic and efficient strategies to transfer therapeutic genes into target cells. Over the past few decades, considerable progress has been made in gene transfer technologies, and thus far, three different delivery systems have been developed with merits and demerits characterizing each system. Viral and chemical methods of gene transfer utilize specialized carrier to overcome membrane barrier and facilitate gene transfer into cells. Physical methods, on the other hand, utilize various forms of mechanical forces to enforce gene entry into cells. Starting in 1980s, physical methods have been introduced as alternatives to viral and chemical methods to overcome various extra- and intracellular barriers that limit the amount of DNA reaching the intended cells. Accumulating evidence suggests that it is quite feasible to directly translocate genes into cytoplasm or even nuclei of target cells by means of mechanical force, bypassing endocytosis, a common pathway for viral and nonviral vectors. Indeed, several methods have been developed, and the majority of them share the same underlying mechanism of gene transfer, i.e., physically created transient pores in cell membrane through which genes get into cells. Here, we provide an overview of the current status and future research directions in the field of physical methods of gene transfer. PMID:25620006

Alsaggar, Mohammad; Liu, Dexi

2015-01-01

165

Venom evolution through gene duplications.  

PubMed

Venoms contain highly complex mixtures that typically include hundreds of different components and have evolved independently in a diverse range of animals including platypuses, shrews, snakes, lizards, fishes, echinoderms, spiders, wasps, centipedes, sea snails, cephalopods, jellyfish and sea anemones. Many venom genes evolved through gene duplication. Gene duplication occurs in all domains of life and provides the raw substrate from which novel function arise. In this review, we focus on the role that gene duplication has played in the origin and diversification of venom genes. We outline the selective advantages of venom gene duplicates and the role that selection has played in the retention of these duplicates. We use toxin gene intermediates to help trace the evolution of toxin innovation. We also focus on other genomic processes, such as exon and domain duplications, in venom evolution. Finally, we conclude by focusing on the use of high throughput sequencing technology in understanding venom evolution. PMID:22285376

Wong, Emily S W; Belov, Katherine

2012-03-15

166

Human disease genes: patterns and predictions  

Microsoft Academic Search

We compared genes at which mutations are known to cause human disease (disease genes) with other human genes (nondisease genes) using a large set of human–rodent alignments to infer evolutionary patterns. Such comparisons may be of use both in predicting disease genes and in understanding the general evolution of human genes. Four features were found to differ significantly between disease

Nick G. C. Smith; Adam Eyre-Walker

2003-01-01

167

Relocating a gene for herbicide tolerance: A chloroplast gene is converted into a nuclear gene.  

PubMed

The chloroplast gene psbA codes for the photosynthetic quinone-binding membrane protein Q(B), which is the target of the herbicide atrazine. This gene has been converted into a nuclear gene. The psbA gene from an atrazine-resistant biotype of Amaranthus hybridus has been modified by fusing its coding region to transcription-regulation and transit-peptide-encoding sequences of a bona fide nuclear gene. The constructs were introduced into the nuclear genome of tobacco by using the Agrobacterium tumor-inducing (Ti) plasmid system, and the protein product of nuclear psbA has been identified in the photosynthetic membranes of chloroplasts. Recovery of atrazine-tolerant transgenic plants shows that the product of the transplanted gene functions in photosynthesis. These experiments show that it is possible to modify chloroplast-gene-specified functions via nuclear-genome transformation and also raise evolutionary questions. PMID:16593905

Cheung, A Y; Bogorad, L; Van Montagu, M; Schell, J

1988-01-01

168

Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria.  

PubMed

Among the bilaterally symmetrical, triploblastic animals (the Bilateria), a conserved set of developmental regulatory genes are known to function in patterning the anterior-posterior (AP) axis. This set includes the well-studied Hox cluster genes, and the recently described genes of the ParaHox cluster, which is believed to be the evolutionary sister of the Hox cluster (Brooke et al. 1998). The conserved role of these axial patterning genes in animals as diverse as frogs and flies is believed to reflect an underlying homology (i.e., all bilaterians derive from a common ancestor which possessed an AP axis and the developmental mechanisms responsible for patterning the axis). However, the origin and early evolution of Hox genes and ParaHox genes remain obscure. Repeated attempts have been made to reconstruct the early evolution of Hox genes by analyzing data from the triphoblastic animals, the Bilateria (Schubert et al. 1993; Zhang and Nei 1996). A more precise dating of Hox origins has been elusive due to a lack of sufficient information from outgroup taxa such as the phylum Cnidaria (corals, hydras, jellyfishes, and sea anemones). In combination with outgroup taxa, another potential source of information about Hox origins is outgroup genes (e.g., the genes of the ParaHox cluster). In this article, we present cDNA sequences of two Hox-like genes (anthox2 and anthox6) from the sea anemone, Nematostella vectensis. Phylogenetic analysis indicates that anthox2 (= Cnox2) is homologous to the GSX class of ParaHox genes, and anthox6 is homologous to the anterior class of Hox genes. Therefore, the origin of Hox genes and ParaHox genes occurred prior to the evolutionary split between the Cnidaria and the Bilateria and predated the evolution of the anterior-posterior axis of bilaterian animals. Our analysis also suggests that the central Hox class was invented in the bilaterian lineage, subsequent to their split from the Cnidaria. PMID:11324016

Finnerty, J R; Martindale, M Q

1999-01-01

169

Aberrant Gene Expression in Humans  

PubMed Central

Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating complex traits and conditions. PMID:25617623

Yang, Ence; Ji, Guoli; Brinkmeyer-Langford, Candice L.; Cai, James J.

2015-01-01

170

Candidate reference genes for gene expression studies in water lily  

Microsoft Academic Search

The selection of an appropriate reference gene(s) is a prerequisite for the proper interpretation of quantitative Real-Time polymerase chain reaction data. We report the evaluation of eight candidate reference genes across various tissues and treatments in the water lily by the two software packages geNorm and NormFinder. Across all samples, clathrin adaptor complexes medium subunit (AP47) and actin 11 (ACT11)

Huolin Luo; Sumei Chen; Hongjian Wan; Fadi Chen; Chunsun Gu; Zhaolei Liu

2010-01-01

171

Genes affecting tooth morphogenesis.  

PubMed

The development of dentition is a fascinating process that encompasses a complex series of epithelial-mesenchymal interactions involving growth factors, transcription factors, signal receptors and other soluble morphogens. It is not surprising that such a complex process is prone to disturbances and may result in tooth agenesis. Initial discoveries indicating that the homeo-domain protein MSX1 and the paired-domain transcription factor PAX9 are causative genes in tooth morphogenesis were made in mice. Both genes are co-expressed in dental mesenchyme and either one, when homozygously deleted, results in an arrest at an early developmental stage. Heterozygous Pax9 or Msx1 mice have normal teeth, however, double heterozygous Pax9/Msx1 mice show a phenotype of arrested tooth development which can be rescued by transgenic expression of Bmp4, a very influential signaling factor in many developmental processes. We have obtained mounting evidence for a partnership between PAX9 and MSX1 within the tooth-specific Bmp4 signaling pathway. In humans, unlike in mice, a heterozygous mutation in either PAX9 or MSX1 suffices to cause tooth agenesis of a predominantly molar or more premolar pattern, respectively. Our laboratory and others have identified several PAX9 and MSX1 mutations in families with non-syndromic forms of autosomal dominant posterior tooth agenesis. We have also identified families with tooth agenesis in whom PAX9 and MSX1 mutations have been excluded opening up the possibilities for the discovery of other genes that contribute to human tooth agenesis. PMID:17651126

Kapadia, H; Mues, G; D'Souza, R

2007-08-01

172

Gene: a gene-centered information resource at NCBI.  

PubMed

The National Center for Biotechnology Information's (NCBI) Gene database (www.ncbi.nlm.nih.gov/gene) integrates gene-specific information from multiple data sources. NCBI Reference Sequence (RefSeq) genomes for viruses, prokaryotes and eukaryotes are the primary foundation for Gene records in that they form the critical association between sequence and a tracked gene upon which additional functional and descriptive content is anchored. Additional content is integrated based on the genomic location and RefSeq transcript and protein sequence data. The content of a Gene record represents the integration of curation and automated processing from RefSeq, collaborating model organism databases, consortia such as Gene Ontology, and other databases within NCBI. Records in Gene are assigned unique, tracked integers as identifiers. The content (citations, nomenclature, genomic location, gene products and their attributes, phenotypes, sequences, interactions, variation details, maps, expression, homologs, protein domains and external databases) is available via interactive browsing through NCBI's Entrez system, via NCBI's Entrez programming utilities (E-Utilities and Entrez Direct) and for bulk transfer by FTP. PMID:25355515

Brown, Garth R; Hem, Vichet; Katz, Kenneth S; Ovetsky, Michael; Wallin, Craig; Ermolaeva, Olga; Tolstoy, Igor; Tatusova, Tatiana; Pruitt, Kim D; Maglott, Donna R; Murphy, Terence D

2015-01-28

173

Identification of additional genes that influence baculovirus late gene expression.  

PubMed

We were unable to confirm transient late gene expression using constructs of 18 genes that had been reported to support Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) late gene expression when transfected into Spodoptera frugiperda cells [Lu, A., and Miller, L. K. (1995). J. Virol. 69, 975-982]. Three genes (orf66, orf68, and orf41) were included, all or in part, in the constructs used in that study, but they had not been independently tested. Therefore we investigated these and neighboring orfs for their influence on late gene expression. We found that orf41 was required for late gene expression and that sequences within orf45 appeared to be required for the expression of orf41. Although orf66 and orf68 did not appear to affect late gene expression, orf69 stimulated expression. orf69 was found to have high homology to recent entries in GenBank from a variety of organisms. In addition, it was found that orf121, which was shown to be involved in early gene expression, and the viral homolog of pcna did not influence late gene expression. PMID:10049816

Li, L; Harwood, S H; Rohrmann, G F

1999-03-01

174

GeneMark.hmm: new solutions for gene finding.  

PubMed Central

The number of completely sequenced bacterial genomes has been growing fast. There are computer methods available for finding genes but yet there is a need for more accurate algorithms. The GeneMark. hmm algorithm presented here was designed to improve the gene prediction quality in terms of finding exact gene boundaries. The idea was to embed the GeneMark models into naturally derived hidden Markov model framework with gene boundaries modeled as transitions between hidden states. We also used the specially derived ribosome binding site pattern to refine predictions of translation initiation codons. The algorithm was evaluated on several test sets including 10 complete bacterial genomes. It was shown that the new algorithm is significantly more accurate than GeneMark in exact gene prediction. Interestingly, the high gene finding accuracy was observed even in the case when Markov models of order zero, one and two were used. We present the analysis of false positive and false negative predictions with the caution that these categories are not precisely defined if the public database annotation is used as a control. PMID:9461475

Lukashin, A V; Borodovsky, M

1998-01-01

175

Measuring gene interactions.  

PubMed

Measurement is the assignment of numbers to reality, and valid measurement requires that these numbers represent relevant aspects of reality. I discuss epistatic gene interactions from a measurement-theoretical perspective and argue that the standard measurements of epistasis in classical quantitative genetics have failed to capture aspects of epistasis that are relevant to selection dynamics and adaptation. Instead, the use of statistically motivated measurements such as epistatic variance components has led to the misconception that epistasis is dynamically inert. Here, I review work showing that patterns of epistasis may have profound effects on evolutionary dynamics and discuss how these patterns can be measured. PMID:25403530

Hansen, Thomas F

2015-01-01

176

Flies, genes, and learning.  

PubMed

Flies can learn. For the past 25 years, researchers have isolated mutants, engineered mutants with transgenes, and tested likely suspect mutants from other screens for learning ability. There have been notable surprises-conventional second messenger systems co-opted for intricate associative learning tasks, two entirely separate forms of long-term memory, a cell-adhesion molecule that is necessary for short-term memory. The most recent surprise is the mechanistic kinship revealed between learning and addictive drug response behaviors in flies. The flow of new insight is likely to quicken with the completion of the fly genome and the arrival of more selective methods of gene expression. PMID:11520934

Waddell, S; Quinn, W G

2001-01-01

177

The Y specific growth gene(s): how does it promote stature?  

PubMed Central

Although the presence of a Y specific growth gene(s) (Y growth gene(s) on Yq has widely been accepted, it remains unknown how this gene promotes stature. In this report, we discuss the growth pattern in normal boys and girls and in patients with growth disorders informative for the Y growth gene(s). The results suggest that the Y growth gene(s) augments statural growth by controlling the sex steroid independent childhood growth pattern. PMID:9138158

Ogata, T; Matsuo, N

1997-01-01

178

Compositional gene landscapes in vertebrates.  

PubMed

The existence of a well conserved linear relationship between GC levels of genes' second and third codon positions (GC2, GC3) prompted us to focus on the landscape, or joint distribution, spanned by these two variables. In human, well curated coding sequences now cover at least 15%-30% of the estimated total gene set. Our analysis of the landscape defined by this gene set revealed not only the well documented linear crest, but also the presence of several peaks and valleys along that crest, a property that was also indicated in two other warm-blooded vertebrates represented by large gene databases, that is, mouse and chicken. GC2 is the sum of eight amino acid frequencies, whereas GC3 is linearly related to the GC level of the chromosomal region containing the gene. The landscapes therefore portray relations between proteins and the DNA environments of the genes that encode them. PMID:15123586

Cruveiller, Stéphane; Jabbari, Kamel; Clay, Oliver; Bernardi, Giorgio

2004-05-01

179

Compositional Gene Landscapes in Vertebrates  

PubMed Central

The existence of a well conserved linear relationship between GC levels of genes' second and third codon positions (GC2, GC3) prompted us to focus on the landscape, or joint distribution, spanned by these two variables. In human, well curated coding sequences now cover at least 15%–30% of the estimated total gene set. Our analysis of the landscape defined by this gene set revealed not only the well documented linear crest, but also the presence of several peaks and valleys along that crest, a property that was also indicated in two other warm-blooded vertebrates represented by large gene databases, that is, mouse and chicken. GC2 is the sum of eight amino acid frequencies, whereas GC3 is linearly related to the GC level of the chromosomal region containing the gene. The landscapes therefore portray relations between proteins and the DNA environments of the genes that encode them. PMID:15123586

Cruveiller, Stéphane; Jabbari, Kamel; Clay, Oliver; Bernardi, Giorgio

2004-01-01

180

Understanding Cancer Series: Gene Testing  

Cancer.gov

Lydia Schindler Donna Kerrigan, M.S. Jeanne Kelly Brian Hollen Illustrates what genes are, explains how mutations occur and are identified within genes, and discusses the benefits and limitations of gene testing for cancer and other disorders. These PowerPoint slides are not locked files. You can mix and match slides from different tutorials as you prepare your own lectures. In the Notes section, you will find explanations of the graphics.

181

Serial analysis of gene expression  

Microsoft Academic Search

Serial analysis of gene expression (SAGE) is a method used to obtain comprehensive, unbiased and quantitative gene-expression profiles. Its major advantage over arrays is that it does not require a priori knowledge of the genes to be analyzed and reflects absolute mRNA levels. Since the original SAGE protocol was developed in a short-tag (10-bp) format, several modifications have been made

Min Hu; Kornelia Polyak

2006-01-01

182

Local Gene Therapy for Cancer  

Microsoft Academic Search

Cancer is an important problem in public health worldwide. Gene therapy has the potential for improved treatment of cancer\\u000a patients, particularly if used in combination with other, conventional therapies. To date, many strategies of gene therapy\\u000a have been explored, including correction of mutant genes, immunstimulation, prodrug activation, interference of oncogene expression,\\u000a and genetically modified oncolytic viruses. Although the preclinical results

Wolfgang Walther; Ulrike S. Stein; Peter M. Schlag

183

Show Me the Genes  

NSDL National Science Digital Library

By this point in the unit, students have learned all the necessary information and conceptualized a design for how an optical biosensor could be used to detect a target strand of DNA associated with a cancer-causing gene as their solution to the unit's challenge question. Now student groups act as engineers again, using a poster format to communicate and prove the validity of the design. Successful posters include a description of refraction, explanations of refraction in a thin film, and the factors that can alter the interference pattern of a thin film. The posters culminate with an explanation of what is expected to be seen in a biosensing device of this type if it were coupled to a target molecule, proven with a specific example and illustrated with drawings and diagrams throughout. All the poster elements combine to prove the accuracy and viability of this method of gene detection. Together with its associated lesson, this activity functions as part of the summative assessment for this unit.

Vu Bioengineering Ret Program

184

XLMR genes: Update 1996  

SciTech Connect

A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 non-specific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of {ge}2.0 has more than doubled, with 42 (including FRAXE) now being known. A summary of the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of non-specific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process. 105 refs., 2 figs., 6 tabs.

Lubs, H.A.; Tranebjaerg, L. [Univ. Hospital of Tromso (Norway)] [Univ. Hospital of Tromso (Norway); Arena, J.F. [Univ. of Miami School of Medicine, FL (United States)] [and others] [Univ. of Miami School of Medicine, FL (United States); and others

1996-07-12

185

Conotoxin Gene Superfamilies  

PubMed Central

Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing. PMID:25522317

Robinson, Samuel D.; Norton, Raymond S.

2014-01-01

186

RNAi induced gene silencing in crop improvement  

Microsoft Academic Search

The RNA silencing is one of the innovative and efficient molecular biology tools to harness the down-regulation of expression\\u000a of gene(s) specifically. To accomplish such selective modification of gene expression of a particular trait, homology dependent\\u000a gene silencing uses a stunning variety of gene silencing viz. co-suppression, post-transcriptional gene silencing, virus-induced\\u000a gene silencing etc. This family of diverse molecular phenomena

Subodh Kumar Sinha

2010-01-01

187

Importance of Combinatorial Gene Control  

NSDL National Science Digital Library

A hypothetical scheme illustrating how combinations of a few gene regulatory proteins can generate many different cell types during development. In this simple scheme a "decision" to make a new gene regulatory protein (shown as a numbered circle) is made after each cell division. Repetition of this simple rule enables eight cell types (A through H) to be created using only three different regulatory proteins. Each of these hypothetical cell types would then express different genes, as dictated by the combination of gene regulatory proteins that are present within it.

Bruce Alberts

1998-07-01

188

Selector Genes, Polymorphisms, and Evolution  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. Evolution has been thought to act on small changes in the characteristics of organisms coded by genes called realizator genes. D. Tautz explains how a new result in this issue of Science by Gibson and Hogness (p. 200) shows that this may not always be true. A small phenotypic variation in Drosophila (sensitivity to ether), apparent only under environmental stress, turns out to be coded by a polymorphism in a selector gene, Ultrabithorax, a member of a class of genes that specifies whole body parts and anatomical regions.

Diethard Tautz (Zoologisches Institut der Universität München;)

1996-01-12

189

Coronary restenosis and gene therapy.  

PubMed Central

Restenosis continues to limit the efficacy of coronary angioplasty, despite the various mechanical and pharmaceutical interventions that have been employed. The migration, proliferation, and extracellular matrix production by vascular smooth muscle cells are processes integral to restenosis, and sustained local delivery of drugs at high concentration should curtail these vascular responses to balloon angioplasty. Our laboratory and others are exploring the potential of using somatic cell gene therapy to provide such treatment and thereby prevent restenosis. However, conventional methods of gene transfer fail to produce physiologic levels of recombinant protein in vivo. This obstacle might be overcome by using adenoviral vectors to mediate efficient direct gene transfer. Herein we summarize these developments and focus upon our laboratory's progress towards evaluating adenovirus-mediated gene therapy in porcine coronary arteries. Recombinant adenoviruses directing the expression of the beta-galactosidase and luciferase reporter genes were evaluated in cultured coronary vascular smooth muscle cells in vitro and in porcine coronary arteries in vivo. Following percutaneous transluminal gene transfer in vivo, recombinant adenoviruses were shown to produce 70- to 240-fold more reporter protein than that produced by Lipofectin-DNA complexes. Furthermore, the high levels of adenovirus-mediated gene expression were shown to persist for at least 14 days following catheterization. Additional histologic studies will be required to determine the cellular distribution of gene expression and to elucidate potential interactions between adenovirus and the host's immune system, but recombinant adenovirus appears to be a promising vector for evaluating gene therapy against coronary restenosis. PMID:8180504

Mazur, W; Ali, N M; Raizner, A E; French, B A

1994-01-01

190

From gene expression to gene regulatory networks in Arabidopsis thaliana  

Microsoft Academic Search

BACKGROUND: The elucidation of networks from a compendium of gene expression data is one of the goals of systems biology and can be a valuable source of new hypotheses for experimental researchers. For Arabidopsis, there exist several thousand microarrays which form a valuable resource from which to learn. RESULTS: A novel Bayesian network-based algorithm to infer gene regulatory networks from

Chris J Needham; Iain W Manfield; Andrew J Bulpitt; Philip M Gilmartin; David R Westhead

2009-01-01

191

Gene 245 (2000) 119126 www.elsevier.com/locate/gene  

E-print Network

Gene 245 (2000) 119­126 www.elsevier.com/locate/gene Isolation and analysis of two cellulase c Abstract Two cellulase cDNAs, celB29 and celB2, were isolated from a cDNA library derived from m@pbi.nrc.ca ( X. Qiu) cellulases. Many cellulolytic systems from a wide array 1 Present address: Plant

Selinger, Brent

192

Bioinformatic analysis for exploring relationships between genes and gene products  

Microsoft Academic Search

To carry out their specific roles in the cell, genes and gene products often work together in groups, forming many relationships among themselves and with other molecules. Such relationships include physical protein-protein interaction relationships, regulatory relationships, metabolic relationships, genetic relationships, and much more. With advances in science and technology, some high throughput technologies have been developed to simultaneously detect tens

Erliang Zeng

2008-01-01

193

Contributions of Gene Marking to Cell and Gene Therapies  

PubMed Central

Abstract The first human genetic modification studies used replication-incompetent integrating vector vectors to introduce marker genes into T lymphocytes and subsequently into hematopoietic stem cells. Such studies have provided numerous insights into the biology of hematopoiesis and immune reconstitution and contributed to clinical development of gene and cell therapies. Tracking of hematopoietic reconstitution and analysis of the origin of residual malignant disease after hematopoietic transplantation has been possible via gene marking. Introduction of selectable marker genes has enabled preselection of specific T-cell populations for tumor and viral immunotherapy and reduced the threat of graft-versus-host disease, improving the survival of patients after allogeneic marrow transplantation. Marking studies in humans, murine xenografts, and large animals have helped optimize conditions for gene transfer into CD34+ hematopoietic progenitors, contributing to the achievement of gene transfer efficiencies sufficient for clinical benefit in several serious genetic diseases such as X-linked severe combined immunodeficiency and adrenoleukodystropy. When adverse events linked to insertional mutagenesis arose in clinical gene therapy trials for inherited immunodeficiencies, additional animal studies using gene-marking vectors have greatly increased our understanding of genotoxicity. The knowledge gained from these studies is being translated into new vector designs and clinical protocols, which we hope will continue to improve the efficiency, effectiveness and safety of these promising therapeutic approaches. PMID:21261461

Barese, Cecilia N.

2011-01-01

194

Targeted gene alteration in Caenorhabditis elegans by gene conversion  

Microsoft Academic Search

Now that some genomes have been completely sequenced, the ability to direct specific mutations into genomes is particularly desirable. Here we present a method to create mutations in the Caenorhabditis elegans genome efficiently through transgene-directed, transposon-mediated gene conversion. Engineered deletions targeted into two genes show that the frequency of obtaining the desired mutation was higher using this approach than using

Peter L Barrett; John T Fleming; Verena Göbel

2004-01-01

195

Gene 240 (1999) 4555 www.elsevier.com/locate/gene  

E-print Network

by the same gene Annie C.Y. Chang a,1, Bjo¨rn Sohlberg a,1, Laura Trinkle-Mulcahy b, Felix Claverie-Martin a,2 Science B.V. All rights reserved. Keywords: Alternative splicing; ARD-1; Gene expression; NIPP-1; rnase 1

Trinkle-Mulcahy, Laura

196

Gene therapy for hemophilia.  

PubMed

Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

Rogers, Geoffrey L; Herzog, Roland W

2015-01-01

197

See the Genes  

NSDL National Science Digital Library

Through this concluding lesson and its associated activity, students experience one valuable and often overlooked skill of successful scientists and engineersâcommunicating your work and ideas. They explore the importance of scientific communication, including the basic, essential elements of communicating new information to the public and pitfalls to avoid. In the associated activity, student groups create posters depicting their solutions to the unit's challenge questionâaccurate, efficient methods for detecting cancer-causing genes using optical biosensorsâwhich includes providing a specific example with relevant equations. Students are also individually assessed on their understanding of refraction via a short quiz. This lesson and its associated activity conclude the unit and serve as the culminating Go Public phase of the Legacy Cycle, providing unit review and summative assessment.

Vu Bioengineering Ret Program

198

Gene therapy for Deafness  

PubMed Central

Hearing loss is the most common sensory deficit in humans and can result from genetic, environmental, or combined etiologies that prevent normal function of the cochlea, the peripheral sensory organ. Recent advances in understanding the genetic pathways that are critical for the development and maintenance of cochlear function, as well as the molecular mechanisms that underlie cell trauma and death have provided exciting opportunities for modulating these pathways to correct genetic mutations, to enhance endogenous protective pathways for hearing preservation and to regenerate lost sensory cells with the possibility of ameliorating hearing loss. A number of recent animal studies have used gene-based therapies in innovative ways toward realizing these goals. With further refinement, some of the protective and regenerative approaches reviewed here may become clinically applicable. PMID:23864018

Kohrman, David C.; Raphael, Yehoash

2014-01-01

199

In planta gene targeting  

PubMed Central

The development of designed site-specific endonucleases boosted the establishment of gene targeting (GT) techniques in a row of different species. However, the methods described in plants require a highly efficient transformation and regeneration procedure and, therefore, can be applied to very few species. Here, we describe a highly efficient GT system that is suitable for all transformable plants regardless of transformation efficiency. Efficient in planta GT was achieved in Arabidopsis thaliana by expression of a site-specific endonuclease that not only cuts within the target but also the chromosomal transgenic donor, leading to an excised targeting vector. Progeny clonal for the targeted allele could be obtained directly by harvesting seeds. Targeted events could be identified up to approximately once per 100 seeds depending on the target donor combination. Molecular analysis demonstrated that, in almost all events, homologous recombination occurred at both ends of the break. No ectopic integration of the GT vector was found. PMID:22529367

Fauser, Friedrich; Roth, Nadine; Pacher, Michael; Ilg, Gabriele; Sánchez-Fernández, Rocío; Biesgen, Christian; Puchta, Holger

2012-01-01

200

MRI-guided gene therapy Xiaoming Yanga  

E-print Network

Minireview MRI-guided gene therapy Xiaoming Yanga , Ergin Atalara,b,* a Department of Radiology gene expression. This review summarizes the current status of MRI- guided gene therapy. Ã? 2006 resonance imaging; MRI-guided therapy; Gene therapy 1. Introduction Gene therapy is an exciting frontier

Atalar, Ergin

201

Evolutionary significance of gene expression divergence  

Microsoft Academic Search

Recent large-scale studies of evolutionary changes in gene expression among mammalian species have led to the proposal that gene expression divergence may be neutral with respect to organismic fitness. Here, we employ a comparative analysis of mammalian gene sequence divergence and gene expression divergence to test the hypothesis that the evolution of gene expression is predominantly neutral. Two models of

I. King Jordan; Leonardo Mariño-Ramírez; Eugene V. Koonin

2005-01-01

202

Gene transfer technology in aquaculture  

Microsoft Academic Search

The gene transfer technique, transgenesis, has permitted the transfer of genes from one organism to another to create new lineages of organisms with improvement in traits important to aquaculture. Genetically modified organisms (GMOs), therefore, hold promise for producing genetic improvements, such as enhanced growth rate, increased production and efficiency, disease resistance and expanded ecological ranges. The basic procedure to generate

J. A. Levy; L. F. Marins; A. Sanchez

2000-01-01

203

Genome position and gene amplification  

Microsoft Academic Search

BACKGROUND: Amplifications, regions of focal high-level copy number change, lead to overexpression of oncogenes or drug resistance genes in tumors. Their presence is often associated with poor prognosis; however, the use of amplification as a mechanism for overexpression of a particular gene in tumors varies. To investigate the influence of genome position on propensity to amplify, we integrated a mutant

Pavla Gajduskova; Antoine M Snijders; Serena Kwek; Ritu Roydasgupta; Jane Fridlyand; Taku Tokuyasu; Daniel Pinkel; Donna G Albertson

2007-01-01

204

Animal Body Plans: Homeobox Genes  

NSDL National Science Digital Library

The homeobox genes that define the basic body plan of mice and fruit flies are illustrated in this graphic from The Human Evolution Coloring Book by Adrienne Zihlman. The accompanying article describes how these genes act as molecular architects in all animal species.

WGBH Educational Foundation

2003-09-26

205

Progress toward Human Gene Therapy  

Microsoft Academic Search

Current therapies for most human genetic diseases are inadequate. In response to the need for effective treatments, modern molecular genetics is providing tools for an unprecedented new approach to disease treatment through an attack directly on mutant genes. Recent results with several target organs and gene transfer techniques have led to broad medical and scientific acceptance of the feasibility of

Theodore Friedmann

1989-01-01

206

Method of controlling gene expression  

DOEpatents

A method of controlling expression of a DNA segment under the control of a nod gene promoter which comprises administering to a host containing a nod gene promoter an amount sufficient to control expression of the DNA segment of a compound of the formula: ##STR1## in which each R is independently H or OH, is described.

Peters, Norman K. (Berkeley, CA); Frost, John W. (Menlo Park, CA); Long, Sharon R. (Palo Alto, CA)

1991-12-03

207

HOX genes in ovarian cancer  

PubMed Central

The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease. PMID:21906307

2011-01-01

208

Gene therapy on the move  

PubMed Central

The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders. PMID:24106209

Kaufmann, Kerstin B; Büning, Hildegard; Galy, Anne; Schambach, Axel; Grez, Manuel

2013-01-01

209

Nonviral Vectors for Gene Delivery  

NASA Astrophysics Data System (ADS)

The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,L-lactide- co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (˜200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less cytotoxic than PEI suggesting the use of these vehicles for localized, sustained gene delivery to the pulmonary epithelium. On the other hand, a more simple method to synthesize 50-200 nm complexes capable of high transfection efficiency or high gene knockdown was also explored. Positively charged CPPs were complexed with pDNA or siRNA, which resulted in 'loose' (˜1 micron) particles. These were then condensed into small nanoparticles by using calcium, which formed "soft" crosslinks by interacting with both phosphates on nucleic acids and amines on CPPs. An optimal amount of CaCl2 produced stable, ˜100 nm complexes that exhibited higher transfection efficiency and gene silencing than PEI polyplexes. CPPs also displayed negligible cytotoxicity up to 5 mg/mL. Biophysical studies of the pDNA structure within complexes suggested that pDNA within CPP complexes (condensed with calcium) had similar structure, but enhanced thermal stability compared to PEI complexes. Thus, CPP complexes emerged as simple, attractive candidates for future studies on nonviral gene delivery in vivo.

Baoum, Abdulgader Ahmed

2011-12-01

210

Systems Biophysics of Gene Expression  

E-print Network

Gene expression is a central process to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and extracellular changes. This diversity in scales poses fundamental challenges among traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses.

Jose M. G. Vilar; Leonor Saiz

2013-07-03

211

GenePRIMP: A GENE PRediction IMprovement Pipeline for Prokaryotic genomes  

SciTech Connect

We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies.

Pati, Amrita; Ivanova, Natalia N.; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D.; Lykidis, Athanasios; Kyrpides, Nikos C.

2010-04-01

212

Gene expression analysis identifies global gene dosage sensitivity in cancer.  

PubMed

Many cancer-associated somatic copy number alterations (SCNAs) are known. Currently, one of the challenges is to identify the molecular downstream effects of these variants. Although several SCNAs are known to change gene expression levels, it is not clear whether each individual SCNA affects gene expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene expression and enable us to predict the biological function of genes. On correcting expression profiles for these components, we observed that the residual expression levels (in 'functional genomic mRNA' profiling) correlated strongly with copy number. DNA copy number correlated positively with expression levels for 99% of all abundantly expressed human genes, indicating global gene dosage sensitivity. By applying this method to 16,172 patient-derived tumor samples, we replicated many loci with aberrant copy numbers and identified recurrently disrupted genes in genomically unstable cancers. PMID:25581432

Fehrmann, Rudolf S N; Karjalainen, Juha M; Krajewska, Ma?gorzata; Westra, Harm-Jan; Maloney, David; Simeonov, Anton; Pers, Tune H; Hirschhorn, Joel N; Jansen, Ritsert C; Schultes, Erik A; van Haagen, Herman H H B M; de Vries, Elisabeth G E; Te Meerman, Gerard J; Wijmenga, Cisca; van Vugt, Marcel A T M; Franke, Lude

2015-02-01

213

Exploiting gene x gene interaction in linkage analysis.  

PubMed

When two genes interact to cause a clinically important phenotype, it would seem reasonable to expect that we could leverage genotypic information at one of the loci in order to improve our ability to detect the other. We were therefore interested in extending the posterior probability of linkage (PPL), a class of linkage statistics we have been developing over the past decade, in order to explicitly allow for gene x gene interaction. In this report we utilize a new implementation of the PPL incorporating liability classes (LCs), which provide a direct parameterization of gene x gene interaction by allowing the penetrances at the locus being evaluated to depend upon measured genotypes at a known locus. With knowledge of the generating model for the simulated rheumatoid arthritis (RA) data, we selected two loci for examination: Locus A, which in interaction with the HLA-DR antigen locus affects risk of the dichotomous RA phenotype; and Locus E, which in interaction with DR affects quantitative levels of the anti-CCP phenotype. The data comprised nuclear families of two parents and an affected sib pair (ASP). Our results confirm theoretical work suggesting that gene x gene interactions CANNOT be leveraged to improve linkage detection for dichotomous traits based on affecteds-only data structures. However, incorporation of DR-based LCs did lead to appreciably higher quantitative trait PPLs. This suggests that gene x gene interactions could be effectively used in quantitative trait analyses even when families have been ascertained as ASPs for a related dichotomous trait. PMID:18466565

Huang, Yungui; Bartlett, Christopher W; Segre, Alberto M; O'Connell, Jeffrey R; Mangin, Lavonne; Vieland, Veronica J

2007-01-01

214

Gene Help: Integrated Access to Genes of Genomes in the Reference Sequence Collection  

E-print Network

Gene Help: Integrated Access to Genes of Genomes in the Reference Sequence Collection Garth Brown Craig Wallin Tatiana Tatusova Kim Pruitt Terence Murphy Donna Maglott Introduction Gene supplies gene. Unique identifiers are assigned to genes with defining sequences, genes with known map positions

Levin, Judith G.

215

A Gene Recommender Algorithm to Identify Coexpressed Genes in C. elegans  

E-print Network

A Gene Recommender Algorithm to Identify Coexpressed Genes in C. elegans Art B. Owen,1,4 Josh is for the discovery of new genes with similar function to a given list of genes (the query) already known to have closely related function. We have developed an algorithm, called the gene recommender, that ranks genes

Stuart, Josh

216

Gene conversion in the rice genome  

E-print Network

Background: Gene conversion causes a non-reciprocal transfer of genetic information between similar sequences. Gene conversion can both homogenize genes and recruit point mutations thereby shaping the evolution of multigene families. In the rice...

Xu, Shuqing; Clark, Terry; Zheng, Hongkun; Vang, SÃ ¸ ren; Li, Ruiqiang; Wong, Gane Ka-Shu; Wang, Jun; Zheng, Xiaoguang

2008-02-25

217

Personalized Medicine: Matching Treatments to Your Genes  

MedlinePLUS

... disclaimer . Subscribe Personalized Medicine Matching Treatments to Your Genes You’re one of a kind. It’s not ... personalized medicine begins with the unique set of genes you inherited from your parents. Genes are stretches ...

218

Gene Therapy for Diseases and Genetic Disorders  

MedlinePLUS

Gene Therapy for Diseases Gene Therapy has made important medical advances in less than two decades. Within ... Among the most notable advancements are the following: Gene Therapy for Genetic Disorders Severe Combined Immune Deficiency ( ...

219

Is Violent Crime in Some People's Genes?  

MedlinePLUS

... enable JavaScript. Is Violent Crime in Some People's Genes? New study shows certain DNA may raise odds ... 2015) Tuesday, October 28, 2014 Related MedlinePlus Page Genes and Gene Therapy TUESDAY, Oct. 28, 2014 (HealthDay ...

220

Detecting Highways of Horizontal Gene Transfer  

E-print Network

In a horizontal gene transfer (HGT) event, a gene is transferred between two species that do not have an ancestor-descendant relationship. Typically, no more than a few genes are horizontally transferred between any two ...

Bansal, Mukul S.

221

Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins.  

PubMed

Understanding the genetic architecture of gene expression is an intermediate step in understanding the genetic architecture of complex diseases. RNA sequencing technologies have improved the quantification of gene expression and allow measurement of allele-specific expression (ASE). ASE is hypothesized to result from the direct effect of cis regulatory variants, but a proper estimation of the causes of ASE has not been performed thus far. In this study, we take advantage of a sample of twins to measure the relative contributions of genetic and environmental effects to ASE, and we find substantial effects from gene × gene (G×G) and gene × environment (G×E) interactions. We propose a model where ASE requires genetic variability in cis, a difference in the sequence of both alleles, but where the magnitude of the ASE effect depends on trans genetic and environmental factors that interact with the cis genetic variants. PMID:25436857

Buil, Alfonso; Brown, Andrew Anand; Lappalainen, Tuuli; Viñuela, Ana; Davies, Matthew N; Zheng, Hou-Feng; Richards, J Brent; Glass, Daniel; Small, Kerrin S; Durbin, Richard; Spector, Timothy D; Dermitzakis, Emmanouil T

2015-01-01

222

Target genes of homeodomain proteins.  

PubMed

Homeodomain proteins are transcription factors that share a related DNA binding domain, the homeodomain. This class of proteins was first recognized in the fruitfly Drosophila melanogaster where they cause homeotic transformations such as a fly with four wings instead of two (Lewis EB. A gene complex controlling segmentation in Drosophila. Nature 1978;276:565-570 [Ref. 18]). They are now known to exist in all eukaryotes where they perform important functions during development. Given that homeodomain proteins are transcription factors, they control the expression of downstream genes to regulate development. Which genes are controlled by homeodomain proteins and how many of them are there? This review focuses on a recent paper by Liang and Biggin (Liang Z, Biggin MD. Eve and Ftz regulate a wide array of genes in blastoderm embryos: the selector homeoproteins directly or indirectly regulate most genes in Drosophila. Development 1998; 125:4471-4482 [Ref. 1]), which proposes that the Drosophila homeodomain proteins Even-skipped and Fushi-tarazu directly control the expression of the majority of genes in the Drosophila genome. An alternative view, that most genes are only indirectly affected by homeodomain proteins is also discussed. PMID:10377888

Mannervik, M

1999-04-01

223

GENES IN SPORT AND DOPING  

PubMed Central

Genes control biological processes such as muscle production of energy, mitochondria biogenesis, bone formation, erythropoiesis, angiogenesis, vasodilation, neurogenesis, etc. DNA profiling for athletes reveals genetic variations that may be associated with endurance ability, muscle performance and power exercise, tendon susceptibility to injuries and psychological aptitude. Already, over 200 genes relating to physical performance have been identified by several research groups. Athletes’ genotyping is developing as a tool for the formulation of personalized training and nutritional programmes to optimize sport training as well as for the prediction of exercise-related injuries. On the other hand, development of molecular technology and gene therapy creates a risk of non-therapeutic use of cells, genes and genetic elements to improve athletic performance. Therefore, the World Anti-Doping Agency decided to include prohibition of gene doping within their World Anti-Doping Code in 2003. In this review article, we will provide a current overview of genes for use in athletes’ genotyping and gene doping possibilities, including their development and detection techniques. PMID:24744482

Kaliszewski, P.; Majorczyk, E.; Zembro?-?acny, A.

2013-01-01

224

Perspectives of gene combinations in phenotype presentation  

PubMed Central

Cells exhibit a variety of phenotypes in different stages and diseases. Although several markers for cellular phenotypes have been identified, gene combinations denoting cellular phenotypes have not been completely elucidated. Recent advances in gene analysis have revealed that various gene expression patterns are observed in each cell species and status. In this review, the perspectives of gene combinations in cellular phenotype presentation are discussed. Gene expression profiles change during cellular processes, such as cell proliferation, cell differentiation, and cell death. In addition, epigenetic regulation increases the complexity of the gene expression profile. The role of gene combinations and panels of gene combinations in each cellular condition are also discussed. PMID:23951387

Tanabe, Shihori

2013-01-01

225

The Gene Resource Locator: gene locus maps for transcriptome analysis  

PubMed Central

Since the advent of the draft human genome sequence there has been growing interest in transcriptome analysis based on genomic data. The Gene Resource Locator (GRL) assembles gene maps that include information on gene-expression patterns, cis-elements in regulatory regions and alternatively spliced transcripts. The database was constructed using customized software, and currently contains 2.2 million alignments (exon–intron structures). The alignments have been annotated and integrated into a system that encompasses approximately 90 000 EST loci sharing common exons, 8091 alternatively spliced transcript groups, 10 801 expression-profile groups, 8066 candidate regulatory regions in full-length cDNAs, and 1 million SNP loci. We have used Flash technology to build a dynamic web viewer that facilitates browsing through the millions of alignments. All of the information is available through the World Wide Web at the Gene Resource Locator web site (http://grl.gi.k.u-tokyo.ac.jp). PMID:11752299

Honkura, Toshihiko; Ogasawara, Jun; Yamada, Tomoyuki; Morishita, Shinichi

2002-01-01

226

COMPARISON OF THE METHYL REDUCTASE GENES AND GENE PRODUCTS  

EPA Science Inventory

The DNA sequences encoding component C of methyl coenzyme M reductase (mcr genes) in Methanothermus fervidus, Methanobacterium thermoautotrophicum, Methanococcus vannielii, and Methanosarcina barkeri have been published. omparisons of transcription initiation and termination site...

227

Genes-R-Us  

NSDL National Science Digital Library

Genetics and genetic counseling--- How can the modern student relate to the classic principles of genetics? How about forming a genetic counseling agency with your students and "serve" the entire senior class during their "marriage project" in senior health? Genetic counseling can introduce students to basic genetics, an important interface of the biological sciences and the human condition. Many high schools throughout the U.S. have "marriage" or family living programs in which students are randomly paired early in the school year. They work to plan a wedding, a household budget that includes rent, car bills, food bills, and so on, including a future family. It is this future family that attracted my attention a few years back. The students were randomly given a baby to care for (the baby was either an uncooked egg, or a five pound sack of flour.) This is a perfect time to introduce human genetics to the soon-to-be parents. Hence, GENES-R-US !

BEGIN:VCARD VERSION:2.1 FN:Richard Benz N:Benz; Richard ORG:Wickliffe High School REV:2005-04-12 END:VCARD

1994-07-30

228

Environment, genes, and cancer  

SciTech Connect

In January, comedian George Burns turned 100 years old. In recent appearances in the media, he still seems sharp as a tack, and is still seen smoking his trademark cigars. Others of us, however, were never very funny, and would die of cancer at age 60 if we continuously smoked cigars or cigarettes. Burns presents a common but perplexing paradox; some people are able to tolerate at least moderate exposure to toxins such as cigarette smoke with little adverse affect, while others develop cancer, emphysema, or heart disease. New studies support the idea that there is an interaction between genes and the environment, and that this interaction may be an important determinant of cancer risk. To understand such risks, it is essential to look at both an individual`s genetic makeup and environmental exposures. Such studies require the collaboration of molecular epidemiologists and molecular biologists. At the NIEHS, Jack A. Taylor, a lead clinical investigator in the Epidemiology Branch, and Douglas A. Bell, an investigator with the Genetic Risk Group of the Laboratory of Biochemical Risk Analysis, have worked together and with other scientists to uncover new information in this area.

Manuel, J.

1996-03-01

229

Genes to Cognition Online  

NSDL National Science Digital Library

The Dolan DNA Learning Center at Cold Spring Harbor, NY has created this fantastic website to explore neuroscience, and it is focused on cognitive disorders, cognitive processes, and research approaches. There are many activities on the site, and each is broken down into six categories of analysis, "Genes", "Biochemicals", "Cells", "Brain Anatomy", "Cognition", and "Environment". Thus, clicking on "Bipolar Disorder" under the "Disorders" tab at the top of the page, will take the visitor to a "subway line" at the top of the page. There are several "stops" on the line, and each allows the visitor to learn about the key areas of bipolar disorder research. Scrolling over the stops opens up a small window with a blurb about the content to view. The blurb also shows whether the content is a video, an application, animation, etc. Visitors wishing to see all the research available, should click on the network map, which is the screen behind the smaller "subway line" page. The "Teacher Feature", under the "Targeted Content" tab, and next to the small model of the brain, offers lessons on such topics as autism, memory, and ethical decision-making. "Teacher Pages," "Student Worksheets", and "Test Items" are offered in PDF form.

230

Retroviral vectors for gene transfer.  

PubMed

INTRODUCTIONRetroviral vectors from the ?-retrovirus genus were the first retroviral vectors to be developed. They have been called oncoretroviral vectors or simple retroviral vectors because of their derivation from oncogenic retroviruses having a simple gag-pol-env genome structure. Later additions to the retroviral vector family include the lentiviral and foamy viral vectors derived from more complex retroviruses that contain multiple accessory genes in addition to the standard gag-pol-env genes. This article describes the advantages and disadvantages of retroviral vectors for gene therapy. It also discusses the issues that must be considered in designing retroviral vectors and in choosing retroviral packaging cell lines. PMID:21356814

Cornetta, Kenneth; Pollok, Karen E; Miller, A Dusty

2008-01-01

231

Gene Delivery to the Airway  

PubMed Central

This unit describes generation of and gene transfer to several commonly used airway models. Isolation and transduction of primary airway epithelial cells are first described. Next, the preparation of polarized airway epithelial monolayers is outlined. Transduction of these polarized cells is also described. Methods are presented for generation of tracheal xenografts as well as both ex vivo and in vivo gene transfer to these xenografts. Finally, a method for in vivo gene delivery to the lungs of rodents is included. Methods for evaluating transgene expression are given in the support protocols. PMID:23853081

Keiser, Nicholas W.; Engelhardt, John F.

2013-01-01

232

Regulation of Primary Response Genes  

PubMed Central

Primary response genes (PRGs) are a set of genes that are induced in response to both cell-extrinsic and cell-intrinsic signals and do not require de novo protein synthesis for their expression. These 'first responders' in the waves of transcription of signal responsive genes play pivotal roles in a wide rage of biological responses, including neuronal survival and plasticity, cardiac stress response, innate and adaptive immune responses, glucose metabolism and oncogeneic transformation. Here we bring together recent advances and our current understanding of the signal-induced transcriptional and epigenetic regulation of PRGs. PMID:22055182

Fowler, Trent; Sen, Ranjan; Roy, Ananda L

2011-01-01

233

Panspermia and horizontal gene transfer  

NASA Astrophysics Data System (ADS)

Evidence that extremophiles are hardy and ubiquitous is helping to make panspermia a respectable theory. But even if life on Earth originally came from space, biologists assume that the subsequent evolution of life is still governed by the darwinian paradigm. In this review we show how panspermia could amend darwinism and point to a cosmic source for, not only extremophiles but, all of life. This version of panspermia can be called "strong panspermia." To support this theory we will discuss recent evidence pertaining to horizontal gene transfer, viruses, genes apparently older than the Earthly evolution of the features they encode, and primate-specific genes without identifiable precursors.

Klyce, Brig

2009-08-01

234

Stochastic gene expression with delay.  

PubMed

The expression of genes usually follows a two-step procedure. First, a gene (encoded in the genome) is transcribed resulting in a strand of (messenger) RNA. Afterwards, the RNA is translated into protein. We extend the classical stochastic jump model by adding delays (with arbitrary distributions) to transcription and translation. Already in the classical model, production of RNA and protein comes in bursts by activation and deactivation of the gene, resulting in a large variance of the number of RNA and proteins in equilibrium. We derive precise formulas for this second-order structure with the model including delay in equilibrium. PMID:25285895

Jansen, Martin; Pfaffelhuber, Peter

2015-01-01

235

Mutagenesis of diploid mammalian genes by gene entrapment  

Microsoft Academic Search

The present study describes a genome-wide method for biallelic mutagenesis in mammalian cells. Novel poly(A) gene trap vectors, which contain features for direct cloning vector-cell fusion transcripts and for post-entrapment genome engineering, were used to generate a library of 979 mutant ES cells. The entrapment mutations generally disrupted gene expression and were readily transmitted through the germline, establishing the library

Qing Lin; Sarah L. Donahue; Tracy Moore-Jarrett; Shang Cao; Anna B. Osipovich; H. E. Ruley

2006-01-01

236

Antivirulence Genes: Insights into Pathogen Evolution through Gene Loss  

PubMed Central

The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation—a “fine-tuning” process—for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in Shigella, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as Salmonella, Yersinia pestis, and the virulent Francisella tularensis subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (lpxL) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens. PMID:23045475

Bliven, Kimberly A.

2012-01-01

237

Microarray analysis of genes and gene functions in disc degeneration  

PubMed Central

The aim of the present study was to screen differentially expressed genes (DEGs) in human degenerative intervertebral discs (IVDs), and to perform functional analysis on these DEGs. The gene expression profile was downloaded from the Gene Expression Omnibus database (GSE34095)and included six human IVD samples: three degenerative and three non-degenerative. The DEGs between the normal and disease samples were identified using R packages. The online software WebGestalt was used to perform the functional analysis of the DEGs, followed by Osprey software to search for interactions between the DEGs. The Database for Annotation, Visualization and Integrated Discovery was utilized to annotate the DEGs in the interaction network and then the DEGs were uploaded to the Connectivity Map database to search for small molecules. In addition, the active binding sites for the hub genes in the network were obtained, based on the Universal Protein database. By comparing the gene expression profiles of the non-degenerative and degenerative IVDs, the DEGs between the samples were identified. The DEGs were significantly associated with transforming growth factor ? and the extracellular matrix. Matrix metalloproteinase 2 (MMP2) was identified as the hub gene of the interaction network of DEGs. In addition, MMP2 was found to be upregulated in degenerative IVDs. The screened small molecules and the active binding sites of MMP2 may facilitate the development of methods to inhibit overexpression of MMP2. PMID:24396401

TANG, YANCHUN; WANG, SHAOKUN; LIU, YING; WANG, XUYUN

2014-01-01

238

New Gene Evolution: Little Did We Know  

PubMed Central

Genes are perpetually added to and deleted from genomes during evolution. Thus, it is important to understand how new genes are formed and evolve as critical components of the genetic systems determining the biological diversity of life. Two decades of effort have shed light on the process of new gene origination, and have contributed to an emerging comprehensive picture of how new genes are added to genomes, ranging from the mechanisms that generate new gene structures to the presence of new genes in different organisms to the rates and patterns of new gene origination and the roles of new genes in phenotypic evolution. We review each of these aspects of new gene evolution, summarizing the main evidence for the origination and importance of new genes in evolution. We highlight findings showing that new genes rapidly change existing genetic systems that govern various molecular, cellular and phenotypic functions. PMID:24050177

Long, Manyuan; VanKuren, Nicholas W.; Chen, Sidi; Vibranovski, Maria D.

2014-01-01

239

Insight into the microphthalmia gene.  

PubMed

The murine microphthalmia gene (mi) is one of the last multi-allelic, classic coat-colour genes to be cloned in the mouse and, similar to many of these genes, encodes an exciting molecule that is is involved in multiple developmental processes. The existence of the numerous alleles has allowed the molecular dissection of the function of the MI bHLH-Zip transcription factor in vivo and offers a unique opportunity to understand the function of a multimeric transcription factor throughout development and in many tissues. It is also the gene mutated in some patients with the human deafness syndrome, Waardenburg's syndrome type II, and hence helps to understand this syndrome. PMID:8578601

Moore, K J

1995-11-01

240

The GENCODE human gene set  

E-print Network

The GENCODE consortium is a sub group of the ENCODE consortium. Its aim is to provide complete annotation of genes in the human genome including protein-coding loci, non-coding loci and pseudogenes, based on experimental ...

Searle, S.

241

How eukaryotic genes are transcribed  

PubMed Central

Summary Regulation of eukaryotic gene expression is far more complex than one might have imagined thirty years ago. However, progress towards understanding gene regulatory mechanisms has been rapid and comprehensive, which has made the integration of detailed observations into broadly connected concepts a challenge. This review attempts to integrate the following concepts: 1) a well-defined organization of nucleosomes and modification states at most genes, 2) regulatory networks of sequence-specific transcription factors, 3) chromatin remodeling coupled to promoter assembly of the general transcription factors and RNA polymerase II, and 4) phosphorylation states of RNA polymerase II coupled to chromatin modification states during transcription. The wealth of new insights arising from the tools of biochemistry, genomics, cell biology, and genetics is providing a remarkable view into the mechanics of gene regulation. PMID:19514890

Venters, Bryan J.; Pugh, B. Franklin

2009-01-01

242

Incorrectly predicted genes in rice?  

PubMed

Between one third and one half of the proposed rice genes appear to have no homologs in other species, including Arabidopsis. Compositional considerations, and a comparison of curated rice sequences with ex novo predictions, suggest that many or most of the putative genes without homologs may be false positive predictions, i.e., sequences that are never translated into functional proteins in vivo. PMID:15177695

Cruveiller, Stéphane; Jabbari, Kamel; Clay, Oliver; Bernardi, Giorgio

2004-05-26

243

Fusion genes in breast cancer  

E-print Network

Fusion genes in breast cancer Elizabeth M. Batty Clare College, University of Cambridge A dissertation submitted to the University of Cambridge in candidature for the degree of Doctor of Philosophy November 2010 ii... is the outcome of work done in collaboration except where specifically indicated in the text. It has not been submitted whole or in part for any other qualification at any other University. iii Summary Fusion genes in breast cancer Elizabeth Batty...

Batty, Elizabeth

2012-02-07

244

Selection for the ?-Thalassemia Genes  

PubMed Central

Extremely high incidences of single and double deletions of ?-globin genes are known among Asian populations. To study possible mechanisms for the maintenance of such deletions, mathematical analyses have been conducted. It has been shown that a stable polymorphism can be achieved easily through heterozygote advantage using deterministic models. The results strongly suggest that high incidences of single and double deletion of ?-globin genes among Asian populations are maintained by some type of heterozygote advantage. PMID:6840536

Yokoyama, Shozo

1983-01-01

245

RNA-triggered gene silencing  

Microsoft Academic Search

Double-stranded RNA (dsRNA) has recently been shown to trigger sequence-specific gene silencing in a wide variety of organisms, including nematodes, plants, trypanosomes, fruit flies and planaria; meanwhile an as yet uncharacterized RNA trigger has been shown to induce DNA methylation in several different plant systems. In addition to providing a surprisingly effective set of tools to interfere selectively with gene

Andrew Fire

1999-01-01

246

Nonviral Vectors for Gene Delivery  

E-print Network

in formulation design and can be tailored to fit the size and topology of the gene. 1.4.2.1. Natural polymers Over the years, a significant number of natural polymers, such as chitosan 174 , cationic proteins (e.g., polylysine, protamine and histones... polymers, the cationic polysaccharide chitosan has attracted considerable attention as a nonviral gene delivery vector. Although chitosan showed effective nucleic acid binding and compaction, the transfection efficiency was significantly lower compared...

Baoum, Abdulgader Ahmed

2011-04-26

247

Gene activation by bioactive glasses  

Microsoft Academic Search

Bioactive glasses have been shown to regulate gene expression in both hard and soft tissue repair. New resorbable bioactive\\u000a glass constructs are now being developed that can influence gene expression in the local environment by manipulating material\\u000a properties such as the surface chemistry, topography and the release of dissolution ions. The success of these scaffolds,\\u000a however, may depend upon a

G. Jell; M. M. Stevens

2006-01-01

248

Building Developmental Gene Regulatory Networks  

PubMed Central

Animal development is an elaborate process programmed by genomic regulatory instructions. Regulatory genes encode transcription factors and signal molecules, and their expression is under the control of cis-regulatory modules that define the logic of transcriptional responses to the inputs of other regulatory genes. The functional linkages amongst regulatory genes constitute the gene regulatory networks (GRNs) that govern cell specification and patterning in development. Constructing such networks requires identification of the regulatory genes involved and characterization of their temporal and spatial expression patterns. Interactions (activation/repression) among transcription factors or signals can be investigated by large-scale perturbation analysis, in which the function of each gene is specifically blocked. Resultant expression changes are then integrated to identify direct linkages, and to reveal the structure of the GRN. Predicted GRN linkages can be tested and verified by cis-regulatory analysis. The explanatory power of the GRN was shown in the lineage specification of sea urchin endomesoderm. Acquiring such networks is essential for a systematic and mechanistic understanding of the developmental process. PMID:19530131

Li, Enhu; Davidson, Eric H.

2009-01-01

249

Hydrogels for Lentiviral Gene Delivery  

PubMed Central

Introduction Gene delivery from hydrogel biomaterials provides a fundamental tool for a variety of clinical applications including regenerative medicine, gene therapy for inherited disorders and drug delivery. The high water content and mild gelation conditions of hydrogels support their use for gene delivery by preserving activity of lentiviral vectors and acting to shield vectors from any host immune response. Areas Covered Strategies to control lentiviral entrapment within and retention/release from hydrogels are reviewed. We discuss the ability of hydrogel design parameters to control the transgene expression profile and the capacity of hydrogels to protect vectors from (and even modulate) the host immune response. Expert Opinion Delivery of genetic vectors from scaffolds provides a unique opportunity to capitalize on the potential synergy between the biomaterial design for cell processes and gene delivery. Hydrogel properties can be tuned to directly control the events that determine the tissue response to controlled gene delivery, which include the extent of cell infiltration, preservation of vector activity and vector retention. While some design parameters have been identified, numerous opportunities for investigation are available in order to develop a complete model relating the biomaterial properties and host response to gene delivery. PMID:23347508

Seidlits, Stephanie K.; Gower, R. Michael; Shepard, Jaclyn A.; Shea, Lonnie D.

2013-01-01

250

Genes, Environments, and Behavior 2  

NSDL National Science Digital Library

In this lesson students will study how genetic research on behavior is conducted. Genes, Environment, and Behavior 2 is the second of two lessons about the field called behavioral genetics, in which scientists study the reciprocating influences of genes and environments on behavior, particularly human behavior. Genes, Environment and Behavior 2 introduces students to the various approaches scientists use to explore the interaction of genetic and environmental forces which shape behavior.An important objective of these lessons is to help students overcome the common public misperception that genes can have a direct relationship with behavior; for example, that there may be a "gene for criminality" or a "gene for religiosity." Another common misperception that can be dispelled through these lessons is that the development of an organism is determined solely by genetic factors; this is called genetic determinism. Possibly the most important value of these lessons, therefore, is that they can help students understand why such beliefs are false.These chapters are character-based and have relatively easy context. Provided are quizzes that that are administered after the short readings. These quizzes foster a discussion on each topic in behavior and genetics. Students will also perform a scavenger hunt on a scientific research article for phrases that reference research methods including: family studies, molecular studies, and brain imaging studies.

American Association for the Advancement of Science (;)

2006-04-25

251

Why genes overlap in viruses  

PubMed Central

The genomes of most virus species have overlapping genes—two or more proteins coded for by the same nucleotide sequence. Several explanations have been proposed for the evolution of this phenomenon, and we test these by comparing the amount of gene overlap in all known virus species. We conclude that gene overlap is unlikely to have evolved as a way of compressing the genome in response to the harmful effect of mutation because RNA viruses, despite having generally higher mutation rates, have less gene overlap on average than DNA viruses of comparable genome length. However, we do find a negative relationship between overlap proportion and genome length among viruses with icosahedral capsids, but not among those with other capsid types that we consider easier to enlarge in size. Our interpretation is that a physical constraint on genome length by the capsid has led to gene overlap evolving as a mechanism for producing more proteins from the same genome length. We consider that these patterns cannot be explained by other factors, namely the possible roles of overlap in transcription regulation, generating more divergent proteins and the relationship between gene length and genome length. PMID:20610432

Chirico, Nicola; Vianelli, Alberto; Belshaw, Robert

2010-01-01

252

Homologous gene replacement in Physarum  

SciTech Connect

The protist Physarum polycephalum is useful for analysis of several aspects of cellular and developmental biology. To expand the opportunities for experimental analysis of this organism, we have developed a method for gene replacement. We transformed Physarum amoebae with plasmid DNA carrying a mutant allele, ardD{Delta}1, of the ardD actin gene; ardD{Delta}1 mutates the critical carboxy-terminal region of the gene product. Because ardD is not expressed in the amoeba, replacement of ardD{sup +} with ardD{Delta}1 should not be lethal for this cell type. Transformants were obtained only when linear plasmid DNA was used. Most transformants carried one copy of ardD{Delta}1 in addition to ardD{sup +}, but in two (5%), ardD{sup +} was replaced by a single copy of ardD{Delta}1. This is the first example of homologous gene replacement in Physarum. ardD{Delta}1 was stably maintained in the genome through growth, development and meiosis. We found no effect of ardD{Delta}l on viability, growth, or development of any of the various cell types of Physarum. Thus, the carboxy-terminal region of the ardD product appears not to perform a unique essential role in growth or development. Nevertheless, this method for homologous gene replacement can be applied to analyze the function of any cloned gene. 38 refs., 6 figs., 1 tab.

Burland, T.G. [Univ. of Wisconsin, Madison, WI (United States); Pallotta, D. [Laval Univ., Quebec (Canada)

1995-01-01

253

ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel  

PubMed Central

Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G0/G1 phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation. PMID:23917377

Wei, Xiaoli; Sun, Hongliang; Yan, Haitao; Zhang, Cheng; Zhang, Shuzhuo; Liu, Xiaoyan; Hua, Nan; Ma, Xiaoyun; Zheng, Jianquan

2013-01-01

254

ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel.  

PubMed

Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G?/G? phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation. PMID:23917377

Wei, Xiaoli; Sun, Hongliang; Yan, Haitao; Zhang, Cheng; Zhang, Shuzhuo; Liu, Xiaoyan; Hua, Nan; Ma, Xiaoyun; Zheng, Jianquan

2013-05-01

255

Gene Therapy Progress and Prospects: Nonviral vectors  

Microsoft Academic Search

The success of gene therapy is largely dependent on the development of the gene delivery vector. Recently, gene transfection into target cells using naked DNA, which is a simple and safe approach, has been improved by combining several physical techniques, for example, electroporation, gene gun, ultrasound and hydrodynamic pressure. Chemical approaches have been utilized to improve the efficiency and cell

T Niidome; L Huang

2002-01-01

256

ADENOVIRAL GENE THERAPY FOR OVARIAN CANCER  

E-print Network

ADENOVIRAL GENE THERAPY FOR OVARIAN CANCER Anna Kanerva Cancer Gene Therapy Group Rational Drug;SUPERVISED BY Docent Akseli Hemminki, M.D., Ph.D. Cancer Gene Therapy Group, Rational Drug Design Program ................................................................................26 9. Adenoviral gene therapy trials for ovarian cancer

Hemminki, Akseli

257

What is Gene Therapy? Rafael Yez  

E-print Network

What is Gene Therapy? Rafael Yáñez rafael.yanez@rhul.ac.uk Rare Disease Day @ Royal Holloway 28th therapy strategies: "random" integration transgene transgene * #12;Gene Therapy successes;Gene therapy strategies: episomal vectors transgene transgene * #12;DNA repair #12;Gene therapy

Royal Holloway, University of London

258

Analysis of Microarray Gene Expression Data  

Microsoft Academic Search

Microarrays provide the biological research community with tremendously rich, sensitive and detailed information on gene expression profiles. Gene expression profiling and gene expression patterns have been found useful for solving a wide variety of important biological and biomedical problems, including the study of metabolic pathways, inference of the functions of unknown genes, diagnosis of diseased states, as well as facilitating

Tuan D. Pham; Christine Wells; Denis I. Crane

2006-01-01

259

Mechanoregulation of gene expression in fibroblasts  

Microsoft Academic Search

Mechanical loads placed on connective tissues alter gene expression in fibroblasts through mechanotransduction mechanisms by which cells convert mechanical signals into cellular biological events, such as gene expression of extracellular matrix components (e.g., collagen). This mechanical regulation of ECM gene expression affords maintenance of connective tissue homeostasis. However, mechanical loads can also interfere with homeostatic cellular gene expression and consequently

James H.-C. Wang; Bhavani P. Thampatty; Jeen-Shang Lin; Hee-Jeong Im

2007-01-01

260

Gene Assembly Through Cyclic Graph Decomposition  

E-print Network

Gene Assembly Through Cyclic Graph Decomposition A. Ehrenfeucht #3; T. Harju y G. Rozenberg zx Abstract We present in this paper a graph theoretical model of gene assem- bly, where (segments of) genes are distributed over a set of circular molecules. This model is motivated by the process of gene assembly

Harju, Tero

261

Basics on Genes and Genetic Disorders  

MedlinePLUS

The Basics on Genes and Genetic Disorders KidsHealth > Teens > Body > Health Basics > The Basics on Genes and Genetic Disorders Print A A A ... such as treating health problems. What Is a Gene? To understand how genes work, let's review some ...

262

Practice Note Establishing and managing gene  

E-print Network

Practice Note Establishing and managing gene conservation units 1FCPN021 Jason Hubert and Joan are called gene conservation units. This Practice Note sets out what you need to do to establish a gene in a way that would make them suitable, but a more formal recognition of a network of gene conservation

263

Hox genes in hematopoiesis and leukemogenesis  

Microsoft Academic Search

Gene expression analyses, gene targeting experiments and retroviral overexpression studies in the murine bone marrow transplantation model have provided strong correlative evidence for the involvement of clustered Hox genes in normal hematopoiesis. The data strongly support the hypothesis that the role of Hox genes in normal hematopoiesis is primarily at the level of hematopoietic stem cell function. A large body

B Argiropoulos; R K Humphries

2007-01-01

264

Gradient Descent Optimization in Gene Regulatory Pathways  

Microsoft Academic Search

BackgroundGene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of

Mouli Das; Subhasis Mukhopadhyay; Rajat K. De

2010-01-01

265

Horizontal gene transfer in eukaryotic evolution  

Microsoft Academic Search

Horizontal gene transfer (HGT; also known as lateral gene transfer) has had an important role in eukaryotic genome evolution, but its importance is often overshadowed by the greater prevalence and our more advanced understanding of gene transfer in prokaryotes. Recurrent endosymbioses and the generally poor sampling of most nuclear genes from diverse lineages have also complicated the search for transferred

Jeffrey D. Palmer; Patrick J. Keeling

2008-01-01

266

The Stability of Gene Network Dynamics  

E-print Network

. PNAS (,,09)]! #12;Network Instability and Cancer · Tumor dissections show that nearby cells in cancer instability in the gene network may be a causal mechanism contributing to the occurrence of cancer. #12;Gene Expression and Regulation · Genes: Functional segments of DNA. · Gene expression: The function of a given

Maryland at College Park, University of

267

Markov process modelling of gene regulation  

Microsoft Academic Search

This paper discusses the mathematical modelling of gene regulation with emphasis on the bottom-up modelling of genetic componentry rather than the reverse-engineering of networks from gene expression data. Reflecting the stochastic nature of gene regulation, the chemical master equation is used as a tool to study Markovian models of networks of gene states between which probabilistic transitions occur. These states

Hilary S. Booth; Conrad J. Burden; Markus Hegland; Lucia Santoso

268

Novel gene transfer systems: intelligent gene transfer vectors for gene medicines.  

PubMed

Drug delivery systems for gene transfer are called 'vectors'. These systems were originally invented as a delivery system for the transfection in vitro or in vivo. Several vectors are then developed for clinical use of gene medicines and currently some of them are approved as animal drugs. Conventional drug delivery system generally consists of approved (existing) materials to avoid additional pre-clinical or clinical studies. However, current vectors contain novel materials to improve an efficacy of gene medicines. Thus, these vectors have functions more than a mere delivery of active ingredients. For example some vectors have immunological functions such as adjuvants in vaccines. These new types of vectors are called 'intelligent' or 'innovative' vector system', since the concept or strategy for the development is completely different from conventional drug delivery systems. In this article, we described a current status of 'intelligent gene transfer vectors and discussed on the potentials of them. PMID:22762555

Nakajima, Toshihiro

2012-01-01

269

Newer gene editing technologies toward HIV gene therapy.  

PubMed

Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called "Berlin patient" who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. PMID:24284874

Manjunath, N; Yi, Guohua; Dang, Ying; Shankar, Premlata

2013-11-01

270

Newer Gene Editing Technologies toward HIV Gene Therapy  

PubMed Central

Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. PMID:24284874

Manjunath, N.; Yi, Guohua; Dang, Ying; Shankar, Premlata

2013-01-01

271

The biology of novel animal genes: Mouse APEX gene knockout  

SciTech Connect

This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The controlled breeding of novel genes into mice, including the gene knockout (KO), or conversely by adding back transgenes provide powerful genetic technologies that together suffice to determine in large part the biological role(s) of novel genes. Inbred mouse remains the best understood and most useful mammalian experimental system available for tackling the biology of novel genes. The major mammalian apurinic/apyrimidinic (AP) endonuclease (APE), is involved in a key step in the repair of spontaneous and induced AP sites in DNA. Efficient repair of these lesions is imperative to prevent the stable incorporation of mutations into the cellular genome which may lead to cell death or transformation. Loss or modulation of base excison repair activity in vivo may elevate the spontaneous mutation rate in cells, and may lead to a substantial increase in the incidence of cancer. Despite extensive biochemical analysis, however, the significance of these individual APE functions in vivo has not been elucidated. Mouse embryonic stem (ES) cells heterozygous for a deletion mutation in APE have been generated and whole animals containing the APE mutation have been derived from these ES cells. Animals homozygous for the APE null mutation die early in gestation, underscoring the biological significance of this DNA repair gene.

MacInnes, M.; Altherr, M.R.; Ludwig, D. [Los Alamos National Lab., NM (United States); Pedersen, R.; Mold, C. [Univ. of California, San Francisco, CA (United States)

1997-07-01

272

Advancement and prospects of tumor gene therapy  

PubMed Central

Gene therapy is one of the most attractive fields in tumor therapy. In past decades, significant progress has been achieved. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. Several therapeutic strategies have evolved, including gene-based (tumor suppressor genes, suicide genes, antiangiogenic genes, cytokine and oxidative stress-based genes) and RNA-based (antisense oligonucleotides and RNA interference) approaches. In addition, immune response-based strategies (dendritic cell– and T cell–based therapy) are also under investigation in tumor gene therapy. This review highlights the progress and recent developments in gene delivery systems, therapeutic strategies, and possible clinical directions for gene therapy. PMID:21352695

Zhang, Chao; Wang, Qing-Tao; Liu, He; Zhang, Zhen-Zhu; Huang, Wen-Lin

2011-01-01

273

Evolution of Hemoglobin and Its Genes  

PubMed Central

Insights into the evolution of hemoglobins and their genes are an abundant source of ideas regarding hemoglobin function and regulation of globin gene expression. This article presents the multiple genes and gene families encoding human globins, summarizes major events in the evolution of the hemoglobin gene clusters, and discusses how these studies provide insights into regulation of globin genes. Although the genes in and around the ?-like globin gene complex are relatively stable, the ?-like globin gene clusters are more dynamic, showing evidence of transposition to a new locus and frequent lineage-specific expansions and deletions. The cis-regulatory modules controlling levels and timing of gene expression are a mix of conserved and lineage-specific DNA, perhaps reflecting evolutionary constraint on core regulatory functions shared broadly in mammals and adaptive fine-tuning in different orders of mammals. PMID:23209182

Hardison, Ross C.

2012-01-01

274

Genes and Abdominal Aortic Aneurysm  

PubMed Central

Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since first candidate gene studies were published 20 years ago, nearly 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. The studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, if appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called CNTN3 which is located on chromosome 3p12.3. Two follow-up studies, however, could not replicate the association. Two other SNPs, which are located on chromosome 9p21 and 9q33 were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense RNA that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute to AAA pathogenesis. PMID:21146954

Hinterseher, Irene; Tromp, Gerard; Kuivaniemi, Helena

2010-01-01

275

Microfluidic approaches for gene delivery and gene therapy Jungkyu Kim,a  

E-print Network

Microfluidic approaches for gene delivery and gene therapy Jungkyu Kim,a Inseong Hwang,b Derek for gene delivery and therapy. The micro-scaled environment within microfluidic systems enables precise are producing increased efficiency in gene delivery and promise improved gene therapy results. Introduction Many

Sun, Yu

276

Gene targeting using a promoterless gene trap vector (``targeted trapping'') is an efficient method to  

E-print Network

Gene targeting using a promoterless gene trap vector (``targeted trapping'') is an efficient method to mutate a large fraction of genes Roland H. Friedel* , Andrew Plump* , Xiaowei Lu* , Kerri Spilker-Lavigne, July 11, 2005 A powerful tool for postgenomic analysis of mammalian gene function is gene targeting

McConnell, Susan

277

Virtual Gene: a Gene Selection Algorithm for Sample Classification on Microarray Datasets  

E-print Network

Virtual Gene: a Gene Selection Algorithm for Sample Classification on Microarray Datasets Xian Xu, USA Abstract. Gene Selection is one class of most used data analysis algorithms on microarray dataset. The goal of gene selection algorithms is to filter out a small set of informative genes that best explains

Buffalo, State University of New York

278

GeneSeqer@PlantGDB: gene structure prediction in plant genomes  

E-print Network

GeneSeqer@PlantGDB: gene structure prediction in plant genomes Shannon D. Schlueter1 , Qunfeng Dong, 2003 ABSTRACT The GeneSeqer@PlantGDB Web server (http:// www.plantgdb.org/cgi-bin/GeneSeqer.cgi) provides a gene structure prediction tool tailored for applica- tions to plant genomic sequences

Brendel, Volker

279

Multi-gene linear separability of gene expression data in linear time  

E-print Network

Multi-gene linear separability of gene expression data in linear time Md. Shafiul Alam, Satish] Unger and Chor showed how to test for linear sep- arability of gene expression data with respect to pairs of genes. Their method however is not amenable to an efficient test when more than 2 genes

Mukhopadhyay, Asish

280

Sexy Gene Conversions: Locating Gene Conversions on the X-Chromosome  

E-print Network

Sexy Gene Conversions: Locating Gene Conversions on the X-Chromosome Mark J. Lawson1 , Liqing Zhang Gene conversion can have a profound impact on both the short-term and long-term evolution of genes and genomes. Here we examined the gene families that are located on the X-chromosomes of human, chimp, mouse

Zhang, Liqing

281

Gene tree of the HoxA11 genes in vertebrates illustrating several  

E-print Network

Gene tree of the HoxA11 genes in vertebrates illustrating several whole genome duplications (WGD with all the other vertebrate animals, and many developmental genes with invertebrate animals as well. The Hox genes are one class of toolkit genes that specify body plan features such as limbs and fins

282

Novel methods to identify biologically relevant genes for leukemia and prostate cancer from gene expression profiles  

Microsoft Academic Search

BACKGROUND: High-throughput microarray experiments now permit researchers to screen thousands of genes simultaneously and determine the different expression levels of genes in normal or cancerous tissues. In this paper, we address the challenge of selecting a relevant and manageable subset of genes from a large microarray dataset. Currently, most gene selection methods focus on identifying a set of genes that

Austin H Chen; Yin-Wu Tsau; Ching-Heng Lin

2010-01-01

283

Evaluation of five ab initio gene prediction programs for the discovery of maize genes  

E-print Network

Evaluation of five ab initio gene prediction programs for the discovery of maize genes Hong Yao1 Key words: ab initio gene prediction, a1-sh2 interval, maize, maize assembled genomic islands, maizeR and Grail) were evaluated for their accuracy in predicting maize genes. Two of these programs, Gene

Schnable, Patrick S.

284

Identification of Tuberculosis Susceptibility Genes with Human Macrophage Gene Expression Profiles  

Microsoft Academic Search

Although host genetics influences susceptibility to tuberculosis (TB), few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different clinical manifestations of Mycobacterium tuberculosis (Mtb) infection would have distinct gene expression profiles and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from

Nguyen Thuy Thuong Thuong; Sarah J. Dunstan; Tran Thi Hong Chau; Vesteinn Thorsson; Cameron P. Simmons; Nguyen Than Ha Quyen; Guy E. Thwaites; Nguyen Thi Ngoc Lan; Martin Hibberd; Yik Y. Teo; Mark Seielstad; Alan Aderem; Jeremy J. Farrar; Thomas R. Hawn

2008-01-01

285

A Hierarchical Method for Selecting Feature Genes from Gene-Expression Profiles  

NASA Astrophysics Data System (ADS)

A novel feature genes selection method is presented for detecting disease causal genes from gene expression profiles. In this paper, we take three steps and combine genetic algorithm, k-nearest neighbor and statistical test to detect the most important genes. Experiments on colorectal cancer gene-expression profiles prove the performance of our method.

Rui-xue, Huang; Shu-yang, Lin; Di-wei, Wu; Yan-yun, Qu; Quan, Zou

286

Concepts of Marker Genes for Plants  

Microsoft Academic Search

\\u000a Marker genes, more exactly named selectable marker genes, are absolutely essential for the production of transgenic plants.\\u000a They are required to identify, to “mark” the introduced genes and finally to enable the selective growth of transformed cells.\\u000a These marker genes are co-transformed with the gene of interest (GOI); they are linked to the GOI and therefore remain in\\u000a the transformed

Josef Kraus

287

Genetic variation in human gene expression.  

PubMed

Gene expression variation has been the focus of many studies in the past few years. The relevance of gene regulation and gene expression to disease and the development of the technologies used to screen large numbers of genes simultaneously have allowed this rapid development. In this review we discuss issues relating to the biological information one obtains from such studies and the biological significance and use of signals from mapping of gene expression variation. PMID:16783632

Dermitzakis, Emmanouil T; Stranger, Barbara E

2006-06-01

288

Combination of Gene Therapy with Radiation  

Microsoft Academic Search

To date tremendous progress has been made in the field of cancer gene therapy. Strategies have been explored for achieving\\u000a therapeutic benefit using various genes and several clinical trials for cancer gene therapy have been carried out demonstrating\\u000a that gene therapy is well tolerated. However, in most cases the efficacy of gene transfer has been very limited. As an alternative,

Anupama Munshi; Raymond E. Meyn

289

Does inbreeding affect gene expression in birds?  

PubMed

Inbreeding increases homozygosity, exposes genome-wide recessive deleterious alleles and often reduces fitness. The physiological and reproductive consequences of inbreeding may be manifested already during gene regulation, but the degree to which inbreeding influences gene expression is unknown in most organisms, including in birds. To evaluate the pattern of inbreeding-affected gene expression over the genome and in relation to sex, we performed a transcriptome-wide gene expression (10 695 genes) study of brain tissue of 10-day-old inbred and outbred, male and female zebra finches. We found significantly lower gene expression in females compared with males at Z-linked genes, confirming that dosage compensation is incomplete in female birds. However, inbreeding did not affect gene expression at autosomal or sex-linked genes, neither in males nor in females. Analyses of single genes again found a clear sex-biased expression at Z-linked genes, whereas only a single gene was significantly affected by inbreeding. The weak effect of inbreeding on gene expression in zebra finches contrasts to the situation, for example, in Drosophila where inbreeding has been found to influence gene expression more generally and at stress-related genes in particular. PMID:25232028

Hansson, Bengt; Naurin, Sara; Hasselquist, Dennis

2014-09-01

290

Gene expression throughout a vertebrate's embryogenesis  

PubMed Central

Background Describing the patterns of gene expression during embryonic development has broadened our understanding of the processes and patterns that define morphogenesis. Yet gene expression patterns have not been described throughout vertebrate embryogenesis. This study presents statistical analyses of gene expression during all 40 developmental stages in the teleost Fundulus heteroclitus using four biological replicates per stage. Results Patterns of gene expression for 7,000 genes appear to be important as they recapitulate developmental timing. Among the 45% of genes with significant expression differences between pairs of temporally adjacent stages, significant differences in gene expression vary from as few as five to more than 660. Five adjacent stages have disproportionately more significant changes in gene expression (> 200 genes) relative to other stages: four to eight and eight to sixteen cell stages, onset of circulation, pre and post-hatch, and during complete yolk absorption. The fewest differences among adjacent stages occur during gastrulation. Yet, at stage 16, (pre-mid-gastrulation) the largest number of genes has peak expression. This stage has an over representation of genes in oxidative respiration and protein expression (ribosomes, translational genes and proteases). Unexpectedly, among all ribosomal genes, both strong positive and negative correlations occur. Similar correlated patterns of expression occur among all significant genes. Conclusions These data provide statistical support for the temporal dynamics of developmental gene expression during all stages of vertebrate development. PMID:21356103

2011-01-01

291

Gene methylation in gastric cancer.  

PubMed

Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field. PMID:23669186

Qu, Yiping; Dang, Siwen; Hou, Peng

2013-09-23

292

Genes, Environments, and Behavior 1  

NSDL National Science Digital Library

Genes, Environment, and Behavior 1 is the first of two lessons about the field called behavioral genetics, in which scientists study the reciprocating influences of genes and environments on behavior, particularly human behavior. It provides students with a clear understanding of how behavior is defined by scientists and an overview of the genetic and environmental forces that interact to shape behavior.In this lesson, students are assigned reading materials from the book Behavioral Genetics: An introduction to how genes and environments interact through development to shape differences in mood, personality, and intelligence, published by AAAS and The Hastings Center. These chapters are character-based and have relatively easy context. Provided are quizzes that that are administered after the short readings. These quizzes foster a discussion on each topic in behavior and genetics. The titles of the chapters in this lesson are: 1) "What is behavioral genetics?", 2) "How do genes work within their environments?", 3) "How do environments impinge upon the genes?"

American Association for the Advancement of Science (;)

2006-04-25

293

Metazoan Gene Families from Metazome  

DOE Data Explorer

Metazome is a joint project of the Department of Energy's Joint Genome Institute and the Center for Integrative Genomics to facilitate comparative genomic studies amongst metazoans. Clusters of orthologous and paralogous genes that represent the modern descendents of ancestral gene sets are constructed at key phylogenetic nodes. These clusters allow easy access to clade specific orthology/paralogy relationships as well as clade specific genes and gene expansions. As of version 2.0.4, Metazome provides access to twenty-four sequenced and annotated metazoan genomes, clustered at nine evolutionarily significant nodes. Where possible, each gene has been annotated with PFAM, KOG, KEGG, and PANTHER assignments, and publicly available annotations from RefSeq, UniProt, Ensembl, and JGI are hyper-linked and searchable. The included organisms (by common name) are: Human, Mouse, Rat, Dog, Opossum, Chicken, Frog, Stickleback, Medaka, Fugu pufferfish; Zebrafish, Seasquirt - savignyi, Seasquirt - intestinalis, Amphioxus, Sea Urchin, Fruitfly, Mosquite, Yellow Fever Mosquito, Silkworm, Red Flour Beetle, Worm, Briggsae Worm, Owl limpet (snail), and Sea anemone. [Copied from Metazome Overview at http://www.metazome.net/Metazome_info.php

294

Gene Ontology Consortium: going forward.  

PubMed

The Gene Ontology (GO; http://www.geneontology.org) is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology. PMID:25428369

2015-01-28

295

Stochastic Mechanisms in Gene Expression  

NASA Astrophysics Data System (ADS)

In cellular regulatory networks, genetic activity is controlled by molecular signals that determine when and how often a given gene is transcribed. In genetically controlled pathways, the protein product encoded by one gene often regulates expression of other genes. The time delay, after activation of the first promoter, to reach an effective level to control the next promoter depends on the rate of protein accumulation. We have analyzed the chemical reactions controlling transcript initiation and translation termination in a single such ``genetically coupled'' link as a precursor to modeling networks constructed from many such links. Simulation of the processes of gene expression shows that proteins are produced from an activated promoter in short bursts of variable numbers of proteins that occur at random time intervals. As a result, there can be large differences in the time between successive events in regulatory cascades across a cell population. In addition, the random pattern of expression of competitive effectors can produce probabilistic outcomes in switching mechanisms that select between alternative regulatory paths. The result can be a partitioning of the cell population into different phenotypes as the cells follow different paths. There are numerous unexplained examples of phenotypic variations in isogenic populations of both prokaryotic and eukaryotic cells that may be the result of these stochastic gene expression mechanisms.

McAdams, Harley H.; Arkin, Adam

1997-02-01

296

Combinatorial methods for gene recognition  

SciTech Connect

The major result of the project is the development of a new approach to gene recognition called spliced alignment algorithm. They have developed an algorithm and implemented a software tool (for both IBM PC and UNIX platforms) which explores all possible exon assemblies in polynomial time and finds the multi-exon structure with the best fit to a related protein. Unlike other existing methods, the algorithm successfully performs exons assemblies even in the case of short exons or exons with unusual codon usage; they also report correct assemblies for the genes with more than 10 exons provided a homologous protein is already known. On a test sample of human genes with known mammalian relatives the average overlap between the predicted and the actual genes was 99%, which is remarkably well as compared to other existing methods. At that, the algorithm absolute correctly reconstructed 87% of genes. The rare discrepancies between the predicted and real axon-intron structures were restricted either to extremely short initial or terminal exons or proved to be results of alternative splicing. Moreover, the algorithm performs reasonably well with non-vertebrate and even prokaryote targets. The spliced alignment software PROCRUSTES has been in extensive use by the academic community since its announcement in August, 1996 via the WWW server (www-hto.usc.edu/software/procrustes) and by biotech companies via the in-house UNIX version.

Pevzner, P.A.

1997-10-29

297

Using GenePattern for Gene Expression Analysis  

PubMed Central

The abundance of genomic data now available in biomedical research has stimulated the development of sophisticated statistical methods for interpreting the data, and of special visualization tools for displaying the results in a concise and meaningful manner. However, biologists often find these methods and tools difficult to understand and use correctly. GenePattern is a freely available software package that addresses this issue by providing more than 100 analysis and visualization tools for genomic research in a comprehensive user-friendly environment for users at all levels of computational experience and sophistication. This unit demonstrates how to prepare and analyze microarray data in GenePattern. PMID:18551415

Kuehn, Heidi; Liberzon, Arthur; Reich, Michael; Mesirov, Jill P.

2013-01-01

298

Analysis of human genes with protein-protein interaction network for detecting disease genes  

NASA Astrophysics Data System (ADS)

The topological features of disease genes and non-disease genes were widely utilized in disease genes prediction. However, previous studies neglected to exploit essential genes to distinguish disease genes and non-disease genes. Therefore, this paper firstly takes essential genes as reference to analyze the topological properties of human genes with protein-protein interaction network. Empirical results demonstrate that nonessential disease genes are topologically more important and closer to the center of the network than other genes (unknown genes, which are deemed as non-disease genes in disease genes prediction). Although disease genes are closer to essential genes, we find that the influence of disease genes on essential genes is similar with other genes, or even weaker. Further, we generate new topological features according to our findings and validate the effectiveness of combining the additional features for detecting disease genes. In addition, we find that the k-shell index (ks) of protein-protein network follows a power law distribution, and the function of the proteins with the largest ks may deserve further research.

Wu, Shun-yao; Shao, Feng-jing; Sun, Ren-cheng; Sui, Yi; Wang, Ying; Wang, Jin-long

2014-03-01

299

Modelling Nonstationary Gene Regulatory Processes  

PubMed Central

An important objective in systems biology is to infer gene regulatory networks from postgenomic data, and dynamic Bayesian networks have been widely applied as a popular tool to this end. The standard approach for nondiscretised data is restricted to a linear model and a homogeneous Markov chain. Recently, various generalisations based on changepoint processes and free allocation mixture models have been proposed. The former aim to relax the homogeneity assumption, whereas the latter are more flexible and, in principle, more adequate for modelling nonlinear processes. In our paper, we compare both paradigms and discuss theoretical shortcomings of the latter approach. We show that a model based on the changepoint process yields systematically better results than the free allocation model when inferring nonstationary gene regulatory processes from simulated gene expression time series. We further cross-compare the performance of both models on three biological systems: macrophages challenged with viral infection, circadian regulation in Arabidopsis thaliana, and morphogenesis in Drosophila melanogaster. PMID:20721277

Grzegorcyzk, Marco; Husmeier, Dirk; Rahnenführer, Jörg

2010-01-01

300

Gene Therapy in Corneal Transplantation  

PubMed Central

Corneal transplantation is the most commonly performed organ transplantation. Immune privilege of the cornea is widely recognized, partly because of the relatively favorable outcome of corneal grafts. The first-time recipient of corneal allografts in an avascular, low-risk setting can expect a 90% success rate without systemic immunosuppressive agents and histocompatibility matching. However, immunologic rejection remains the major cause of graft failure, particularly in patients with a high risk for rejection. Corticosteroids remain the first-line therapy for the prevention and treatment of immune rejection. However, current pharmacological measures are limited in their side-effect profiles, repeated application, lack of targeted response, and short duration of action. Experimental ocular gene therapy may thus present new horizons in immunomodulation. From efficient viral vectors to sustainable alternative splicing, we discuss the progress of gene therapy in promoting graft survival and postulate further avenues for gene-mediated prevention of allogeneic graft rejection. PMID:24138037

Qazi, Yureeda; Hamrah, Pedram

2014-01-01

301

Genes and brain sex differences.  

PubMed

Throughout development, numerous biological events occur that differentially affect males and females. Specifically, sex-determining genes that are triggered by the sex-chromosome complement initiate a series of events that determine an organism's sex and lead to the differentiation of the body in sex-specific ways. Such events contribute to many unique sex differences, including the susceptibility to different diseases. Although it was believed that sex hormones singularly differentiated the brain and body, there is emerging research showing that genes also play a direct role. In this chapter, we review this line of work and focus on the use of a unique mouse model that separates the effect of gonadal hormones and sex chromosomes. As genetic technology continues to advance, our understanding of the role that hormones and genes play in sex differences can be used to advance the physical and mental health of both men and women. PMID:21094886

Sánchez, Francisco J; Vilain, Eric

2010-01-01

302

Gene Therapy for Bone Engineering  

PubMed Central

Bone has an intrinsic healing capacity that may be exceeded when the fracture gap is too big or unstable. In that moment, osteogenic measures need to be taken by physicians. It is important to combine cells, scaffolds and growth factors, and the correct mechanical conditions. Growth factors are clinically administered as recombinant proteins. They are, however, expensive and needed in high supraphysiological doses. Moreover, their half-life is short when administered to the fracture. Therefore, gene therapy may be an alternative. Cells can constantly produce the protein of interest in the correct folding, with the physiological glycosylation and in the needed amounts. Genes can be delivered in vivo or ex vivo by viral or non-viral methods. Adenovirus is mostly used. For the non-viral methods, hydrogels and recently sonoporation seem to be promising means. This review will give an overview of recent advancements in gene therapy approaches for bone regeneration strategies.

Balmayor, Elizabeth Rosado; van Griensven, Martijn

2015-01-01

303

Gene Expression Studies in Mosquitoes  

PubMed Central

Research on gene expression in mosquitoes is motivated by both basic and applied interests. Studies of genes involved in hematophagy, reproduction, olfaction, and immune responses reveal an exquisite confluence of biological adaptations that result in these highly-successful life forms. The requirement of female mosquitoes for a bloodmeal for propagation has been exploited by a wide diversity of viral, protozoan and metazoan pathogens as part of their life cycles. Identifying genes involved in host-seeking, blood feeding and digestion, reproduction, insecticide resistance and susceptibility/refractoriness to pathogen development is expected to provide the bases for the development of novel methods to control mosquito-borne diseases. Advances in mosquito transgenesis technologies, the availability of whole genome sequence information, mass sequencing and analyses of transcriptomes and RNAi techniques will assist development of these tools as well as deepen the understanding of the underlying genetic components for biological phenomena characteristic of these insect species. PMID:19161831

Chen, Xlao-Guang; Mathur, Geetika; James, Anthony A.

2009-01-01

304

Transients in chloroplast gene transcription  

SciTech Connect

Transcriptional regulation of chloroplast genes is demonstrated by Quantitative Polymerase Chain Reaction (qPCR). These genes encode apoproteins of the reaction centres of photosystem I and photosystem II. Their transcription is regulated by changes in wavelength of light selectively absorbed by photosystem I and photosystem II, and therefore by the redox state of an electron carrier located between the two photosystems. Chloroplast transcriptional redox regulation is shown to have greater amplitude, and the kinetics of transcriptional changes are more complex, than suggested by previous experiments using only DNA probes in Northern blot experiments. Redox effects on chloroplast transcription appear to be superimposed on an endogenous rhythm of mRNA abundance. The functional significance of these transients in chloroplast gene transcription is discussed.

Puthiyaveetil, Sujith [School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS (United Kingdom); Allen, John F. [School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS (United Kingdom)], E-mail: j.f.allen@qmul.ac.uk

2008-04-18

305

Gene therapy for lung cancer.  

PubMed

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery due to the usual finding of advanced disease at diagnosis. Attempts to improve survival in advanced disease using various combinations of chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Techniques have been developed that allow transfer of functional genes into mammalian cells, such as those that block activated tumor-promoting oncogenes and/or those that replace inactivated tumor-suppressing or apoptosis-promoting genes. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas, and will then review the status of gene therapies for treatment of lung cancer. PMID:17240826

Toloza, Eric M

2006-11-01

306

Global gene disruption in human cells to assign genes to phenotypes  

E-print Network

Insertional mutagenesis in a haploid background can disrupt gene function[superscript 1]. We extend our earlier work by using a retroviral gene-trap vector to generate insertions in >98% of the genes expressed in a human ...

Ploegh, Hidde

307

Models, algorithms, and programs for phylogeny reconciliation Keywords: phylogeny; gene duplication, loss, horizontal gene transfer;  

E-print Network

Models, algorithms, and programs for phylogeny reconciliation Keywords: phylogeny; gene duplication, loss, horizontal gene transfer; parsimony; probability; reconciliation. 1. Institut des Sciences de l on comparative genomics, especially combinatorial and probabilistic aspects of reconciliations between gene

Paris-Sud XI, Université de

308

Genes 2010, 1, 452-468; doi:10.3390/genes1030452 ISSN 2073-4425  

E-print Network

OPEN ACCESS #12;Genes 2010, 1 453 1. Introduction The expansion of gene number within organisms predictions for gene duplicate evolution that were established in the pre-genomic era [1­3]. The canonical

Bergthorsson, Ulfar

309

Electroporation-mediated gene delivery.  

PubMed

Electroporation has been used extensively to transfer DNA to bacteria, yeast, and mammalian cells in culture for the past 30 years. Over this time, numerous advances have been made, from using fields to facilitate cell fusion, delivery of chemotherapeutic drugs to cells and tissues, and most importantly, gene and drug delivery in living tissues from rodents to man. Electroporation uses electrical fields to transiently destabilize the membrane allowing the entry of normally impermeable macromolecules into the cytoplasm. Surprisingly, at the appropriate field strengths, the application of these fields to tissues results in little, if any, damage or trauma. Indeed, electroporation has even been used successfully in human trials for gene delivery for the treatment of tumors and for vaccine development. Electroporation can lead to between 100 and 1000-fold increases in gene delivery and expression and can also increase both the distribution of cells taking up and expressing the DNA as well as the absolute amount of gene product per cell (likely due to increased delivery of plasmids into each cell). Effective electroporation depends on electric field parameters, electrode design, the tissues and cells being targeted, and the plasmids that are being transferred themselves. Most importantly, there is no single combination of these variables that leads to greatest efficacy in every situation; optimization is required in every new setting. Electroporation-mediated in vivo gene delivery has proven highly effective in vaccine production, transgene expression, enzyme replacement, and control of a variety of cancers. Almost any tissue can be targeted with electroporation, including muscle, skin, heart, liver, lung, and vasculature. This chapter will provide an overview of the theory of electroporation for the delivery of DNA both in individual cells and in tissues and its application for in vivo gene delivery in a number of animal models. PMID:25620008

Young, Jennifer L; Dean, David A

2015-01-01

310

Essential genes of a minimal bacterium.  

PubMed

Mycoplasma genitalium has the smallest genome of any organism that can be grown in pure culture. It has a minimal metabolism and little genomic redundancy. Consequently, its genome is expected to be a close approximation to the minimal set of genes needed to sustain bacterial life. Using global transposon mutagenesis, we isolated and characterized gene disruption mutants for 100 different nonessential protein-coding genes. None of the 43 RNA-coding genes were disrupted. Herein, we identify 382 of the 482 M. genitalium protein-coding genes as essential, plus five sets of disrupted genes that encode proteins with potentially redundant essential functions, such as phosphate transport. Genes encoding proteins of unknown function constitute 28% of the essential protein-coding genes set. Disruption of some genes accelerated M. genitalium growth. PMID:16407165

Glass, John I; Assad-Garcia, Nacyra; Alperovich, Nina; Yooseph, Shibu; Lewis, Matthew R; Maruf, Mahir; Hutchison, Clyde A; Smith, Hamilton O; Venter, J Craig

2006-01-10

311

Essential genes of a minimal bacterium  

PubMed Central

Mycoplasma genitalium has the smallest genome of any organism that can be grown in pure culture. It has a minimal metabolism and little genomic redundancy. Consequently, its genome is expected to be a close approximation to the minimal set of genes needed to sustain bacterial life. Using global transposon mutagenesis, we isolated and characterized gene disruption mutants for 100 different nonessential protein-coding genes. None of the 43 RNA-coding genes were disrupted. Herein, we identify 382 of the 482 M. genitalium protein-coding genes as essential, plus five sets of disrupted genes that encode proteins with potentially redundant essential functions, such as phosphate transport. Genes encoding proteins of unknown function constitute 28% of the essential protein-coding genes set. Disruption of some genes accelerated M. genitalium growth. PMID:16407165

Glass, John I.; Assad-Garcia, Nacyra; Alperovich, Nina; Yooseph, Shibu; Lewis, Matthew R.; Maruf, Mahir; Hutchison, Clyde A.; Smith, Hamilton O.; Venter, J. Craig

2006-01-01

312

Amplification of kinetic oscillations in gene expression  

NASA Astrophysics Data System (ADS)

Because of the feedbacks between the DNA transcription and mRNA translation, the gene expression in cells may exhibit bistability and oscillations. The deterministic and stochastic calculations presented illustrate how the bistable kinetics of expression of one gene in a cell can be influenced by the kinetic oscillations in the expression of another gene. Due to stability of the states of the bistable kinetics of gene 1 and the relatively small difference between the maximum and minimum protein amounts during the oscillations of gene 2, the induced oscillations of gene 1 are found to typically be related either to the low-or high-reactive state of this gene. The quality of the induced oscillations may be appreciably better than that of the inducing oscillations. This means that gene 1 can serve as an amplifier of the kinetic oscillations of gene 2.

Zhdanov, V. P.

2008-10-01

313

Concerted evolution of human amylase genes  

SciTech Connect

Cosmid clones containing 250 kilobases of genomic DNA from the human amylase gene cluster have been isolated. These clones contain seven distinct amylase genes which appear to comprise the complete multigene family. By sequence comparison with the cDNAs, the authors have identified two pancreatic amylase gene and three salivary amylase genes. Two truncated pseudogenes were also recovered. Intergenic distances of 17 to 22 kilobases separate the amylase gene copies. Within the past 10 million years, duplications, gene conversion, and unequal crossover events have resulted in a very high level of sequence similarity among human amylase gene copies. To identify sequence elements involved in tissue-specific expression and hormonal regulation, the promoter regions of the human amylase genes were sequenced and compared with those of the corresponding mouse genes. The promoters of the human and mouse pancreatic amylase genes are highly homologous between nucleotide - 160 and the cap site. Two sequence elements througth to influence pancreas-specific expression of the rodent genes are present in the human genes. In contrast, similarity in the 5' lanking sequences of the salivary amylase genes is limited to several short sequence elements whose positions and orientations differ in the two species. Some of these sequence elements are also associated with other parotid-specific genes and may be involved in their tissue-specific expression. A glucocorticoid response element and a general enhancer element are closely associated in several of the amylase promoters.

Gumucio, D.L.; Wiebauer, K.; Caldwell, R.M.; Samuelson, L.C.; Meisler, M.H.

1988-03-01

314

Decoding Gene Patents in Australia.  

PubMed

Patents directed to naturally occurring genetic material, such as DNA, RNA, chromosomes, and genes, in an isolated or purified form have been granted in Australia for many years. This review provides scientists with a summary of the gene patent debate from an Australian perspective and specifically reviews how the various levels of the legal system as they apply to patents-the Australian Patent Office, Australian courts, and Australian government-have dealt with the issue of whether genetic material is proper subject matter for a patent. PMID:25280901

Denley, Adam; Cherry, James

2014-10-01

315

Gene therapy in clinical medicine  

PubMed Central

Although the field of gene therapy has experienced significant setbacks and limited success, it is one of the most promising and active research fields in medicine. Interest in this therapeutic modality is based on the potential for treatment and cure of some of the most malignant and devastating diseases affecting humans. Over the next decade, the relevance of gene therapy to medical practices will increase and it will become important for physicians to understand the basic principles and strategies that underlie the therapeutic intervention. This report reviews the history, basic strategies, tools, and several current clinical paradigms for application. PMID:15466989

Selkirk, S

2004-01-01

316

A literature network of human genes for high-throughput analysis of gene expression  

Microsoft Academic Search

We have carried out automated extraction of explicit and implicit biomedical knowledge from publicly available gene and text databases to create a gene-to-gene co-citation network for 13,712 named human genes by automated analysis of titles and abstracts in over 10 million MEDLINE records. The associations between genes have been annotated by linking genes to terms from the medical subject heading

Tor-Kristian Jenssen; Astrid Lægreid; Jan Komorowski; Eivind Hovig

2001-01-01

317

Identification of genes and gene clusters involved in mycotoxin synthesis  

Technology Transfer Automated Retrieval System (TEKTRAN)

Research methods to identify and characterize genes involved in mycotoxin biosynthetic pathways have evolved considerably over the years. Before whole genome sequences were available (e.g. pre-genomics), work focused primarily on chemistry, biosynthetic mutant strains and molecular analysis of sing...

318

GenePRIMP: Improving Microbial Gene Prediction Quality  

SciTech Connect

Amrita Pati of the DOE Joint Genome Institute's Genome Biology group talks about a computational pipeline that evaluates the accuracy of gene models in genomes and metagenomes at different stages of finishing at the "Sequencing, Finishing, Analysis in the Future" meeting in Santa Fe, NM

Pati, Amrita [DOE Joint Genome Institute's Genome Biology group

2009-05-29

319

UConn Behavioral Gene Bank The UConn Behavioral Gene Bank  

E-print Network

, obsessive-compulsive disorder, panic disorder, and addiction. Many mental illnesses run in families to establish a Gene Bank to support research to find causes of illnesses or behavioral disorders. Participation illness? Mental illnesses include disorders such as schizophrenia, bipolar disorder, depression, anxiety

Oliver, Douglas L.

320

Gene selection and classification of microarray data using random forest  

Microsoft Academic Search

Background: Selection of relevant genes for sample classification is a common task in most gene expression studies, where researchers try to identify the smallest possible set of genes that can still achieve good predictive performance (for instance, for future use with diagnostic purposes in clinical practice). Many gene selection approaches use univariate (gene-by-gene) rankings of gene relevance and arbitrary thresholds

Ramón Díaz-uriarte; Sara Alvarez De Andrés

2006-01-01

321

The P450 gene superfamily: recommended nomenclature.  

PubMed

A nomenclature for the P450 gene superfamily is proposed based on evolution. Recommendations include Roman numerals for distinct gene families, capital letters for subfamilies, and Arabic numerals for individual genes. An updating of this list, which presently includes 65 entries, will be required every 1-2 years. Assignment of orthologous genes is presently uncertain in some cases--between widely diverged species and especially in the P450II family due to the large number of genes. As more is known, it might become necessary to change some gene assignments that are based on our present knowledge. PMID:3829886

Nebert, D W; Adesnik, M; Coon, M J; Estabrook, R W; Gonzalez, F J; Guengerich, F P; Gunsalus, I C; Johnson, E F; Kemper, B; Levin, W

1987-02-01

322

Genes Contributing to the Development of Alcoholism  

PubMed Central

Genetic factors (i.e., variations in specific genes) account for a substantial portion of the risk for alcoholism. However, identifying those genes and the specific variations involved is challenging. Researchers have used both case–control and family studies to identify genes related to alcoholism risk. In addition, different strategies such as candidate gene analyses and genome-wide association studies have been used. The strongest effects have been found for specific variants of genes that encode two enzymes involved in alcohol metabolism—alcohol dehydrogenase and aldehyde dehydrogenase. Accumulating evidence indicates that variations in numerous other genes have smaller but measurable effects. PMID:23134049

Edenberg, Howard J.

2012-01-01

323

Gene transfer: anything goes in plant mitochondria  

PubMed Central

Parasitic plants and their hosts have proven remarkably adept at exchanging fragments of mitochondrial DNA. Two recent studies provide important mechanistic insights into the pattern, process and consequences of horizontal gene transfer, demonstrating that genes can be transferred in large chunks and that gene conversion between foreign and native genes leads to intragenic mosaicism. A model involving duplicative horizontal gene transfer and differential gene conversion is proposed as a hitherto unrecognized source of genetic diversity. See research article: http://www.biomedcentral.com/1741-7007/8/150 PMID:21176244

2010-01-01

324

Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism  

PubMed Central

Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis—with the pedigree disequilibrium test and the family-based association test—and for genotypic and haplotypic association analysis—with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions. PMID:16080114

Ma, D. Q.; Whitehead, P. L.; Menold, M. M.; Martin, E. R.; Ashley-Koch, A. E.; Mei, H.; Ritchie, M. D.; DeLong, G. R.; Abramson, R. K.; Wright, H. H.; Cuccaro, M. L.; Hussman, J. P.; Gilbert, J. R.; Pericak-Vance, M. A.

2005-01-01

325

Phytochrome-regulated Gene Expression  

Technology Transfer Automated Retrieval System (TEKTRAN)

Identification of all genes involved in the phytochrome (phy)-mediated responses of plants to their light environment is an important goal in providing an overall understanding of light-regulated growth and development. This article highlights and integrates the central findings of two recent compre...

326

Horizontal gene transfer in chromalveolates  

Microsoft Academic Search

BACKGROUND: Horizontal gene transfer (HGT), the non-genealogical transfer of genetic material between different organisms, is considered a potentially important mechanism of genome evolution in eukaryotes. Using phylogenomic analyses of expressed sequence tag (EST) data generated from a clonal cell line of a free living dinoflagellate alga Karenia brevis, we investigated the impact of HGT on genome evolution in unicellular chromalveolate

Tetyana Nosenko; Debashish Bhattacharya

2007-01-01

327

(gene expression) DNA (DNA microarrays).  

E-print Network

µ µ DNA . , µ . , µ . , . µ µµ µ µ (gene expression) . µ, µ µ DNA (DNA microarrays). µ µ µ µ µ µ µ DNA µ . µ µµ: ) . . µ µ µ µ. B) µ. µ µ (Support Vector Machines) µ µ. µ µ µ µ DNA. 62 µ (40 22 ) µ

Athens, University of

328

Circadian gene variants in cancer.  

PubMed

Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment. PMID:24901356

Kettner, Nicole M; Katchy, Chinenye A; Fu, Loning

2014-06-01

329

Gene-Culture Coevolutionary Games  

ERIC Educational Resources Information Center

Gene-culture interactions have largely been modelled employing population genetic-type models. Moreover, in the most notable application to date, the "interactive" modes have been one way rather than bidirectional. This paper suggests using game theoretic, fully interactive models. Employing the logic utilized in population ecology for coevolution…

Blute, Marion

2006-01-01

330

Ethics of Gene Therapy Debated.  

ERIC Educational Resources Information Center

Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)

Borman, Stu

1991-01-01

331

Gene therapy using retroviral vectors.  

PubMed

Gene therapy is a novel approach for treating various congenital and acquired genetic disorders, including cancer, heart disease, and acquired immune deficiency syndrome. Amongst possible gene delivery systems, retroviral vector mediated gene transfer has been the most extensively studied and has been approved for use in over 40 current Phase I/II clinical trials for the treatment of various disorders, primarily cancers. Recent technological improvements include the optimization of vector production by concentration and lyophilization, resulting in high titers of vectors, as well as the large-scale production of vector-produced cells for the treatment of brain cancer. Present clinical protocols require specialized care centers with expertise in molecular biology and cell transplantation. Considerable effort is under way to develop retroviral vectors that can be both injected directly into the body and targeted to specific cell types within the body. Such vectors could be administered to patients by physicians in their offices. Successful development of this new technology would greatly expand the clinical potential of gene therapy. PMID:7765744

Gordon, E M; Anderson, W F

1994-12-01

332

Patching genes to fight disease  

SciTech Connect

The National Institutes of Health has approved the first gene therapy experiments, one of which will try to cure cancer by bolstering the immune system. The applications of such therapy are limited, but the potential aid to people with genetic diseases is great.

Holzman, D.

1990-09-03

333

PERSPECTIVE Candidate Mycobacterium tuberculosis genes  

E-print Network

PERSPECTIVE Candidate Mycobacterium tuberculosis genes targeted by human microRNAs WeiRui Guo1-wu@northwestern.edu (J. Y. Wu), weilp@mail.cbi.pku.edu.cn (L. Wei) Tuberculosis (TB) remains a major health issue in 1882, Mycobacterium tuberculosis (M. tuberculosis), the causative agent for tuberculosis, remains one

Wu, Jane Y.

334

Molecular Genetics: Proteins and Genes  

NSDL National Science Digital Library

In this chapter, the authors focus conceptually on the connection between genotype and phenotype, specifically the role of genes and proteins in that connection. They also consider the importance of proteins to the work of cells and the impact of proteins

Tweed, Susan K.

2009-05-22

335

Interactive Fly: Genes regulating behavior  

NSDL National Science Digital Library

A list and description of Drosophila genes involved in behavior (agression, anaesthesia sensitivity and resistance, circadian rhythms, courtship, convulsive, equilibrium, feeding, ecdysis, geotaxis, gustatory, habituation, learning, hearing, locomotor, olfactory learning, pattern recognition, pain response, seizure, sleep, thermosensory, visual discrimiation, and wing expansion). Links to many papers. A subset of the Interactive Fly collection.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-18

336

Reverse engineering gene regulatory networks  

Microsoft Academic Search

Statistical models for reverse engineering gene regulatory networks are surveyed in this article. To provide readers with a system-level view of the modeling issues in this research, a graphical modeling framework is proposed. This framework serves as the scaffolding on which the review of different models can be systematically assembled. Based on the framework, we review many existing models for

Yufei Huang; Isabel M. Tienda-Luna; Yufeng Wang

2009-01-01

337

Genes, Environment, and Human Behavior.  

ERIC Educational Resources Information Center

This curriculum module explores genes, environment, and human behavior. This book provides materials to teach about the nature and methods of studying human behavior, raise some of the ethical and public policy dilemmas emerging from the Human Genome Project, and provide professional development for teachers. An extensive Teacher Background…

Bloom, Mark V.; Cutter, Mary Ann; Davidson, Ronald; Dougherty, Michael J.; Drexler, Edward; Gelernter, Joel; McCullough, Laurence B.; McInerney, Joseph D.; Murray, Jeffrey C.; Vogler, George P.; Zola, John

338

Evolution of primate gene expression  

Microsoft Academic Search

It has been suggested that evolutionary changes in gene expression account for most phenotypic differences between species, in particular between humans and apes. What general rules can be described governing expression evolution? We find that a neutral model where negative selection and divergence time are the major factors is a useful null hypothesis for both transcriptome and genome evolution. Two

Philipp Khaitovich; Wolfgang Enard; Michael Lachmann; Svante Pääbo

2006-01-01

339

Clean Thoughts about Dirty Genes  

Microsoft Academic Search

The mouse has joined the fruit fly, bread mold, and cyanobacteria as a tractable genetic system for studying mechanisms of circadian rhythms. The circadian rhythms of “knock-out” mice for specific clock genes, however, have demonstrated significant variability between laboratories. In this brief review, the authors discuss possible sources of this variability, focusing particularly on questions of modifier loci of circadian

Russell N. van Gelder; John B. Hogenesch

2004-01-01

340

Seed Targeted Gene Confinement Strategies  

Technology Transfer Automated Retrieval System (TEKTRAN)

The genetic improvement of plants using biotechnology is now centrally important to agriculture, food security, and the biofuels industry. It is also important to the continued health of the environment as the need for food (on existing arable land) and renewable energy becomes critical. New genes c...

341

ACTH resistance: genes and mechanisms.  

PubMed

ACTH resistance is a rare disorder typified by familial glucocorticoid deficiency (FGD), a genetically heterogeneous disease. Previously, genetic defects in FGD have been identified in the ACTH receptor gene (MC2R), its accessory protein (MRAP) and the steroidogenic acute regulatory protein gene (STAR). The defective mechanisms here are failures in ACTH ligand binding and/or receptor trafficking for MC2R and MRAP and, in the case of STAR mutations, inefficient cholesterol transport to allow steroidogenesis to proceed. Novel gene defects in FGD have recently been recognised in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT). MCM4 is one part of a DNA repair complex essential for DNA replication and genome stability, whilst NNT is involved in the glutathione redox system that protects cells against reactive oxygen species. The finding of mutations in these two genes implicates new pathogenetic mechanisms at play in FGD, and implies that the adrenal cortex is exquisitely sensitive to replicative and oxidative stresses. PMID:23392095

Meimaridou, E; Hughes, C R; Kowalczyk, J; Chan, L F; Clark, A J L; Metherell, L A

2013-01-01

342

Gene therapy for lung cancer.  

PubMed

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. However, multimodality strategies using conventional therapies only minimally improve survival rates even in early stages of lung cancer. Attempts to improve survival in advanced disease using various combinations of platinum-based chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Over the past three decades, the genetic etiology of cancer has been gradually delineated, albeit not yet completely. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. During these same three decades, techniques have been developed which allow transfer of functional genes into mammalian cells. For example, blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas and will then review the status of gene therapies for treatment of lung cancer. PMID:16767697

Toloza, Eric M; Morse, Michael A; Lyerly, H Kim

2006-09-01

343

Orthopedic Gene Therapy in 2008  

Microsoft Academic Search

Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic

Christopher H Evans; Steven C Ghivizzani; Paul D Robbins

2009-01-01

344

Genomic evidence for adaptation by gene duplication.  

PubMed

Gene duplication is widely believed to facilitate adaptation, but unambiguous evidence for this hypothesis has been found in only a small number of cases. Although gene duplication may increase the fitness of the involved organisms by doubling gene dosage or neofunctionalization, it may also result in a simple division of ancestral functions into daughter genes, which need not promote adaptation. Hence, the general validity of the adaptation by gene duplication hypothesis remains uncertain. Indeed, a genome-scale experiment found similar fitness effects of deleting pairs of duplicate genes and deleting individual singleton genes from the yeast genome, leading to the conclusion that duplication rarely results in adaptation. Here we contend that the above comparison is unfair because of a known duplication bias among genes with different fitness contributions. To rectify this problem, we compare homologous genes from the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. We discover that simultaneously deleting a duplicate gene pair in S. cerevisiae reduces fitness significantly more than deleting their singleton counterpart in S. pombe, revealing post-duplication adaptation. The duplicates-singleton difference in fitness effect is not attributable to a potential increase in gene dose after duplication, suggesting that the adaptation is owing to neofunctionalization, which we find to be explicable by acquisitions of binary protein-protein interactions rather than gene expression changes. These results provide genomic evidence for the role of gene duplication in organismal adaptation and are important for understanding the genetic mechanisms of evolutionary innovation. PMID:24904045

Qian, Wenfeng; Zhang, Jianzhi

2014-08-01

345

Genomic evidence for adaptation by gene duplication  

PubMed Central

Gene duplication is widely believed to facilitate adaptation, but unambiguous evidence for this hypothesis has been found in only a small number of cases. Although gene duplication may increase the fitness of the involved organisms by doubling gene dosage or neofunctionalization, it may also result in a simple division of ancestral functions into daughter genes, which need not promote adaptation. Hence, the general validity of the adaptation by gene duplication hypothesis remains uncertain. Indeed, a genome-scale experiment found similar fitness effects of deleting pairs of duplicate genes and deleting individual singleton genes from the yeast genome, leading to the conclusion that duplication rarely results in adaptation. Here we contend that the above comparison is unfair because of a known duplication bias among genes with different fitness contributions. To rectify this problem, we compare homologous genes from the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. We discover that simultaneously deleting a duplicate gene pair in S. cerevisiae reduces fitness significantly more than deleting their singleton counterpart in S. pombe, revealing post-duplication adaptation. The duplicates–singleton difference in fitness effect is not attributable to a potential increase in gene dose after duplication, suggesting that the adaptation is owing to neofunctionalization, which we find to be explicable by acquisitions of binary protein–protein interactions rather than gene expression changes. These results provide genomic evidence for the role of gene duplication in organismal adaptation and are important for understanding the genetic mechanisms of evolutionary innovation. PMID:24904045

Qian, Wenfeng; Zhang, Jianzhi

2014-01-01

346

Concerted gene recruitment in early plant evolution  

PubMed Central

Background Horizontal gene transfer occurs frequently in prokaryotes and unicellular eukaryotes. Anciently acquired genes, if retained among descendants, might significantly affect the long-term evolution of the recipient lineage. However, no systematic studies on the scope of anciently acquired genes and their impact on macroevolution are currently available in eukaryotes. Results Analyses of the genome of the red alga Cyanidioschyzon identified 37 genes that were acquired from non-organellar sources prior to the split of red algae and green plants. Ten of these genes are rarely found in cyanobacteria or have additional plastid-derived homologs in plants. These genes most likely provided new functions, often essential for plant growth and development, to the ancestral plant. Many remaining genes may represent replacements of endogenous homologs with a similar function. Furthermore, over 78% of the anciently acquired genes are related to the biogenesis and functionality of plastids, the defining character of plants. Conclusion Our data suggest that, although ancient horizontal gene transfer events did occur in eukaryotic evolution, the number of acquired genes does not predict the role of horizontal gene transfer in the adaptation of the recipient organism. Our data also show that multiple independently acquired genes are able to generate and optimize key evolutionary novelties in major eukaryotic groups. In light of these findings, we propose and discuss a general mechanism of horizontal gene transfer in the macroevolution of eukaryotes. PMID:18611267

Huang, Jinling; Gogarten, J Peter

2008-01-01

347

Database for exchangeable gene trap clones: pathway and gene ontology analysis of exchangeable gene trap clone mouse lines.  

PubMed

Gene trapping in embryonic stem (ES) cells is a proven method for large-scale random insertional mutagenesis in the mouse genome. We have established an exchangeable gene trap system, in which a reporter gene can be exchanged for any other DNA of interest through Cre/mutant lox-mediated recombination. We isolated trap clones, analyzed trapped genes, and constructed the database for Exchangeable Gene Trap Clones (EGTC) [http://egtc.jp]. The number of registered ES cell lines was 1162 on 31 August 2013. We also established 454 mouse lines from trap ES clones and deposited them in the mouse embryo bank at the Center for Animal Resources and Development, Kumamoto University, Japan. The EGTC database is the most extensive academic resource for gene-trap mouse lines. Because we used a promoter-trap strategy, all trapped genes were expressed in ES cells. To understand the general characteristics of the trapped genes in the EGTC library, we used Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway analysis and found that the EGTC ES clones covered a broad range of pathways. We also used Gene Ontology (GO) classification data provided by Mouse Genome Informatics (MGI) to compare the functional distribution of genes in each GO term between trapped genes in the EGTC mouse lines and total genes annotated in MGI. We found the functional distributions for the trapped genes in the EGTC mouse lines and for the RefSeq genes for the whole mouse genome were similar, indicating that the EGTC mouse lines had trapped a wide range of mouse genes. PMID:24444128

Araki, Masatake; Nakahara, Mai; Muta, Mayumi; Itou, Miharu; Yanai, Chika; Yamazoe, Fumika; Miyake, Mikiko; Morita, Ayaka; Araki, Miyuki; Okamoto, Yoshiyuki; Nakagata, Naomi; Yoshinobu, Kumiko; Yamamura, Ken-ichi; Araki, Kimi

2014-02-01

348

Utility of gene-specific algorithms for predicting pathogenicity of uncertain gene variants  

PubMed Central

The rapid advance of gene sequencing technologies has produced an unprecedented rate of discovery of genome variation in humans. A growing number of authoritative clinical repositories archive gene variants and disease phenotypes, yet there are currently many more gene variants that lack clear annotation or disease association. To date, there has been very limited coverage of gene-specific predictors in the literature. Here the evaluation is presented of “gene-specific” predictor models based on a naïve Bayesian classifier for 20 gene–disease datasets, containing 3986 variants with clinically characterized patient conditions. The utility of gene-specific prediction is then compared with “all-gene” generalized prediction and also with existing popular predictors. Gene-specific computational prediction models derived from clinically curated gene variant disease datasets often outperform established generalized algorithms for novel and uncertain gene variants. PMID:22037892

Lyon, Elaine; Williams, Marc S; Narus, Scott P; Facelli, Julio C; Mitchell, Joyce A

2011-01-01

349

Common Worldwide Variation Discovered in Human Taste Receptor Genes  

MedlinePLUS

... Taste Receptor Genes Common Worldwide Variation Discovered In Human Taste Receptor Genes Common Worldwide Variation Discovered In Human Taste Receptor Genes Background : Differences in our sense ...

350

MGC: a metagenomic gene caller  

PubMed Central

Background Computational gene finding algorithms have proven their robustness in identifying genes in complete genomes. However, metagenomic sequencing has presented new challenges due to the incomplete and fragmented nature of the data. During the last few years, attempts have been made to extract complete and incomplete open reading frames (ORFs) directly from short reads and identify the coding ORFs, bypassing other challenging tasks such as the assembly of the metagenome. Results In this paper we introduce a metagenomics gene caller (MGC) which is an improvement over the state-of-the-art prediction algorithm Orphelia. Orphelia uses a two-stage machine learning approach and computes a model that classifies extracted ORFs from fragmented sequences. We hypothesise and demonstrate evidence that sequences need separate models based on their local GC-content in order to avoid the noise introduced to a single model computed with sequences from the entire GC spectrum. We have also added two amino-acid features based on the benefit of amino-acid usage shown in our previous research. Our algorithm is able to predict genes and translation initiation sites (TIS) more accurately than Orphelia which uses a single model. Conclusions Learning separate models for several pre-defined GC-content regions as opposed to a single model approach improves the performance of the neural network as demonstrated by the experimental results presented in this paper. The inclusion of amino-acid usage features also helps improve the overall accuracy of our algorithm. MGC's improvement sets the ground for further investigation into the use of GC-content to separate data for training models in machine learning based gene finders. PMID:23901840

2013-01-01

351

Vascular gene expression: a hypothesis  

PubMed Central

The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a “primitive” vascular tissue (a lycophyte), as well as from others that lack a true vascular tissue (a bryophyte), and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non-vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT, and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants. PMID:23882276

Martínez-Navarro, Angélica C.; Galván-Gordillo, Santiago V.; Xoconostle-Cázares, Beatriz; Ruiz-Medrano, Roberto

2013-01-01

352

Gene expression profiles in skeletal muscle after gene electrotransfer  

PubMed Central

Background Gene transfer by electroporation (DNA electrotransfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of DNA electrotransfer on muscle fibres. We have therefore investigated transcriptional changes through gene expression profile analyses, morphological changes by histological analysis, and physiological changes by force generation measurements. DNA electrotransfer was obtained using a combination of a short high voltage pulse (HV, 1000 V/cm, 100 ?s) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. Results Differentially expressed genes were investigated by microarray analysis, and descriptive statistics were performed to evaluate the effects of 1) electroporation, 2) DNA injection, and 3) time after treatment. The biological significance of the results was assessed by gene annotation and supervised cluster analysis. Generally, electroporation caused down-regulation of structural proteins e.g. sarcospan and catalytic enzymes. Injection of DNA induced down-regulation of intracellular transport proteins e.g. sentrin. The effects on muscle fibres were transient as the expression profiles 3 weeks after treatment were closely related with the control muscles. Most interestingly, no changes in the expression of proteins involved in inflammatory responses or muscle regeneration was detected, indicating limited muscle damage and regeneration. Histological analysis revealed structural changes with loss of cell integrity and striation pattern in some fibres after DNA+HV+LV treatment, while HV+LV pulses alone showed preservation of cell integrity. No difference in the force generation capacity was observed in the muscles 2 weeks after DNA electrotransfer. Conclusion The small and transient changes found in the gene expression profiles are of great importance, as this demonstrates that DNA electrotransfer is safe with minor effects on the muscle host cells. These findings are essential for introducing the DNA electrotransfer to muscle for clinical use. Indeed the HV+LV pulse combination used has been optimised to ensure highly efficient and safe DNA electrotransfer. PMID:17598924

Hojman, Pernille; Zibert, John R; Gissel, Hanne; Eriksen, Jens; Gehl, Julie

2007-01-01

353

Wistar Institute study finds multiple 'siblings' from every gene: Alternate gene reading leads to alternate gene products:  

Cancer.gov

A genome-wide survey by researchers at The Wistar Institute shows how our cells create alternate versions of mRNA transcripts by altering how they "read" DNA. Many genes are associated with multiple gene promoters, the researchers say, which is the predominant way multiple variants of a given gene, for example, can be made with the same genetic instructions.

354

Gene Coexpression Network Analysis as a Source of Functional Annotation for Rice Genes  

PubMed Central

With the existence of large publicly available plant gene expression data sets, many groups have undertaken data analyses to construct gene coexpression networks and functionally annotate genes. Often, a large compendium of unrelated or condition-independent expression data is used to construct gene networks. Condition-dependent expression experiments consisting of well-defined conditions/treatments have also been used to create coexpression networks to help examine particular biological processes. Gene networks derived from either condition-dependent or condition-independent data can be difficult to interpret if a large number of genes and connections are present. However, algorithms exist to identify modules of highly connected and biologically relevant genes within coexpression networks. In this study, we have used publicly available rice (Oryza sativa) gene expression data to create gene coexpression networks using both condition-dependent and condition-independent data and have identified gene modules within these networks using the Weighted Gene Coexpression Network Analysis method. We compared the number of genes assigned to modules and the biological interpretability of gene coexpression modules to assess the utility of condition-dependent and condition-independent gene coexpression networks. For the purpose of providing functional annotation to rice genes, we found that gene modules identified by coexpression analysis of condition-dependent gene expression experiments to be more useful than gene modules identified by analysis of a condition-independent data set. We have incorporated our results into the MSU Rice Genome Annotation Project database as additional expression-based annotation for 13,537 genes, 2,980 of which lack a functional annotation description. These results provide two new types of functional annotation for our database. Genes in modules are now associated with groups of genes that constitute a collective functional annotation of those modules. Additionally, the expression patterns of genes across the treatments/conditions of an expression experiment comprise a second form of useful annotation. PMID:21799793

Childs, Kevin L.; Davidson, Rebecca M.; Buell, C. Robin

2011-01-01

355

Efficient Gene Transfer in Bacterial Cell Chains  

E-print Network

Horizontal gene transfer contributes to evolution and the acquisition of new traits. In bacteria, horizontal gene transfer is often mediated by conjugative genetic elements that transfer directly from cell to cell. Integrative ...

Babic, Ana

356

Gene Conversion in Human Genetic Disease  

PubMed Central

Gene conversion is a specific type of homologous recombination that involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’. We have recently reviewed the molecular mechanisms underlying gene conversion, explored the key part that this process has played in fashioning extant human genes, and performed a meta-analysis of gene-conversion events known to have caused human genetic disease. Here we shall briefly summarize some of the latest developments in the study of pathogenic gene conversion events, including (i) the emerging idea of minimal efficient sequence homology (MESH) for homologous recombination, (ii) the local DNA sequence features that appear to predispose to gene conversion, (iii) a mechanistic comparison of gene conversion and transient hypermutability, and (iv) recently reported examples of pathogenic gene conversion events. PMID:24710102

Chen, Jian-Min; Férec, Claude; Cooper, David N.

2010-01-01

357

Enhanced polymeric nanoparticles for gene delivery  

E-print Network

The potential of gene therapy to treat disease and improve human health is tremendous. The failure of viral gene therapy clinical trials due to toxicity, immunogenicity, and carcinogenicity has been tragic and strongly ...

Green, Jordan Jamieson

2007-01-01

358

In The Genes? Searching for Methuselah  

MedlinePLUS

... Current Issue Past Issues Special Section In The Genes? Searching for Methuselah Past Issues / Winter 2007 Table ... 18 million effort to learn more about the genes, lifestyle or other factors that contribute to long, ...

359

American Society of Gene & Cell Therapy  

MedlinePLUS

... Professor University of Iowa The American Society of Gene & Cell Therapy ASGCT's MISSION is to advance knowledge, ... Therapeutics Official Journal of the American Society of Gene & Cell Therapy 2013 Impact Factor: 6.425 Current ...

360

NIH Researchers Identify OCD Risk Gene  

MedlinePLUS

... News From NIH NIH Researchers Identify OCD Risk Gene Past Issues / Summer 2006 Table of Contents For ... and Alcoholism (NIAAA) have identified a previously unknown gene variant that doubles an individual's risk for obsessive- ...

361

The Evolution of Gene Regulatory Interactions  

NSDL National Science Digital Library

Changes in the timing and level at which genes are expressed are known to play an important role in evolution, but the mechanisms underlying changes in gene expression remain relatively obscure. Until quite recently, evolutionary biologists, like most biologists, tended to study single genes as isolated entities. These studies have added enormously to our understanding of biological evolution. But because gene regulation by its very nature involves interactions between two (or more) genes, researchers have missed a range of evolutionary phenomena that can be observed only at the level of networks of interacting genes. In this article, we consider the change in perspective that genomic technologiesâ??particularly the advent of large-scale platforms for DNA sequencing, genotyping, and measuring gene expressionâ??are bringing to evolutionary biology. We focus specifically on how these technologies can and are being used to increase our understanding of how and why gene expression evolves.

Gregory Wray (Duke University; Department of Biology)

2010-01-04

362

Interactive Fly: Early Zygotic Gene Expression Images  

NSDL National Science Digital Library

In situ images from an award-winning and comprehensive site, The Interactive Fly. Entering through an expression pattern, this site thoroughly discusses each genes and shows its expression relative to other genes at this stage.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-12

363

Environment Trumps Genes at Shaping Immune System  

MedlinePLUS

... on this page, please enable JavaScript. Environment Trumps Genes at Shaping Immune System: Study In twins study, ... HealthDay News) -- Environment plays a larger role than genes in shaping people's immune systems, a new study ...

364

NewGenesSyndromes060305.pdf  

Cancer.gov

New Cancer Genes and Syndromes Mark H. Greene, M.D. Chief, Clinical Genetics Branch Division of Cancer Epidemiology & Genetics National Cancer Institute Less Familiar Cancer Genes and Syndromes Heterozygous ATM Mutation Carriers • This

365

Multidrug resistant protein-three gene regulation  

E-print Network

gene: clues to cancer etiology and molecular pathogenesis.gene: clues to cancer etiology and molecular pathogenesis.molecular mechanism of resistance to methotrexate in mouse methotrexate-resistant cells by cancer

Mahaffey, Christopher M.

2010-01-01

366

Towards integrative gene functional similarity measurement  

PubMed Central

Background In Gene Ontology, the "Molecular Function" (MF) categorization is a widely used knowledge framework for gene function comparison and prediction. Its structure and annotation provide a convenient way to compare gene functional similarities at the molecular level. The existing gene similarity measures, however, solely rely on one or few aspects of MF without utilizing all the rich information available including structure, annotation, common terms, lowest common parents. Results We introduce a rank-based gene semantic similarity measure called InteGO by synergistically integrating the state-of-the-art gene-to-gene similarity measures. By integrating three GO based seed measures, InteGO significantly improves the performance by about two-fold in all the three species studied (yeast, Arabidopsis and human). Conclusions InteGO is a systematic and novel method to study gene functional associations. The software and description are available at http://www.msu.edu/~jinchen/InteGO. PMID:24564710

2014-01-01

367

Impulse Control: Temporal Dynamics in Gene Transcription  

E-print Network

Regulatory circuits controlling gene expression constantly rewire to adapt to environmental stimuli, differentiation cues, and disease. We review our current understanding of the temporal dynamics of gene expression in ...

Yosef, Nir

368

GENE THERAPY IN ORAL CANCER: AN OVERVIEW  

E-print Network

The treatment and prevention of oral cancer is one of the major hurdles in the field of cancer. Gene therapy is one of the recent advances in this field to tackle this hurdle with promising prospects. This overview introduces the reader into the basic idea of gene therapy, types of gene therapy and the various modes of introduction of therapeutic gene into the cancer affected cell.

unknown authors

369

Plant nitrogen regulatory P-PII genes  

DOEpatents

The present invention generally relates to plant nitrogen regulatory PII gene (hereinafter P-PII gene), a gene involved in regulating plant nitrogen metabolism. The invention provides P-PII nucleotide sequences, expression constructs comprising said nucleotide sequences, and host cells and plants having said constructs and, optionally expressing the P-PII gene from said constructs. The invention also provides substantially pure P-PII proteins. The P-PII nucleotide sequences and constructs of the

Coruzzi, Gloria M. (New York, NY); Lam, Hon-Ming (Hong Kong, HK); Hsieh, Ming-Hsiun (Woodside, NY)

2001-01-01

370

Function of the DISC1 Gene  

NSDL National Science Digital Library

As a result of the human genome project, we now know largely where our genes are, and what structure they have. The search to uncover each gene's function, on the other hand, is only in its infancy. Functional genomics is an area of research dedicated to studying what protein is produced by a gene, and what happens in the body when it is activated. Understanding gene function is the next major hurdle in genomic research, which holds the key to developing revolutionary therapeutics.

2009-04-14

371

Gene Trapping Using Gal4 in Zebrafish  

PubMed Central

Large clutch size and external development of optically transparent embryos make zebrafish an exceptional vertebrate model system for in vivo insertional mutagenesis using fluorescent reporters to tag expression of mutated genes. Several laboratories have constructed and tested enhancer- and gene-trap vectors in zebrafish, using fluorescent proteins, Gal4- and lexA- based transcriptional activators as reporters 1-7. These vectors had two potential drawbacks: suboptimal stringency (e.g. lack of ability to differentiate between enhancer- and gene-trap events) and low mutagenicity (e.g. integrations into genes rarely produced null alleles). Gene Breaking Transposon (GBTs) were developed to address these drawbacks 8-10. We have modified one of the first GBT vectors, GBT-R15, for use with Gal4-VP16 as the primary gene trap reporter and added UAS:eGFP as the secondary reporter for direct detection of gene trap events. Application of Gal4-VP16 as the primary gene trap reporter provides two main advantages. First, it increases sensitivity for genes expressed at low expression levels. Second, it enables researchers to use gene trap lines as Gal4 drivers to direct expression of other transgenes in very specific tissues. This is especially pertinent for genes with non-essential or redundant functions, where gene trap integration may not result in overt phenotypes. The disadvantage of using Gal4-VP16 as the primary gene trap reporter is that genes coding for proteins with N-terminal signal sequences are not amenable to trapping, as the resulting Gal4-VP16 fusion proteins are unlikely to be able to enter the nucleus and activate transcription. Importantly, the use of Gal4-VP16 does not pre-select for nuclear proteins: we recovered gene trap mutations in genes encoding proteins which function in the nucleus, the cytoplasm and the plasma membrane. PMID:24121167

Balciuniene, Jorune; Balciunas, Darius

2013-01-01

372

Fungal avirulence genes: structure and possible functions.  

PubMed

Avirulence (Avr) genes exist in many fungi that share a gene-for-gene relationship with their host plant. They represent unique genetic determinants that prevent fungi from causing disease on plants that possess matching resistance (R) genes. Interaction between elicitors (primary or secondary products of Avr genes) and host receptors in resistant plants causes induction of various defense responses often involving a hypersensitive response. Avr genes have been successfully isolated by reverse genetics and positional cloning. Five cultivar-specific Avr genes (Avr4, Avr9, and Ecp2 from Cladosporium fulvum; nip1 from Rhynchosporium secalis; and Avr2-YAMO from Magnaporthe grisea) and three species-specific Avr genes (PWL1 and PWL2 from M. grisea and inf1 from Phytophthora infestans) have been cloned. Isolation of additional Avr genes from these fungi, but also from other fungi such as Uromyces vignae, Melampsora lini, Phytophthora sojae, and Leptosphaeria maculans, is in progress. Molecular analyses of nonfunctional Avr gene alleles show that these originate from deletions or mutations in the open reading frame or the promoter sequence of an Avr gene. Although intrinsic biological functions of most Avr gene products are still unknown, recent studies have shown that two Avr genes, nip1 and Ecp2, encode products that are important pathogenicity factors. All fungal Avr genes cloned so far have been demonstrated or predicted to encode extracellular proteins. Current studies focus on unraveling the mechanisms of perception of avirulence factors by plant receptors. The exploitation of Avr genes and the matching R genes in engineered resistance is also discussed. PMID:9756710

Laugé, R; De Wit, P J

1998-08-01

373

Bayesian variable selection for hierarchical gene-environment and gene-gene interactions.  

PubMed

We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions and gene by environment interactions in the same model. Our approach incorporates the natural hierarchical structure between the main effects and interaction effects into a mixture model, such that our methods tend to remove the irrelevant interaction effects more effectively, resulting in more robust and parsimonious models. We consider both strong and weak hierarchical models. For a strong hierarchical model, both the main effects between interacting factors must be present for the interactions to be considered in the model development, while for a weak hierarchical model, only one of the two main effects is required to be present for the interaction to be evaluated. Our simulation results show that the proposed strong and weak hierarchical mixture models work well in controlling false-positive rates and provide a powerful approach for identifying the predisposing effects and interactions in gene-environment interaction studies, in comparison with the naive model that does not impose this hierarchical constraint in most of the scenarios simulated. We illustrate our approach using data for lung cancer and cutaneous melanoma. PMID:25154630

Liu, Changlu; Ma, Jianzhong; Amos, Christopher I

2015-01-01

374

Are TMEM genes potential candidate genes for panic disorder?  

PubMed

We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a previously reported candidate region for PD. Three single nucleotide polymorphisms (rs887231, rs887230 and rs4795942) located upstream and within TMEM132E showed a nominal significant association with PD primarily in the Danish cohort. No nominal significant associations were observed between TMEM98 and PD. Our data indicate that TMEM132E might contribute moderately towards the risk of developing PD. PMID:24362369

Gregersen, Noomi O; Buttenschøn, Henriette N; Hedemand, Anne; Dahl, Hans A; Kristensen, Ann S; Clementsen, Birita; Woldbye, David P D; Koefoed, Pernille; Erhardt, Angelika; Kruse, Torben A; Wang, August G; Børglum, Anders D; Mors, Ole

2014-02-01

375

Network Topology Reveals Key Cardiovascular Disease Genes  

PubMed Central

The structure of protein-protein interaction (PPI) networks has already been successfully used as a source of new biological information. Even though cardiovascular diseases (CVDs) are a major global cause of death, many CVD genes still await discovery. We explore ways to utilize the structure of the human PPI network to find important genes for CVDs that should be targeted by drugs. The hope is to use the properties of such important genes to predict new ones, which would in turn improve a choice of therapy. We propose a methodology that examines the PPI network wiring around genes involved in CVDs. We use the methodology to identify a subset of CVD-related genes that are statistically significantly enriched in drug targets and “driver genes.” We seek such genes, since driver genes have been proposed to drive onset and progression of a disease. Our identified subset of CVD genes has a large overlap with the Core Diseasome, which has been postulated to be the key to disease formation and hence should be the primary object of therapeutic intervention. This indicates that our methodology identifies “key” genes responsible for CVDs. Thus, we use it to predict new CVD genes and we validate over 70% of our predictions in the literature. Finally, we show that our predicted genes are functionally similar to currently known CVD drug targets, which confirms a potential utility of our methodology towards improving therapy for CVDs. PMID:23977067

Stojkovi?, Neda; Radak, Djordje; Pržulj, Nataša

2013-01-01

376

Epilepsy and fragile X gene mutations  

Microsoft Academic Search

We used two strategies to investigate a possible link between predisposition for epilepsy and mutations in the fragile X mental retardation-1 gene. The first entailed performing electroencephalography on 14 patients with an amplification in the fragile X mental retardation-1 gene, and the second involved molecular genetic analysis of the fragile X mental retardation-1 gene in 16 children with benign childhood

Gerhard Kluger; Ingolf Böhm; Michael C. Laub; Claus Waldenmaier

1996-01-01

377

Zebrafish orthologs of human muscular dystrophy genes  

PubMed Central

Background Human muscular dystrophies are a heterogeneous group of genetic disorders which cause decreased muscle strength and often result in premature death. There is no known cure for muscular dystrophy, nor have all causative genes been identified. Recent work in the small vertebrate zebrafish Danio rerio suggests that mutation or misregulation of zebrafish dystrophy orthologs can also cause muscular degeneration phenotypes in fish. To aid in the identification of new causative genes, this study identifies and maps zebrafish orthologs for all known human muscular dystrophy genes. Results Zebrafish sequence databases were queried for transcripts orthologous to human dystrophy-causing genes, identifying transcripts for 28 out of 29 genes of interest. In addition, the genomic locations of all 29 genes have been found, allowing rapid candidate gene discovery during genetic mapping of zebrafish dystrophy mutants. 19 genes show conservation of syntenic relationships with humans and at least two genes appear to be duplicated in zebrafish. Significant sequence coverage on one or more BAC clone(s) was also identified for 24 of the genes to provide better local sequence information and easy updating of genomic locations as the zebrafish genome assembly continues to evolve. Conclusion This resource supports zebrafish as a dystrophy model, suggesting maintenance of all known dystrophy-associated genes in the zebrafish genome. Coupled with the ability to conduct genetic screens and small molecule screens, zebrafish are thus an attractive model organism for isolating new dystrophy-causing genes/pathways and for use in high-throughput therapeutic discovery. PMID:17374169

Steffen, Leta S; Guyon, Jeffrey R; Vogel, Emily D; Beltre, Rosanna; Pusack, Timothy J; Zhou, Yi; Zon, Leonard I; Kunkel, Louis M

2007-01-01

378

Human Lineage-Specific Gene Inactivation  

E-print Network

Human Lineage-Specific Gene Inactivation Wendy E Grus, University of Michigan, Ann Arbor, Michigan vestiges of genes. Inves- tigating genes that were inactivated specifically on the human lineage or within humans can reveal the genetic basis of interspecies differences between humans and chimpanzees

Zhang, Jianzhi

379

Human Lineage-specific Gene Inactivation  

E-print Network

Human Lineage-specific Gene Inactivation Wendy E Grus, University of Michigan, Ann Arbor, Michigan vestiges of genes. Investigating genes that were inactivated specifically on the human lineage can reveal the genetic basis of inter- species differences between humans and chimpanzees and inter

Zhang, Jianzhi

380

Prokaryotic Evolution in Light of Gene Transfer  

Microsoft Academic Search

Accumulating prokaryotic gene and genome sequences reveal that the exchange of genetic information through both homology-dependent recombination and horizontal (lateral) gene transfer (HGT) is far more important, in quantity and quality, than hitherto imagined. The traditional view, that prokaryotic evolution can be understood primarily in terms of clonal divergence and periodic selection, must be augmented to embrace gene exchange as

J. Peter Gogarten; W. Ford Doolittle; Jeffrey G. Lawrence

2002-01-01

381

Improving enzymes for cancer gene therapy  

Microsoft Academic Search

New techniques now make it feasible to tailor enzymes for cancer gene therapy. Novel enzymes with desired properties can be created and selected from vast libraries of mutants containing random substitutions within catalytic domains. In this review, we first consider genes for the ablation of tumors, namely, genes that have been mutated (or potentially can be mutated) to afford enhanced

Lance P. Encell; Daniel M. Landis; Lawrence A. Loeb

1999-01-01

382

Relational Descriptive Analysis of Gene Expression Data  

Microsoft Academic Search

This paper presents a method that uses gene ontologies, to- gether with the paradigm of relational subgroup discovery, to help nd description of groups of genes dieren tialy expressed in specic can- cers. The descriptions are represented by means of relational features, extracted from publicly available gene ontology information, and are straightforwardly interpretable by medical\\/biology researchers. We ap- plied the

Igor Trajkovski; Filip Zelezný; Nada Lavrac; Jakub Tolar

2006-01-01

383

Gene Expression Profiling in Developing Human Hippocampus  

E-print Network

Gene Expression Profiling in Developing Human Hippocampus Yan Zhang,1,2 Pinchao Mei,1­3 Rong Lou,1 Molecular Biology, Beijing, China 4 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York The gene into the developmental and functional character- istics, we analyzed the expression profile of active genes in developing

384

Gene silencing mechanisms in Phytophthora infestans  

E-print Network

Gene silencing mechanisms in Phytophthora infestans Ramesh Raju Vetukuri Faculty of Natural Cover: Confocal images of P.infestans mycelium structure #12;Gene silencing mechanisms in Phytophthora. This thesis focuses on the molecular basis of gene (RNA) silencing in P. infestans and the role it may have

385

Problem-Solving Test: Targeted Gene Disruption  

ERIC Educational Resources Information Center

Mutational inactivation of a specific gene is the most powerful technique to analyze the biological function of the gene. This approach has been used for a long time in viruses, bacteria, yeast, and fruit fly, but looked quite hopeless in more complex organisms. Targeted inactivation of specific genes (also known as knock-out mutation) in mice is…

Szeberenyi, Jozsef

2008-01-01

386

Smoothing Gene Expression Using Biological Networks  

Microsoft Academic Search

Gene expression (micro array) data have been used widely in bioinformatics. The expression data of a large number of genes from small numbers of subjects are used to identify informative biomarkers that may predict or help in diagnosing some disorders. More recently, increasing amounts of information from underlying relationships of the expressed genes have become available, and workers have started

Yue Fan; Mark A. Kon; Shinuk Kim; Charles DeLisi

2010-01-01

387

Current approaches to gene regulatory network modelling  

Microsoft Academic Search

Many different approaches have been developed to model and simulate gene regulatory networks. We proposed the following categories for gene regulatory network models: network parts lists, network topology models, network control logic models, and dynamic models. Here we will describe some examples for each of these categories. We will study the topology of gene regulatory networks in yeast in more

Thomas Schlitt; Alvis Brazma

2007-01-01

388

Identifying Significant Genes from Microarray Data  

Microsoft Academic Search

Microarray technology is a recent development in experimental molecular biology which can produce quantitative expression measurements for thousands of genes in a single, cellular mRNA sample. These many gene expression measurements form a composite profile of the sample, which can be used to differentiate samples from different classes such as tissue types or treatments. However, for the gene expression profile

Han-yu Chuang; Hongfang Liu; Stuart Brown; Cameron Mcmunn-coffran; Cheng-yan Kao; D. Frank Hsu

2004-01-01

389

A Critical Review of Gene Prediction Software  

E-print Network

. Gene prediction in eukaryotes is somewhat more difficult than in prokaryotes, due in part to the decreased gene density in eukaryotic genomes compared to prokaryotic genomes, and in part to the increased complexity of the "gene unit" in eukaryotes compared to prokaryotes. The structure of a "typical" eukaryotic

390

Aeromonas hydrophila Lateral Flagellar Gene Transcriptional Hierarchy  

PubMed Central

Aeromonas hydrophila AH-3 lateral flagella are not assembled when bacteria grow in liquid media; however, lateral flagellar genes are transcribed. Our results indicate that A. hydrophila lateral flagellar genes are transcribed at three levels (class I to III genes) and share some similarities with, but have many important differences from, genes of Vibrio parahaemolyticus. A. hydrophila lateral flagellum class I gene transcription is ?70 dependent, which is consistent with the fact that lateral flagellum is constitutively transcribed, in contrast to the characteristics of V. parahaemolyticus. The fact that multiple genes are included in class I highlights that lateral flagellar genes are less hierarchically transcribed than polar flagellum genes. The A. hydrophila lafK-fliEJL gene cluster (where the subscript L distinguishes genes for lateral flagella from those for polar flagella) is exclusively from class I and is in V. parahaemolyticus class I and II. Furthermore, the A. hydrophila flgAMNL cluster is not transcribed from the ?54/LafK-dependent promoter and does not contain class II genes. Here, we propose a gene transcriptional hierarchy for the A. hydrophila lateral flagella. PMID:23335410

Wilhelms, Markus; Gonzalez, Victor; Merino, Susana

2013-01-01

391

Error margin analysis for feature gene extraction  

PubMed Central

Background Feature gene extraction is a fundamental issue in microarray-based biomarker discovery. It is normally treated as an optimization problem of finding the best predictive feature genes that can effectively and stably discriminate distinct types of disease conditions, e.g. tumors and normals. Since gene microarray data normally involves thousands of genes at, tens or hundreds of samples, the gene extraction process may fall into local optimums if the gene set is optimized according to the maximization of classification accuracy of the classifier built from it. Results In this paper, we propose a novel gene extraction method of error margin analysis to optimize the feature genes. The proposed algorithm has been tested upon one synthetic dataset and two real microarray datasets. Meanwhile, it has been compared with five existing gene extraction algorithms on each dataset. On the synthetic dataset, the results show that the feature set extracted by our algorithm is the closest to the actual gene set. For the two real datasets, our algorithm is superior in terms of balancing the size and the validation accuracy of the resultant gene set when comparing to other algorithms. Conclusion Because of its distinct features, error margin analysis method can stably extract the relevant feature genes from microarray data for high-performance classification. PMID:20459827

2010-01-01

392

Redundant Gene Functions and Natural Selection  

Microsoft Academic Search

Redundant gene functions are ubiquitous, and they are a potentially important source of evolutionary innovations on the biochemical level. It is therefore highly desirable to understand the mechanisms governing their evolution. Gene duplication is clearly a prominent mechanism generating redundant genes. However, because redundancy provides a protective effect against deleterious mutations, natural selection might be involved in generating and maintaining

Andreas Wagner

1997-01-01

393

Uses of antimicrobial genes from microbial genome  

DOEpatents

We describe a method for mining microbial genomes to discover antimicrobial genes and proteins having broad spectrum of activity. Also described are antimicrobial genes and their expression products from various microbial genomes that were found using this method. The products of such genes can be used as antimicrobial agents or as tools for molecular biology.

Sorek, Rotem; Rubin, Edward M.

2013-08-20

394

Visualization of gene activity in living cells  

Microsoft Academic Search

Chromatin structure is thought to play a critical role in gene expression. Using the lac operator\\/repressor system and two colour variants of green fluorescent protein (GFP), we developed a system to visualize a gene and its protein product directly in living cells, allowing us to examine the spatial organization and timing of gene expression in vivo. Dynamic morphological changes in

Toshiro Tsukamoto; Noriyo Hashiguchi; Susan M. Janicki; Tudorita Tumbar; Andrew S. Belmont; David L. Spector

2000-01-01

395

Mapping and Functional Characterization of Candidate Genes  

E-print Network

Mapping and Functional Characterization of Candidate Genes and Mutations for Chicken Growth: GeneticAssociation) #12;Mapping and Functional Characterization of Candidate Genes and Mutations Karyotype 17! 2.4! Gene Mapping and Association Studies 19! 2.4.1! QTL Analysis 19! 2.4.2! Genome

396

Environmental and Behavioral Influences on Gene Activity  

Microsoft Academic Search

The central dogma of molecular biology holds that “information” flows from the genes to the structure of the proteins that the genes bring about through the formula DNA ? RNA ? protein. In this view, a set of master genes activates the DNA necessary to produce the appropriate proteins that the organism needs during development. In contrast to this view,

Gilbert Gottlieb

2000-01-01

397

Gene Family Evolution across 12 Drosophila Genomes  

Microsoft Academic Search

Comparison of whole genomes has revealed large and frequent changes in the size of gene families. These changes occur because of high rates of both gene gain (via duplication) and loss (via deletion or pseudogenization), as well as the evolution of entirely new genes. Here we use the genomes of 12 fully sequenced Drosophila species to study the gain and

Matthew W Hahn; Mira V Han; Sang-Gook Han

2007-01-01

398

Infrared lasermediated gene induction in targeted  

E-print Network

a heat shock promoter­driven transgene is required. Most importantly, it enables the induction of geneInfrared laser­mediated gene induction in targeted single cells in vivo Yasuhiro Kamei1 laser­evoked gene operator (IR-LEGO), a microscope system optimized for heating cells without

Cai, Long

399

Global functional proling of gene expression  

Microsoft Academic Search

The typical result of a microarray experiment is a list of tens or hundreds of genes found to be dieren tially regulated in the condition under study. Independently of the methods used to select these genes, the common task faced by any researcher is to translate these lists of genes into a better understanding of the biological phenomena involved. Currently,

Sorin Draghici; Purvesh Khatri; Rui P. Martins; G. Charles Ostermeier; Stephen A. Krawetz

400

Gene-gene interactions in breast cancer susceptibility.  

PubMed

There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation. PMID:22072393

Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Warren-Perry, Margaret; Hughes, Deborah; Elliott, Anna; Pernet, David; Peock, Susan; Adlard, Julian W; Barwell, Julian; Berg, Jonathan; Brady, Angela F; Brewer, Carole; Brice, Glen; Chapman, Cyril; Cook, Jackie; Davidson, Rosemarie; Donaldson, Alan; Douglas, Fiona; Greenhalgh, Lynn; Henderson, Alex; Izatt, Louise; Kumar, Ajith; Lalloo, Fiona; Miedzybrodzka, Zosia; Morrison, Patrick J; Paterson, Joan; Porteous, Mary; Rogers, Mark T; Shanley, Susan; Walker, Lisa; Ahmed, Munaza; Eccles, Diana; Evans, D Gareth; Donnelly, Peter; Easton, Douglas F; Stratton, Michael R; Rahman, Nazneen

2012-02-15

401

Gene–gene interactions in breast cancer susceptibility  

PubMed Central

There have been few definitive examples of gene–gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10–4; ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10?4; CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation. PMID:22072393

Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Warren-Perry, Margaret; Hughes, Deborah; Elliott, Anna; Pernet, David; Peock, Susan; Adlard, Julian W.; Barwell, Julian; Berg, Jonathan; Brady, Angela F.; Brewer, Carole; Brice, Glen; Chapman, Cyril; Cook, Jackie; Davidson, Rosemarie; Donaldson, Alan; Douglas, Fiona; Greenhalgh, Lynn; Henderson, Alex; Izatt, Louise; Kumar, Ajith; Lalloo, Fiona; Miedzybrodzka, Zosia; Morrison, Patrick J; Paterson, Joan; Porteous, Mary; Rogers, Mark T.; Shanley, Susan; Walker, Lisa; Ahmed, Munaza; Eccles, Diana; Evans, D. Gareth; Donnelly, Peter; Easton, Douglas F.; Stratton, Michael R.; Rahman, Nazneen

2012-01-01

402

Gene therapy for the hemophilias.  

PubMed

There are many lines of evidence that suggest the eventual success of gene therapy as a treatment strategy for hemophilia. Because current treatment protocols using plasma-derived or recombinant proteins are far from ideal, the safe and efficient substitution of the defective gene by a normal copy of the gene, or at least its addition, would be of great benefit to the patient and may even be a potential cure. However, the construction of efficient gene therapy vehicles has proven quite difficult in the past and, so far, there is no system that promises to have all the desired features without any serious disadvantages. In general, either the levels of transgene expression are too low (because of the low titers achieved during the generation of the virus) or shortlived (e.g., because of the specific shut-off of the transferred promoter) as is often seen with retroviruses, or in the case of adenoviral vectors, expression is limited because of a strong immune response of the host. Clearly, much work remains to be done to optimize these promising though still imperfect vector systems. In the case of adenovirus, the development of less immunogenic vectors or in vivo modulation of the host immune system may hold promise for improvements. Reports by Yang et al. (1995) and Kay et al. (1995) are promising steps in the direction of immunomodulation. Both attenuate the immune reaction to the adenoviral vector by simultaneous application of either an interleukin or an immunoglobulin, respectively. When IL-2 was administered, the amounts of IgA were reduced and successful administration of a second dose of virus was possible. When CTLA4-Ig, an immunoglobulin that blocks the second signal during antigen presentation, was administered, a markedly prolonged expression of the transgene resulted. In vivo trials with AAV vectors have been carried out for some diseases (Flotte et al., 1993; Kaplitt et al., 1994) but not for hemophilia. Advances in high-titer AAV vector preparation will make this approach more feasible. The pace continues to quicken in the development of nonviral modes of gene delivery (Perales et al., 1994). Although these results are encouraging for the future of gene therapy as a treatment for genetic diseases, much work remains to be done to make this potential alternative a reality for treatment of hemophilia. PMID:9395731

Walter, J; High, K A

1997-01-01

403

Gene Expression Omnibus: NCBI gene expression and hybridization array data repository  

Microsoft Academic Search

The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expres- sion databases

Ron Edgar; Michael Domrachev; Alex E. Lash

2002-01-01

404

Gene teams: a new formalization of gene clusters for comparative genomics  

Microsoft Academic Search

This paper describes an efficient algorithm based on a new concept called gene team for detecting conserved gene clusters among an arbitrary number of chromosomes. Within the clusters, neither the order of the genes nor their orientation need be conserved. In addition, insertion of foreign genes within the clusters are permitted to a user-defined extent. This algorithm has been implemented

Nicolas Luc; Jean-loup Risler; Anne Bergeron; Mathieu Raffinot

2003-01-01

405

Heat-induced Gene Expression as a Novel Targeted Cancer Gene Therapy Strategy1  

Microsoft Academic Search

One of the main advantages of gene therapy over traditional therapy is the potential to target the expression of therapeutic genes in desired cells or tissues. To achieve targeted gene expression, we experimented with a new approach based on the long-established phenomenon of the heat shock response. By using the green fluorescence protein as a reporter gene, it was demonstrated

Qian Huang; Jim K. Hu; Frank Lohr; Li Zhang; Rod Braun; Jennifer Lanzen; John B. Little; Mark W. Dewhirst; Chuan-Yuan Li

2000-01-01

406

gene encoding enhanced green fluorescent protein to the repressor gene, and quantify  

E-print Network

gene encoding enhanced green fluorescent protein to the repressor gene, and quantify of gene expression in the feedback network, compared with the control networks. They also show concentrations of anhydrotetra- cycline--achemicalinhibitorofTetR. In past theoretical studies of gene

Weeks, Eric R.

407

Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes  

E-print Network

Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes by Wen-Hsiung Li, January 5, 2011 (sent for review November 5, 2010) A balance between gene expression studied whether the genetic and epigenetic properties of the promoter affect gene expression variability

Zhang, Jianzhi

408

Gene loss rate: a probabilistic measure for the conservation of eukaryotic genes  

E-print Network

Gene loss rate: a probabilistic measure for the conservation of eukaryotic genes Elhanan Borenstein; Accepted October 2, 2006 ABSTRACT The rate of conservation of a gene in evolution is believed for genes and have shown that they are correlated with several biological characteristics of functional

Borenstein, Elhanan

409

Estimation of Gene Induction Enables a Relevance-Based Ranking of Gene Sets  

E-print Network

Estimation of Gene Induction Enables a Relevance-Based Ranking of Gene Sets KILIAN BARTHOLOME´,1 produced by microarray ex- periments, the analysis of sets of genes with a common biological functionality has been shown to be advantageous compared to single gene analyses. Some statistical methods have been

Timmer, Jens

410

Special Issue: Gene Expression in the Immune System Gene regulatory networks in the  

E-print Network

Special Issue: Gene Expression in the Immune System Gene regulatory networks in the immune system transitionsandcellularactivation states within the immune system. The architectures of simple gene regulatory networks (GRNs cascades to regulators of gene expres- sion. The latter include transcription factors (TFs), chro- matin

Dinner, Aaron

411

From Gene to Organismal Phylogeny: Reconciled Trees and the Gene Tree/Species Tree Problem  

E-print Network

From Gene to Organismal Phylogeny: Reconciled Trees and the Gene Tree/Species Tree Problem Roderic The processes of gene duplication, loss, and lineage sorting can result in incongruence between the phylog- enies of genes and those of species. This incongruence complicates the task of inferring the latter from

Page, Roderic

412

Mining Coherent Gene Clusters from Gene-Sample-Time Microarray Data  

E-print Network

Mining Coherent Gene Clusters from Gene-Sample-Time Microarray Data Daxin Jiang Jian Pei Murali research and biomedical applications. In this paper, we explore a novel type of gene- sample-time microarray data sets, which records the expres- sion levels of various genes under a set of samples during

Buffalo, State University of New York

413

Gene identication in bacterial and organellar genomes using GeneScan  

E-print Network

Gene identi®cation in bacterial and organellar genomes using GeneScan Ramaswamy Ramakrishnaa, 110 067, India Received 23 June 1998; accepted 13 November 1998 Abstract The performance of the GeneScan algorithm for gene identi®cation has been improved by incorporation of a directed iterative scanning

Ramaswamy, Ram

414

Estimation of gene induction enables a relevance-based ranking of gene sets  

E-print Network

Estimation of gene induction enables a relevance-based ranking of gene sets Kilian Bartholom by microarray experiments, the analysis of sets of genes with a common biological functionality has been shown to be advantageous compared to single gene analyses. Some statistical methods have been proposed to analyse

Timmer, Jens

415

Identification of disease-causing genes using microarray data mining and Gene Ontology  

Microsoft Academic Search

BACKGROUND: One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is

Azadeh Mohammadi; Mohammad H Saraee; Mansoor Salehi

2011-01-01

416

Neural Networks Approaches for Discovering the Learnable Correlation between Gene Function and Gene  

E-print Network

applications. Identifying gene function based on gene expression data is much easier in prokaryotes than eukaryotes due to the relatively simple structure of prokaryotes. Recent studies have shown in many ways, especially in Gene Therapy [18]. Identifying gene function in prokaryotes is much easier

Bonner, Anthony

417

Genome-scale comparative analysis of gene fusions, gene fissions, and the fungal tree of life.  

PubMed

During the course of evolution genes undergo both fusion and fission by which ORFs are joined or separated. These processes can amend gene function and represent an important factor in the evolution of protein interaction networks. Gene fusions have been suggested to be useful characters for identifying evolutionary relationships because they constitute synapomorphies or cladistic characters. To investigate the fidelity of gene-fusion characters, we developed an approach for identifying differentially distributed gene fusions among whole-genome datasets: fdfBLAST. Applying this tool to the Fungi, we identified 63 gene fusions present in two or more genomes. Using a combination of phylogenetic and comparative genomic analyses, we then investigated the evolution of these genes across 115 fungal genomes, testing each gene fusion for evidence of homoplasy, including gene fission, convergence, and horizontal gene transfer. These analyses demonstrated 110 gene-fission events. We then identified a minimum of three mechanisms that drive gene fission: separation, degeneration, and duplication. These data suggest that gene fission plays an important and hitherto underestimated role in gene evolution. Gene fusions therefore are highly labile characters, and their use for polarizing evolutionary relationships, without reference to gene and species phylogenies, is limited. Accounting for these considerable sources of homoplasy, we identified fusion characters that provide support for multiple nodes in the phylogeny of the Fungi, including relationships within the deeply derived flagellum-forming fungi (i.e., the chytrids). PMID:23236161

Leonard, Guy; Richards, Thomas A

2012-12-26

418

Genome-scale comparative analysis of gene fusions, gene fissions, and the fungal tree of life  

PubMed Central

During the course of evolution genes undergo both fusion and fission by which ORFs are joined or separated. These processes can amend gene function and represent an important factor in the evolution of protein interaction networks. Gene fusions have been suggested to be useful characters for identifying evolutionary relationships because they constitute synapomorphies or cladistic characters. To investigate the fidelity of gene-fusion characters, we developed an approach for identifying differentially distributed gene fusions among whole-genome datasets: fdfBLAST. Applying this tool to the Fungi, we identified 63 gene fusions present in two or more genomes. Using a combination of phylogenetic and comparative genomic analyses, we then investigated the evolution of these genes across 115 fungal genomes, testing each gene fusion for evidence of homoplasy, including gene fission, convergence, and horizontal gene transfer. These analyses demonstrated 110 gene-fission events. We then identified a minimum of three mechanisms that drive gene fission: separation, degeneration, and duplication. These data suggest that gene fission plays an important and hitherto underestimated role in gene evolution. Gene fusions therefore are highly labile characters, and their use for polarizing evolutionary relationships, without reference to gene and species phylogenies, is limited. Accounting for these considerable sources of homoplasy, we identified fusion characters that provide support for multiple nodes in the phylogeny of the Fungi, including relationships within the deeply derived flagellum-forming fungi (i.e., the chytrids). PMID:23236161

Leonard, Guy; Richards, Thomas A.

2012-01-01

419

Log-linear model-based multifactor dimensionality reduction method to detect gene-gene interactions  

Microsoft Academic Search

Motivation: The identification and characterization of susceptibility genes that influence the risk of common and complex diseases remains a statistical and computational challenge in genetic association studies. This is partly because the effect of any single genetic variant for a common and complex disease may be dependent on other genetic variants (gene-gene interaction) and environmental factors (gene-environment interaction). To address

Seung Yeoun Lee; Yujin Chung; Robert C. Elston; Youngchul Kim; Taesung Park

2007-01-01

420

Gene Ther . Author manuscript Coagulation factor X mediates adenovirus type 5 liver gene transfer in  

E-print Network

Gene Ther . Author manuscript Page /1 4 Coagulation factor X mediates adenovirus type 5 liver gene. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver while FX-binding ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. Therefore, the Ad

Paris-Sud XI, Université de

421

Deposition of Histone Variant H2A.Z within Gene Bodies Regulates Responsive Genes  

E-print Network

DNA. RNA sequencing and genomic mapping of H2A.Z show that H2A.Z enrichment across gene bodies, ratherDeposition of Histone Variant H2A.Z within Gene Bodies Regulates Responsive Genes Devin Coleman at the transcriptional start sites of genes, has been implicated in a variety of chromosomal processes. Recently, we

422

Expression of a truncated tomato polygalacturonase gene inhibits expression of the endogenous gene in transgenic plants  

Microsoft Academic Search

Tomato plants were transformed with a chimaeric polygalacturonase (PG) gene, designed to produce a truncated PG transcript constitutively. In these plants expression of the endogenous PG gene was inhibited during ripening, resulting in a substantial reduction in PG mRNA and enzyme accumulation. This inhibition was comparable to that achieved previously using antisense genes. The expression of the truncated gene in

C. J. S. Smith; C. F. Watson; C. R. Bird; J. Ray; W. Schuch; D. Grierson

1990-01-01

423

Reranking candidate gene models with cross-species comparison for improved gene prediction  

PubMed Central

Background Most gene finders score candidate gene models with state-based methods, typically HMMs, by combining local properties (coding potential, splice donor and acceptor patterns, etc). Competing models with similar state-based scores may be distinguishable with additional information. In particular, functional and comparative genomics datasets may help to select among competing models of comparable probability by exploiting features likely to be associated with the correct gene models, such as conserved exon/intron structure or protein sequence features. Results We have investigated the utility of a simple post-processing step for selecting among a set of alternative gene models, using global scoring rules to rerank competing models for more accurate prediction. For each gene locus, we first generate the K best candidate gene models using the gene finder Evigan, and then rerank these models using comparisons with putative orthologous genes from closely-related species. Candidate gene models with lower scores in the original gene finder may be selected if they exhibit strong similarity to probable orthologs in coding sequence, splice site location, or signal peptide occurrence. Experiments on Drosophila melanogaster demonstrate that reranking based on cross-species comparison outperforms the best gene models identified by Evigan alone, and also outperforms the comparative gene finders GeneWise and Augustus+. Conclusion Reranking gene models with cross-species comparison improves gene prediction accuracy. This straightforward method can be readily adapted to incorporate additional lines of evidence, as it requires only a ranked source of candidate gene models. PMID:18854050

Liu, Qian; Crammer, Koby; Pereira, Fernando CN; Roos, David S

2008-01-01

424

A Chitinase Encoding Gene (chit1 Gene) from the Entomopathogen Metarhizium anisopliae: Isolation and Characterization  

E-print Network

A Chitinase Encoding Gene (chit1 Gene) from the Entomopathogen Metarhizium anisopliae: Isolation. There are no reports to date of entire gene sequences coding for chitinolytic enzymes from entomopathogenic fungi, even-length cDNAcopies of the regulated gene (chit1) coding one of the chitinases produced by the biocontrol

Eizirik, Eduardo

425

Integrating Ontological Knowledge and Textual Evidence in Estimating Gene and Gene Product Similarity  

SciTech Connect

With the rising influence of the Gene On-tology, new approaches have emerged where the similarity between genes or gene products is obtained by comparing Gene Ontology code annotations associ-ated with them. So far, these approaches have solely relied on the knowledge en-coded in the Gene Ontology and the gene annotations associated with the Gene On-tology database. The goal of this paper is to demonstrate that improvements to these approaches can be obtained by integrating textual evidence extracted from relevant biomedical literature.

Sanfilippo, Antonio P.; Posse, Christian; Gopalan, Banu; Tratz, Stephen C.; Gregory, Michelle L.

2006-06-08

426

Mining Association Rules among Gene Functions in Clusters of Similar Gene Expression Maps  

PubMed Central

Association rules mining methods have been recently applied to gene expression data analysis to reveal relationships between genes and different conditions and features. However, not much effort has focused on detecting the relation between gene expression maps and related gene functions. Here we describe such an approach to mine association rules among gene functions in clusters of similar gene expression maps on mouse brain. The experimental results show that the detected association rules make sense biologically. By inspecting the obtained clusters and the genes having the gene functions of frequent itemsets, interesting clues were discovered that provide valuable insight to biological scientists. Moreover, discovered association rules can be potentially used to predict gene functions based on similarity of gene expression maps.

An, Li; Obradovic, Zoran; Smith, Desmond; Bodenreider, Olivier; Megalooikonomou, Vasileios

2015-01-01

427

A Review for Detecting Gene-Gene Interactions Using Machine Learning Methods in Genetic Epidemiology  

PubMed Central

Recently, the greatest statistical computational challenge in genetic epidemiology is to identify and characterize the genes that interact with other genes and environment factors that bring the effect on complex multifactorial disease. These gene-gene interactions are also denoted as epitasis in which this phenomenon cannot be solved by traditional statistical method due to the high dimensionality of the data and the occurrence of multiple polymorphism. Hence, there are several machine learning methods to solve such problems by identifying such susceptibility gene which are neural networks (NNs), support vector machine (SVM), and random forests (RFs) in such common and multifactorial disease. This paper gives an overview on machine learning methods, describing the methodology of each machine learning methods and its application in detecting gene-gene and gene-environment interactions. Lastly, this paper discussed each machine learning method and presents the strengths and weaknesses of each machine learning method in detecting gene-gene interactions in complex human disease. PMID:24228248

Koo, Ching Lee; Liew, Mei Jing; Mohamad, Mohd Saberi

2013-01-01

428

Gene Expression Correlation and Gene Ontology-Based Similarity: An Assessment of Quantitative Relationships  

PubMed Central

The Gene Ontology and annotations derived from the S. cerivisiae Genome Database were analyzed to calculate functional similarity of gene products. Three methods for measuring similarity (including a distance-based approach) were implemented. Significant, quantitative relationships between similarity and expression correlation of pairs of genes were detected. Using a known gene expression dataset in yeast, this study compared more than three million pairs of gene products on the basis of these functional properties. Highly correlated genes exhibit strong similarity based on information originating from the gene ontology taxonomies. Such a similarity is significantly stronger than that observed between weakly correlated genes. This study supports the feasibility of applying gene ontology-driven similarity methods to functional prediction tasks, such as the validation of gene expression analyses and the identification of false positives in protein interaction studies.

Wang, Haiying; Azuaje, Francisco; Bodenreider, Olivier; Dopazo, Joaquín

2015-01-01

429

Exploring Interactions Between Rat Hepatocytes and Nonparenchymal Cells Using Gene  

E-print Network

correlated with fibroblast gene expression profiles obtained using Affymetrix GeneChips. Microarray dataExploring Interactions Between Rat Hepatocytes and Nonparenchymal Cells Using Gene Expression their interaction with surrounding epithelia, a correlation of nonparenchymal gene expression with epithelial

Bhatia, Sangeeta

430

Diametric gene-dosage effects as windows into neurogenetic architecture  

E-print Network

Diametric gene-dosage effects as windows into neurogenetic architecture Bernard Crespi Gene diametric changes in gene dosage influence neurological development and function? Recent studies of transgenic and knockout mouse models, genomic copy-number variants, imprinted- gene expression alterations

Crespi, Bernard J.

431

Taste Genes Associatedwith Dental Caries  

PubMed Central

Dental caries is influenced by a complex interplay of genetic and environmental factors, including dietary habits. Previous reports have characterized the influence of genetic variation on taste preferences and dietary habits. We therefore hypothesized that genetic variation in taste pathway genes (TAS2R38, TAS1R2, GNAT3) may be associated with dental caries risk and/or protection. Families were recruited by the Center for Oral Health Research in Appalachia (COHRA) for collection of biological samples, demographic data, and clinical assessment of oral health, including caries scores. Multiple single-nucleotide polymorphism (SNP) assays for each gene were performed and analyzed by transmission disequilibrium test (TDT) analysis (FBAT software) for three dentition groups: primary, mixed, and permanent. Statistically significant associations were seen in TAS2R38 and TAS1R2 for caries risk and/or protection. PMID:20858777

Wendell, S.; Wang, X.; Brown, M.; Cooper, M.E.; DeSensi, R.S.; Weyant, R.J.; Crout, R.; McNeil, D.W.; Marazita, M.L.

2010-01-01

432

Nickel and Epigenetic Gene Silencing  

PubMed Central

Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing. PMID:24705264

Sun, Hong; Shamy, Magdy; Costa, Max

2013-01-01

433

Phenotypic deconstruction of gene circuitry.  

PubMed

It remains a challenge to obtain a global perspective on the behavioral repertoire of complex nonlinear gene circuits. In this paper, we describe a method for deconstructing complex systems into nonlinear sub-systems, based on mathematically defined phenotypes, which are then represented within a system design space that allows the repertoire of qualitatively distinct phenotypes of the complex system to be identified, enumerated, and analyzed. This method efficiently characterizes large regions of system design space and quickly generates alternative hypotheses for experimental testing. We describe the motivation and strategy in general terms, illustrate its use with a detailed example involving a two-gene circuit with a rich repertoire of dynamic behavior, and discuss experimental means of navigating the system design space. PMID:23822506

Lomnitz, Jason G; Savageau, Michael A

2013-06-01

434

Phenotypic deconstruction of gene circuitry  

NASA Astrophysics Data System (ADS)

It remains a challenge to obtain a global perspective on the behavioral repertoire of complex nonlinear gene circuits. In this paper, we describe a method for deconstructing complex systems into nonlinear sub-systems, based on mathematically defined phenotypes, which are then represented within a system design space that allows the repertoire of qualitatively distinct phenotypes of the complex system to be identified, enumerated, and analyzed. This method efficiently characterizes large regions of system design space and quickly generates alternative hypotheses for experimental testing. We describe the motivation and strategy in general terms, illustrate its use with a detailed example involving a two-gene circuit with a rich repertoire of dynamic behavior, and discuss experimental means of navigating the system design space.

Lomnitz, Jason G.; Savageau, Michael A.

2013-06-01

435

The insect SNMP gene family.  

PubMed

SNMPs are membrane proteins observed to associate with chemosensory neurons in insects; in Drosophila melanogaster, SNMP1 has been shown to be essential for the detection of the pheromone cis-vaccenyl acetate (CVA). SNMPs are one of three insect gene clades related to the human fatty acid transporter CD36. We previously characterized the CD36 gene family in 4 insect Orders that effectively cover the Holometabola, or some 80% of known insect species and the 300 million years of evolution since this lineage emerged: Lepidoptera (e.g. Bombyx mori, Antheraea polyphemus, Manduca sexta, Heliothis virescens, Helicoverpa assulta, Helicoverpa armigera, Mamestra brassicae); Diptera (D. melanogaster, Drosophila pseudoobscura, Aedes aegypti, Anopheles gambiae, Culex pipiens quinquefasciatus); Hymenoptera (Apis mellifera); and Coleoptera (Tribolium castaneum). This previous study suggested a complex topography within the SNMP clade including a strongly supported SNMP1 sub-clade plus additional SNMP genes. To further resolve the SNMP clade here, we used cDNA sequences of SNMP1 and SNMP2 from various Lepidoptera species, D. melanogaster and Ae. aegypti, as well as BAC derived genomic sequences from Ae. aegypti as models for proposing corrected sequences of orthologues in the D. pseudoobscura and An. gambiae genomes, and for identifying orthologues in the B. mori and C. pipiens q. genomes. We then used these sequences to analyze the SNMP clade of the insect CD36 gene family, supporting the existence of two well supported sub-clades, SNMP1 and SNMP2, throughout the dipteran and lepidopteran lineages, and plausibly throughout the Holometabola and across a broad evolutionary time scale. We present indirect evidence based on evolutionary selection (dN/dS) that the dipteran SNMPs are expressed as functional proteins. We observed expansions of the SNMP1 sub-clade in C. pipiens q. and T. castaneum suggesting that the SNMP1s may have an expanded functional role in these species. PMID:19364529

Vogt, Richard G; Miller, Natalie E; Litvack, Rachel; Fandino, Richard A; Sparks, Jackson; Staples, Jon; Friedman, Robert; Dickens, Joseph C

2009-07-01

436

Method for determining gene knockouts  

DOEpatents

A method for determining candidates for gene deletions and additions using a model of a metabolic network associated with an organism, the model includes a plurality of metabolic reactions defining metabolite relationships, the method includes selecting a bioengineering objective for the organism, selecting at least one cellular objective, forming an optimization problem that couples the at least one cellular objective with the bioengineering objective, and solving the optimization problem to yield at least one candidate.

Maranas, Costa D; Burgard, Anthony R; Pharkya, Priti

2013-06-04

437

Method for determining gene knockouts  

DOEpatents

A method for determining candidates for gene deletions and additions using a model of a metabolic network associated with an organism, the model includes a plurality of metabolic reactions defining metabolite relationships, the method includes selecting a bioengineering objective for the organism, selecting at least one cellular objective, forming an optimization problem that couples the at least one cellular objective with the bioengineering objective, and solving the optimization problem to yield at least one candidate.

Maranas, Costas D. (Port Matilda, PA); Burgard, Anthony R. (State College, PA); Pharkya, Priti (State College, PA)

2011-09-27

438

Gene therapy for ovarian cancer  

Microsoft Academic Search

Ovarian cancer remains the leading cause of death due to gynecologic cancer in women in the United States. Gene and viral-based\\u000a therapies represent novel therapeutic approaches for cancer. The manipulation of genetic content of tumor cells toward a therapeutic\\u000a end has been divided into several general strategies, including molecular chemotherapy, mutation compensation, immunopotentiation,\\u000a and virotherapy. Improvements in delivery vehicles and

Kristopher J. Kimball; T. Michael Numnum; Rodney P. Rocconi; Ronald D. Alvarez

2006-01-01

439

NME genes in epithelial morphogenesis  

Microsoft Academic Search

The NME family of genes encodes highly conserved multifunctional proteins that have been shown to participate in nucleic acid metabolism,\\u000a energy homeostasis, cell signaling, and cancer progression. Some family members, particularly isoforms 1 and 2, have attracted\\u000a extensive interests because of their potential anti-metastasis activity. Unfortunately, there have been few consensus mechanistic\\u000a explanations for this critical function because of the

Tien Hsu

440

Transgenic plants with cyanobacterial genes  

Microsoft Academic Search

Over the years, cyanobacteria have been regarded as ideal model systems for studying fundamental biochemical processes like\\u000a oxygenic photosynthesis and carbon and nitrogen assimilation. Additionally, they have been used as human foods, sources for\\u000a vitamins, proteins, fine chemicals, and bioactive compounds. Aiming to increase plant productivity as well as nutritional\\u000a values, cyanobacterial genes involved in carbon metabolism, fatty acid biosynthesis,

Youn-Il Park; Sang-Bong Choi; Jang R. Liu

2009-01-01

441

Tissue-specific functions based on information content of gene ontology using cap analysis gene expression  

Microsoft Academic Search

Gene expressions differ depending on tissue types and developmental stages. Analyzing how each gene is expressed is thus important.\\u000a One way of analyzing gene expression patterns is to identify tissue-specific functions. This is useful for understanding how\\u000a vital activities are performed. DNA microarray has been widely used to observe gene expressions exhaustively. However, comparing\\u000a the expression value of a gene

Sami Maekawa; Atsuko Matsumoto; Yoichi Takenaka; Hideo Matsuda

2007-01-01

442

Mytilus edulis Core Histone Genes Are Organized in Two Clusters Devoid of Linker Histone Genes  

Microsoft Academic Search

  Abstract\\u000a \\u000a Comparison of histone gene cluster arrangements in several species has revealed a broad spectrum of histone gene patterns.\\u000a To elucidate the core histone gene organization in a mollusk, we have analyzed a Mytilus edulis genomic library and have isolated eight phage clones containing core histone genes. Analysis of insert DNA revealed that\\u000a the core histone genes are arranged as

Werner Albig; Ursula Warthorst; Birgit Drabent; Eva Prats; Luis Cornudella; Detlef Doenecke

2003-01-01

443

Nomenclature of the human immunoglobulin genes.  

PubMed

The human immunoglobulins (Ig) are the products of three unlinked sets of genes: the immunoglobulin heavy (IGH), the immunoglobulin kappa (IGK), and the immunoglobulin lambda (IGL) genes, localized on chromosome 14 (14q32.33), 2 (2p12), and 22 (22q11.2), respectively. This appendix presents tabulated lists of the human immunoglobulin heavy, kappa, and lambda genes named in accordance with the International ImMunoGeneTics database (IMGT) and approved by the Human Genome Organization (HUGO) Nomenclature Committee in 1999. Three additional tables list corresponding nomenclatures for these genes. PMID:18432650

Lefranc, M P

2001-05-01

444

Evolutionary Dynamics of Plant R-Genes  

NSDL National Science Digital Library

Plant R-genes involved in gene-for-gene interactions with pathogens are expected to undergo coevolutionary arms races in which plant specificity and pathogen virulence continually adapt in response to each other. Lending support to this idea, the solvent-exposed amino acid residues of leucine-rich repeats, a region of R-genes involved in recognizing pathogens, often evolve at unusually fast rates. But within-species polymorphism is also common in R-genes, implying that the adaptive substitution process is not simply one of successive selective sweeps. Here we document these features in available data and discuss them in light of the evolutionary dynamics they likely reflect.

Joy Bergelson (University of Chicago;Department of Ecology and Evolution); Martin Kreitman (University of Chicago;Department of Ecology and Evolution); Eli Stahl (University of Chicago;Department of Ecology and Evolution); Dacheng Tian (University of Chicago;Department of Ecology and Evolution)

2001-06-22

445

Thermostable cellulase from a thermomonospora gene  

DOEpatents

The invention relates to a gene isolated from Thermomonospora fusca, wherein the gene encodes a thermostable cellulase. Disclosed is the nucleotide sequence of the T. fusca gene; and nucleic acid molecules comprising the gene, or a fragment of the gene, that can be used to recombinantly express the cellulase or a catalytically active polypeptide thereof, respectively. The isolated and purified recombinant cellulase or catalytically active polypeptide may be used to hydrolyze substrate either by itself; or in combination with other cellulases, with the resultant combination having unexpected hydrolytic activity. 3 figs.

Wilson, D.B.; Walker, L.P.; Zhang, S.

1997-10-14

446

Thermostable cellulase from a thermomonospora gene  

DOEpatents

The invention relates to a gene isolated from Thermomonospora fusca, wherein the gene encodes a thermostable cellulase. Disclosed is the nucleotide sequence of the T. fusca gene; and nucleic acid molecules comprising the gene, or a fragment of the gene, that can be used to recombinantly express the cellulase or a catalytically active polypeptide thereof, respectively. The isolated and purified recombinant cellulase or catalytically active polypeptide may be used to hydrolyze substrate either by itself; or in combination with other cellulases, with the resultant combination having unexpected hydrolytic activity.

Wilson, David B. (Ithaca, NY); Walker, Larry P. (Ithaca, NY); Zhang, Sheng (Ithaca, NY)

1997-10-14

447

University of Washington: GeneTests  

NSDL National Science Digital Library

This GeneTests website "is a publicly funded medical genetics information resource for physicians, other healthcare providers, and researchers, available at no cost to all interested persons." The GeneTests site features _Gene Reviews_, an online publication of expert-authored disease reviews. The site also offers international directories of genetic testing laboratories and genetics and prenatal diagnosis clinics. Some new site features include Expanded Molecular Genetics in _Gene Reviews_, and Printable Resources. The site also offers usage statistics and is currently posting 4,603 daily hits for _Gene Reviews_ and an impressive 16,536 daily hits for their Laboratory Directory.

448

NME genes in epithelial morphogenesis.  

PubMed

The NME family of genes encodes highly conserved multifunctional proteins that have been shown to participate in nucleic acid metabolism, energy homeostasis, cell signaling, and cancer progression. Some family members, particularly isoforms 1 and 2, have attracted extensive interests because of their potential anti-metastasis activity. Unfortunately, there have been few consensus mechanistic explanations for this critical function because of the numerous molecular functions ascribed to these proteins, including nucleoside diphosphate kinase, protein kinase, nuclease, transcription factor, growth factor, among others. In addition, different studies showed contradictory prognostic correlations between NME expression levels and tumor progression in clinical samples. Thus, analyses using pliable in vivo systems have become critical for unraveling at least some aspects of the complex functions of this family of genes. Recent works using the Drosophila genetic system have suggested a role for NME in regulating epithelial cell motility and morphogenesis, which has also been demonstrated in mammalian epithelial cell culture. This function is mediated by promoting internalization of growth factor receptors in motile epithelial cells, and the adherens junction components such as E-cadherin and ?-catenin in epithelia that form the tissue linings. Interestingly, NME genes in epithelial cells appear to function in a defined range of expression levels. Either down-regulation or over-expression can perturb epithelial integrity, resulting in different aspects of epithelial abnormality. Such biphasic functions provide a plausible explanation for the documented anti-metastatic activity and the suspected oncogenic function. This review summarizes these recent findings and discusses their implications. PMID:21336542

Hsu, Tien

2011-10-01

449

Horizontal gene transfer in chromalveolates  

PubMed Central

Background Horizontal gene transfer (HGT), the non-genealogical transfer of genetic material between different organisms, is considered a potentially important mechanism of genome evolution in eukaryotes. Using phylogenomic analyses of expressed sequence tag (EST) data generated from a clonal cell line of a free living dinoflagellate alga Karenia brevis, we investigated the impact of HGT on genome evolution in unicellular chromalveolate protists. Results We identified 16 proteins that have originated in chromalveolates through ancient HGTs before the divergence of the genera Karenia and Karlodinium and one protein that was derived through a more recent HGT. Detailed analysis of the phylogeny and distribution of identified proteins demonstrates that eight have resulted from independent HGTs in several eukaryotic lineages. Conclusion Recurring intra- and interdomain gene exchange provides an important source of genetic novelty not only in parasitic taxa as previously demonstrated but as we show here, also in free-living protists. Investigating the tempo and mode of evolution of horizontally transferred genes in protists will therefore advance our understanding of mechanisms of adaptation in eukaryotes. PMID:17894863

Nosenko, Tetyana; Bhattacharya, Debashish

2007-01-01

450

Uncovering legumain genes in rice.  

PubMed

Legumains are Asn specific cysteine proteases physiologically related to the biosynthesis of vacuolar components, degradation of storage proteins and programmed cell death. The present work identifies and characterizes the genic family of legumains in rice (Oryza sativa), which comprises five different loci. Rice legumains (OsaLegs) were ubiquitously detected in all plant tissues analyzed. However, phylogenetic analyses and gene expression studies demonstrated greater association of OsaLeg2 and OsaLeg3 to seed-related legumains, whereas OsaLeg1, 4 and 5 would act as vegetative-related proteases. Additionally, OsaLeg1 mRNA is strongly induced in senescent leaves. All rice legumain genes respond in different ways to environmental conditions such as wounding, salt and abscisic acid treatments. Mainly, wounding is capable of inducing all the four expressed genes OsaLeg1, 2, 3 and 4. Alternative splicing isoforms, with potential to generate pre-activated OsaLeg1 and OsaLeg2 nonvacuolar enzymes under different environmental situations were also observed. PMID:24388520

Christoff, Ana Paula; Turchetto-Zolet, Andreia Carina; Margis, Rogerio

2014-02-01

451

Orthopedic Gene Therapy in 2008  

PubMed Central

Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic joints, and the development of bone-healing applications is at an advanced, preclinical stage. Other potential uses include the treatment of Mendelian diseases and orthopedic tumors, as well as the repair and regeneration of cartilage, ligaments, and tendons. Many of these goals should be achievable with existing technologies. The main barriers to clinical application are funding and regulatory issues, which in turn reflect major safety concerns and the opinion, in some quarters, that gene therapy should not be applied to nonlethal, nongenetic diseases. For some indications, advances in nongenetic treatments have also diminished enthusiasm. Nevertheless, the preclinical and early clinical data are impressive and provide considerable optimism that gene therapy will provide straightforward, effective solutions to the clinical management of several common debilitating disorders that are otherwise difficult and expensive to treat. PMID:19066598

Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D

2008-01-01

452

DMRT genes in vertebrate gametogenesis.  

PubMed

Genes containing the DM domain DNA-binding motif regulate sex determination and sexual differentiation in a broad variety of metazoans, including nematodes, insects, and vertebrates. They can function in primary sex determination or downstream in sexual differentiation, and they can act either throughout the body or in highly restricted cell types. In vertebrates, several DM domain genes--DMRT genes--play critical roles in gonadal differentiation or gametogenesis. DMRT1 has the most prominent role and likely regulates testicular differentiation in all vertebrates. In the mammalian gonad, DMRT1 exerts both intrinsic and extrinsic control of gametogenesis; it is required for germ cell differentiation in males and regulates meiosis in both sexes, and it is required in supporting cells for the establishment and maintenance of male fate in the testis. These varied functions of DMRT1 serve to coordinate gonadal development and function. In other vertebrates, DMRT1 regulates gonadal differentiation, and it also appears to have played a central role in the evolution of new sex-determining mechanisms in at least three vertebrate clades. This chapter focuses on the regulation of vertebrate gametogenesis by DMRT1. PMID:23287039

Zarkower, David

2013-01-01

453

NME genes in epithelial morphogenesis  

PubMed Central

The NME family of genes encodes highly conserved multifunctional proteins that have been shown to participate in nucleic acid metabolism, energy homeostasis, cell signaling, and cancer progression. Some family members, particularly isoforms 1 and 2, have attracted extensive interests because of their potential anti-metastasis activity. Unfortunately, there have been few consensus mechanistic explanations for this critical function because of the numerous molecular functions ascribed to these proteins, including nucleoside diphosphate kinase, protein kinase, nuclease, transcription factor, growth factor, among others. In addition, different studies showed contradictory prognostic correlations between NME expression levels and tumor progression in clinical samples. Thus, analyses using pliable in vivo systems have become critical for unraveling at least some aspects of the complex functions of this family of genes. Recent works using the Drosophila genetic system have suggested a role for NME in regulating epithelial cell motility and morphogenesis, which has also been demonstrated in mammalian epithelial cell culture. This function is mediated by promoting internalization of growth factor receptors in motile epithelial cells, and the adherens junction components such as E-cadherin and ?-catenin in epithelia that form the tissue linings. Interestingly, NME genes in epithelial cells appear to function in a defined range of expression levels. Either down-regulation or over-expression can perturb epithelial integrity, resulting in different aspects of epithelial abnormality. Such biphasic functions provide a plausible explanation for the documented anti-metastatic activity and the suspected oncogenic function. This review summarizes these recent findings and discusses their implications. PMID:21336542

2012-01-01

454

Collaborative computing for gene mapping  

SciTech Connect

The authors are investigating mechanisms for utilizing advances in high performance computing and alignment algorithm development which will allow the analysis of newly acquired sequence data in real time and eliminate the global alignments problems associated with existing datasets. The presence of repetitive DNA sequences in the human genome complicates the process of homology comparisons. Three approaches have been used to address this problem. Two of the approaches involve elimination of the repetitive elements either by removing the repetitive element from the query or scoring words due to the repetitive elements poorly or not at all during the alignment process. The approach involves identification of the repetitive element in the query by comparison to a known repeat set prior to comparison to the large database. Any homologies returned which are contained within a previously identified repeat are ignored unless the homology exceeds set quality parameters. The homologies which extend outside the bounds of the repetitive element are reported. Using this approach the repeat is not eliminated from larger homologous units which may exist, and is returned as part of the overall homology result. The method the authors utilize in the laboratory for gene mapping is fluorescent in situ hybridization (FISH). This approach involves labelling a gene segment with a fluorescent molecule and then mixing the labeled gene segment (probe) with chromosomes.

Gatewood, J.M.

1993-12-01

455

Does FACS perturb gene expression?  

PubMed

Fluorescence activated cell sorting is the technique most commonly used to separate primary mammary epithelial sub-populations. Many studies incorporate this technique before analyzing gene expression within specific cellular lineages. However, to our knowledge, no one has examined the effects of fluorescence activated cell sorting (FACS) separation on short-term transcriptional profiles. In this study, we isolated a heterogeneous mixture of cells from the mouse mammary gland. To determine the effects of the isolation and separation process on gene expression, we harvested RNA from the cells before enzymatic digestion, following enzymatic digestion, and following a mock FACS sort where the entire cohort of cells was retained. A strict protocol was followed to minimize disruption to the cells, and to ensure that no subpopulations were enriched or lost. Microarray analysis demonstrated that FACS causes minimal disruptions to gene expression patterns, but prior steps in the mammary cell isolation process are followed by upregulation of 18 miRNA's and rapid decreases in their predicted target transcripts. © 2015 International Society for Advancement of Cytometry. PMID:25598345

Richardson, Graham M; Lannigan, Joanne; Macara, Ian G

2015-02-01

456

GeneTack database: genes with frameshifts in prokaryotic genomes and eukaryotic mRNA sequences  

PubMed Central

Database annotations of prokaryotic genomes and eukaryotic mRNA sequences pay relatively low attention to frame transitions that disrupt protein-coding genes. Frame transitions (frameshifts) could be caused by sequencing errors or indel mutations inside protein-coding regions. Other observed frameshifts are related to recoding events (that evolved to control expression of some genes). Earlier, we have developed an algorithm and software program GeneTack for ab initio frameshift finding in intronless genes. Here, we describe a database (freely available at http://topaz.gatech.edu/GeneTack/db.html) containing genes with frameshifts (fs-genes) predicted by GeneTack. The database includes 206?991 fs-genes from 1106 complete prokaryotic genomes and 45?295 frameshifts predicted in mRNA sequences from 100 eukaryotic genomes. The whole set of fs-genes was grouped into clusters based on sequence similarity between fs-proteins (conceptually translated fs-genes), conservation of the frameshift position and frameshift direction (?1, +1). The fs-genes can be retrieved by similarity search to a given query sequence via a web interface, by fs-gene cluster browsing, etc. Clusters of fs-genes are characterized with respect to their likely origin, such as pseudogenization, phase variation, etc. The largest clusters contain fs-genes with programed frameshifts (related to recoding events). PMID:23161689

Antonov, Ivan; Baranov, Pavel; Borodovsky, Mark

2013-01-01

457

GeneTack database: genes with frameshifts in prokaryotic genomes and eukaryotic mRNA sequences.  

PubMed

Database annotations of prokaryotic genomes and eukaryotic mRNA sequences pay relatively low attention to frame transitions that disrupt protein-coding genes. Frame transitions (frameshifts) could be caused by sequencing errors or indel mutations inside protein-coding regions. Other observed frameshifts are related to recoding events (that evolved to control expression of some genes). Earlier, we have developed an algorithm and software program GeneTack for ab initio frameshift finding in intronless genes. Here, we describe a database (freely available at http://topaz.gatech.edu/GeneTack/db.html) containing genes with frameshifts (fs-genes) predicted by GeneTack. The database includes 206?991 fs-genes from 1106 complete prokaryotic genomes and 45?295 frameshifts predicted in mRNA sequences from 100 eukaryotic genomes. The whole set of fs-genes was grouped into clusters based on sequence similarity between fs-proteins (conceptually translated fs-genes), conservation of the frameshift position and frameshift direction (-1, +1). The fs-genes can be retrieved by similarity search to a given query sequence via a web interface, by fs-gene cluster browsing, etc. Clusters of fs-genes are characterized with respect to their likely origin, such as pseudogenization, phase variation, etc. The largest clusters contain fs-genes with programed frameshifts (related to recoding events). PMID:23161689

Antonov, Ivan; Baranov, Pavel; Borodovsky, Mark

2013-01-01

458

Gametocidal genes in wheat and its relatives. IV. Functional relationships between six gametocidal genes.  

PubMed

Gametocidal (Gc) genes in Aegilops species are known to cause gamete abortion and chromosome breakage when they are introduced into the wheat genetic background. Interactions of five Gc genes so far identified were investigated by analysis of wheat hybrids among lines carrying different gametocidal genes. As a result, the genes were classified into three functional groups. The first group includes two Gc genes of Ae. speltoides (Gc1a and Gc1b) and one gene (Gc-Sl3) on chromosome 2S1 of Ae. sharonensis. These genes were hypostatic to the genes (Gc-Sl1, Gc-Sl2) on chromosome 4S1 of Ae. longissima and Ae. sharonensis, which constitute the second group. In addition, plants carrying Gc genes of both the first and the second group produced progeny with higher frequencies of chromosome breakage than those found in the progeny of single gene carriers. It was concluded that there were specific interactions between these genes to enhance chromosome breakage. On the other hand, there was no interaction between the Gc gene (Gc-C) of Ae. triuncialis, the third group, and Gc genes belonging to the former two groups. These functional groups might be a reflection of the mechanisms by which Gc genes induce gamete abortion and chromosome breakage. Based on functional and local relationships, the symbols of the Gc genes were systematically redesignated. PMID:18470167

Tsujimoto, H

1995-04-01

459

HOX GENES: Seductive Science, Mysterious Mechanisms  

PubMed Central

HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21.2, 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network. PMID:16457401

Lappin, Terrence RJ; Grier, David G; Thompson, Alexander; Halliday, Henry L

2006-01-01

460

Apolipoprotein gene involved in lipid metabolism  

DOEpatents

Methods and materials for studying the effects of a newly identified human gene, APOAV, and the corresponding mouse gene apoAV. The sequences of the genes are given, and transgenic animals which either contain the gene or have the endogenous gene knocked out are described. In addition, single nucleotide polymorphisms (SNPs) in the gene are described and characterized. It is demonstrated that certain SNPs are associated with diseases involving lipids and triglycerides and other metabolic diseases. These SNPs may be used alone or with SNPs from other genes to study individual risk factors. Methods for intervention in lipid diseases, including the screening of drugs to treat lipid-related or diabetic diseases are also disclosed.

Rubin, Edward (Berkeley, CA); Pennacchio, Len A. (Sebastopol, CA)

2007-07-03

461

Gene therapy for sensorineural hearing loss.  

PubMed

Gene therapy is a promising treatment modality that is being explored for several inherited disorders. Multiple human gene therapy clinical trials are currently ongoing, but few are directed at hearing loss. Hearing loss is one of the most prevalent sensory disabilities in the world, and genetics play an important role in the pathophysiology of hearing loss. Gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations. In addition, gene therapy could potentially be used to induce hair cell regeneration by delivering genes that are critical to hair cell differentiation into the cochlea. In this review, we examine the promises and challenges of applying gene therapy to the cochlea. We also summarize recent studies that have applied gene therapy to animal models of hearing loss. PMID:25166629

Chien, Wade W; Monzack, Elyssa L; McDougald, Devin S; Cunningham, Lisa L

2015-01-01

462

Going nuclear: gene family evolution and vertebrate phylogeny reconciled  

Microsoft Academic Search

Gene duplications have been common throughout vertebrate evolution, introducing paralogy and so com- plicating phylogenetic inference from nuclear genes. Reconciled trees are one method capable of dealing with paralogy, using the relationship between a gene phylogeny and the phylogeny of the organisms con- taining those genes to identify gene duplication events. This allows us to infer phylogenies from gene families

James A. Cotton; Roderic D. M. Page

2002-01-01

463

Mathematical Morphology applied to Spot Segmentation and Quantification of Gene  

E-print Network

1 Mathematical Morphology applied to Spot Segmentation and Quantification of Gene Microarray Images for identification of sequence (gene/gene mutation) and determination of gene expression. A typical gene microarray determines the level of gene ex- pression (abundance) in the sample. The massive scale and variability

Hero, Alfred O.

464

GRank: a middleware search engine for ranking genes by relevance to given genes  

PubMed Central

Background Biologists may need to know the set of genes that are semantically related to a given set of genes. For instance, a biologist may need to know the set of genes related to another set of genes known to be involved in a specific disease. Some works use the concept of gene clustering in order to identify semantically related genes. Others propose tools that return the set of genes that are semantically related to a given set of genes. Most of these gene similarity measures determine the semantic similarities among the genes based solely on the proximity to each other of the GO terms annotating the genes, while overlook the structural dependencies among these GO terms, which may lead to low recall and precision of results. Results We propose in this paper a search engine called GRank, which overcomes the limitations of the current gene similarity measures outlined above as follows. It employs the concept of existence dependency to determine the structural dependencies among the GO terms annotating a given set of gene. After determining the set of genes that are semantically related to input genes, GRank would use microarray experiment to rank these genes based on their degree of relativity to the input genes. We evaluated GRank experimentally and compared it with a comparable gene prediction tool called DynGO, which retrieves the genes and gene products that are relatives of input genes. Results showed marked improvement. Conclusions The experimental results demonstrated that GRank overcomes the limitations of current gene similarity measures. We attribute this performance to GRank’s use of existence dependency concept for determining the semantic relationships among gene annotations. The recall and precision values for two benchmarking datasets showed that GRank outperforms DynGO tool, which does not employ the concept of existence dependency. The demo of GRank using 11000 KEGG yeast genes and a Gene Expression Omnibus (GEO) microarray file named “GSM34635.pad” is available at: http://ecesrvr.kustar.ac.ae:8080/ (click on the link labelled Gene Ontology 2). PMID:23957362

2013-01-01

465

Altered patterns of gene duplication and differential gene gain and loss in fungal pathogens  

PubMed Central

Background Duplication, followed by fixation or random loss of novel genes, contributes to genome evolution. Particular outcomes of duplication events are possibly associated with pathogenic life histories in fungi. To date, differential gene gain and loss have not been studied at genomic scales in fungal pathogens, despite this phenomenon's known importance in virulence in bacteria and viruses. Results To determine if patterns of gene duplication differed between pathogens and non-pathogens, we identified gene families across nine euascomycete and two basidiomycete species. Gene family size distributions were fit to power laws to compare gene duplication trends in pathogens versus non-pathogens. Fungal phytopathogens showed globally altered patterns of gene duplication, as indicated by differences in gene family size distribution. We also identified sixteen examples of gene family expansion and five instances of gene family contraction in pathogenic lineages. Expanded gene families included those predicted to be important in melanin biosynthesis, host cell wall degradation and transport functions. Contracted families included those encoding genes involved in toxin production, genes with oxidoreductase activity, as well as subunits of the vacuolar ATPase complex. Surveys of the functional distribution of gene duplicates indicated that pathogens show enrichment for gene duplicates associated with receptor and hydrolase activities, while euascomycete pathogens appeared to have not only these differences, but also significantly more duplicates associated with regulatory and carbohydrate binding functions. Conclusion Differences in the overall levels of gene duplication in phytopathogenic species versus non-pathogenic relatives implicate gene inventory flux as an important virulence-associated process in fungi. We hypothesize that the observed patterns of gene duplicate enrichment, gene family expansion and contraction reflect adaptation within pathogenic life histories. These adaptations were likely shaped by ancient, as well as contemporary, intimate associations with monocot hosts. PMID:18373860

Powell, Amy J; Conant, Gavin C; Brown, Douglas E; Carbone, Ignazio; Dean, Ralph A

2008-01-01

466

Genes  

NSDL National Science Digital Library

Students will explore Genetics. All About Genetics These pages teach you how genetics work. Genetics: Decoding Life What students need to know about genetics Genetic Activities Websites that give you ideas for classroom activities. Comparing Apples and Oranges TRB 5:5 Activity 1 Students will learn differnces in organisms. The Living Corn Necklace TRB 5:5 Activity 2 Students will learn to compare similarities and differnces in a similar organism. Paint's Family Tree TRB 5:5 Activity 3 Students will discover family traits. Mealworms and Earthworms TRB 5:5 Activity 4 Students will learn about ...

Smith, John

2004-11-29

467

Highthroughput soybean gene expression analysis The changes in the atmosphere are altering gene expression and affecting the interaction  

E-print Network

High­throughput soybean gene expression analysis The changes in the atmosphere are altering gene soybean oligoarrays to analyze changes in the gene expression profile. Affymetrix GeneChip® Soybean Genome with Virus Induced Gene Silencing (VIGS) VIGS is used to suppress genes at transcript level by using a viral

DeLucia, Evan H.

468

A portal to gene-centered information from different sources http://www.ncbi.nlm.nih.gov/gene/  

E-print Network

NCBI Gene A portal to gene-centered information from different sources http://www.ncbi.nlm.nih.gov/gene of Health · Department of Health and Human Services NCBI Handout Series | Gene | Last Update December 18, 2013 Contact: info@ncbi.nlm.nih.gov NCBI Gene A portal to gene-centered information from different

Levin, Judith G.

469

Multivariate Gene Selection and Testing in Studying the Exposure Effects on a Gene Set.  

PubMed

Studying the association between a gene set (e.g., pathway) and exposures using multivariate regression methods is of increasing importance in genomic studies. Such an analysis is often more powerful and interpretable than individual gene analysis. Since many genes in a gene set are likely not affected by exposures, one is often interested in identifying a subset of genes in the gene set that are affected by exposures. This allows for better understanding of the underlying biological mechanism and for pursuing further biological investigation of these genes. The selected subset of "signal" genes also provides an attractive vehicle for a more powerful test for the association between the gene set and exposures. We propose two computationally simple Canonical Correlation Analysis (CCA) based variable selection methods: Sparse Outcome Selection (SOS) CCA and step CCA, to jointly select a subset of genes in a gene set that are associated with exposures. Several model selection criteria, such as BIC and the new Correlation Information Criterion (CIC), are proposed and compared. We also develop a global test procedure for testing the exposure effects on the whole gene set, accounting for gene selection. Through simulation studies, we show that the proposed methods improve upon an existing method when the genes are correlated and are more computationally efficient. We apply the proposed methods to the analysis of the Normative Aging DNA methylation Study to examine the effects of airborne particular matter exposures on DNA methylations in a genetic pathway. PMID:23264831

Sofer, Tamar; Maity, Arnab; Coull, Brent; Baccarelli, Andrea; Schwartz, Joel; Lin, Xihong

2012-11-01

470

Computing gene expression data with a knowledge-based gene clustering approach  

PubMed Central

Computational analysis methods for gene expression data gathered in microarray experiments can be used to identify the functions of previously unstudied genes. While obtaining the expression data is not a difficult task, interpreting and extracting the information from the datasets is challenging. In this study, a knowledge-based approach which identifies and saves important functional genes before filtering based on variability and fold change differences was utilized to study light regulation. Two clustering methods were used to cluster the filtered datasets, and clusters containing a key light regulatory gene were located. The common genes to both of these clusters were identified, and the genes in the common cluster were ranked based on their coexpression to the key gene. This process was repeated for 11 key genes in 3 treatment combinations. The initial filtering method reduced the dataset size from 22,814 probes to an average of 1134 genes, and the resulting common cluster lists contained an average of only 14 genes. These common cluster lists scored higher gene enrichment scores than two individual clustering methods. In addition, the filtering method increased the proportion of light responsive genes in the dataset from 1.8% to 15.2%, and the cluster lists increased this proportion to 18.4%. The relatively short length of these common cluster lists compared to gene groups generated through typical clustering methods or coexpression networks narrows the search for novel functional genes while increasing the likelihood that they are biologically relevant. PMID:21968910

Rosa, Bruce A.; Oh, Sookyung; Montgomery, Beronda L.; Chen, Jin; Qin, Wensheng

2010-01-01

471

FragGeneScan: predicting genes in short and error-prone reads.  

PubMed

The advances of next-generation sequencing technology have facilitated metagenomics research that attempts to determine directly the whole collection of genetic material within an environmental sample (i.e. the metagenome). Identification of genes directly from short reads has become an important yet challenging problem in annotating metagenomes, since the assembly of metagenomes is often not available. Gene predictors developed for whole genomes (e.g. Glimmer) and recently developed for metagenomic sequences (e.g. MetaGene) show a significant decrease in performance as the sequencing error rates increase, or as reads get shorter. We have developed a novel gene prediction method FragGeneScan, which combines sequencing error models and codon usages in a hidden Markov model to improve the prediction of protein-coding region in short reads. The performance of FragGeneScan was comparable to Glimmer and MetaGene for complete genomes. But for short reads, FragGeneScan consistently outperformed MetaGene (accuracy improved ?62% for reads of 400 bases with 1% sequencing errors, and ?18% for short reads of 100 bases that are error free). When applied to metagenomes, FragGeneScan recovered substantially more genes than MetaGene predicted (>90% of the genes identified by homology search), and many novel genes with no homologs in current protein sequence database. PMID:20805240

Rho, Mina; Tang, Haixu; Ye, Yuzhen

2010-11-01

472

Identification of Nitrogen-Fixing Genes and Gene Clusters from Metagenomic Library of Acid Mine Drainage  

PubMed Central

Biological nitrogen fixation is an essential function of acid mine drainage (AMD) microbial communities. However, most acidophiles in AMD environments are uncultured microorganisms and little is known about the diversity of nitrogen-fixing genes and structure of nif gene cluster in AMD microbial communities. In this study, we used metagenomic sequencing to isolate nif genes in the AMD microbial community from Dexing Copper Mine, China. Meanwhile, a metagenome microarray containing 7,776 large-insertion fosmids was constructed to screen novel nif gene clusters. Metagenomic analyses revealed that 742 sequences were identified as nif genes including structural subunit genes nifH, nifD, nifK and various additional genes. The AMD community is massively dominated by the genus Acidithiobacillus. However, the phylogenetic diversity of nitrogen-fixing microorganisms is much higher than previously thought in the AMD community. Furthermore, a 32.5-kb genomic sequence harboring nif, fix and associated genes was screened by metagenome microarray. Comparative genome analysis indicated that most nif genes in this cluster are most similar to those of Herbaspirillum seropedicae, but the organization of the nif gene cluster had significant differences from H. seropedicae. Sequence analysis and reverse transcription PCR also suggested that distinct transcription units of nif genes exist in this gene cluster. nifQ gene falls into the same transcription unit with fixABCX genes, which have not been reported in other diazotrophs before. All of these results indicated that more novel diazotrophs survive in the AMD community. PMID:24498417

Yin, Huaqun; Liang, Yili; Cong, Jing; Liu, Xueduan

2014-01-01

473

Sequence analysis of porothramycin biosynthetic gene cluster.  

PubMed

The biosynthetic gene cluster of porothramycin, a sequence-selective DNA alkylating compound, was identified in the genome of producing strain Streptomyces albus subsp. albus (ATCC 39897) and sequentially characterized. A 39.7 kb long DNA region contains 27 putative genes, 18 of them revealing high similarity with homologous genes from biosynthetic gene cluster of closely related pyrrolobenzodiazepine (PBD) compound anthramycin. However, considering the structures of both compounds, the number of differences in the gene composition of compared biosynthetic gene clusters was unexpectedly high, indicating participation of alternative enzymes in biosynthesis of both porothramycin precursors, anthranilate, and branched L-proline derivative. Based on the sequence analysis of putative NRPS modules Por20 and Por21, we suppose that in porothramycin biosynthesis, the methylation of anthranilate unit occurs prior to the condensation reaction, while modifications of branched proline derivative, oxidation, and dimethylation of the side chain occur on already condensed PBD core. Corresponding two specific methyltransferase encoding genes por26 and por25 were identified in the porothramycin gene cluster. Surprisingly, also methyltransferase gene por18 homologous to orf19 from anthramycin biosynthesis was detected in porothramycin gene cluster even though the appropriate biosynthetic step is missing, as suggested by ultra high-performance liquid chromatography-diode array detection-mass spectrometry (UHPLC-DAD-MS) analysis of the product in the S. albus culture broth. PMID:25128200

Najmanova, Lucie; Ulanova, Dana; Jelinkova, Marketa; Kamenik, Zdenek; Kettnerova, Eliska; Koberska, Marketa; Gazak, Radek; Radojevic, Bojana; Janata, Jiri

2014-11-01

474

The Dynein Gene Family in Chlamydomonas Reinhardtii  

PubMed Central

To correlate dynein heavy chain (Dhc) genes with flagellar mutations and gain insight into the function of specific dynein isoforms, we placed eight members of the Dhc gene family on the genetic map of Chlamydomonas. Using a PCR-based strategy, we cloned 11 Dhc genes from Chlamydomonas. Comparisons with other Dhc genes indicate that two clones correspond to genes encoding the alpha and beta heavy chains of the outer dynein arm. Alignment of the predicted amino acid sequences spanning the nucleotide binding site indicates that the remaining nine clones can be subdivided into three groups that are likely to include representatives of the inner-arm Dhc isoforms. Gene-specific probes reveal that each clone represents a single-copy gene that is expressed as a transcript of the appropriate size (>13 kb) sufficient to encode a high molecular weight Dhc polypeptide. The expression of all nine genes is upregulated in response to deflagellation, suggesting a role in axoneme assembly or motility. Restriction fragment length polymorphisms between divergent C. reinhardtii strains have been used to place each Dhc gene on the genetic map of Chlamydomonas. These studies lay the groundwork for correlating defects in different Dhc genes with specific flagellar mutations. PMID:8889521

Porter, M. E.; Knott, J. A.; Myster, S. H.; Farlow, S. J.

1996-01-01

475

Detection of EPO gene doping in blood.  

PubMed

Gene doping--or the abuse of gene therapy--will continue to threaten the sports world. History has shown that progress in medical research is likely to be abused in order to enhance human performance. In this review, we critically discuss the progress and the risks associated with the field of erythropoietin (EPO) gene therapy and its applicability to EPO gene doping. We present typical vector systems that are employed in ex vivo and in vivo gene therapy trials. Due to associated risks, gene doping is not a feasible alternative to conventional EPO or blood doping at this time. Nevertheless, it is well described that about half of the elite athlete population is in principle willing to risk its health to gain a competitive advantage. This includes the use of technologies that lack safety approval. Sophisticated detection approaches are a prerequisite for prevention of unapproved and uncontrolled use of gene therapy technology. In this review, we present current detection approaches for EPO gene doping, with a focus on blood-based direct and indirect approaches. Gene doping is detectable in principle, and recent DNA-based detection strategies enable long-term detection of transgenic DNA (tDNA) following in vivo gene transfer. PMID:22508654

Neuberger, Elmo W I; Jurkiewicz, Magdalena; Moser, Dirk A; Simon, Perikles

2012-11-01

476

Arabidopsis gene expression patterns during spaceflight  

NASA Astrophysics Data System (ADS)

The exposure of Arabidopsis thaliana (Arabidopsis) plants to spaceflight environments resulted in the differential expression of hundreds of genes. A 5 day mission on orbiter Columbia in 1999 (STS-93) carried transgenic Arabidopsis plants engineered with a transgene composed of the alcohol dehydrogenase (Adh) gene promoter linked to the ? -Glucuronidase (GUS) reporter gene. The plants were used to evaluate the effects of spaceflight on two fronts. First, expression patterns visualized with the Adh/GUS transgene were used to address specifically the possibility that spaceflight induces a hypoxic stress response, and to assess whether any spaceflight response was similar to control terrestrial hypoxia-induced gene expression patterns. (Paul et al., Plant Physiol. 2001, 126:613). Second, genome-wide patterns of native gene expression were evaluated utilizing the Affymetrix ATH1 GeneChip? array of 8,000 Arabidopsis genes. As a control for the veracity of the array analyses, a selection of genes identified with the arrays was further characterized with quantitative Real-Time RT PCR (ABI - TaqmanTM). Comparison of the patterns of expression for arrays of hybridized with RNA isolated from plants exposed to spaceflight compared to the control arrays revealed hundreds of genes that were differentially expressed in response to spaceflight, yet most genes that are hallmarks of hypoxic stress were unaffected. These results will be discussed in light of current models for plant responses to the spaceflight environment, and with regard to potential future flight opportunities.

Paul, A.-L.; Ferl, R. J.

477

Clustered arrangement of keratin intermediate filament genes.  

PubMed Central

We report here that component members of the keratin intermediate filament (IF) type I and type II gene families of sheep are closely linked but apparently the two families are not. Nine genes, accounting for up to half of the keratin IF gene repertoire, were mapped in four cosmid clones and the linkage between the genes ranged from several kilobases to 20 kilobases. In one cosmid, three tandem type I genes had the same transcriptional arrangement and were regularly spaced. In another cosmid, tandem genes encoding type II keratins were identified and, surprisingly, a solitary exon was discovered in the intergene region between the two type II genes. In a normal gene this exon encodes one of the most conserved amino acid regions of IF proteins, the C-terminal end of the alpha-helical core. Homologous C-terminal protein subdomains were encoded by two wool keratin type II genes and we suggest that this arrangement may also exist in the other wool keratin type II genes. Images PMID:2425360

Powell, B C; Cam, G R; Fietz, M J; Rogers, G E

1986-01-01

478

IL26 gene inactivation in Equidae.  

PubMed

Interleukin-26 (IL26) is a member of the IL10 cytokine family. The IL26 gene is located between two other well-known cytokines genes of this family encoding interferon-gamma (IFNG) and IL22 in an evolutionary conserved gene cluster. In contrast to humans and most other mammals, mice lack a functional Il26 gene. We analyzed the genome sequences of other vertebrates for the presence or absence of functional IL26 orthologs and found that the IL26 gene has also become inactivated in several equid species. We detected a one-base pair frameshift deletion in exon 2 of the IL26 gene in the domestic horse (Equus caballus), Przewalski horse (Equus przewalskii) and donkey (Equus asinus). The remnant IL26 gene in the horse is still transcribed and gives rise to at least five alternative transcripts. None of these transcripts share a conserved open reading frame with the human IL26 gene. A comparative analysis across diverse vertebrates revealed that the IL26 gene has also independently been inactivated in a few other mammals, including the African elephant and the European hedgehog. The IL26 gene thus appears to be highly variable, and the conserved open reading frame has been lost several times during mammalian evolution. PMID:23808390

Shakhsi-Niaei, M; Drögemüller, M; Jagannathan, V; Gerber, V; Leeb, T

2013-12-01

479