Jespersen, Thomas; Grunnet, Morten; Olesen, Søren-Peter
The voltage-gated KCNQ1 (KvLQT1, Kv7.1) potassium channel plays a crucial role in shaping the cardiac action potential as well as in controlling the water and salt homeostasis in several epithelial tissues. KCNQ1 channels in these tissues are tightly regulated by auxiliary proteins and accessory...... factors, capable of modulating the properties of the channel complexes. This paper reviews the current knowledge about the KCNQ1 channel with a major focus on interacting proteins and physiological functions....
Schmitt, N; Schwarz, M; Peretz, A
The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IK(s) K...
Liin, Sara I; Barro-Soria, Rene; Larsson, H Peter
The KCNQ1 channel (also called Kv7.1 or KvLQT1) belongs to the superfamily of voltage-gated K(+) (Kv) channels. KCNQ1 shares several general features with other Kv channels but also displays a fascinating flexibility in terms of the mechanism of channel gating, which allows KCNQ1 to play different physiological roles in different tissues. This flexibility allows KCNQ1 channels to function as voltage-independent channels in epithelial tissues, whereas KCNQ1 function as voltage-activated channels with very slow kinetics in cardiac tissues. This flexibility is in part provided by the association of KCNQ1 with different accessory KCNE β-subunits and different modulators, but also seems like an integral part of KCNQ1 itself. The aim of this review is to describe the main mechanisms underlying KCNQ1 flexibility. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.
Liin, Sara I; Barro-Soria, Rene; Larsson, H Peter
The KCNQ1 channel (also called Kv7.1 or KvLQT1) belongs to the superfamily of voltage-gated K+ (Kv) channels. KCNQ1 shares several general features with other Kv channels but also displays a fascinating flexibility in terms of the mechanism of channel gating, which allows KCNQ1 to play different physiological roles in different tissues. This flexibility allows KCNQ1 channels to function as voltage-independent channels in epithelial tissues, whereas KCNQ1 function as voltage-activated channels with very slow kinetics in cardiac tissues. This flexibility is in part provided by the association of KCNQ1 with different accessory KCNE β-subunits and different modulators, but also seems like an integral part of KCNQ1 itself. The aim of this review is to describe the main mechanisms underlying KCNQ1 flexibility. PMID:25653179
Ren, Xiao-Qin; Liu, Gong Xin; Organ-Darling, Louise E.; Zheng, Renjian; Roder, Karim; Jindal, Hitesh K.; Centracchio, Jason; McDonald, Thomas V.
We previously reported a transgenic rabbit model of long QT syndrome based on overexpression of pore mutants of repolarizing K+ channels KvLQT1 (LQT1) and HERG (LQT2).The transgenes in these rabbits eliminated the slow and fast components of the delayed rectifier K+ current (IKs and IKr, respectively), as expected. Interestingly, the expressed pore mutants of HERG and KvLQT1 downregulated the remaining reciprocal repolarizing currents, IKs and IKr, without affecting the steady-state levels of the native polypeptides. Here, we sought to further explore the functional interactions between HERG and KvLQT1 in heterologous expression systems. Stable Chinese hamster ovary (CHO) cell lines expressing KvLQT1-minK or HERG were transiently transfected with expression vectors coding for mutant or wild-type HERG or KvLQT1. Transiently expressed pore mutant or wild-type KvLQT1 downregulated IKr in HERG stable CHO cell lines by 70% and 44%, respectively. Immunostaining revealed a severalfold lower surface expression of HERG, which could account for the reduction in IKr upon KvLQT1 expression. Deletion of the KvLQT1 NH2-terminus did not abolish the downregulation, suggesting that the interactions between the two channels are mediated through their COOH-termini. Similarly, transiently expressed HERG reduced IKs in KvLQT1-minK stable cells. Coimmunoprecipitations indicated a direct interaction between HERG and KvLQT1, and surface plasmon resonance analysis demonstrated a specific, physical association between the COOH-termini of KvLQT1 and HERG. Here, we present an in vitro model system consistent with the in vivo reciprocal downregulation of repolarizing currents seen in transgenic rabbit models, illustrating the importance of the transfection method when studying heterologous ion channel expression and trafficking. Moreover, our data suggest that interactions between KvLQT1 and HERG are mediated through COOH-termini. PMID:20833965
Splawski, I; Shen, J; Timothy, K W; Lehmann, M H; Priori, S; Robinson, J L; Moss, A J; Schwartz, P J; Towbin, J A; Vincent, G M; Keating, M T
...: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion...
Full Text Available The KCNE1 gene product (minK protein associates with the cardiac KvLQT1 potassium channel (encoded by KCNQ1 to create the cardiac slowly activating delayed rectifier, I(Ks. Mutations throughout both genes are linked to the hereditary cardiac arrhythmias in the Long QT Syndrome (LQTS. KCNE1 exerts its specific regulation of KCNQ1 activation via interactions between membrane-spanning segments of the two proteins. Less detailed attention has been focused on the role of the KCNE1 C-terminus in regulating channel behavior. We analyzed the effects of an LQT5 point mutation (D76N and the truncation of the entire C-terminus (Delta70 on channel regulation, assembly and interaction. Both mutations significantly shifted voltage dependence of activation in the depolarizing direction and decreased I(Ks current density. They also accelerated rates of channel deactivation but notably, did not affect activation kinetics. Truncation of the C-terminus reduced the apparent affinity of KCNE1 for KCNQ1, resulting in impaired channel formation and presentation of KCNQ1/KCNE1 complexes to the surface. Complete saturation of KCNQ1 channels with KCNE1-Delta70 could be achieved by relative over-expression of the KCNE subunit. Rate-dependent facilitation of K(+ conductance, a key property of I(Ks that enables action potential shortening at higher heart rates, was defective for both KCNE1 C-terminal mutations, and may contribute to the clinical phenotype of arrhythmias triggered by heart rate elevations during exercise in LQTS mutations. These results support several roles for KCNE1 C-terminus interaction with KCNQ1: regulation of channel assembly, open-state destabilization, and kinetics of channel deactivation.
Full Text Available BACKGROUND: KCNQ1 (potassium voltage-gated channel KQT-like sub-family, member 1 encodes a pore-forming subunit of a voltage-gated K(+ channel (KvLQT1 that plays a key role for the repolarization of the cardiac action potential as well as water and salt transport in epithelial tissues. Recently, genome-wide association studies have identified KCNQ1 as a type 2 diabetes (T2D susceptibility gene in populations of Asian descent. After that, a number of studies reported that the rs2237892 and rs2237895 polymorphism in KCNQ1 has been implicated in T2D risk. However, studies on the association between these polymorphism and T2D remain conflicting. To investigate this inconsistency, we performed this meta-analysis. METHODS: Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI were searched to find relevant studies. Odds ratios (ORs with 95% confidence intervals (CIs were used to assess the strength of association. Potential sources of heterogeneity were also assessed by subgroup analysis and meta-regression. RESULTS: A total of 25 articles involving 70,577 T2D cases and 99,068 controls were included. Overall, the summary odds ratio of C allele for T2D was 1.32 (95% CI 1.26-1.38; P<10-5 and 1.24 (95% CI: 1.20-1.29; P<10-5 for KCNQ1 rs2237892 and rs2237895 polymorphisms, respectively. Significant results were also observed using co-dominant, dominant and recessive genetic models. After stratifying by ethnicity, sample size, and diagnostic criteria, significant associations were also obtained. CONCLUSIONS: This meta-analysis suggests that the rs2237892 and rs2237895 polymorphisms in KCNQ1 are associated with elevated type 2 diabetes susceptibility.
Pan, Q; Sang, Y; Sun, C; Li, G; Wang, Y
KCNQ1 (KvLQT1) is the pore-forming a-subunit of the potassium channel. To uncover its role in electrolyte metabolism, we investigated the effects of KCNQ1 A340E, a loss-of-function mutant, on J343 mice. Compared with the normal controls (C57BL/6J mice) bearing the wild-type KCNQ1 gene, J343 mice bearing KCNQ1 A340E demonstrated a much higher 24-h intake of electrolytes (potassium, sodium, and chloride). However, they suffered from significant electrolyte loss through both the feces and urine during a period of 24 h. Unbalance in electrolyte metabolism disrupted the electrolyte homeostasis in the J343 mice, which was characterized by the comparatively lower level of serum potassium (J343 vs C57BL/6J: 12.06 ± 1.47 vs 14.44 ± 3.58 mM, P = 0.01) and higher levels of serum sodium (J343 vs C57BL/6J: 148.05 ± 4.47 vs 115.15 ± 17.25 mM, P = 4.20 x 10(-4)) and chloride (J343 vs C57BL/6J: 118.0 ± 4.47 vs 85.21 ± 11.90 mM, P = 2.47 x 10(-5)). Between the J343 and C57BL/6J mice, there was no statistically significant difference in KCNQ1 expression in the gastrointestinal tract and kidney. Normal concentrations of plasma renin, angiotensin I, and aldosterone were also detected in both lines of mice. KCNQ1, therefore, is suggested to play a central role in electrolyte metabolism. KCNQ1 A340E, with the loss-of-function phenotype, may dysregulate electrolyte homeostasis in mice independently of the activity of the renin-angiotensin-aldosterone system.
Nishino, Atsuo; Okamura, Yasushi; Kubo, Yoshihiro
KCNQ1 channels are voltage-gated potassium channels that are widely expressed in various non-neuronal tissues, such as the heart, pancreas, and intestine. KCNE proteins are known as the auxiliary subunits for KCNQ1 channels. The effects and functions of the different KCNE proteins on KCNQ1 modulation are various; the KCNQ1–KCNE1 ion channel complex produces a slowly activating potassium channel that is crucial for heartbeat regulation, while the KCNE3 protein makes KCNQ1 channels constitutively active, which is important for K+ and Cl− transport in the intestine. The mechanisms by which KCNE proteins modulate KCNQ1 channels have long been studied and discussed; however, it is not well understood how different KCNE proteins exert considerably different effects on KCNQ1 channels. Here, we approached this point by taking advantage of the recently isolated Ci-KCNQ1, a KCNQ1 homologue from marine invertebrate Ciona intestinalis. We found that Ci-KCNQ1 alone could be expressed in Xenopus laevis oocytes and produced a voltage-dependent potassium current, but that Ci-KCNQ1 was not properly modulated by KCNE1 and totally unaffected by coexpression of KCNE3. By making chimeras of Ci-KCNQ1 and human KCNQ1, we determined several amino acid residues located in the pore region of human KCNQ1 involved in KCNE1 modulation. Interestingly, though, these amino acid residues of the pore region are not important for KCNE3 modulation, and we subsequently found that the S1 segment plays an important role in making KCNQ1 channels constitutively active by KCNE3. Our findings indicate that different KCNE proteins use different domains of KCNQ1 channels, and that may explain why different KCNE proteins give quite different outcomes by forming a complex with KCNQ1 channels. PMID:22042987
Peng, Dungeng; Kim, Ji-Hun; Kroncke, Brett M; Law, Cheryl L; Xia, Yan; Droege, Kristin D; Van Horn, Wade D; Vanoye, Carlos G; Sanders, Charles R
KCNQ1 (also known as KV7.1 or KVLQT1) is a voltage-gated potassium channel modulated by members of the KCNE protein family. Among multiple functions, KCNQ1 plays a critical role in the cardiac action potential. This channel is also subject to inherited mutations that cause certain cardiac arrhythmias and deafness. In this study, we report the overexpression, purification, and preliminary structural characterization of the voltage-sensor domain (VSD) of human KCNQ1 (Q1-VSD). Q1-VSD was expressed in Escherichia coli and purified into lyso-palmitoylphosphatidylglycerol micelles, conditions under which this tetraspan membrane protein yields excellent nuclear magnetic resonance (NMR) spectra. NMR studies reveal that Q1-VSD shares a common overall topology with other channel VSDs, with an S0 helix followed by transmembrane helices S1-S4. The exact sequential locations of the helical spans do, however, show significant variations from those of the homologous segments of previously characterized VSDs. The S4 segment of Q1-VSD was seen to be α-helical (with no 310 component) and underwent rapid backbone amide H-D exchange over most of its length. These results lay the foundation for more advanced structural studies and can be used to generate testable hypotheses for future structure-function experiments.
Nakajo, Koichi; Nishino, Atsuo; Okamura, Yasushi; Kubo, Yoshihiro
KCNQ1 channels are voltage-gated potassium channels that are widely expressed in various non-neuronal tissues, such as the heart, pancreas, and intestine. KCNE proteins are known as the auxiliary subunits for KCNQ1 channels. The effects and functions of the different KCNE proteins on KCNQ1 modulation are various; the KCNQ1–KCNE1 ion channel complex produces a slowly activating potassium channel that is crucial for heartbeat regulation, while the KCNE3 protein makes KCNQ1 channels constitutive...
Geoffrey W. Abbott
Full Text Available Ion channels are essential for basic cellular function and for processes including sensory perception and intercellular communication in multicellular organisms. Voltage-gated potassium (Kv channels facilitate dynamic cellular repolarization during an action potential, opening in response to membrane depolarization to facilitate K+ efflux. In both excitable and nonexcitable cells other, constitutively active, K+ channels provide a relatively constant repolarizing force to control membrane potential, ion homeostasis, and secretory processes. Of the forty known human Kv channel pore-forming α subunits that coassemble in various combinations to form the fundamental tetrameric channel pore and voltage sensor module, KCNQ1 is unique. KCNQ1 stands alone in having the capacity to form either channels that are voltage-dependent and require membrane depolarization for activation, or constitutively active channels. In mammals, KCNQ1 regulates processes including gastric acid secretion, thyroid hormone biosynthesis, salt and glucose homeostasis, and cell volume and in some species is required for rhythmic beating of the heart. In this review, the author discusses the unique functional properties, regulation, cell biology, diverse physiological roles, and involvement in human disease states of this chameleonic K+ channel.
Almilaji, Ahmad; Pakladok, Tatsiana; Muñoz, Carlos; Elvira, Bernat; Sopjani, Mentor; Lang, Florian
Klotho is a transmembrane protein expressed primarily in kidney, parathyroid gland, and choroid plexus. The extracellular domain could be cleaved off and released into the systemic circulation. Klotho is in part effective as β-glucuronidase regulating protein stability in the cell membrane. Klotho is a major determinant of aging and life span.Overexpression of Klotho increases and Klotho deficiency decreases life span. Klotho deficiency may further result in hearing loss and cardiac arrhythmia. The present study explored whether Klotho modifies activity and protein abundance of KCNQ1/KCNE1, a K(+) channel required for proper hearing and cardiac repolarization. To this end, cRNA encoding KCNQ1/KCNE1 was injected in Xenopus oocytes with or without additional injection of cRNA encoding Klotho. KCNQ1/KCNE1 expressing oocytes were treated with human recombinant Klotho protein (30 ng/mL) for 24 h. Moreover, oocytes which express both KCNQ1/KCNE1 and Klotho were treated with 10 μM DSA L (D-saccharic acid-1,4-lactone), a β-glucuronidase inhibitor. The KCNQ1/KCNE1 depolarization-induced current (I(Ks)) was determined utilizing dual electrode voltage clamp, while KCNQ1/KCNE1 protein abundance in the cell membrane was visualized utilizing specific antibody binding and quantified by chemiluminescence. KCNQ1/KCNE1 channel activity and KCNQ1/KCNE1 protein abundance were upregulated by coexpression of Klotho. The effect was mimicked by treatment with human recombinant Klotho protein (30 ng/mL) and inhibited by DSA L (10 μM). In conclusion, Klotho upregulates KCNQ1/KCNE1 channel activity by “mainly” enhancing channel protein abundance in the plasma cell membrane, an effect at least partially mediated through the β-glucuronidase activity of Klotho protein.
Grunnet, Morten; Jespersen, Thomas; MacAulay, Nanna
Many important physiological processes involve changes in cell volume, e.g. the transport of salt and water in epithelial cells and the contraction of cardiomyocytes. In this study, we show that voltage-gated KCNQ1 channels, which are strongly expressed in epithelial cells or cardiomyocytes......, and KCNQ4 channels, expressed in hair cells and the auditory tract, are tightly regulated by small cell volume changes when co-expressed with aquaporin 1 water-channels (AQP1) in Xenopus oocytes. The KCNQ1 and KCNQ4 current amplitudes precisely reflect the volume of the oocytes. By contrast, the related...... KCNQ2 and KCNQ3 channels, which are prominently expressed in neurons, are insensitive to cell volume changes. The sensitivity of the KCNQ1 and KCNQ4 channels to cell volume changes is independent of the presence of the auxiliary KCNE1-3 subunits, although modulated by KCNE1 in the case of KCNQ1...
Sameera F. Qureshi
Results and Conclusion: It is thus predicted that the variations may lead to a change in the position of the splicing enhancer/inhibitor in KCNQ1 leading to the formation of a truncated S2–S3 fragment of KCNQ1 transmembrane protein in cardiac cells as well as epithelial cells of inner ear leading to deafness and aberrant repolarization causing prolonged QTc.
Fröhlich, Henning; Boini, Krishna M.; Seebohm, Guiscard; Strutz-Seebohm, Nathalie; Ureche, Oana N.; Föller, Michael; Eichenmüller, Melanie; Shumilina, Ekaterina; Pathare, Ganesh; Singh, Anurag Kumar; Seidler, Ursula; Pfeifer, Karl E.; Lang, Florian
Thyroid hormones T3/T4 participate in the fine tuning of development and performance. The formation of thyroid hormones requires the accumulation of I− by the electrogenic Na+/I− symporter, which depends on the electrochemical gradient across the cell membrane and thus on K+ channel activity. The present paper explored whether Kcnq1, a widely expressed voltage-gated K+ channel, participates in the regulation of thyroid function. To this end, Kcnq1 expression was determined by RT-PCR, confocal...
Torekov, Signe S; Iepsen, Eva; Christiansen, Michael
Patients with loss-of-function mutations in KCNQ1 have KCNQ1 long QT syndrome (LQTS). KCNQ1 encodes a voltage-gated K+ channel located in both cardiomyocytes and pancreatic b-cells. Inhibition of KCNQ1 in b-cells increases insulin secretion. Therefore KCNQ1 LQTS patients may exhibit increased...... insulin secretion. Fourteen patients, from six families, diagnosed with KCNQ1 LQTS were individually matched to two randomly chosen BMI-, age-, and sex-matched control participants and underwent an oral glucose tolerance test (OGTT), a hypoglycemia questionnaire, and continuous glucose monitoring. KCNQ1...... min (KCNQ1 LQTS, caused by mutations in KCNQ1, includes, besides long QT, hyperinsulinemia, clinically relevant symptomatic reactive hypoglycemia, and low potassium after an oral glucose challenge, suggesting that KCNQ1...
Tiron, Coloma; de Llano, Coloma Tiron; Campuzano, Oscar; Pérez-Serra, Alexandra; Mademont, Irene; Coll, Monica; Allegue, Catarina; Iglesias, Anna; Partemi, Sara; Striano, Pasquale; Oliva, Antonio; Brugada, Ramon
Ion channels are expressed both in the heart and in the brain, being advocated as responsible for sudden unexpected death in epilepsy but few pathogenic mutations have been identified. We aim to identify a novel gen associated with channelopathies and epilepsy in a family. We assessed a family showing epilepsy concomitant with LQTS. Index case showed prolonged QT interval. His father suffers of LQT and epilepsy. We performed a direct sequencing analysis of KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A genes. We identified a non-synonymous heterozygous missense pathogenic mutation (p.L273F) in exon 6 of the KCNQ1 gene. All clinically affected relatives carried the same mutation. We report, for a first time, a KCNQ1 mutation in a family suffering of both phenotypes, suggesting that KCNQ1 genetic variations may confer susceptibility for recurrent seizure activity increasing the risk or lead to sudden death. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Agsten, Marianne; Hessler, Sabine; Lehnert, Sandra; Volk, Tilmann; Rittger, Andrea; Hartmann, Stephanie; Raab, Christian; Kim, Doo Yeon; Groemer, Teja W; Schwake, Michael; Alzheimer, Christian; Huth, Tobias
KCNQ1 (Kv7.1) proteins form a homotetrameric channel, which produces a voltage-dependent K(+) current. Co-assembly of KCNQ1 with the auxiliary β-subunit KCNE1 strongly up-regulates this current. In cardiac myocytes, KCNQ1/E1 complexes are thought to give rise to the delayed rectifier current IKs, which contributes to cardiac action potential repolarization. We report here that the type I membrane protein BACE1 (β-site APP-cleaving enzyme 1), which is best known for its detrimental role in Alzheimer's disease, but is also, as reported here, present in cardiac myocytes, serves as a novel interaction partner of KCNQ1. Using HEK293T cells as heterologous expression system to study the electrophysiological effects of BACE1 and KCNE1 on KCNQ1 in different combinations, our main findings were the following: (1) BACE1 slowed the inactivation of KCNQ1 current producing an increased initial response to depolarizing voltage steps. (2) Activation kinetics of KCNQ1/E1 currents were significantly slowed in the presence of co-expressed BACE1. (3) BACE1 impaired reconstituted cardiac IKs when cardiac action potentials were used as voltage commands, but interestingly augmented the IKs of ATP-deprived cells, suggesting that the effect of BACE1 depends on the metabolic state of the cell. (4) The electrophysiological effects of BACE1 on KCNQ1 reported here were independent of its enzymatic activity, as they were preserved when the proteolytically inactive variant BACE1 D289N was co-transfected in lieu of BACE1 or when BACE1-expressing cells were treated with the BACE1-inhibiting compound C3. (5) Co-immunoprecipitation and fluorescence recovery after photobleaching (FRAP) supported our hypothesis that BACE1 modifies the biophysical properties of IKs by physically interacting with KCNQ1 in a β-subunit-like fashion. Strongly underscoring the functional significance of this interaction, we detected BACE1 in human iPSC-derived cardiomyocytes and murine cardiac tissue and observed
volume alterations is not yet fully understood. The KCNQ1 channel belonging to the voltage gated KCNQ family is considered a precise sensor of volume changes. The goal of this thesis was to elucidate the mechanism that induces cell volume sensitivity. Until now, a number of investigators have implicitly......) osmotic cell swelling and (2) local membrane stretch on the highly volume sensitive KCNQ1 channel and the highly stretch sensitive BK channel. In this study we present evidence against this assumption by showing that activation of BK channels by local membrane stretch is not mimicked by cell swelling......, and activation of KCNQ1 channels by cell volume increase is not mimicked by stretch of the cell membrane. Thus, we conclude that stretch- and volume-sensitivity can be considered two independent regulatory mechanisms. Alternatively, volume-activation of ion channels could be mediated by an autocrine mechanism...
Zhang, He; Zeitz, Michael J.; Wang, Hong; Niu, Beibei; Ge, Shengfang; Li, Wei; Cui, Jiuwei; Wang, Guanjun; Qian, Guanxiang; Higgins, Michael J.
Kcnq1ot1 is a long noncoding ribonucleic acid (RNA; lncRNA) that participates in the regulation of genes within the Kcnq1 imprinting domain. Using a novel RNA-guided chromatin conformation capture method, we demonstrate that the 5′ region of Kcnq1ot1 RNA orchestrates a long-range intrachromosomal loop between KvDMR1 and the Kcnq1 promoter that is required for maintenance of imprinting. PRC2 (polycomb repressive complex 2), which participates in the allelic repression of Kcnq1, is also recruited by Kcnq1ot1 RNA via EZH2. Targeted suppression of Kcnq1ot1 lncRNA prevents the creation of this long-range intrachromosomal loop and causes loss of Kcnq1 imprinting. These observations delineate a novel mechanism by which an lncRNA directly builds an intrachromosomal interaction complex to establish allele-specific transcriptional gene silencing over a large chromosomal domain. PMID:24395636
Grunnet, Morten; Jespersen, Thomas; Rasmussen, Hanne Borger
subunit to KCNQ1 channels. Co-expression of KCNQ1 and KCNE4 in Xenopus oocytes completely inhibited the KCNQ1 current. This was reproduced in mammalian CHO-K1 cells. Experiments with delayed expression of mRNA coding for KCNE4 in KCNQ1-expressing oocytes suggested that KCNE4 exerts its effect on KCNQ1...... channels already expressed in the plasma membrane. This notion was supported by immunocytochemical studies and Western blotting, showing no significant difference in plasma membrane expression of KCNQ1 channels in the presence or absence of KCNE4. The impact of KCNE4 on KCNQ1 was specific since no effect...... of KCNE4 could be detected if co-expressed with KCNQ2-5 channels or hERG1 channels. RT-PCR studies revealed high KCNE4 expression in embryos and adult uterus, where significant expression of KCNQ1 channels has also been demonstrated....
Gating of voltage-dependent cation channels involves three general molecular processes: voltage sensor activation, sensor-pore coupling, and pore opening. KCNQ1 is a voltage-gated potassium (Kv) channel whose distinctive properties have provided novel insights on fundamental principles of voltage-dependent gating. 1) Similar to other Kv channels, KCNQ1 voltage sensor activation undergoes two resolvable steps; but, unique to KCNQ1, the pore opens at both the intermediate and activated state of voltage sensor activation. The voltage sensor-pore coupling differs in the intermediate-open and the activated-open states, resulting in changes of open pore properties during voltage sensor activation. 2) The voltage sensor-pore coupling and pore opening require the membrane lipid PIP2 and intracellular ATP, respectively, as cofactors, thus voltage-dependent gating is dependent on multiple stimuli, including the binding of intracellular signaling molecules. These mechanisms underlie the extraordinary KCNE1 subunit modification of the KCNQ1 channel and have significant physiological implications. PMID:26745405
Korostowski, Lisa; Sedlak, Natalie; Engel, Nora
Although many of the questions raised by the discovery of imprinting have been answered, we have not yet accounted for tissue- or stage-specific imprinting. The Kcnq1 imprinted domain exhibits complex tissue-specific expression patterns co-existing with a domain-wide cis-acting control element. Transcription of the paternally expressed antisense non-coding RNA Kcnq1ot1 silences some neighboring genes in the embryo, while others are unaffected. Kcnq1 is imprinted in early cardiac development but becomes biallelic after midgestation. To explore this phenomenon and the role of Kcnq1ot1, we used allele-specific assays and chromosome conformational studies in wild-type mice and mice with a premature termination mutation for Kcnq1ot1. We show that Kcnq1 imprinting in early heart is established and maintained independently of Kcnq1ot1 expression, thus excluding a role for Kcnq1ot1 in repressing Kcnq1, even while silencing other genes in the domain. The exact timing of the mono- to biallelic transition is strain-dependent, with the CAST/EiJ allele becoming activated earlier and acquiring higher levels than the C57BL/6J allele. Unexpectedly, Kcnq1ot1 itself also switches to biallelic expression specifically in the heart, suggesting that tissue-specific loss of imprinting may be common during embryogenesis. The maternal Kcnq1ot1 transcript is shorter than the paternal ncRNA, and its activation depends on an alternative transcriptional start site that bypasses the maternally methylated promoter. Production of Kcnq1ot1 on the maternal chromosome does not silence Cdkn1c. We find that in later developmental stages, however, Kcnq1ot1 has a role in modulating Kcnq1 levels, since its absence leads to overexpression of Kcnq1, an event accompanied by an aberrant three-dimensional structure of the chromatin. Thus, our studies reveal regulatory mechanisms within the Kcnq1 imprinted domain that operate exclusively in the heart on Kcnq1, a gene crucial for heart development and function
Angelo, Kamilla; Jespersen, Thomas; Grunnet, Morten; Nielsen, Morten Schak; Klaerke, Dan A.; Olesen, Søren-Peter
The function of the KCNE5 (KCNE1-like) protein has not previously been described. Here we show that KCNE5 induces both a time- and voltage-dependent modulation of the KCNQ1 current. Interaction of the KCNQ1 channel with KCNE5 shifted the voltage activation curve of KCNQ1 by more than 140 mV in the positive direction. The activation threshold of the KCNQ1+KCNE5 complex was +40 mV and the midpoint of activation was +116 mV. The KCNQ1+KCNE5 current activated slowly and deactivated rapidly as com...
Poulsen, Asser Nyander; Klærke, Dan Arne
The KCNE1 beta-subunit is a modulatory one-trans-membrane segment accessory protein that alters KCNQ1 K(+) channel current characteristics, though it is not required for channel expression. The KCNE1 and KCNQ1 interaction was investigated by looking for effects of expression time on channel...... currents in Xenopus laevis oocytes. We found that long-time expression of KCNQ1+KCNE1 (2-14 days) resulted in gradual changes in current characteristics resembling a disappearance of KCNE1 from the oocyte plasma membrane. Towards the end of the expression period the current of oocytes expressing KCNQ1+KCNE......1 was indistinguishable from those expressing KCNQ1 alone. No time dependent effect was seen in oocytes expressing KCNQ1 alone or a concatamer of KCNQ1 and KCNE1. Brefeldin A was tested, showing that measured current was independent of exocytosis (decreased capacitance) thus eliminating a continuous...
Hayashi, Kenshi; Shuai, Wen; Sakamoto, Yuichiro; Higashida, Haruhiro; Yamagishi, Masakazu; Kupershmidt, Sabina
Background Mutations in the KCNQ1 and HERG genes cause the Long QT Syndromes, LQTS1 and LQTS2, due to reductions in the cardiac repolarizing IKs and IKr currents, respectively. It was previously reported that KCNQ1 co-expression modulates HERG function by enhancing membrane expression of HERG, and that the two proteins co-immunoprecipitate, and co-localize in myocytes. In vivo studies in genetically modified rabbits also support a HERG-KCNQ1 interaction. Objective We sought to determine whether KCNQ1 influences the current characteristics of HERG genetic variants. Methods Expression of HERG and KCNQ1 wild type (WT) and mutant channels in heterologous systems, combined with whole cell patch clamp analysis and biochemistry. Results Supporting the notion that KCNQ1 needs to be trafficking competent to influence HERG function, we found that although the tail current density of HERG expressed in CHO cells was approximately doubled by WT KCNQ1 co-expression, it was not altered in the presence of the trafficking-defective KCNQ1T587M variant. Activation and deactivation kinetics of HERG variants were not altered. The HERGM124T variant, previously shown to be mildly impaired functionally, was restored to WT levels by KCNQ1-WT but not KCNQ1T587M co-expression. The tail current densities of the severely trafficking-impaired HERGG601S and HERGF805C variants were only slightly improved by KCNQ1 co-expression. The trafficking competent, but incompletely processed HERGN598Q, and a mutation in the selectivity filter, HERGG628S, were not improved by KCNQ1 co-expression. Conclusions These findings suggest a functional co-dependence of HERG on KCNQ1 during channel biogenesis. Moreover, KCNQ1 variably modulates LQTS2 mutations with distinct underlying pathologies. PMID:20348026
Torekov, Signe S; Iepsen, Eva; Christiansen, Michael; Linneberg, Allan; Pedersen, Oluf; Holst, Jens J; Kanters, Jørgen K; Hansen, Torben
Patients with loss-of-function mutations in KCNQ1 have KCNQ1 long QT syndrome (LQTS). KCNQ1 encodes a voltage-gated K(+) channel located in both cardiomyocytes and pancreatic β-cells. Inhibition of KCNQ1 in β-cells increases insulin secretion. Therefore KCNQ1 LQTS patients may exhibit increased insulin secretion. Fourteen patients, from six families, diagnosed with KCNQ1 LQTS were individually matched to two randomly chosen BMI-, age-, and sex-matched control participants and underwent an oral glucose tolerance test (OGTT), a hypoglycemia questionnaire, and continuous glucose monitoring. KCNQ1 mutation carriers showed increased insulin release (area under the curve 45.6 ± 6.3 vs. 26.0 ± 2.8 min ⋅ nmol/L insulin) and β-cell glucose sensitivity and had lower levels of plasma glucose and serum potassium upon oral glucose stimulation and increased hypoglycemic symptoms. Prolonged OGTT in four available patients and matched control subjects revealed hypoglycemia in carriers after 210 min (range 1.4-3.6 vs. 4.1-5.3 mmol/L glucose), and 24-h glucose profiles showed that the patients spent 77 ± 18 min per 24 h in hypoglycemic states (KCNQ1 LQTS, caused by mutations in KCNQ1, includes, besides long QT, hyperinsulinemia, clinically relevant symptomatic reactive hypoglycemia, and low potassium after an oral glucose challenge, suggesting that KCNQ1 mutations may explain some cases of "essential" reactive hypoglycemia.
Li, Pan; Liu, Haowen; Lai, Chaohua; Sun, Peibei; Zeng, Wenping; Wu, Fangming; Zhang, Longhua; Wang, Sheng; Tian, Changlin; Ding, Jiuping
KCNQ1 channels play vital roles in cardiovascular, gastric and other systems. The conductance and dynamics of KCNQ1 could be modulated by different single transmembrane helical auxiliary proteins (such as KCNE1, KCNE2 and others). In this study, detail KCNQ1 function modulations by different regions of KCNE1 or KCNE2 were examined using combinational methods of electrophysiology, immunofluorescence, solution NMR and related backbone flexibility analysis. In the presence of KCNE2 N-terminus, decreased surface expression and consequent low activities of KCNQ1 were observed. The transmembrane domains (TMDs) of KCNE1 and KCNE2 were illustrated to associate with the KCNQ1 channel in different modes: Ile64 in KCNE2-TMD interacting with Phe340 and Phe275 in KCNQ1, while two pairs of interacting residues (Phe340-Thr58 and Ala244-Tyr65) in the KCNQ1/KCNE1 complex. The KCNE1 C-terminus could modulate gating property of KCNQ1, whereas KCNE2 C-terminus had only minimal influences on KCNQ1. All of the results demonstrated different KCNQ1 function modulations by different regions of the two auxiliary proteins.
Tommiska, Johanna; Känsäkoski, Johanna; Skibsbye, Lasse
unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β......-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency...... associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations....
Jespersen, Thomas; Grunnet, Morten; Rasmussen, Hanne B
. To study a potential regulatory effect of the CHIF subunit on KCNQ1 channels, co-expression experiments were performed in Xenopus laevis oocytes and mammalian CHO-K1 cells. Electrophysiological characterization was obtained by two-electrode voltage-clamp and patch-clamp, respectively. In both expression...... systems, we find that CHIF drastically modulates the KCNQ1 current; in the presence of CHIF, the KCNQ1 channels open at all membrane potentials. Thereby, CHIF is the first accessory subunit shown to be capable of modulating both the Na,K-pump and an ion channel. To find a possible physiological function...... of the constitutively open KCNQ1/CHIF complex, the precise localization of KCNQ1 and CHIF in distal colon and kidney from control and salt-depleted rats was determined by confocal microscopy. However, in these tissues, we did not detect an obvious overlap in expression between KCNQ1 and CHIF. In conclusion, the hormone...
Rapetti-Mauss, Raphael; Bustos, Viviana; Thomas, Warren; McBryan, Jean; Harvey, Harry; Lajczak, Natalia; Madden, Stephen F; Pellissier, Bernard; Borgese, Franck; Soriani, Olivier; Harvey, Brian J
The K + channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:β-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/β-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by β-catenin:T-cell factor (TCF)-4. In well-differentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with β-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of β-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped β-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of β-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/β-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.
Li, Jin; Maguy, Ange; Duverger, James Elber; Vigneault, Patrick; Comtois, Philippe; Shi, Yanfen; Tardif, Jean-Claude; Thomas, Dierk; Nattel, Stanley
Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, autoantibodies targeting the cardiac voltage-gated KCNQ1 K(+) channel were associated with shortened corrected QT intervals (QTc). However, the electrophysiologic actions of KCNQ1 autoimmunity have not been assessed experimentally in a direct fashion. The purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model. Rabbits were immunized with KCNQ1 channel peptide. ECG recordings were obtained during a 1-month follow-up period. Rabbits then underwent in vivo electrophysiologic study, after which cardiomyocytes were isolated for analysis of slow delayed rectifier current (IKs) and action potential properties via patch-clamp. KCNQ1-immunized rabbits exhibited shortening of QTc compared to sham-immunized controls. Reduced ventricular effective refractory periods and increased susceptibility to ventricular tachyarrhythmia induction were noted in KCNQ1-immunized rabbits upon programmed ventricular stimulation. Action potential durations were shortened in cardiomyocytes isolated from KCNQ1-immunized rabbits compared to the sham group. IKs step and tail current densities were enhanced after KCNQ1 immunization. Functional and structural changes of the heart were not observed. The potential therapeutic significance of KCNQ1 immunization was then explored in a dofetilide-induced long QT rabbit model. KCNQ1 immunization prevented dofetilide-induced QTc prolongation and attenuated long QT-related arrhythmias. Induction of KCNQ1 autoimmunity accelerates cardiac repolarization and increases susceptibility to ventricular tachyarrhythmia induction through IKs enhancement. On the other hand, vaccination against KCNQ1 ameliorates drug-induced QTc prolongation and might be useful therapeutically to
Naohiro Sunamura; Takahito Ohira; Miki Kataoka; Daigo Inaoka; Hideyuki Tanabe; Yuji Nakayama; Mitsuo Oshimura; Hiroyuki Kugoh
Long noncoding RNAs (lncRNAs) have been implicated in many biological processes through epigenetic mechanisms. We previously reported that KCNQ1OT1, an imprinted antisense lncRNA in the human KCNQ1 locus on chromosome 11p15.5, is involved in cis-limited silencing within an imprinted KCNQ1 cluster. Furthermore, aberration of KCNQ1OT1 transcription was observed with a high frequency in colorectal cancers. However, the molecular mechanism of the transcriptional regulation and the functional role...
Wang, Yuhong; Zhang, Mei; Xu, Yu; Jiang, Min; Zankov, Dimitar P.; Cui, Meng
KCNE1 associates with KCNQ1 to increase its current amplitude and slow the activation gating process, creating the slow delayed rectifier channel that functions as a “repolarization reserve” in human heart. The transmembrane domain (TMD) of KCNE1 plays a key role in modulating KCNQ1 pore conductance and gating kinetics, and the extracellular juxtamembrane (EJM) region plays a modulatory role by interacting with the extracellular surface of KCNQ1. KCNE2 is also expressed in human heart and can associate with KCNQ1 to suppress its current amplitude and slow the deactivation gating process. KCNE1 and KCNE2 share the transmembrane topology and a high degree of sequence homology in TMD and surrounding regions. The structural basis for their distinctly different effects on KCNQ1 is not clear. To address this question, we apply cysteine (Cys) scanning mutagenesis to TMDs and EJMs of KCNE1 and KCNE2. We analyze the patterns of functional perturbation to identify high impact positions, and probe disulfide formation between engineered Cys side chains on KCNE subunits and native Cys on KCNQ1. We also use methanethiosulfonate reagents to probe the relationship between EJMs of KCNE subunits and KCNQ1. Our data suggest that the TMDs of both KCNE subunits are at about the same location but interact differently with KCNQ1. In particular, the much closer contact of KCNE2 TMD with KCNQ1, relative to that of KCNE1, is expected to impact the allosteric modulation of KCNQ1 pore conductance and may explain their differential effects on the KCNQ1 current amplitude. KCNE1 and KCNE2 also differ in the relationship between their EJMs and KCNQ1. Although the EJM of KCNE1 makes intimate contacts with KCNQ1, there appears to be a crevice between KCNQ1 and KCNE2. This putative crevice may perturb the electrical field around the voltage-sensing domain of KCNQ1, contributing to the differential effects of KCNE2 versus KCNE1 on KCNQ1 gating kinetics. PMID:23183700
Nakajo, Koichi; Kubo, Yoshihiro
The gating of the KCNQ1 potassium channel is drastically regulated by auxiliary subunit KCNE proteins. KCNE1, for example, slows the activation kinetics of KCNQ1 by two orders of magnitude. Like other voltage-gated ion channels, the opening of KCNQ1 is regulated by the voltage-sensing domain (VSD; S1-S4 segments). Although it has been known that KCNE proteins interact with KCNQ1 via the pore domain, some recent reports suggest that the VSD movement may be altered by KCNE. The altered VSD movement of KCNQ1 by KCNE proteins has been examined by site-directed mutagenesis, the scanning cysteine accessibility method (SCAM), voltage clamp fluorometry (VCF) and gating charge measurements. These accumulated data support the idea that KCNE proteins interact with the VSDs of KCNQ1 and modulate the gating of the KCNQ1 channel. In this review, we will summarize recent findings and current views of the KCNQ1 modulation by KCNE via the VSD. In this context, we discuss our recent findings that KCNE1 may alter physical interactions between the S4 segment (VSD) and the S5 segment (pore domain) of KCNQ1. Based on these findings from ourselves and others, we propose a hypothetical mechanism for how KCNE1 binding alters the VSD movement and the gating of the channel. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.
Boini, Krishna M.; Graf, Dirk; Hennige, Anita M.; Koka, Saisudha; Kempe, Daniela S.; Wang, Kan; Ackermann, Teresa F.; Föller, Michael; Vallon, Volker; Pfeifer, Karl; Schleicher, Erwin; Ullrich, Susanne; Häring, Hans-Ulrich; Häussinger, Dieter; Lang, Florian
The pore-forming K+-channel α-subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, liver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular K+ uptake and glucose metabolism...
Angelo, Kamilla; Jespersen, Thomas; Grunnet, Morten
The function of the KCNE5 (KCNE1-like) protein has not previously been described. Here we show that KCNE5 induces both a time- and voltage-dependent modulation of the KCNQ1 current. Interaction of the KCNQ1 channel with KCNE5 shifted the voltage activation curve of KCNQ1 by more than 140 m......V in the positive direction. The activation threshold of the KCNQ1+KCNE5 complex was +40 mV and the midpoint of activation was +116 mV. The KCNQ1+KCNE5 current activated slowly and deactivated rapidly as compared to the KCNQ1+KCNE1 at 22 degrees C; however, at physiological temperature, the activation time constant...... of the KCNQ1+KCNE5 current decreased fivefold, thus exceeding the activation rate of the KCNQ1+KCNE1 current. The KCNE5 subunit is specific for the KCNQ1 channel, as none of other members of the KCNQ-family or the human ether a-go-go related channel (hERG1) was affected by KCNE5. Four residues...
SUNAMURA, Naohiro; OHIRA, Takahito; KATAOKA, Miki; INAOKA, Daigo; TANABE, Hideyuki; NAKAYAMA, Yuji; OSHIMURA, Mitsuo; KUGOH, Hiroyuki
Long noncoding RNAs (lncRNAs) have been implicated in many biological processes through epigenetic mechanisms. We previously reported that KCNQ1OT1, an imprinted antisense lncRNA in the human KCNQ1 locus on chromosome 11p15.5, is involved in cis-limited silencing within an imprinted KCNQ1 cluster. Furthermore, aberration of KCNQ1OT1 transcription was observed with a high frequency in colorectal cancers. However, the molecular mechanism of the transcriptional regulation and the functional role...
Krzystanek, Katarzyna; Rasmussen, Hanne Borger; Grunnet, Morten
KCNQ1 (Kv7.1), together with its KCNE ß subunits, plays a pivotal role both in the repolarization of cardiac tissue and in water and salt transport across epithelial membranes. Nedd4/Nedd4-like (neuronal precursor cell-expressed developmentally downregulated 4) ubiquitin-protein ligases interact...... with the KCNQ1 potassium channel through a PY motif located in the C terminus of KCNQ1. This interaction induces ubiquitylation of KCNQ1, resulting in a reduced surface density of the channel. It was reported recently that the epithelial sodium channel is regulated by the reverse process...
Xie, Chang; Liu, Hao-wen; Pan, Na; Ding, Jiu-ping; Yao, Jing
KCNQ1 and KCNE1 form a complex in human ventricular cardiomyocytes, which are important in maintaining a normal heart rhythm. In the present study we investigated the effects of a homologous series of 1-alkanols on KCNQ1/KCNE1 channels expressed in Xenopus oocytes. ECG recording was made in rats injected with ethanol-containing solution (0.3 mL, ip). Human KCNQ1 channel and its auxiliary subunit KCNE1 were heterologously coexpressed in Xenopus oocytes, which were superfused with ND96 solution; 1-alkanols (ethanol, 1-butanol and 1-hexanol) were delivered through a gravity-driven perfusion device. The slow-delayed rectifier potassium currents IKs (KCNQ1/KCNE1 currents) were recorded using a two-electrode voltage clamp method. Site-directed mutations (I257A) were made in KCNQ1. In ECG recordings, a low concentration of ethanol (3%, v/v) slightly increased the heart rate of rats, whereas the higher concentrations of ethanol (10%, 50%, v/v) markedly reduced it. In oocytes coexpressing KCNQ1/KCNE1 channels, ethanol, 1-butanol and 1-hexanol dose-dependently inhibited IKs currents with IC50 values of 80, 11 and 2.7 mmol/L, respectively. Furthermore, the 1-alkanols blocked the KCNQ1 channel in both open and closed states, and a four-state model could adequately explain the effects of 1-alkanols on the closed-state channel block. Moreover, the mutation of I257A at the intracellular loop between S4 and S5 in KCNQ1 greatly decreased the sensitivity to 1-alkanols; and the IC50 values of ethanol, 1-butanol and 1-hexanol were increased to 634, 414 and 7.4 mmol/L, respectively. The mutation also caused the ablation of closed-state channel block. These findings provide new insight into the intricate mechanisms of the blocking effects of ethanol on the KCNQ1 channel.
Kimoto, Katsuya; Kinoshita, Koshi; Yokoyama, Tomoki; Hata, Yukiko; Komatsu, Takuto; Tsushima, Eikichi; Nishide, Kohki; Yamaguchi, Yoshiaki; Mizumaki, Koichi; Tabata, Toshihide; Inoue, Hiroshi; Nishida, Naoki; Fukurotani, Kenkichi
A mutation of KCNQ1 gene encoding the alpha subunit of the channel mediating the slow delayed rectifier K(+) current in cardiomyocytes may cause severe arrhythmic disorders. We identified KCNQ1(Y461X), a novel mutant gene encoding KCNQ1 subunit whose C-terminal domain is truncated at tyrosine 461 from a man with a mild QT interval prolongation. We made whole-cell voltage-clamp recordings from HEK-293T cells transfected with either of wild-type KCNQ1 [KCNQ1(WT)], KCNQ1(Y461X), or their mixture plus KCNE1 auxiliary subunit gene. The KCNQ1(Y461X)-transfected cells showed no delayed rectifying current. The cells transfected with both KCNQ1(WT) and KCNQ1(Y461X) showed the delayed rectifying current that is thought to be mediated largely by homomeric channel consisting of KCNQ1(WT) subunit because its voltage-dependence of activation, activation rate, and deactivation rate were similar to the current in the KCNQ1(WT)-transfected cells. The immunoblots of HEK-293T cell-derived lysates showed that KCNQ1(Y461X) subunit cannot form channel tetramers by itself or with KCNQ1(WT) subunit. Moreover, immunocytochemical analysis in HEK-293T cells showed that the surface expression level of KCNQ1(Y461X) subunit was very low with or without KCNQ1(WT) subunit. These findings suggest that the massive loss of the C-terminal domain of KCNQ1 subunit impairs the assembly, trafficking, and function of the mutant subunit-containing channels, whereas the mutant subunit does not interfere with the functional expression of the homomeric wild-type channel. Therefore, the homozygous but not heterozygous inheritance of KCNQ1(Y461X) might cause major arrhythmic disorders. This study provides a new insight into the structure-function relation of KCNQ1 channel and treatments of cardiac channelopathies. Copyright © 2013 Elsevier Inc. All rights reserved.
Than, B L N; Goos, J A C M; Sarver, A L; O'Sullivan, M G; Rod, A; Starr, T K; Fijneman, R J A; Meijer, G A; Zhao, L; Zhang, Y; Largaespada, D A; Scott, P M; Cormier, R T
Kcnq1, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer, we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wild-type littermate controls, suggesting a role for Kcnq1 in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor
Barro-Soria, Rene; Perez, Marta E; Larsson, H Peter
KCNE β-subunits assemble with and modulate the properties of voltage-gated K(+) channels. In the colon, stomach, and kidney, KCNE3 coassembles with the α-subunit KCNQ1 to form K(+) channels important for K(+) and Cl(-) secretion that appear to be voltage-independent. How KCNE3 subunits turn voltage-gated KCNQ1 channels into apparent voltage-independent KCNQ1/KCNE3 channels is not completely understood. Different mechanisms have been proposed to explain the effect of KCNE3 on KCNQ1 channels. Here, we use voltage clamp fluorometry to determine how KCNE3 affects the voltage sensor S4 and the gate of KCNQ1. We find that S4 moves in KCNQ1/KCNE3 channels, and that inward S4 movement closes the channel gate. However, KCNE3 shifts the voltage dependence of S4 movement to extreme hyperpolarized potentials, such that in the physiological voltage range, the channel is constitutively conducting. By separating S4 movement and gate opening, either by a mutation or PIP2 depletion, we show that KCNE3 directly affects the S4 movement in KCNQ1. Two negatively charged residues of KCNE3 (D54 and D55) are found essential for the effect of KCNE3 on KCNQ1 channels, mainly exerting their effects by an electrostatic interaction with R228 in S4. Our results suggest that KCNE3 primarily affects the voltage-sensing domain and only indirectly affects the gate.
Bomholtz, Sofia Hammami; Willumsen, Niels J.; Meinild, A.-K.
to ion channel stimulation and cell volume back-regulation. Our aim was to investigate whether volume sensitivity of the voltage-gated K(+) channel, KCNQ1, is dependent on ATP release and regulation by purinergic signalling. METHODS: We used Xenopus oocytes heterologously expressing human KCNQ1, KCNE1...... stimuli. Basal ATP release was approx. three times higher in the KCNQ1 + AQP1 and KCNQ1 injected oocytes compared to the non-injected ones. Exogenously added ATP (0.1 mm) did not have any substantial effect on volume-induced KCNQ1 currents. Nevertheless, apyrase decreased all currents by about 50......%. Suramin inhibited about 23% of the KCNQ1 volume sensitivity. Expression of P2Y2 receptors stimulated endogenous Cl(-) channels, but it also led to 68% inhibition of the KCNQ1 currents. Adenosine (0.1 mm) also inhibited the KCNQ1 currents by about 56%. CONCLUSION: Xenopus oocytes release ATP in response...
Barro-Soria, Rene; Rebolledo, Santiago; Liin, Sara I.; Perez, Marta E.; Sampson, Kevin J.; Kass, Robert S.; Larsson, H. Peter
The functional properties of KCNQ1 channels are highly dependent on associated KCNE-β subunits. Mutations in KCNQ1 or KCNE subunits can cause congenital channelopathies, such as deafness, cardiac arrhythmias and epilepsy. The mechanism by which KCNE1-β subunits slow the kinetics of KCNQ1 channels is a matter of current controversy. Here we show that KCNQ1/KCNE1 channel activation occurs in two steps: first, mutually independent voltage sensor movements in the four KCNQ1 subunits generate the main gating charge movement and underlie the initial delay in the activation time course of KCNQ1/KCNE1 currents. Second, a slower and concerted conformational change of all four voltage sensors and the gate, which opens the KCNQ1/KCNE1 channel. Our data show that KCNE1 divides the voltage sensor movement into two steps with widely different voltage dependences and kinetics. The two voltage sensor steps in KCNQ1/KCNE1 channels can be pharmacologically isolated and further separated by a disease-causing mutation.
Jespersen, Thomas; Membrez, Mathieu; Nicolas, Céline S
OBJECTIVE: The voltage-gated KCNQ1 potassium channel regulates key physiological functions in a number of tissues. In the heart, KCNQ1 alpha-subunits assemble with KCNE1 beta-subunits forming a channel complex constituting the delayed rectifier current I(Ks). In epithelia, KCNQ1 channels...... participate in controlling body electrolyte homeostasis. Several regulatory mechanisms of the KCNQ1 channel complexes have been reported, including protein kinase A (PKA)-phosphorylation and beta-subunit interactions. However, the mechanisms controlling the membrane density of KCNQ1 channels have attracted...... less attention. METHODS AND RESULTS: Here we demonstrate that KCNQ1 proteins expressed in HEK293 cells are down-regulated by Nedd4/Nedd4-like ubiquitin-protein ligases. KCNQ1 and KCNQ1/KCNE1 currents were reduced upon co-expression of Nedd4-2, the isoform among the nine members of the Nedd4/Nedd4-like...
Lee, Hsiang-Chun; Rudy, Yoram; Po-Yuan, Phd; Sheu, Sheng-Hsiung; Chang, Jan-Gowth; Cui, Jianmin
Slow delayed-rectifier potassium current (IKs) channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown. To study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in IKs and action potentials (APs) in ventricular myocytes. Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by using the reverse transcriptase-polymerase chain reaction and Western blot. The effect of amiloride-induced changes in the KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch clamp with and without isoproterenol. With 50 μmol/L of amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial myocytes but decreased in endo- and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for AP simulations under beta-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-electrocardiogram. Amiloride regulates IKs and APs with transmural differences and reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested that the modulation of KCNQ1 splicing may help prevent arrhythmia. Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Rapetti-Mauss, Raphael; O'Mahony, Fiona; Sepulveda, Francisco V; Urbach, Valerie; Harvey, Brian J
The cAMP-regulated potassium channel KCNQ1:KCNE3 plays an essential role in transepithelial Cl− secretion. Recycling of K+ across the basolateral membrane provides the driving force necessary to maintain apical Cl− secretion. The steroid hormone oestrogen (17β-oestradiol; E2), produces a female-specific antisecretory response in rat distal colon through the inhibition of the KCNQ1:KCNE3 channel. It has previously been shown that rapid inhibition of the channel conductance results from E2-induced uncoupling of the KCNE3 regulatory subunit from the KCNQ1 channel pore complex. The purpose of this study was to determine the mechanism required for sustained inhibition of the channel function. We found that E2 plays a role in regulation of KCNQ1 cell membrane abundance by endocytosis. Ussing chamber experiments have shown that E2 inhibits both Cl− secretion and KCNQ1 current in a colonic cell line, HT29cl.19A, when cultured as a confluent epithelium. Following E2 treatment, KCNQ1 was retrieved from the plasma membrane by a clathrin-mediated endocytosis, which involved the association between KCNQ1 and the clathrin adaptor, AP-2. Following endocytosis, KCNQ1 was accumulated in early endosomes. Following E2-induced endocytosis, rather than being degraded, KCNQ1 was recycled by a biphasic mechanism involving Rab4 and Rab11. Protein kinase Cδ and AMP-dependent kinase were rapidly phosphorylated in response to E2 on their activating phosphorylation sites, Ser643 and Thr172, respectively (as previously shown). Both kinases are necessary for the E2-induced endocytosis, because E2 failed to induce KCNQ1 internalization following pretreatment with specific inhibitors of both protein kinase Cδ and AMP-dependent kinase. The ubiquitin ligase Nedd4.2 binds KCNQ1 in response to E2 to induce channel internalization. This study has provided the first demonstration of hormonal regulation of KCNQ1 trafficking. In conclusion, we propose that internalization of KCNQ1 is a key event
Jalily Hasani, Horia; Ahmed, Marawan; Barakat, Khaled
The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (I Ks ) current in the heart, which plays an important role in heart signaling. The importance of KCNQ1/KCNE1 channel's function is further implicated by the linkage between loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1, and long QT syndromes, congenital atrial fibrillation, and short QT syndrome. Also, KCNQ1/KCNE1 channels are an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities. One solution to address and study the mentioned aspects of KCNQ1/KNCE1 channel would be the structural studies using a validated and accurate model. Along the same line in this study, we have used several top-notch modeling approaches to build a structural model for the open state of KCNQ1 protein, which is both accurate and compatible with available experimental data. Next, we included the KCNE1 protein components using data-driven protein-protein docking simulations, encompassing a 4:2 stoichiometry to complete the picture of the channel complex formed by these two proteins. All the protein systems generated through these processes were refined by long Molecular Dynamics simulations. The refined models were analyzed extensively to infer data about the interaction of KCNQ1 channel with its accessory KCNE1 beta subunits. Copyright © 2017 Elsevier Inc. All rights reserved.
Zheng, Yueming; Zhu, Xuejing; Zhou, Pingzheng; Lan, Xi; Xu, Haiyan; Li, Min; Gao, Zhaobing
The voltage-gated KCNQ1 potassium channel is expressed in cardiac tissues, and coassembly of KCNQ1 with an auxiliary KCNE1 subunit mediates a slowly activating current that accelerates the repolarization of action potential in cardiomyocytes. Mutations of KCNQ1 genes that result in reduction or loss of channel activity cause prolongation of repolarization during action potential, thereby causing long QT syndrome (LQTs). Small molecule activators of KCNQ1/KCNE1 are useful both for understanding the mechanism of the complex activity and for developing therapeutics for LQTs. In this study we report that hexachlorophene (HCP), the active component of the topical anti-infective prescription drug pHisoHex, is a KCNQ1/KCNE1 activator. HCP potently increases the current amplitude of KCNQ1/KCNE1 expressed by stabilizing the channel in an open state with an EC50 of 4.61±1.29 μM. Further studies in cardiomyocytes showed that HCP significantly shortens the action potential duration at 1 μM. In addition, HCP is capable of rescuing the loss of function of the LQTs mutants caused by either impaired activation gating or phosphatidylinositol-4,5-bisphosphate (PIP2) binding affinity. Our results indicate HCP is a novel KCNQ1/KCNE1 activator and may be a useful tool compound for the development of LQTs therapeutics. PMID:23251633
Full Text Available Background/Aims: Janus kinase 3 (JAK3, a kinase mainly expressed in hematopoietic cells, has been shown to down-regulate the Na+/K+ ATPase and participate in the regulation of several ion channels and carriers. Channels expressed in thymus and regulating the abundance of T lymphocytes include the voltage gated K+ channel KCNE1/KCNQ1. The present study explored whether JAK3 contributes to the regulation of KCNE1/KCNQ1. Methods: cRNA encoding KCNE1/KCNQ1 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type JAK3, constitutively active A568VJAK3, or inactive K851AJAK3. Voltage gated K+ channel activity was measured utilizing two electrode voltage clamp. Results: KCNE1/KCNQ1 activity was significantly increased by wild-type JAK3 and A568VJAK3, but not by K851AJAK3. The difference between oocytes expressing KCNE1/KCNQ1 alone and oocytes expressing KCNE1/KCNQ1 with A568VJAK3 was virtually abrogated by JAK3 inhibitor WHI-P154 (22 µM but not by inhibition of transcription with actinomycin D (50 nM. Inhibition of KCNE1/KCNQ1 protein insertion into the cell membrane by brefeldin A (5 µM resulted in a decline of the voltage gated current, which was similar in the absence and presence of A568VJAK3, suggesting that A568VJAK3 did not accelerate KCNE1/KCNQ1 protein retrieval from the cell membrane. Conclusion: JAK3 contributes to the regulation of membrane KCNE1/KCNQ1 activity, an effect sensitive to JAK3 inhibitor WHI-P154.
Warsi, Jamshed; Abousaab, Abeer; Fezai, Myriam; Elvira, Bernat; Lang, Florian
Janus kinase 3 (JAK3), a kinase mainly expressed in hematopoietic cells, has been shown to down-regulate the Na+/K+ ATPase and participate in the regulation of several ion channels and carriers. Channels expressed in thymus and regulating the abundance of T lymphocytes include the voltage gated K+ channel KCNE1/KCNQ1. The present study explored whether JAK3 contributes to the regulation of KCNE1/KCNQ1. cRNA encoding KCNE1/KCNQ1 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type JAK3, constitutively active A568VJAK3, or inactive K851AJAK3. Voltage gated K+ channel activity was measured utilizing two electrode voltage clamp. KCNE1/KCNQ1 activity was significantly increased by wild-type JAK3 and A568VJAK3, but not by K851AJAK3. The difference between oocytes expressing KCNE1/KCNQ1 alone and oocytes expressing KCNE1/KCNQ1 with A568VJAK3 was virtually abrogated by JAK3 inhibitor WHI-P154 (22 µM) but not by inhibition of transcription with actinomycin D (50 nM). Inhibition of KCNE1/KCNQ1 protein insertion into the cell membrane by brefeldin A (5 µM) resulted in a decline of the voltage gated current, which was similar in the absence and presence of A568VJAK3, suggesting that A568VJAK3 did not accelerate KCNE1/KCNQ1 protein retrieval from the cell membrane. JAK3 contributes to the regulation of membrane KCNE1/KCNQ1 activity, an effect sensitive to JAK3 inhibitor WHI-P154. © 2015 The Author(s) Published by S. Karger AG, Basel.
Osteen, Jeremiah D.; Barro-Soria, Rene; Robey, Seth; Sampson, Kevin J.; Kass, Robert S.; Larsson, H. Peter
KCNQ1 (Kv7.1) is a unique member of the superfamily of voltage-gated K+ channels in that it displays a remarkable range of gating behaviors tuned by coassembly with different β subunits of the KCNE family of proteins. To better understand the basis for the biophysical diversity of KCNQ1 channels, we here investigate the basis of KCNQ1 gating in the absence of β subunits using voltage-clamp fluorometry (VCF). In our previous study, we found the kinetics and voltage dependence of voltage-sensor movements are very similar to those of the channel gate, as if multiple voltage-sensor movements are not required to precede gate opening. Here, we have tested two different hypotheses to explain KCNQ1 gating: (i) KCNQ1 voltage sensors undergo a single concerted movement that leads to channel opening, or (ii) individual voltage-sensor movements lead to channel opening before all voltage sensors have moved. Here, we find that KCNQ1 voltage sensors move relatively independently, but that the channel can conduct before all voltage sensors have activated. We explore a KCNQ1 point mutation that causes some channels to transition to the open state even in the absence of voltage-sensor movement. To interpret these results, we adopt an allosteric gating scheme wherein KCNQ1 is able to transition to the open state after zero to four voltage-sensor movements. This model allows for widely varying gating behavior, depending on the relative strength of the opening transition, and suggests how KCNQ1 could be controlled by coassembly with different KCNE family members. PMID:22509038
Wu, Minghua; Obara, Yutaro; Ohshima, Shingo; Nagasawa, Yoshinobu; Ishii, Kuniaki
Diabetes mellitus affects ion channel physiology. We have previously reported that acute application of insulin suppresses the KCNQ1/KCNE1 currents that play an important role in terminating ventricular action potential. In this study, we investigated the effect of long-term insulin treatment on KCNQ1/KCNE1 currents using the Xenopus oocyte expression system. Insulin treatment with a duration longer than 6 h had an opposite effect to acute insulin application, that is, it augmented the KCNQ1/KCNE1 currents. Inhibitors of PI3K, wortmannin and LY294002, and a MEK inhibitor, U0126, abolished the potentiating effect of long-term insulin treatment. The long-term treatment with insulin had no effect on KCNQ1 currents indicating an essential role of KCNE1 in the insulin effect, which is similar to the acute insulin effect. Cycloheximide, an inhibitor of protein synthesis, and brefeldin A, an inhibitor of protein transport from endoplasmic reticulum, suppressed the long-term insulin effect. Western blotting analysis combined with these pharmacological data suggest that long-term insulin treatment augments KCNQ1/KCNE1 currents by increasing KCNE1 protein expression. Copyright © 2017 Elsevier Inc. All rights reserved.
Lundby, Alicia; Ravn, Lasse Steen; Svendsen, Jesper Hastrup
BACKGROUND: Atrial fibrillation (AF) and long QT syndrome (LQTS) are cardiac arrhythmia disorders that have been related to dysfunction of the voltage-gated potassium channel subunit Kv7.1 encoded by the KCNQ1 gene. OBJECTIVE: The purpose of this study was functional assessment of a mutation in Kv7.......1 identified in a proband with permanent AF and prolonged QT interval. We investigated whether this KCNQ1 missense mutation could form the genetic basis for AF and LQTS simultaneously in this patient. METHODS: We investigated the functional consequences of the novel mutation KCNQ1 Q147R by heterologous...
Müssig, Karsten; Staiger, Harald; Machicao, Fausto
OBJECTIVE: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered beta-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different...... and basal or stimulated incretin levels (all P > or = 0.05). CONCLUSIONS: Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems...
Campbell, Courtney M; Campbell, Jonathan D; Thompson, Christopher H; Galimberti, Eleonora Savio; Darbar, Dawood; Vanoye, Carlos G; George, Alfred L
Atrial fibrillation is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-of-function KCNQ1 mutations previously associated with familial atrial fibrillation have distinct pharmacological properties that may enable targeted inhibition. Wild-type (WT) KCNQ1 or the familial atrial fibrillation mutation KCNQ1-S140G was heterologously coexpressed with KCNE1 to enable electrophysiological recording of the slow delayed rectifier current (IKs) and investigation of pharmacological effects of the IKs selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-IKs) that exhibited greater sensitivity to HMR-1556 than WT-IKs. Enhanced HMR-1556 sensitivity was also observed for another gain-of-function atrial fibrillation mutation, KCNQ1-V141M. Heteromeric expression of KCNE1 with both KCNQ1-WT and KCNQ1-S140G generated currents (HET-IKs) with gain-of-function features, including larger amplitude, a constitutively active component, hyperpolarized voltage dependence of activation, and extremely slow deactivation. A low concentration of HMR-1556, which had little effect on WT-IKs but was capable of inhibiting the mutant channel, reduced both instantaneous and steady state HET-IKs to levels that were not significantly different from WT-IKs and attenuated use-dependent accumulation of the current. In cultured adult rabbit left atrial myocytes, expression of S140G-IKs shortened action potential duration compared with WT-IKs. Application of HMR-1556 mitigated S140G-IKs-induced action potential duration shortening and did not alter action potential duration in cells expressing WT-IKs. The enhanced sensitivity of KCNQ1 gain-of-function mutations for HMR-1556 suggests the possibility of selective therapeutic targeting, and, therefore, our data illustrate a potential proof of principle for genotype-specific treatment of this heritable arrhythmia.
Hu, Youtian; Chen, Jing; Wang, Bin; Yang, Weishan; Zhang, Chuangeng; Hu, Jun; Xie, Zili; Cao, Zhijian; Li, Wenxin; Wu, Yingliang; Chen, Zongyun
The KCNQ1/KCNE1 channel (IKs) plays important roles in the physiological and pathological process of heart, but no potent peptide acting on this channel has been reported. In this work, we found that the natural scorpion venom hardly inhibited KCNQ1/KCNE1 channel currents. Based on this observation, we attempted to use three natural scorpion toxins ChTX, BmKTX and OmTx2 with two different structural folds as templates to engineer potent peptide inhibitors towards the KCNQ1/KCNE1 channel. Pharmacological experiments showed that when we screen with 1μM MT2 peptide, an analog derived from BmKTX toxin, KCNQ1/KCNE1 channel currents could be effectively inhibited. Concentration-dependent experiments showed that MT2 inhibited the KCNQ1/KCNE1 channel with an IC50 value of 4.6±1.9μM. The mutagenesis experiments indicated that MT2 peptide likely used Lys26 residue to interact with the KCNQ1/KCNE1 channel. With MT2 as a new template, we further designed a more potent MT2-2 peptide, which selectively inhibited the KCNQ1/KCNE1 channel with an IC50 of 1.51±0.62μM. Together, this work provided a much potent KCNQ1/KCNE1 channel peptide inhibitor so far, and highlighted the role of molecular strategy in developing potent peptide inhibitors for the natural toxin-insensitive orphan receptors. Copyright © 2015 Elsevier Inc. All rights reserved.
Al-Hazza, Adel; Linley, John; Aziz, Qadeer; Hunter, Malcolm; Sandle, Geoffrey
Basolateral K(+) channels hyperpolarize colonocytes to ensure Na(+) (and thus water) absorption. Small conductance basolateral (KCNQ1/KCNE3) K(+) channels have never been evaluated in human colon. We therefore evaluated KCNQ1/KCNE3 channels in distal colonic crypts obtained from normal and active ulcerative colitis (UC) patients. KCNQ1 and KCNE3 mRNA levels were determined by qPCR, and KCNQ1/KCNE3 channel activity in normal and UC crypts, and the effects of forskolin (activator of adenylate cyclase) and UC-related proinflammatory cytokines on normal crypts, studied by patch clamp recording. Whereas KCNQ1 and KCNE3 mRNA expression was similar in normal and UC crypts, single 6.8 pS channels were seen in 36% of basolateral patches in normal crypts, and to an even greater extent (74% of patches, P KCNQ1/KCNE3 channels make only a small contribution to basolateral conductance in normal colonic crypts, with increased channel activity in UC appearing insufficient to prevent colonic cell depolarization in this disease. This supports the proposal that defective Na(+) absorption rather than enhanced Cl(-) secretion, is the dominant pathophysiological mechanism of diarrhea in UC. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Tommiska, Johanna; Känsäkoski, Johanna; Skibsbye, Lasse; Vaaralahti, Kirsi; Liu, Xiaonan; Lodge, Emily J; Tang, Chuyi; Yuan, Lei; Fagerholm, Rainer; Kanters, Jørgen K; Lahermo, Päivi; Kaunisto, Mari; Keski-Filppula, Riikka; Vuoristo, Sanna; Pulli, Kristiina; Ebeling, Tapani; Valanne, Leena; Sankila, Eeva-Marja; Kivirikko, Sirpa; Lääperi, Mitja; Casoni, Filippo; Giacobini, Paolo; Phan-Hug, Franziska; Buki, Tal; Tena-Sempere, Manuel; Pitteloud, Nelly; Veijola, Riitta; Lipsanen-Nyman, Marita; Kaunisto, Kari; Mollard, Patrice; Andoniadou, Cynthia L; Hirsch, Joel A; Varjosalo, Markku; Jespersen, Thomas; Raivio, Taneli
Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.
Aromolaran, Ademuyiwa S; Subramanyam, Prakash; Chang, Donald D; Kobertz, William R; Colecraft, Henry M
Long QT syndrome 1 (LQT1) mutations in KCNQ1 that decrease cardiac IKs (slowly activating delayed rectifier K(+) current) underlie ventricular arrhythmias and sudden death. LQT1 mutations may suppress IKs by preventing KCNQ1 assembly, disrupting surface trafficking, or inhibiting gating. We investigated mechanisms underlying how three LQT1 mutations in KCNQ1 C-terminus assembly domain (R555H/G589D/L619M) decrease IKs in heterologous cells and cardiomyocytes. In Chinese hamster ovary (CHO) cells, mutant KCNQ1 + KCNE1 channels either produced no currents (G589D/L619M) or displayed markedly reduced IKs with a right-shifted voltage-dependence of activation (R555H). When co-expressed with wild-type (wt) KCNQ1, the mutant KCNQ1s displayed varying intrinsic dominant-negative capacities that were affected by auxiliary KCNE1. All three mutant KCNQ1s assembled with wt KCNQ1 as determined by fluorescence resonance energy transfer (FRET). We developed an optical quantum dot labelling assay to measure channel surface density. G589D/R555H displayed substantial reductions in surface density, which were either partially (G589D) or fully (R555H) rescued by wt KCNQ1. Unexpectedly, L619M showed no trafficking defect. In adult rat cardiomyocytes, adenovirus-expressed homotetrameric G589D/L619M + KCNE1 channels yielded no currents, whereas R555H + KCNE1 produced diminished IKs with a right-shifted voltage-dependence of activation, mimicking observations in CHO cells. In contrast to heterologous cells, homotetrameric R555H channels showed no trafficking defect in cardiomyocytes. Distinct LQT1 mutations in KCNQ1 assembly domain decrease IKs using unique combinations of biophysical and trafficking mechanisms. Functional deficits in IKs observed in heterologous cells are mostly, but not completely, recapitulated in adult rat cardiomyocytes. A 'methodological chain' combining approaches in heterologous cells and cardiomyocytes provides mechanistic insights that may help advance personalized
Ki, Chang-Seok; Jung, Chae Lim; Kim, Hyun-ji; Baek, Kwan-Hyuck; Park, Seung Jung; On, Young Keun; Kim, Ki-Suk; Noh, Su Jin; Youm, Jae Boum; Kim, June Soo; Cho, Hana
Atrial fibrillation (AF) is the most common arrhythmia. Gain-of-function mutations in KCNQ1, the pore-forming α-subunit of the slow delayed rectifier K current (IKs) channel, have been associated with AF. The purpose of this study was functional assessment of a mutation in KCNQ1 identified in a family with persistent AF and sinus bradycardia. We investigated whether this KCNQ1 missense mutation could form the genetic basis for AF and bradycardia simultaneously in this family. Sanger sequencing in a family with hereditary persistent AF identified a novel KCNQ1 variant (V241F) in a highly conserved region of S4 domain. The proband and her son developed bradycardia and persistent AF in an age-dependent fashion. The other son was a mutation carrier but he showed sinus bradycardia and not AF. Whole-cell patch clamp electrophysiology showed that V241F mutation in KCNQ1 shifted the activation curve to the left and dramatically slowed deactivation, leading to a constitutively open-like phenotype. Computer modeling showed that V241F would slow pacemaker activity. Also, simulations of atrial excitation predicted that V241F results in extreme shortening of action potential duration, possibly resulting in AF. Our study indicates that V241F might cause sinus bradycardia by increasing IKs. Additionally, V241F likely shortens atrial refractoriness to promote a substrate for reentry. KCNQ1 mutations have previously been described in AF, yet this is the first time a mutation in KCNQ1 is associated with age-dependent bradycardia and persistent AF. This finding further supports the hypothesis that sinus node dysfunction contributes to the development of AF.
Jespersen, Thomas; Rasmussen, Hanne B; Grunnet, Morten
KCNQ1 potassium channels are expressed in many epithelial tissues as well as in the heart. In epithelia KCNQ1 channels play an important role in salt and water transport and the channel has been reported to be located apically in some cell types and basolaterally in others. Here we show that KCNQ1...... channels are located basolaterally when expressed in polarised MDCK cells. The basolateral localisation of KCNQ1 is not affected by co-expression of any of the five KCNE beta-subunits. We characterise two independent basolateral sorting signals present in the N-terminal tail of KCNQ1. Mutation...... located protein, to the basolateral plasma membrane. Furthermore, a di-leucine-like motif at residues 38-40 (LEL) was found to affect the basolateral localisation of KCNQ1. Mutation of these two leucines resulted in a primarily intracellular localisation of the channel....
Grunnet, Morten; Behr, Elijah Raphael; Calloe, Kirstine
of the compound mutations in the KCNQ1 and KCNH2 genes (KCNQ1 R591H, KCNH2 R328C) were analyzed by heterologous expression in Xenopus laevis oocytes using two-electrode voltage clamp and by confocal imaging. RESULTS: KCNH2 R328C did not show any functional phenotype whereas KCNQ1 R591H resulted in severe...... reduction of current. Neither wild-type nor mutant channels affected each other functionally in coexpression experiments. Therefore, a direct interaction between KCNQ1 and KCNH2 was ruled out under these conditions. CONCLUSION: Assessment of novel mutational findings in LQTS should include accurate genetic...
Full Text Available Objective(s: Jervell and Lange–Nielsen syndrome is an autosomal recessive disorder caused by mutations in KCNQ1 or KCNE1 genes. The disease is characterized by sensorineural hearing loss and long QT syndrome. Methods: Here we present a 3.5-year-old female patient, an offspring of consanguineous marriage, who had a history of recurrent syncope and congenital sensorineural deafness. The patient and the family members were screened for mutations in KCNQ1 gene by linkage analysis and DNA sequencing. Results: DNA sequencing showed a c.1532_1534delG (p. A512Pfs*81 mutation in the KCNQ1 gene in homozygous form. The results of short tandem repeat (STR markers showed that the disease in the family is linked to the KCNQ1 gene. The mutation was confirmed in the parents in heterozygous form. Conclusion: This is the first report of this variant in KCNQ1 gene in an Iranian family. The data of this study could be used for early diagnosis of the condition in the family and genetic counseling.
Imaniastuti, Riski; Lee, Hyun Seung; Kim, Nari; Youm, Jae Boum; Shim, Eun Bo; Lim, Ki Moo
Genetic factors play an important role in the pathogenesis of atrial flutter (AF). Although mutation in KCNQ1 has been widely correlated with AF, the mechanism by which mutation promotes AF remains poorly understood. The purpose of this study was to investigate the proarrhythmic effect of V241F KCNQ1 mutation in human atrium using the electrophysiological model of human atrium. Using 2D and 3D cardiac electrophysiological models that incorporate the Courtemanche human atrial model, we simulated electrical conduction through atrial tissue and compared spiral wave dynamics under the wild-type and V241F KCNQ1 conditions. In 2D and 3D simulation, V241F KCNQ1 showed a stable and persistent wave without spiral break-up, whereas the wild-type wave was less stable, resulting in early self-termination. According to the results, we concluded that compared to the wild type, the electrical activity of the V241F KCNQ1 mutation is more likely to sustain spiral wave. Copyright © 2014 Elsevier Ltd. All rights reserved.
Yasuda, Kazuki; Miyake, Kazuaki; Horikawa, Yukio
We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892...... in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9...... or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries....
Gayen, Shovanlal; Li, Qingxin; Kang, CongBao
KCNQ1 plays important roles in the cardiac action potential and consists of an N-terminal domain, a voltage-sensor domain, a pore domain and a C-terminal domain. KCNQ1 is a voltage-gated potassium channel and its channel activity is regulated by membrane potentials. The linker between transmembrane helices 4 and 5 (S4-S5 linker) is important for transferring the conformational changes from the voltage-sensor domain to the pore domain. In this study, the structure of the S4-S5 linker of KCNQ1 was investigated by solution NMR, circular dichroism and fluorescence spectroscopic studies. The S4-S5 linker adopted a helical structure in detergent micelles. The W248 may interact with the cell membrane. Copyright © 2014 Elsevier Inc. All rights reserved.
Full Text Available Background/Aims: KCNQ1/E1 channels are expressed in diverse tissues and serve a variety of functions including endolymph secretion in the inner ear, cardiac repolarization, epithelial transport and cell volume regulation. Kinases involved in regulation of epithelial transport and cell volume include SPAK (SPS1-related proline/alanine-rich kinase and OSR1 (oxidative stress-responsive kinase 1, which are under control of WNK (with-no-K[Lys] kinases. The present study explored whether KCNQ1/E1 channels are regulated by SPAK and/or OSR1. Methods: cRNA encoding KCNQ1/E1 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active T233ESPAK, WNK insensitive T233ASPAK, catalytically inactive D212ASPAK, wild-type OSR1, constitutively active T185EOSR1, WNK insensitive T185AOSR1 and catalytically inactive D164AOSR1. Voltage gated K+ channel activity was quantified utilizing dual electrode voltage clamp and KCNQ1/E1 channel protein abundance in the cell membrane utilizing chemiluminescence of KCNQ1/E1 containing an extracellular Flag tag epitope (KCNQ1-Flag/E1. Results: KCNQ1/E1 activity and KCNQ1-Flag/E1 protein abundance were significantly enhanced by wild-type SPAK and T233ESPAK, but not by T233ASPAK and D212ASPAK. Similarly, KCNQ1/E1 activity and KCNQ1-Flag/E1 protein abundance were significantly increased by wild-type OSR1 and T185EOSR1, but not by T185AOSR1 and D164AOSR1. Conclusions: SPAK and OSR1 participate in the regulation of KCNQ1/E1 protein abundance and activity.
Elvira, Bernat; Warsi, Jamshed; Fezai, Myriam; Munoz, Carlos; Lang, Florian
KCNQ1/E1 channels are expressed in diverse tissues and serve a variety of functions including endolymph secretion in the inner ear, cardiac repolarization, epithelial transport and cell volume regulation. Kinases involved in regulation of epithelial transport and cell volume include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases. The present study explored whether KCNQ1/E1 channels are regulated by SPAK and/or OSR1. cRNA encoding KCNQ1/E1 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active T233ESPAK, WNK insensitive T233ASPAK, catalytically inactive D212ASPAK, wild-type OSR1, constitutively active T185EOSR1, WNK insensitive T185AOSR1 and catalytically inactive D164AOSR1. Voltage gated K+ channel activity was quantified utilizing dual electrode voltage clamp and KCNQ1/E1 channel protein abundance in the cell membrane utilizing chemiluminescence of KCNQ1/E1 containing an extracellular Flag tag epitope (KCNQ1-Flag/E1). KCNQ1/E1 activity and KCNQ1-Flag/E1 protein abundance were significantly enhanced by wild-type SPAK and T233ESPAK, but not by T233ASPAK and D212ASPAK. Similarly, KCNQ1/E1 activity and KCNQ1-Flag/E1 protein abundance were significantly increased by wild-type OSR1 and T185EOSR1, but not by T185AOSR1 and D164AOSR1. SPAK and OSR1 participate in the regulation of KCNQ1/E1 protein abundance and activity. © 2015 S. Karger AG, Basel.
Coto, Eliecer; García-Fernández, Francisco J; Calvo, David; Salgado-Aranda, Ricardo; Martín-González, Javier; Alonso, Belén; Iglesias, Sara; Gómez, Juan
We present the case of a 66-year-old female with early onset deafness and seizures, who was diagnosed with epilepsy at the age of 2 years. She received antiepileptic drugs and was free of syncope episodes for 32 years. After a syncope at the age of 34, the ECG was characteristic of long-QT syndrome and was treated with antiarrhythmic drugs. Sequencing of the KCNQ1 gene identified two novel KCNQ1 variants interpreted to be pathogenic, and the patient was finally diagnosed with Jervell and Lange-Nielsen syndrome. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Chen, Zongyun; Hu, Youtian; Wang, Bin; Cao, Zhijian; Li, Wenxin; Wu, Yingliang
Although many studies concerning the sensitivity mechanism of scorpion toxin-potassium channel interactions have been reported, few have explored the biochemical insensitivity mechanisms of potassium channel receptors toward natural scorpion toxin peptides, such as the KCNQ1 channel. Here, by sequence alignment analyses of the human KCNQ1 channel and scorpion potassium channel MmKv2, which is completely insensitive to scorpion toxins, we proposed that the insensitivity mechanism of KCNQ1 toward natural scorpion toxins might involve two functional regions, the turret and filter regions. Based on this observation, a series of KCNQ1 mutants were constructed to study molecular mechanisms of the KCNQ1 channel insensitivity toward natural scorpion toxins. Electrophysiological studies of chimera channels showed that the channel filter region controls KCNQ1 insensitivity toward the classical scorpion toxin ChTX. Interestingly, further residue mutant experiments showed that a single basic residue in the filter region determined the insensitivity of KCNQ1 channels toward scorpion toxins. Our present work showed that amino acid residue diversification at common sites controls the sensitivity and insensitivity of potassium channels toward scorpion toxins. The unique insensitivity mechanism of KCNQ1 toward natural scorpion toxins will accelerate the rational design of potent peptide inhibitors toward this channel.
Itoh, Hideki; Berthet, Myriam; Fressart, Véronique; Denjoy, Isabelle; Maugenre, Svetlana; Klug, Didier; Mizusawa, Yuka; Makiyama, Takeru; Hofman, Nynke; Stallmeyer, Birgit; Zumhagen, Sven; Shimizu, Wataru; Wilde, Arthur A. M.; Schulze-Bahr, Eric; Horie, Minoru; Tezenas du Montcel, Sophie; Guicheney, Pascale
Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A)
Jonsson, Anna Elisabet; Isomaa, Bo; Tuomi, Tiinamaija
Two independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion...
Huang, Kuo-Chin; Li, Te-Mao; Liu, Xiang; Chen, Jin-Hua; Chien, Wen-Kuei; Shiao, Yi-Tzone; Tsang, Hsinyi; Lin, Ting-Hsu; Liao, Chiu-Chu; Huang, Shao-Mei; Li, Ju-Pi; Lin, Cheng-Wen; Lin, Jung-Chun; Lin, Chih-Chien; Lai, Chih-Ho; Cheng, Chi-Fung; Liang, Wen-Miin; Hung, Chien-Hui; Chen, Ching-Chu; Lin, Ying-Ju; Tsai, Fuu-Jen
KCNQ1 encodes a potassium voltage-gated channel and represents a susceptibility locus for type 2 diabetes mellitus (T2DM). Here, we explored the association between KCNQ1 polymorphisms and hypertension risk in individuals with T2DM, as well as the role of KCNQ1 in vascular smooth muscle cell contraction in vitro. To investigate the relationship between KCNQ1 and the risk of developing hypertension in patients with T2DM, we divided the T2DM cohort into hypertension (n = 452) and non-hypertension (n = 541) groups. The Mann-Whitney U test, chi-square test, and multivariate regression analyses were used to assess the clinical characteristics and genotypic frequencies. In vitro studies utilized the rat aortic smooth muscle A10 cell line. Patients in the hypertension group were significantly older at the time of enrollment and had higher levels of body mass index, waist-to-hip ratio, and triglyceride than those in the non-hypertension group. The KCNQ1 rs3864884 and rs12576239 genetic variants were associated with hypertension in T2DM. KCNQ1 expression was lower in the individuals with the CC versus the CT and TT genotypes. Smooth muscle cell contractility was inhibited by treatment with a KCNQ1 inhibitor. These results suggest that KCNQ1 might be associated with hypertension in individuals with T2DM. © 2017 Wiley Periodicals, Inc.
Sun, Ji; MacKinnon, Roderick
KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (I Ks ) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an "uncoupled," PIP 2 -free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP 2 . CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP 2 , and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS. Copyright © 2017 Elsevier Inc. All rights reserved.
Nakajo, Koichi; Kubo, Yoshihiro
In voltage-gated K(+) channels, membrane depolarization induces an upward movement of the voltage-sensing domains (VSD) that triggers pore opening. KCNQ1 is a voltage-gated K(+) channel and its gating behaviour is substantially modulated by auxiliary subunit KCNE proteins. KCNE1, for example, markedly shifts the voltage dependence of KCNQ1 towards the positive direction and slows down the activation kinetics. Here we identify two phenylalanine residues on KCNQ1, Phe232 on S4 (VSD) and Phe279 on S5 (pore domain) to be responsible for the gating modulation by KCNE1. Phe232 collides with Phe279 during the course of the VSD movement and hinders KCNQ1 channel from opening in the presence of KCNE1. This steric hindrance caused by the bulky amino-acid residues destabilizes the open state and thus shifts the voltage dependence of KCNQ1/KCNE1 channel.
Fatima, Syeda Sadia; Chaudhry, Bushra; Khan, Taseer Ahmed; Farooq, Saad
Genetic studies on gestational diabetes (GDM) are relatively scarce; moreover, limited data is available for KCNQ1 polymorphism in Pakistani pregnant women. We aimed to determine the frequency of KCNQ1 rs2237895 in GDM and normal pregnant controls and its association with GDM-related phenotypes. A total of 637 pregnant females (429 controls and 208 cases) in their second trimester were classified according to the International Association of the Diabetes and Pregnancy Study criteria in this study. Their blood samples were genotyped for KCNQ1 SNP rs2237895 using PCR-RFLP method and sequencing. Fasting and two hour-post glucose load blood levels, serum HbA1c, insulin, and anthropometric assessment was performed.: Pearson's Chi Square test, Mann- Whitney U test, and regression analyses were performed. A p-value of 0.05). The rs2237895 showed an association with GDM (OR 2.281; 1.388-3.746: p KCNQ1 rs2237895 polymorphisms might be associated with risk of GDM in Pakistani population and that it is related to higher glucose levels and insulin resistance. Further large scale studies are required to consolidate on the functional aspect of this polymorphism.
Chan, Priscilla J.; Osteen, Jeremiah D.; Xiong, Dazhi; Bohnen, Michael S.; Doshi, Darshan; Sampson, Kevin J.; Marx, Steven O.; Karlin, Arthur
The IKs potassium channel, critical to control of heart electrical activity, requires assembly of α (KCNQ1) and β (KCNE1) subunits. Inherited mutations in either IKs channel subunit are associated with cardiac arrhythmia syndromes. Two mutations (S140G and V141M) that cause familial atrial fibrillation (AF) are located on adjacent residues in the first membrane-spanning domain of KCNQ1, S1. These mutations impair the deactivation process, causing channels to appear constitutively open. Previous studies suggest that both mutant phenotypes require the presence of KCNE1. Here we found that despite the proximity of these two mutations in the primary protein structure, they display different functional dependence in the presence of KCNE1. In the absence of KCNE1, the S140G mutation, but not V141M, confers a pronounced slowing of channel deactivation and a hyperpolarizing shift in voltage-dependent activation. When coexpressed with KCNE1, both mutants deactivate significantly slower than wild-type KCNQ1/KCNE1 channels. The differential dependence on KCNE1 can be correlated with the physical proximity between these positions and KCNE1 as shown by disulfide cross-linking studies: V141C forms disulfide bonds with cysteine-substituted KCNE1 residues, whereas S140C does not. These results further our understanding of the structural relationship between KCNE1 and KCNQ1 subunits in the IKs channel, and provide mechanisms for understanding the effects on channel deactivation underlying these two atrial fibrillation mutations. PMID:22250012
Diness, Thomas Goldin; Hansen, Rie Schultz; Olesen, Søren-Peter
To obtain information about a possible frequency-dependent modulation of HERG1 and hKCNQ1 channels, we performed heterologous expression in Xenopus laevis oocytes. Channel activation was obtained by voltage protocols roughly imitating cardiac action potentials at frequencies of 1, 3, 5.8, and 8.3Hz....... The activity of HERG1 channels was inhibited down to 65% at high frequencies. In contrast, hKCNQ1 channel activity was increased up to 525% at high frequencies. The general frequency-dependent modulation of the channels was unaffected by both co-expression of hKCNQ1 and HERG1 channels, and by the presence...... of the beta-subunits KCNE1 and KCNE2. In addition, the functional role of HERG1 in native guinea pig cardiac myocytes was demonstrated at different pacing frequencies by application of 10microM of the new HERG1 activator, NS1643. In conclusion, we have demonstrated that HERG1 and hKCNQ1 channels are inversely...
Hancox, J C; Kharche, S; El Harchi, A; Stott, J; Law, P; Zhang, H
Mutations in transmembrane domains of the KCNQ1 subunit of the I(Ks) potassium channel have been associated with familial atrial fibrillation. We have investigated mechanisms by which the S1 domain S140G KCNQ1 mutation influences atrial arrhythmia risk and, additionally, whether it can affect ventricular electrophysiology. In perforated-patch recordings, S140G-KCNQ1+KCNE1 exhibited leftward-shifted activation, slowed deactivation and marked residual current. In human atrial action potential (AP) simulations, AP duration and refractoriness were shortened and rate-dependence flattened. Simulated I(Ks) but not I(Kr) block offset AP shortening produced by the mutation. In atrial tissue simulations, temporal vulnerability to re-entry was little affected by the S140G mutation. Spatial vulnerability was markedly increased, leading to more stable and stationary spiral wave re-entry in 2D stimulations, which was offset by I(Ks) block, and to scroll waves in 3D simulations. These changes account for vulnerability to AF with this mutation. Ventricular AP clamp experiments indicate a propensity for increased ventricular I(Ks) with the S140G KCNQ1 mutation and ventricular AP simulations showed model-dependent ventricular AP abbreviation. Copyright © 2014 Elsevier Inc. All rights reserved.
Wu, Meikui; Takemoto, Makoto; Taniguchi, Makoto; Takumi, Toru; Okazaki, Toshiro; Song, Wen-Jie
Sphingomyelin synthase (SMS) catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and diacylglycerol. We previously showed that SMS1 deficiency leads to a reduction in expression of the K(+) channel KCNQ1 in the inner ear (Lu MH, Takemoto M, Watanabe K, Luo H, Nishimura M, Yano M, Tomimoto H, Okazaki T, Oike Y, and Song WJ. J Physiol 590: 4029-4044, 2012), causing hearing loss. However, it remains unknown whether this change in expression is attributable to a cellular process or a systemic effect in the knockout animal. Here, we examined whether manipulation of SMS1 activity affects KCNQ1/KCNE1 currents in individual cells. To this end, we expressed the KCNQ1/KCNE1 channel in human embryonic kidney 293T cells and evaluated the effect of SMS1 manipulations on the channel using whole cell recording. Application of tricyclodecan-9-yl-xanthogenate, a nonspecific inhibitor of SMSs, significantly reduced current density and altered channel voltage dependence. Knockdown of SMS1 by a short hairpin RNA, however, reduced current density alone. Consistent with this, overexpression of SMS1 increased the current density without changing channel properties. Furthermore, application of protein kinase D inhibitors also suppressed current density without changing channel properties; this effect was nonadditive with that of SMS1 short hairpin RNA. These results suggest that SMS1 positively regulates KCNQ1/KCNE1 channel density in a protein kinase D-dependent manner. Copyright © 2016 the American Physiological Society.
Kruszka, Paul; Weiss, Karin; Hadley, Donald W
The advances in genomic technology of large populations make the potential for genomic screening of military cohorts and recruits feasible, affording the potential to identify at-risk individuals before occurrence of potentially life-threatening events. Exploring sudden cardiac death, known to cause significant morbidity and mortality in young military service members, we focused on the most common gene associated with long QT syndrome (LQTS), KCNQ1. Using the publicly available database Exome Aggregation Consortium as a surrogate for a military population, variants in KCNQ1 were filtered on the basis of population prevalence, classification as a disease mutation in the Human Gene Mutation database, and classification as pathogenic or likely pathogenic in the ClinVar database. Variant prevalence and penetrance estimates were derived using reports from the medical literature. We showed that in a population of over 60,000 individuals, at least 97 (0.2%) individuals would harbor a potentially pathogenic mutation in KCNQ1, which is more prevalent than expected on the basis of current medical literature (p = 0.0004). KCNQ1 variant penetrance was estimated to be only 9% to 17%. Identifying the importance of large genomic studies, our study demonstrates that 46% of pathogenic mutations in KCNQ1 had a population frequency of less than 1:50,000. Screening a large database with genomic screening for a condition that is relevant to active duty service members results in the identification of many individuals with potentially pathogenic mutations in the KCNQ1 gene, which has profound implications for screening military or other adult cohorts in terms of over diagnosis, overtreatment, and increased medical resource usage. This study of KCNQ1 provides a platform for consideration of other genes that cause sudden cardiac death as well as other medically actionable hereditary disorders for which genomic screening is available. We review the potential benefits of genomic screening
Saif-Ali, Riyadh; Ismail, Ikram S; Al-Hamodi, Zaid; Al-Mekhlafi, Hesham M; Siang, Lee C; Alabsi, Aied M; Muniandy, Sekaran
The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) and haplotypes of potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) with type 2 diabetes (T2D) in Malaysian Chinese subjects. The KCNQ1 SNPs rs2237892, rs2283228 and rs2237895 were genotyped in 300 T2D patients and 230 control subjects without diabetes and metabolic syndrome. Two logistic regression models of analysis were applied, the first adjusted for age and gender while the second adjusted for age, gender and body mass index. The additive genetic analysis showed that adjusting for body mass index (BMI) even strengthened association of rs2237892, rs2283228 and rs2237895 with T2D (OR = 2.0, P = 5.1 × 10(-5); OR = 1.9, P = 5.2 × 10(-5); OR = 1.9, P = 7.8 × 10(-5), respectively). The haplotype TCA containing the allele of rs2237892 (T), rs2283228 (C) and rs2237895 (A) was highly protective against T2D (Second model; OR = 0.17, P = 3.7 × 10(-11)). The KCNQ1 rs2237892 (TT), and the protective haplotype (TCA) were associated with higher beta-cell function (HOMA-B) in normal subjects (P = 0.0002; 0.014, respectively). This study found that KCNQ1 SNPs was associated with T2D susceptibility in Malaysian Chinese subjects. In addition, certain KCNQ1 haplotypes were strongly associated with T2D.
Gómez-Úriz, Ana M; Milagro, Fermín I; Mansego, María L; Cordero, Paúl; Abete, Itziar; De Arce, Ana; Goyenechea, Estíbaliz; Blázquez, Vanessa; Martínez-Zabaleta, Maite; Martínez, José Alfredo; López De Munain, Adolfo; Campión, Javier
Obesity and stroke are multifactorial diseases in which genetic, epigenetic and lifestyle factors are involved. The research aims were, first, the description of genes with differential epigenetic regulation obtained by an 'omics' approach in patients with ischemic stroke and, second, to determine the importance of some regions of these selected genes in biological processes depending on the body mass index. A case-control study using two populations was designed. The first population consisted of 24 volunteers according to stroke/non-stroke and normal weight/obesity conditions. The second population included 60 stroke patients and 55 controls classified by adiposity. DNA from the first population was analyzed with a methylation microarray, showing 80 cytosine-guanine dinucleotides (CpG) sites differentially methylated in stroke and 96 CpGs in obesity, whereas 59 CpGs showed interaction. After validating these data by MassArray Epityper, the promoter region of peptidase M20 domain containing 1 (PM20D1) gene was significantly hypermethylated in stroke patients. One CpG site at Caldesmon 1 (CALD1) gene showed an interaction between stroke and obesity. Two CpGs located in the genes Wilms' tumor 1 (WT1) and potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) were significantly hypermethylated in obese patients. In the second population, KCNQ1 was also hypermethylated in the obese subjects. Two CpGs of this gene were subsequently validated by methylation-sensitive high-resolution melting. Moreover, KCNQ1 methylation levels were associated with plasma KCNQ1 protein concentrations. In conclusion, obesity induced changes in the KCNQ1 methylation pattern which were also dependent on stroke. Furthermore, the epigenetic marks differentially methylated in the stroke patients were dependent on the previous obese state. These DNA methylation patterns could be used as future potential stroke biomarkers. © The Author 2014. Published by Oxford University Press
Gotthardová, Ivana; Javorský, Martin; Klimčáková, Lucia; Kvapil, Milan; Schroner, Zbynek; Kozárová, Miriam; Malachovská, Zuzana; Ürgeová, Anna; Židzik, Jozef; Tkáč, Ivan
Only afew gene variants were associated with the response to dipeptidylpeptidase-4 inhibitors (DPP4I). KCNQ1 gene variants were previously related both to type 2 diabetes (T2D) and incretin effect. We hypothesized that T2D related KCNQ1 variants would be associated with smaller glucose-lowering effect of DDP4I. We performed a retrospective study in 137 Caucasian subjects with T2D who were followed for 6months after initiation of DPP4I treatment. Genotyping for KCNQ1 rs163184 and rs151290 was performed using PCR-HRMA and PCR-RFLP methods, respectively. The main clinical outcome was reduction in HbA1c (ΔHbA1c) after 6-month DPP4I treatment. KCNQ1 rs163184 T>G variant was associated with the response to DPP4I treatment in genetic additive model (β=-0.30, p=0.022). For each G allele in the rs163184 genotype, we observed a 0.3% (3.3mmol/mol) less reduction in HbA1c during treatment with a DPP4I. Both the GG homozygotes and G-allele carriers had significantly smaller HbA1c reduction in comparison with the TT homozygotes. KCNQ1 rs163184 T>G variant was associated with a reduced glycaemic response to DPP4I. The difference of 0.6% (6.5mmol/mol) in HbA1c reduction between the TT and GG homozygotes might be of clinical significance if replicated in further studies. Copyright © 2017 Elsevier B.V. All rights reserved.
Wu, Minghua; Obara, Yutaro; Norota, Ikuo; Nagasawa, Yoshinobu; Ishii, Kuniaki
Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia. In an animal model of type 1 diabetes mellitus, several ion currents, including the slowly activating delayed rectifier potassium current (IKs), are altered. The IKs channel is composed of KCNQ1 and KCNE1 subunits, whose genetic mutations are well known to cause long QT syndrome. Although insulin is known to affect many physiological and pathophysiological events in the heart, acute effects of insulin on cardiac ion channels are poorly understood at present. This study was designed to investigate direct electrophysiological effects of insulin on IKs (KCNQ1/KCNE1) currents. KCNQ1 and KCNE1 were co-expressed in Xenopus oocytes, and whole cell currents were measured by a two-microelectrode voltage-clamp method. Acute application of insulin suppressed the KCNQ1/KCNE1 currents and phosphorylated Akt and extracellular signal-regulated kinase (ERK), the two major downstream effectors, in a concentration-dependent manner. Wortmannin (10(-6) M), a phosphoinositide 3-kinase (PI3K) inhibitor, attenuated the suppression of the currents and phosphorylation of Akt by insulin, whereas U0126 (10(-5) M), a mitogen-activated protein kinase kinase (MEK) inhibitor, had no effect on insulin-induced suppression of the currents. In addition, insulin had little effect on KCNQ1 currents without KCNE1, which indicated an essential role of KCNE1 in the acute suppressive effects of insulin. Mutagenesis studies revealed amino acid residues 111-118 within the distal third C-terminus of KCNE1 as an important region. Insulin has direct electrophysiological effects on IKs currents, which may affect cardiac excitability.
Li, Bian; Mendenhall, Jeffrey L; Kroncke, Brett M; Taylor, Keenan C; Huang, Hui; Smith, Derek K; Vanoye, Carlos G; Blume, Jeffrey D; George, Alfred L; Sanders, Charles R; Meiler, Jens
An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity. In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew's correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred. Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools. © 2017 American Heart Association, Inc.
Olszak-Waśkiewicz, Marlena; Kramarz, Elżbieta
Ion channel gene mutations are risk factors for SCD. To assess the prognostic value of A2753831C, C2505734T, C2505846A, G2753881A, T2755854C and T2755875G mutations in the KCNQ1 gene in patients after MI. The study group of 100 patients after MI was divided into two groups: patients with mutations (n=23) and patients without mutations (n=77). The subjects underwent physical examinations, laboratory tests, ECG, Holter ECG and echocardiography. The examinations were repeated every 12 months. Cardiac events including deaths occurred during the observation period. The mean observation time was 8 ± 4,3 years. KCNQ1 gene mutations were found in 23 subjects and were four times more frequent in men than in women. Parameters such as QRS ≥ 110 ms, QTc ≥ 440 ms, VEBs ≥ 100 per 24 hours, nsVT and LVEF ≤40% showed statistically significant differences between the group of patients who died and the group of patients who survived. LVEF ≤ 40% and VEBs ≥ 100/24 h were the factors that correlated the most with deaths. KCNQ1 gene mutations, PQ interval ≥ 200ms and QTd ≥ 60ms had no impact on death. The occurrence of KCNQ1 gene mutations in patients after MI is higher in men than in women. The presence of KCNQ1 gene mutations is not an additional risk factor for increased mortality in patients after MI. LVEF ≤40% and VES ≥100/24 h have a significant prognostic value in predicting deaths in patients after MI.
Turki, Amira; Mtiraoui, Nabil; Al-Busaidi, Amna S; Khirallah, Moncef; Mahjoub, Touhami; Almawi, Wassim Y
Polymorphisms of KCNQ1 were previously associated with type 2 diabetes (T2DM) in select Caucasian and non-Caucasian populations. We investigated the association of rs231361, rs231359, rs151290, rs2237892, rs2283228, rs2237895, and rs2237896 KCNQ1 polymorphisms with T2DM in Tunisian Arabs. Subjects comprised 900 T2DM patients and 600 normoglycemic controls. KCNQ1 genotyping was done by allelic discrimination (real-time PCR) and PCR-RFLP methods; the contribution of KCNQ1 polymorphisms to T2DM were analyzed by Haploview and regression analysis. Minor allele frequency (MAF) of the 7 tested KCNQ1 variants was comparable between T2DM cases and controls. Mild association of rs2237892 genotypes with T2DM was seen (P=0.014), highlighted by the significant association of the C/T genotype with increased T2DM risk (OR, 2.11; 95%CI, 1.25-3.53), after adjusting for BMI, gender, systolic and diastolic blood pressure, and serum lipid profile. Heterogeneity in linkage disequilibrium pattern between tested KCNQ1 variants analyzed was seen. Two-locus (rs231361 and rs231359) and 5-locus (remaining 5 SNPs) haplotype analysis did not reveal any significant association with any of the haplotypes contained in either block 1 or block 2. These results indicate that there was no evidence for an association of KCNQ1 polymorphisms with T2DM in Tunisian Arabs. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Full Text Available Background/Aims: KCNQ channels transport K+ ions and participate in various cellular functions. The channels directly assemble with auxiliary proteins such as a ubiquitous Ca2+-sensor protein, calmodulin (CaM, to configure the physiological properties in a tissue-specific manner. Although many CaM-like Ca2+-sensor proteins have been identified in eukaryotes, how KCNQ channels selectively interact with CaM and how the homologues modulate the functionality of the channels remain unclear. Methods: We developed protocols to evaluate the interaction between the green fluorescent protein-tagged C-terminus of KCNQ1 (KCNQ1cL and Ca2+-sensors by detecting its fluorescence in size exclusion chromatography and electrophoresed gels. The effects of Ca2+-sensor proteins on KCNQ1 activity was measured by two electrode voltage clamp technique of Xenopus oocytes. Results: When co-expressed CaM and KCNQ1cL, they assemble in a 4:4 stoichiometry, forming a hetero-octamer. Among nine CaM homologues tested, Calml3 was found to form a hetero-octamer with KCNQ1cL and to associate with the full-length KCNQ1 in a competitive manner with CaM. When co-expressed in oocytes, Calml3 rendered KCNQ1 channels resistant to the voltage-dependent depletion of phosphatidylinositol 4,5-bisphosphate by voltage-sensitive phosphatase. Conclusion: Since Calml3 is closely related to CaM and is prominently expressed in epithelial cells, Calml3 may be a constituent of epithelial KCNQ1 channels and underscores the molecular diversity of endogenous KCNQ1 channels.
Inanobe, Atsushi; Tsuzuki, Chizuru; Kurachi, Yoshihisa
KCNQ channels transport K+ ions and participate in various cellular functions. The channels directly assemble with auxiliary proteins such as a ubiquitous Ca2+- sensor protein, calmodulin (CaM), to configure the physiological properties in a tissue-specific manner. Although many CaM-like Ca2+-sensor proteins have been identified in eukaryotes, how KCNQ channels selectively interact with CaM and how the homologues modulate the functionality of the channels remain unclear. We developed protocols to evaluate the interaction between the green fluorescent protein-tagged C-terminus of KCNQ1 (KCNQ1cL) and Ca2+-sensors by detecting its fluorescence in size exclusion chromatography and electrophoresed gels. The effects of Ca2+-sensor proteins on KCNQ1 activity was measured by two electrode voltage clamp technique of Xenopus oocytes. When co-expressed CaM and KCNQ1cL, they assemble in a 4:4 stoichiometry, forming a hetero-octamer. Among nine CaM homologues tested, Calml3 was found to form a hetero-octamer with KCNQ1cL and to associate with the full-length KCNQ1 in a competitive manner with CaM. When co-expressed in oocytes, Calml3 rendered KCNQ1 channels resistant to the voltage-dependent depletion of phosphatidylinositol 4,5-bisphosphate by voltage-sensitive phosphatase. Since Calml3 is closely related to CaM and is prominently expressed in epithelial cells, Calml3 may be a constituent of epithelial KCNQ1 channels and underscores the molecular diversity of endogenous KCNQ1 channels. Copyright © 2015 S. Karger AG, Basel
Kharbanda, Mira; Hunter, Amanda; Tennant, Stephen; Moore, David; Curtis, Stephanie; Hancox, Jules C; Murday, Victoria
The association of long QT syndrome and left ventricular noncompaction is uncommon, with only a handful of previous reports, and only one reported case in association with a mutation in KCNQ1. Here we present genetic and phenotypic data for 4 family members across 2 generations who all have evidence of prolonged QT interval and left ventricular noncompaction in association with a pathogenic mutation in KCNQ1, and discuss the potential mechanisms of this association. In conclusion, we suggest that it may be helpful to consider looking for mutations in KCNQ1 in similar patients. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Tzimas, Iliana; Bajanowski, Thomas; Poetsch, Micaela
Drowning remains one of the major causes of death in most developed countries despite the fact that many of the victims are known to be at least moderate swimmers as well as healthy directly before the event. Here, fatal arrhythmias and especially the long QT syndrome (LQTS) have been proposed as the underlying mechanism which may be connected to mutations in one of the associated genes. The KCNQ1 gene is involved in the occurrence of LQT1 which may be triggered by swimming. Therefore, 176 cases of drowning were screened for mutations in the exons 3, 5, 6, 7, and 8 of the KCNQ1 gene which have been shown to harbor major mutation clusters. No variation to the published sequence could be found in the exonic DNA in any of the cases clearly disproving an involvement of these mutation clusters in cases of drowning.
Full Text Available Abstract Background Genomic imprinting occurs in both marsupial and eutherian mammals. The CDKN1C and IGF2 genes are both imprinted and syntenic in the mouse and human, but in marsupials only IGF2 is imprinted. This study examines the evolution of features that, in eutherians, regulate CDKN1C imprinting. Results Despite the absence of imprinting, CDKN1C protein was present in the tammar wallaby placenta. Genomic analysis of the tammar region confirmed that CDKN1C is syntenic with IGF2. However, there are fewer LTR and DNA elements in the region and in intron 9 of KCNQ1. In addition there are fewer LINEs in the tammar compared with human and mouse. While the CpG island in intron 10 of KCNQ1 and promoter elements could not be detected, the antisense transcript KCNQ1OT1 that regulates CDKN1C imprinting in human and mouse is still expressed. Conclusion CDKN1C has a conserved function, likely antagonistic to IGF2, in the mammalian placenta that preceded its acquisition of imprinting. CDKN1C resides in synteny with IGF2, demonstrating that imprinting of the two genes did not occur concurrently to balance maternal and paternal influences on the growth of the placenta. The expression of KCNQ1OT1 in the absence of CDKN1C imprinting suggests that antisense transcription at this locus preceded imprinting of this domain. These findings demonstrate the stepwise accumulation of control mechanisms within imprinted domains and show that CDKN1C imprinting cannot be due to its synteny with IGF2 or with its placental expression in mammals.
Cui, L J; Chang, X Y; Zhu, L Y; Feng, G; Zhou, T; Zhang, C X; Chong, K Y; Sun, K
Recently genome-wide association studies on East Asian populations reported an association between diabetes and several single nucleotide polymorphisms (SNPs) in a 40-kb linkage disequilibrium block in intron 15 of KCNQ1. However, the association between KCNQ1 variants and type 2 diabetes mellitus (T2DM) in Chinese Kazakh populations is unknown. We investigated the relationship between rs2237892 and rs2237895 SNPs in KCNQ1 and susceptibility to and clinical characteristics of T2DM in 100 Chinese Kazakh T2DM subjects and 100 healthy subjects. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism and the main anthropometric and biochemical parameters of individuals were assessed in the genotype groups (rs2237892: CC, CT, or TT, and rs2237895: AA, AC, or CC). Genotype distribution and allele frequencies of these two SNPs were not significantly different between T2DM and control groups (P > 0.05). The frequencies of CT and TT genotypes and T allele for the rs2237892 SNP in females with T2DM were significantly higher than that in the control group (genotype: P = 0.016, allele: P = 0.004). However, there were no significant differences among individuals with different genotypes with respect to the rs2237895 SNP (P > 0.05). The main anthropometric and biochemical parameters did not correlate with the rs2237892 or rs2237895 SNPs in the T2DM group (P > 0.05). Thus, the T allele-containing genotypes of the rs2237892 SNP in KCNQ1 may increase the susceptibility to T2DM in female Chinese Kazakh individuals, whereas the rs2237895 SNP may not be associated with T2DM in the Chinese Kazakh population.
Kılıç, Esra; Ertuğrul, İlker; Özer, Sema; Alikaşifoğlu, Mehmet; Aktaş, Dilek; Boduroğlu, Koray; Ütine, Gülen Eda
Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive cardioauditory ion channel disorder characterized by congenital bilateral sensorineural deafness and long QT interval. JLNS is a ventricular repolarization abnormality and is caused by mutations in the KCNQ1 or KCNE1 gene. It has a high mortality rate in childhood due to ventricular tachyarrhythmias, episodes of torsade de pointes which may cause syncope or sudden cardiac death. Here, we present a 4.5-year-old female patient who had a history of syncope and congenital sensorineural deafness. She had a cochlear implant operation at 15 months of age and received an implantable cardioverter defibrillator (ICD) at 3 years of age because of recurrent syncope attacks. Five months after cochlear implant placement, she could say her first words and is now able to speak. With β-blocker therapy and ICD, she has remained syncope-free for a year. On the current admission, the family visited the genetics department to learn about the possibility of prenatal diagnosis of sensorineural deafness, as the mother was 9 weeks pregnant. A diagnosis of JLNS was established for the first time, and a homozygous missense mutation in the KCNQ1 gene (c.128 G>A, p.R243H) was detected. Heterozygous mutations of KCNQ1 were identified in both parents, thereby allowing future prenatal diagnoses. The family obtained prenatal diagnosis for the current pregnancy, and fetal KCNQ1 analysis revealed the same homozygous mutation. The pregnancy was terminated at the 12th week of gestation. The case presented here is the third molecularly confirmed Turkish JLNS case; it emphasizes the importance of timely genetic diagnosis, which allows appropriate genetic counseling and prenatal diagnosis, as well as proper management of the condition.
The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation, some time-dependent activation at very positive potentials, a linear current-voltage relationship and a 10-fold higher sensitivity to chromanol 293B. KCNQ1:KCNE3 channels are expressed in colonic crypts and mediate basolateral K(+) recycling required for Cl(-) secretion. We have previously reported the female-specific anti-secretory effects of oestrogen via KCNQ1:KCNE3 channel inhibition in colonic crypts. This study was designed to determine whether sex and oestrogen regulate the expression and function of KCNQ1 and KCNE3 in rat distal colon. Colonic crypts were isolated from Sprague-Dawley rats and used for whole-cell patch-clamp and to extract total RNA and protein. Sheets of epithelium were used for short-circuit current recordings. KCNE1 and KCNE3 mRNA and protein abundance were significantly higher in male than female crypts. No expression of KCNE2 was found and no difference was observed in KCNQ1 expression between male and female (at oestrus) colonic crypts. Male crypts showed a 2.2-fold higher level of association of KCNQ1 and KCNE3 compared to female cells. In female colonic crypts, KCNQ1 and KCNE3 protein expression fluctuated throughout the oestrous cycle and 17beta-oestradiol (E2 10 nM) produced a rapid (<15 min) dissociation of KCNQ1 and KCNE3 in female crypts only. Whole-cell K(+) currents showed a linear current-voltage relationship in male crypts, while K(+) currents in colonic crypts isolated from females displayed voltage-dependent outward rectification. Currents in isolated male crypts and epithelial sheets were 10-fold more sensitive to specific KCNQ1 inhibitors, such as chromanol 293B and HMR-1556, than in female. The effect of E2 on K(+) currents mediated by KCNQ1 with or without different beta-subunits was assayed from current
Alzamora, Rodrigo; O'Mahony, Fiona; Bustos, Viviana; Rapetti-Mauss, Raphael; Urbach, Valérie; Cid, L Pablo; Sepúlveda, Francisco V; Harvey, Brian J
Abstract The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation, some time-dependent activation at very positive potentials, a linear current–voltage relationship and a 10-fold higher sensitivity to chromanol 293B. KCNQ1:KCNE3 channels are expressed in colonic crypts and mediate basolateral K+ recycling required for Cl− secretion. We have previously reported the female-specific anti-secretory effects of oestrogen via KCNQ1:KCNE3 channel inhibition in colonic crypts. This study was designed to determine whether sex and oestrogen regulate the expression and function of KCNQ1 and KCNE3 in rat distal colon. Colonic crypts were isolated from Sprague–Dawley rats and used for whole-cell patch-clamp and to extract total RNA and protein. Sheets of epithelium were used for short-circuit current recordings. KCNE1 and KCNE3 mRNA and protein abundance were significantly higher in male than female crypts. No expression of KCNE2 was found and no difference was observed in KCNQ1 expression between male and female (at oestrus) colonic crypts. Male crypts showed a 2.2-fold higher level of association of KCNQ1 and KCNE3 compared to female cells. In female colonic crypts, KCNQ1 and KCNE3 protein expression fluctuated throughout the oestrous cycle and 17β-oestradiol (E2 10 nm) produced a rapid (KCNQ1 and KCNE3 in female crypts only. Whole-cell K+ currents showed a linear current–voltage relationship in male crypts, while K+ currents in colonic crypts isolated from females displayed voltage-dependent outward rectification. Currents in isolated male crypts and epithelial sheets were 10-fold more sensitive to specific KCNQ1 inhibitors, such as chromanol 293B and HMR-1556, than in female. The effect of E2 on K+ currents mediated by KCNQ1 with or without different β-subunits was assayed from current–voltage relations
Full Text Available Abstract Background Four single nucleotide polymorphisms (SNPs (rs2237892, rs2237895, rs2237897, and rs2283228 in KCNQ1 are reported to be associated with type 2 diabetes mellitus (T2DM, possibly caused by a reduction in insulin secretion and higher fasting glucose, but the results are inconsistent. We investigated whether these 4 genetic markers are associated with serum lipid metabolism in a middle-aged Chinese Han population. Methods We enrolled 398 consecutive patients, including 180 with premature coronary artery disease (CAD (male KCNQ1. Results The 3 genotypes AA, AC, and CC were present in rs2283228 and rs2237895, and the 3 genotypes CC, CT, and TT were present in rs2237897 and rs2237892. The minor genotypes CC at rs2283228 and TT at rs2237892 were associated with higher levels of TG (P = 0.007 and 0.026, respectively. Furthermore, subjects with the CC genotype at rs2283228 had lower levels of HDL-C and apo A1 than in the other 2 genotype groups (P = 0.052 and 0.055, respectively. No other associations were detected between these 4 SNPs and FBS or other lipid parameters. Conclusions Our data suggest that rs2283228 and rs2237892 in KCNQ1 are associated with lipid metabolism in a middle-aged Chinese Han population.
Xiong, Qinmei; Cao, Qing; Zhou, Qiongqiong; Xie, Jinyan; Shen, Yang; Wan, Rong; Yu, Jianhua; Yan, Sujuan; Marian, Ali J; Hong, Kui
Ventricular tachycardia (VT) is a common manifestation of advanced cardiomyopathies. In a subset of patients with dilated cardiomyopathy, VT is the initial and the cardinal manifestation of the disease. The molecular genetic basis of this subset of dilated cardiomyopathy is largely unknown. We identified 10 patients with dilated cardiomyopathy who presented with VT and sequenced 14 common causal genes for cardiomyopathies and arrhythmias. Functional studies included cellular patch clamp, confocal microscopy, and immunoblotting. We identified nonsynonymous variants in 4 patients, including a rare missense p.R397Q mutation in the KCNQ1 gene in a 60-year-old man who presented with incessant VT and had mild cardiac dysfunction. The p.R397Q mutation was absent in an ethnically matched control group, affected a conserved amino acid, and was predicted by multiple algorithms to be pathogenic. Co-expression of the mutant KCNQ1 with its partner unit KCNE1 was associated with reduced tail current density of slowly activating delayed rectifier K(+) current (IKs). The mutation reduced membrane localization of the protein. Dilated cardiomyopathy with an initial presentation of VT may be a forme fruste of arrhythmogenic cardiomyopathy caused by mutations in genes encoding the ion channels. The findings implicate KCNQ1 as a possible causal gene for arrhythmogenic cardiomyopathy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
Abbott, Geoffrey W; Tai, Kwok-Keung; Neverisky, Daniel L; Hansler, Alex; Hu, Zhaoyang; Roepke, Torsten K; Lerner, Daniel J; Chen, Qiuying; Liu, Li; Zupan, Bojana; Toth, Miklos; Haynes, Robin; Huang, Xiaoping; Demirbas, Didem; Buccafusca, Roberto; Gross, Steven S; Kanda, Vikram A; Berry, Gerard T
Na(+)-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. We found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K(+) channel β subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavioral responsiveness to stress and seizure susceptibility in Kcne2(-/-) mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na(+)-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but was inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K(+) channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activities of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1 but were suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.
Chang, Ya-Sian; Yang, Yi-Wen; Lin, Yen-Nien; Lin, Kuo-Hung; Chang, Kuan-Cheng; Chang, Jan-Gowth
Long QT syndrome (LQTS) is a genetic cardiac disease. Gene mutation affects the structure or function of ion channels that are associated with a high risk of sudden death. The goal of this study was to determine the frequency of KCNQ1, KCNH2, and SCN5A mutations in LQTS in a Taiwanese population. Genomic DNA was extracted from peripheral blood samples obtained from 5 patients with LQTS and the family members of 3 LQTS patients. High resolution melting (HRM) analysis and direct DNA sequencing were used to characterize the KCNQ1, KCNH2, and SCN5A genetic variations. HRM analysis was successfully optimized for 14 of the 16 exons of the KCNQ1, 5 of the 15 exons of the KCNH2, and 23 of the 27 exons of the SCN5A. HRM and direct DNA sequencing was applied to the cohort of 5 cases and some of their family. The genetic testing revealed two pathogenic mutations (p.T309I in KCNQ1 and p.R744fs in KCNH2) and all of the mutational frequencies in KCNQ1 and KCNH2 were 20%. In the two patients who carry the pathogenic mutation presenting with recurrent syncope due to ventricular fibrillation, an implantable cardioverter defibrillator was implanted. We also discovered 11 polymorphisms in KCNQ1, 3 in KCNH2, and 5 in SCN5A. Two-fifths of cases (40%) presented with one of the three major LQTS-causing gene mutations.
Full Text Available Background. Recent studies suggest that mutation of the slow delayed rectifier potassium channel (IKs contributes to familial atrial fibrillation (FAF. In the current study, we identified common genetic variants of KCNQ1 and explored the potential association between KCNQ1 polymorphism with lone AF (LAF. Methods. Clinical data and blood samples were collected from 190 Han Chinese patients with sporadic AF and matched healthy controls. Variants of the KCNQ1 gene were identified using single-strand conformational polymorphism (SSCP analysis. A case-control association study in KCNQ1 identified six known single-nucleotide polymorphisms (SNPs during SSCP screening of the 190 LAF patients and 190 healthy controls. Results. One of the SNPs in KCNQ1 was strongly associated with LAF; significant allelic association was detected rs59233444 (P=0.013, OR=1.469, 95% confidence interval (CI: 1.083–1.993. A multiple regression analysis indicated that rs59233444 is an independent risk factor for LAF. Twelve new variants were identified in KCNQ1, including one in the 5′-UTR, two in the 3′-UTR, six in introns, two synonymous substitutions, and one missense substitution. Variants c.1009C>T, c.1860C>T, and c.+2285C>T were not present in the 190 controls, and the others were identified in controls at various frequencies. Conclusions. rs59233444, a common SNP but not mutation in the coding regions of the KCNQ1 gene, is a risk factor for LAF in Chinese Han population.
Jalily Hasani, Horia; Ganesan, Aravindhan; Ahmed, Marawan; Barakat, Khaled H
The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research. In this work, we present the structural and mechanistic details of potassium ion permeation through an open KCNQ1 structural model using the combined molecular dynamics and steered molecular dynamics simulations. We discuss the processes and key residues involved in the permeation of a potassium ion through the KCNQ1 ion channel, and how the ion permeation is affected by (i) the KCNQ1-KCNE1 interactions and (ii) the binding of chromanol 293B ligand and its derivatives into the complex. The results reveal that interactions between KCNQ1 with KCNE1 causes a pore constriction in the former, which in-turn forms small energetic barriers in the ion-permeation pathway. These findings correlate with the previous experimental reports that interactions of KCNE1 dramatically slows the activation of KCNQ1. Upon ligand-binding onto the complex, the energy-barriers along ion permeation path are more pronounced, as expected, therefore, requiring higher force in our steered-MD simulations. Nevertheless, pulling the ion when a weak blocker is bound to the channel does not necessitate high force in SMD. This indicates that our SMD simulations have been able to discern between strong and week blockers and reveal their influence on potassium ion permeation. The findings presented here will have some implications in understanding the potential off-target interactions of the drugs with the KCNQ1/KCNE1 channel
Grunnet, Morten; Olesen, Søren-Peter; Klaerke, Dan A
All five members of the KCNE beta-subunit family are capable of modulating the KCNQ1 potassium current. We have previously published that the murine variant of KCNE4 inhibits the human KCNQ1 current [J. Physiol. 542 (2002) 119]. Recently, this finding has been challenged by Teng et al., stating...... that the human variant of KCNE4 does not attenuate the KCNQ1 current but does slightly modulate the activation kinetics of the channel after expression in Xenopus laevis oocytes [Biochem. Biophys. Res. Commun. 303 (2003) 808]. In the present study, a detailed investigation on the ability of human and murine KCNE......4 to affect either human or murine KCNQ1 currents has been performed. We find that the hKCNE4 subunit drastically inhibits the hKCNQ1 current after expression in X. laevis oocytes. This inhibitory effect is also observed for both hKCNE4 and mKCNE4 when either of these subunits is co-expressed with mKCNQ...
Amirian, Azam; Dalili, Seyed Mohammad; Zafari, Zahra; Saber, Siamak; Karimipoor, Morteza; Akbari, Vahid; Fazelifar, Amir Farjam; Zeinali, Sirous
Jervell and Lange-Nielsen syndrome is an autosomal recessive disorder caused by mutations in KCNQ1 or KCNE1 genes. The disease is characterized by sensorineural hearing loss and long QT syndrome. Here we present a 3.5-year-old female patient, an offspring of consanguineous marriage, who had a history of recurrent syncope and congenital sensorineural deafness. The patient and the family members were screened for mutations in KCNQ1 gene by linkage analysis and DNA sequencing. DNA sequencing showed a c.1532_1534delG (p. A512Pfs*81) mutation in the KCNQ1 gene in homozygous form. The results of short tandem repeat (STR) markers showed that the disease in the family is linked to the KCNQ1 gene. The mutation was confirmed in the parents in heterozygous form. This is the first report of this variant in KCNQ1 gene in an Iranian family. The data of this study could be used for early diagnosis of the condition in the family and genetic counseling.
Rasmussen, Hanne Borger; Møller, Morten; Knaus, Hans-Günther
In the heart, several K(+) channels are responsible for the repolarization of the cardiac action potential, including transient outward and delayed rectifier K(+) currents. In the present study, the cellular and subcellular localization of the two delayed rectifier K(+) channels, KCNQ1 and ether......-a-go-go-related gene-1 (ERG1), was investigated in the adult rat heart. Confocal immunofluorescence microscopy of atrial and ventricular cells revealed that whereas KCNQ1 labeling was detected in both the peripheral sarcolemma and a structure transversing the myocytes, ERG1 immunoreactivity was confined to the latter....... Immunoelectron microscopy of atrial and ventricular myocytes showed that the ERG1 channel was primarily expressed in the transverse tubular system and its entrance, whereas KCNQ1 was detected in both the peripheral sarcolemma and in the T tubules. Thus, whereas ERG1 displays a very restricted subcellular...
Wang, Yuhong; Zankov, Dimitar P.; Jiang, Min; Zhang, Mei; Henderson, Scott C.; Tseng, Gea-Ny
Our goals are to simultaneously determine the three-dimensional distribution patterns of KCNQ1 and KCNE1 in cardiac myocytes and to study the mechanism and functional implications for variations in KCNQ1/KCNE1 colocalization in myocytes. We monitored the distribution patterns of KCNQ1, KCNE1, and markers for subcellular compartments/organelles using immunofluorescence/confocal microscopy and confirmed the findings in ventricular myocytes by directly observing fluorescently tagged KCNQ1-GFP and KCNE1-dsRed expressed in these cells. We also monitored the effects of stress on KCNQ1-GFP and endoplasmic reticulum (ER) remodeling during live cell imaging. The data showed that 1) KCNE1 maintained a stable cell surface localization, whereas KCNQ1 exhibited variations in the cytosolic compartment (striations versus vesicles) and the degree of presence on the cell surface; 2) the degree of cell surface KCNQ1/KCNE1 colocalization was positively correlated with slow delayed rectifier (IKs) current density; 3) KCNQ1 and calnexin (an ER marker) shared a cytosolic compartment; and 4) in response to stress ([Ca2+]i elevation, oxidative overload, or AT1R stimulation), KCNQ1 exited the cytosolic compartment and trafficked to the cell periphery in vesicles. This was accompanied by partial ER fragmentation. We conclude that the cellular milieu regulates KCNQ1 distribution in cardiac myocytes and that stressful conditions can increase IKs by inducing KCNQ1 movement to the cell surface. This represents a hitherto unrecognized mechanism by which IKs fulfills its function as a repolarization reserve in ventricular myocytes. PMID:24142691
Wang, Yuhong; Zankov, Dimitar P; Jiang, Min; Zhang, Mei; Henderson, Scott C; Tseng, Gea-Ny
Our goals are to simultaneously determine the three-dimensional distribution patterns of KCNQ1 and KCNE1 in cardiac myocytes and to study the mechanism and functional implications for variations in KCNQ1/KCNE1 colocalization in myocytes. We monitored the distribution patterns of KCNQ1, KCNE1, and markers for subcellular compartments/organelles using immunofluorescence/confocal microscopy and confirmed the findings in ventricular myocytes by directly observing fluorescently tagged KCNQ1-GFP and KCNE1-dsRed expressed in these cells. We also monitored the effects of stress on KCNQ1-GFP and endoplasmic reticulum (ER) remodeling during live cell imaging. The data showed that 1) KCNE1 maintained a stable cell surface localization, whereas KCNQ1 exhibited variations in the cytosolic compartment (striations versus vesicles) and the degree of presence on the cell surface; 2) the degree of cell surface KCNQ1/KCNE1 colocalization was positively correlated with slow delayed rectifier (IKs) current density; 3) KCNQ1 and calnexin (an ER marker) shared a cytosolic compartment; and 4) in response to stress ([Ca(2+)]i elevation, oxidative overload, or AT1R stimulation), KCNQ1 exited the cytosolic compartment and trafficked to the cell periphery in vesicles. This was accompanied by partial ER fragmentation. We conclude that the cellular milieu regulates KCNQ1 distribution in cardiac myocytes and that stressful conditions can increase IKs by inducing KCNQ1 movement to the cell surface. This represents a hitherto unrecognized mechanism by which IKs fulfills its function as a repolarization reserve in ventricular myocytes.
Unoki, Hiroyuki; Takahashi, Atsushi; Kawaguchi, Takahisa
We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes....... We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 x 10(-12); OR = 1.26, 95% CI = 1.18-1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2...
Jons, Christian; Moss, Arthur J.; Lopes, Coeli M.; McNitt, Scott; Zareba, Wojciech; Goldenberg, Ilan; Qi, Ming; Wilde, Arthur A. M.; Shimizu, Wataru; Kanters, Jorgen K.; Towbin, Jeffrey A.; Ackerman, Michael J.; Robinson, Jennifer L.
Background: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events.
Asahara, Shun-ichiro; Etoh, Hiroaki; Inoue, Hiroyuki; Teruyama, Kyoko; Shibutani, Yuki; Ihara, Yuka; Kawada, Yukina; Bartolome, Alberto; Hashimoto, Naoko; Matsuda, Tomokazu; Koyanagi-Kimura, Maki; Kanno, Ayumi; Hirota, Yushi; Hosooka, Tetsuya; Nagashima, Kazuaki; Nishimura, Wataru; Inoue, Hiroshi; Matsumoto, Michihiro; Higgins, Michael J; Yasuda, Kazuki; Inagaki, Nobuya; Seino, Susumu; Kasuga, Masato; Kido, Yoshiaki
Genetic factors are important determinants of the onset and progression of diabetes mellitus. Numerous susceptibility genes for type 2 diabetes, including potassium voltage-gated channel, KQT-like subfamily Q, member1 (KCNQ1), have been identified in humans by genome-wide analyses and other studies. Experiments with genetically modified mice have also implicated various genes in the pathogenesis of diabetes. However, the possible effects of the parent of origin for diabetes susceptibility alleles on disease onset have remained unclear. Here, we show that a mutation at the Kcnq1 locus reduces pancreatic β-cell mass in mice by epigenetic modulation only when it is inherited from the father. The noncoding RNA KCNQ1 overlapping transcript1 (Kcnq1ot1) is expressed from the Kcnq1 locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption of Kcnq1 results in reduced Kcnq1ot1 expression as well as the increased expression of cyclin-dependent kinase inhibitor 1C (Cdkn1c), an imprinted gene that encodes a cell cycle inhibitor, only when the mutation is on the paternal allele. Furthermore, histone modification at the Cdkn1c promoter region in pancreatic islets was found to contribute to this phenomenon. Our observations suggest that the Kcnq1 genomic region directly regulates pancreatic β-cell mass and that genomic imprinting may be a determinant of the onset of diabetes mellitus.
van Vliet-Ostaptchouk, J.V.; van Haeften, T.W.; Landman, G.W.D.; Reiling, E.; Kleefstra, N.; Bilo, H.J.G.; Klungel, O.H.; de Boer, A.; van Diemen, C.C.; Wijmenga, C.; Boezen, H.M.; Dekker, J.M.; van 't Riet, E.; Nijpels, G.; Welschen, L.M.C.; Zavrelová, H.; Bruin, E.J.; Elbers, C.C.; Bauer, F.; Onland-Moret, N.C.; van der Schouw, Y.T.; Grobbee, D.E.; Spijkerman, A.M.W.; van der Aa, D.L.; Bik-Simonis, A.M.C.; Eekhoff, E.M.W.; Diamant, M.; Kramer, M.H.H.; Boomsma, D.I.; de Geus, E.J.C.; Willemsen, G.; Slagboom, P.E.; Hofker, M.H.; Hart, L.M.
Background: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on
van Vliet-Ostaptchouk, Jana V; van Haeften, Timon W; Landman, Gijs W D; Reiling, Erwin; Kleefstra, Nanne; Bilo, Henk J G; Klungel, Olaf H; de Boer, Anthonius; van Diemen, Cleo C; Wijmenga, Cisca; Boezen, Hendrika; Dekker, Jacqueline M; van 't Riet, Esther; Nijpels, Giel; Welschen, Laura M C; Zavrelova, Hata; Bruin, Elinda J; Elbers, Clara C; Bauer, Florianne; Onland-Moret, N Charlotte; van der Schouw, Yvonne T; Grobbee, Diederick E; Spijkerman, Annemieke M W; van der A, Daphne L; Simonis-Bik, Annemarie M; Eekhoff, Elisabeth M W; Diamant, Michaela; Kramer, Mark H H; Boomsma, Dorret I; de Geus, Eco J; Willemsen, Gonneke; Slagboom, P Eline; Hofker, Marten H; 't Hart, Leen M
BACKGROUND: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on
Kinoshita, Koshi; Komatsu, Takuto; Nishide, Kohki; Hata, Yukiko; Hisajima, Nozomi; Takahashi, Hiroyuki; Kimoto, Katsuya; Aonuma, Kei; Tsushima, Eikichi; Tabata, Toshihide; Yoshida, Tomoyuki; Mori, Hisashi; Nishida, Kunihiro; Yamaguchi, Yoshiaki; Ichida, Fukiko; Fukurotani, Kenkichi; Inoue, Hiroshi; Nishida, Naoki
KCNQ1 encodes the α subunit of the voltage-gated channel that mediates the cardiac slow delayed rectifier K(+) current (IKs). Here, we report a KCNQ1 allele encoding an A590T mutation [KCNQ1(A590T)] found in a 39-year-old female with a mild QT prolongation. A590 is located in the C-terminal α helical region of KCNQ1 that mediates subunit tetramerization, membrane trafficking, and interaction with Yotiao. This interaction is known to be required for the proper modulation of IKs by cAMP. Since previous studies reported that mutations in the vicinity of A590 impair IKs channel surface expression and function, we examined whether and how the A590T mutation affects the IKs channel. Electrophysiological measurements in HEK-293T cells showed that the A590T mutation caused a reduction in IKs density and a right-shift of the current-voltage relation of channel activation. Immunocytochemical and immunoblot analyses showed the reduced cell surface expression of KCNQ1(A590T) subunit and its rescue by coexpression of the wild-type KCNQ1 [KCNQ1(WT)] subunit. Moreover, KCNQ1(A590T) subunit interacted with Yotiao and had a cAMP-responsiveness comparable to that of KCNQ1(WT) subunit. These findings indicate that the A590 of KCNQ1 subunit plays important roles in the maintenance of channel surface expression and function via a novel mechanism independent of interaction with Yotiao. Copyright © 2014 Elsevier Ltd. All rights reserved.
Li, Jin; Seyler, Claudia; Wiedmann, Felix; Schmidt, Constanze; Schweizer, Patrick A; Becker, Rüdiger; Katus, Hugo A; Thomas, Dierk
Autoimmune-associated proarrhythmia in dilated cardiomyopathy (DCM) is poorly understood. Given the significance of KCNQ1 potassium channels in heart rhythm disorders, we hypothesized that circulating anti-KCNQ1 autoantibodies directly modulate cardiac electrophysiology in DCM patients. The purpose of this pilot study was to characterize ion channel autoantibodies in DCM targeting the cardiac repolarizing K(+) current, IKs, and the underlying KCNQ1 potassium channel. One hundred and fifty DCM patients were screened for anti-KCNQ1 autoantibodies using an enzyme-linked immunosorbent assay. Autoantibodies targeting the extracellular pore domain of the KCNQ1 channel were detected in 6% of study patients. Seropositive individuals exhibited significantly shorter corrected QT intervals when compared with seronegative patients (371 ± 39.9 ms vs. 408 ± 47.9 ms; P = 0.036). There was no difference in clinical severity of heart failure between groups. The functional significance of anti-KCNQ1 antibodies was determined in human embryonic kidney 293 cells expressing KCNQ1/KCNE1 using the whole-cell patch clamp technique. IKs recordings demonstrated a 2.7-fold increase in mean current density on exposure to patients' sera containing anti-KCNQ1 antibodies in contrast to seronegative controls (8.74 ± 1.44 pA/pF vs. 3.26 ± 0.36 pA/pF; P = 0.003). IKs enhancement was not associated with increased KCNQ1 protein levels or altered cell surface expression of the channel. Anti-KCNQ1 autoantibodies found in a subgroup of DCM patients are associated with QT interval shortening and increased IKs current.
Gibor, Gilad; Yakubovich, Daniel; Peretz, Asher; Attali, Bernard
The pore properties and the reciprocal interactions between permeant ions and the gating of KCNQ channels are poorly understood. Here we used external barium to investigate the permeation characteristics of homomeric KCNQ1 channels. We assessed the Ba2+ binding kinetics and the concentration and voltage dependence of Ba2+ steady-state block. Our results indicate that extracellular Ba2+ exerts a series of complex effects, including a voltage-dependent pore blockade as well as unique gating alterations. External barium interacts with the permeation pathway of KCNQ1 at two discrete and nonsequential sites. (a) A slow deep Ba2+ site that occludes the channel pore and could be simulated by a model of voltage-dependent block. (b) A fast superficial Ba2+ site that barely contributes to channel block and mostly affects channel gating by shifting rightward the voltage dependence of activation, slowing activation, speeding up deactivation kinetics, and inhibiting channel inactivation. A model of voltage-dependent block cannot predict the complex impact of Ba2+ on channel gating in low external K+ solutions. Ba2+ binding to this superficial site likely modifies the gating transitions states of KCNQ1. Both sites appear to reside in the permeation pathway as high external K+ attenuates Ba2+ inhibition of channel conductance and abolishes its impact on channel gating. Our data suggest that despite the high degree of homology of the pore region among the various K+ channels, KCNQ1 channels display significant structural and functional uniqueness. PMID:15226366
Wang, Cuicui; Lu, Yu; Cheng, Jing; Zhang, Lei; Liu, Wei; Peng, Weihua; Zhang, Di; Duan, Hong; Han, Dongyi; Yuan, Huijun
Besides expanding the spectrum of KCNQ1 mutations causing Jervell and Lange-Nielsen Syndrome (JLNS), the results showed diversity of its phenotypes, and emphasized the importance of molecular genetic analysis in confirming clinical diagnosis and making diagnosis possible before the emergency symptoms for deaf individuals. This study aimed to investigate four patients from three Chinese families with congenital hearing loss clinically and genetically. Genetic analysis of previously reported deafness genes based on massively parallel sequencing was conducted in more than five thousand Chinese hearing loss patients. Detailed clinical features of the patients with compound heterozygous or homozygous mutations of KCNQ1 gene were collected and analyzed. Compound mutations of KCNQ1 were found to be the genetic etiology of four patients from three families. Among the six KCNQ1 mutations, c.546C > A was identified as a novel mutation, c.965C > T had been reported in JLNS, while c.683 + 5G > A, c.1484_1485delCT, c.905C > T and c.1831G > A were previously reported in LQT1. In addition to congenital profound hearing loss in all subjects, two sibling subjects showed typical JLNS cardiac phenotype of prolonged QTc and recurrent syncopal episodes. One subject presented not only JLNS, but also iron-deficiency anemia and epilepsy. The other subject did not present any cardiac phenotype.
Matsuzaki, Juntaro; Suzuki, Hidekazu; Minegishi, Yuriko; Sugai, Etsuko; Tsugawa, Hitoshi; Yasui, Masato; Hibi, Toshifumi
The widespread use of proton pump inhibitors (PPIs) is known to cause sporadic gastric fundic gland polyps (FGPs). Altered expression and localization of the water or ion transport proteins might contribute to the excess fluid secretion into the cystic lumen for the development of FGPs. We investigated the alteration of the murine gastric fundic mucosa after PPI treatment, and examined the expression of water channel aquaporin-4 (AQP4) and potassium channel KCNQ1, which are expressed only in the parietal cells in the gastric mucosa. Male 5-week-old C57BL/6J mice were administered lansoprazole (LPZ) by subcutaneous injection for 8 weeks. The expression of AQP4 and KCNQ1 were investigated by Western blotting, quantitative RT-PCR, and immunohistochemistry. The expression of mucin-6 (Muc6), pepsinogen, and sonic hedgehog (Shh) were also investigated as mucosal cell lineage markers. Gastric mucosal hyperplasia with multiple cystic dilatations, exhibiting similar histological findings to the FGPs, was observed in the LPZ-treated mice. An increase in the number of AQP4-positive parietal cells and KCNQ1-positive parietal cells was observed. The extension of the distribution of AQP4-positive cells toward the surface of the fundic glands was also observed. The expression levels of AQP4 mRNA and protein were significantly enhanced. The expression of KCNQ1 mRNA was correlated with that of AQP4 mRNA in the LPZ-treated mice. Mucous neck-to-zymogenic cell lineage differentiation was delayed in association with decreased expression of Shh in the LPZ-treated mice. PPI administration increased the number of parietal cells with enhanced expression of AQP4 and KCNQ1.
Riobello, Cristina; Gómez, Juan; Gil-Peña, Helena; Tranche, Salvador; Reguero, Julián R; de la Hera, Jesús M; Delgado, Elías; Calvo, David; Morís, César; Santos, Fernando; Coto-Segura, Pablo; Iglesias, Sara; Alonso, Belén; Alvarez, Victoria; Coto, Eliecer
Several common KCNQ1 gene polymorphisms have been associated with the risk of type 2 diabetes (T2DM) and diabetic nephropathy. This effect is explained by the role of the kcnq1 protein as a potassium channel that in the pancreatic beta-cells drives an electrical signal that facilitates glucose-stimulated insulin secretion. The KCNQ1 gene is also expressed in the kidney, and could thus be implicated in the risk of developing impaired renal function. To test this hypothesis, we genotyped six common KCNQ1 gene variants (three single nucleotide polymorphisms, rs2237892, rs2237895, and rs231362, and three intronic indels) in 681 healthy elderly individuals (>65 years old) from the Spanish Renastur cohort. None of the six variants was associated with T2DM (180 diabetics vs. 581 non-diabetics). The intron 12 insertion allele was associated with a reduced estimated glomerular filtration rate (eGFRKCNQ1 gene in 100 individuals with the extreme eGFR values. We found two rare amino acid changes (p.K393N and p.P408A) and the 393 Asn variant was found only among diabetics (n = 4; p = 0.05). The two rare alleles were present in the two eGFR groups. Our results suggest that a common KCNQ1 intron 12 indel polymorphism is a risk factor for impaired renal function independent of T2DM. If this association is confirmed by others, further research to determine the mechanism that drives this association would be warranted. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Wu, Zhi-Juan; Huang, Yun; Fu, Yi-Cheng; Zhao, Xiao-Jing; Zhu, Chao; Zhang, Yu; Xu, Bin; Zhu, Qing-Lei; Li, Yang
To evaluate the association between a KCNQ1 mutation, R259H, and short QT syndrome (SQTS) and to explore the electrophysiological mechanisms underlying their association. We performed genetic screening of SQTS genes in 25 probands and their family members (63 patients). We used direct sequencing to screen the exons and intron-exon boundaries of candidate genes that encode ion channels which contribute to the repolarization of the ventricular action potential, including KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, CACNA1c, CACNB2b and CACNA2D1. In one of the 25 SQTS probands screened, we discovered a KCNQ1 mutation, R259H. We cloned R259H and transiently expressed it in HEK-293 cells; then, currents were recorded using whole cell patch clamp techniques. R259H-KCNQ1 showed significantly increased current density, which was approximately 3-fold larger than that of wild type (WT) after a depolarizing pulse at 1 s. The steady state voltage dependence of the activation and inactivation did not show significant differences between the WT and R259H mutation (P > 0.05), whereas the time constant of deactivation was markedly prolonged in the mutant compared with the WT in terms of the test potentials, which indicated that the deactivation of R259H was markedly slower than that of the WT. These results suggested that the R259H mutation can effectively increase the slowly activated delayed rectifier potassium current (I Ks) in phase 3 of the cardiac action potential, which may be an infrequent cause of QT interval shortening. R259H is a gain-of-function mutation of the KCNQ1 channel that is responsible for SQTS2. This is the first time that the R259H mutation was detected in Chinese people.
Zhou, Xueyan; Zhu, Jing; Bao, Zejun; Shang, Zhenhai; Wang, Tao; Song, Jinfang; Sun, Juan; Li, Wei; Adelusi, Temitope Isaac; Wang, Yan; Lv, Dongmei; Lu, Qian; Yin, Xiaoxing
Repaglinide is an insulin secretagogue that often exhibits considerable interindividual variability in therapeutic efficacy. The current study was designed to investigate the impact of KCNQ1 genetic polymorphism on the efficacy of repaglinide and furthermore to identify the potential mechanism of action in patients with type 2 diabetes. A total of 305 patients and 200 healthy subjects were genotyped for the KCNQ1 rs2237892 polymorphism, and 82 patients with T2DM were randomized for the oral administration of repaglinide for 8 weeks. HepG2 cells were incubated with repaglinide in the absence or presence of a KCNQ1 inhibitor or the pcDNA3.1-hKCNQ1 plasmid, after which the levels of Akt, IRS-2 and PI(3)K were determined. Our data showed that repaglinide significantly decreased HOMA-IR in patients with T2DM. Furthermore, the level of HOMA-IR was significantly reduced in those patients with CT or TT genotypes than CC homozygotes. The KCNQ1 inhibitor enhanced repaglinide efficacy on insulin resistance, with IRS-2/PI(3)K/Akt signaling being up-regulated markedly. As in our clinical experiment, these data strongly suggest that KCNQ1 genetic polymorphism influences repaglinide response due to the pivotal role of KCNQ1 in regulating insulin resistance through the IRS-2/PI(3)K/Akt signaling pathway. This study was registered in the Chinese Clinical Trial Register on May 14, 2013. (No. ChiCTR-CCC13003536).
Chang, Qing; Wang, Jianjun; Li, Qi; Kim, Yeunjung; Zhou, Binfei; Wang, Yunfeng; Li, Huawei; Lin, Xi
Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1(-/-) mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0-P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner's membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1(-/-) mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
den Uil, Sjoerd H; Coupé, Veerle M H; Linnekamp, Janneke F; van den Broek, Evert; Goos, Jeroen A C M; Delis-van Diemen, Pien M; Belt, Eric J Th; van Grieken, Nicole C T; Scott, Patricia M; Vermeulen, Louis; Medema, Jan Paul; Bril, Herman; Stockmann, Hein B A C; Cormier, Robert T; Meijer, Gerrit A; Fijneman, Remond J A
Colorectal cancer (CRC) is the third most common cancer worldwide. Accurately identifying stage II CRC patients at risk for recurrence is an unmet clinical need. KCNQ1 was previously identified as a tumour suppressor gene and loss of expression was associated with poor survival in patients with CRC liver metastases. In this study the prognostic value of KCNQ1 in stage II and stage III colon cancer patients was examined. KCNQ1 mRNA expression was assessed in 90 stage II colon cancer patients (AMC-AJCCII-90) using microarray gene expression data. Subsequently, KCNQ1 protein expression was evaluated in an independent cohort of 386 stage II and stage III colon cancer patients by immunohistochemistry of tissue microarrays. Low KCNQ1 mRNA expression in stage II microsatellite stable (MSS) colon cancers was associated with poor disease-free survival (DFS) (P=0.025). Loss of KCNQ1 protein expression from epithelial cells was strongly associated with poor DFS in stage II MSS (PKCNQ1 seemed an independent prognostic value in addition to other high-risk parameters like angio-invasion, nodal stage and microsatellite instability-status. We conclude that KCNQ1 is a promising biomarker for prediction of disease recurrence and may aid stratification of patients with stage II MSS colon cancer for adjuvant chemotherapy.
Jiang, Min; Wang, Yuhong; Tseng, Gea-Ny
KCNQ1 and KCNE1 assemble to form the slow delayed rectifier ( I Ks ) channel critical for shortening ventricular action potentials during high β-adrenergic tone. However, too much I Ks under basal conditions poses an arrhythmogenic risk. Our objective is to understand how adult ventricular myocytes regulate the I Ks amplitudes under basal conditions and in response to stress. We express fluorescently tagged KCNQ1 and KCNE1 in adult ventricular myocytes and follow their biogenesis and trafficking paths. We also study the distribution patterns of native KCNQ1 and KCNE1, and their relationship to I Ks amplitudes, in chronically stressed ventricular myocytes, and use COS-7 cell expression to probe the underlying mechanism. We show that KCNQ1 and KCNE1 are both translated in the perinuclear region but traffic by different routes, independent of each other, to their separate subcellular locations. KCNQ1 mainly resides in the jSR (junctional sarcoplasmic reticulum), whereas KCNE1 resides on the cell surface. Under basal conditions, only a small portion of KCNQ1 reaches the cell surface to support the I Ks function. However, in response to chronic stress, KCNQ1 traffics from jSR to the cell surface to boost the I Ks amplitude in a process depending on Ca binding to CaM (calmodulin). In adult ventricular myocytes, KCNE1 maintains a stable presence on the cell surface, whereas KCNQ1 is dynamic in its localization. KCNQ1 is largely in an intracellular reservoir under basal conditions but can traffic to the cell surface and boost the I Ks amplitude in response to stress. © 2017 American Heart Association, Inc.
Wu, Meikui; Takemoto, Makoto; Luo, Huan; Xu, Jian-Jun; Lu, Mei-Hong; Kameyama, Masaki; Takumi, Toru; Song, Wen-Jie
Tricyclodecan-9-yl-xanthogenate (D609) is widely known for its antitumor and antiviral properties via the inhibition of phosphatidylcholine-specific phospholipase C and sphingomyelin synthase. Previously, we found that chronic application of D609 suppressed the K + channel, KCNQ1/KCNE1, more drastically than expected from its actions on the enzymes, suggesting a direct action of D609 on the channel. Here, we aimed to test this possibility by studying the affinity, specificity, and mechanisms of D609 on KCNQ1/KCNE1. The effect of D609 on KCNQ1/KCNE1 was studied using an in vitro expression system and in native cells, using electrophysiological techniques. We found that D609 rapidly and reversibly inhibited KCNQ1/KCNE1 channels expressed in human embryonic kidney 293 T (HEK293T) cells, in a concentration-dependent manner with a high affinity. D609 neither suppressed endogenous K + currents in HEK293T cells, nor inhibited the sustained and transient K + currents of mouse neostriatal neurons, but blocked a KCNQ1/KCNE1-like current in neostriatal neurons. D609 potently blocked I Ks , the cardiac KCNQ1/KCNE1 channel, in guinea pig cardiac muscle cells. The action of D609 on KCNQ1/KCNE1 depended on the usage of the channel, suggesting that D609 binds to the channel in the open state. We identified D609 as a potent and specific open channel blocker of KCNQ1/KCNE1. Because KCNQ1/KCNE1 is highly expressed in the heart, the inner ear and the pancreas, D609, when used as an antitumor or antiviral drug, may affect the function of a number of organs in vivo even when used at low concentrations. Copyright © 2018 Elsevier B.V. All rights reserved.
Full Text Available Background/Aims: KCNQ1OT1 regulates the expression of tissue-specific imprinted genes within the Kcnq1 domain. Imprinted genes are positive regulators of apoptosis, one of the forms of cell death related to cataract formation, and thus may provide novel therapeutic targets for cataract treatment. Here, we studied the role of non-coding RNAs(ncRNA in cataract formation. Methods: Human lens epithelium cells (HLECs were treated with H2O2, and the expression of KCNQ1OT1 and miR-214 was detected by qRT-PCR. The expression of caspase-1 was detected using qRT-PCR, western blot and immunostaining. To confirm our findings in cell cultures, we analysed KCNQ1OT1, miR-214, and caspase-1 expression in lens anterior capsules of both cataract patients and normal controls by qRT-PCR and western blot analysis. Results: We found that the expression of KCNQ1OT1 was increased in both human cataract lens anterior capsular samples and SRA01/04 cell lines treated with H2O2. Knockdown of KCNQ1OT1 expression significantly suppressed H2O2-induced SRA01/04 cell pyroptosis in vitro, which is the critical step in cataract formation. The expression of microRNA-214 (miR-214 was also decreased in cataract lens anterior capsular tissues and H2O2-induced SRA01/04 cell lines. Knockdown of KCNQ1OT1 significantly increased the expression of miR-214. Conclusions: We demonstrated for the first time that caspase-1 is a functional downstream target of miR-214, and knockdown of KCNQ1OT1 reduced the expression of caspase-1. These results provide evidence that the KCNQ1OT1-miR-214-caspase-1 regulatory network is a novel mechanism for promoting cataract formation.
Liu, Lijie; Wang, Fanfan; Lu, Haiying; Ren, Xiaomei; Zou, Jihong
Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic β-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive β-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.
Brunak, Søren; Holmkvist, J; Banasik, K
Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895...... for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228. CONCLUSION: The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk...
Mousavi Nik, Atefeh
Potassium channels are the most diverse and widely distributed membrane protein in all living organisms. They have various roles in the body such as controlling membrane potential, cell volume, and cell migration. Many studies have shown that mutation in these channels is associated with different diseases for example: Hearing Defect, Cardiac Arrhythmia, Episodic Ataxia, Seizure and Neuromyotonia. One of the most important diseases associated with K+ channel mutations is called Jervell and Lange-Nielsen syndrome (JLNS). This disease causes bilateral congenital deafness and the patients also suffer from Long QT and they usually experience syncopal episodes in their life and eventually die as a result of cardiac arrest. The gene KCNQ1 encodes the Kv7.1 voltage gated potassium channel. This channel expresses in apical membrane of marginal cell in stria vasularis of cochlea and secret K+ ion to endolymp to keep the endocochlear potential stable, which is necessary for the inner ear to function properly. Kv7.1 channel also expresses in cardiac myocytes and mutation in this gene is associated with another syndrome called Romano-Ward syndrome (RWS). Although Romano-Ward patients have mutation in KCNQ1, similar to Jervell and Lange-Nielsen patients, they only suffer from cardiac defect, and their hearing is completely normal. Several studies identified that mutations in Kv7.1 gene is associated with JLNS and RWS, but the biophysical and cellular mechanisms of these mutations are still unknown. To determine the cellular mechanisms of JLNS and RWS, and to provide mechanistic insight on the functional outputs of JLNS versus RWS mutations, we generated several mutant forms of the human Kv7.1 ( KCNQ1) clone, using site-directed mutagenesis to define their sub-cellular localization and examined their electrophysiological properties. We identified JLNS and RWS mutations at the S4-S5-linker, the pore loop (P-loop) and the C-terminus of hKv7.1 which have been found to control
Ware, W A; Reina-Doreste, Y; Stern, J A; Meurs, K M
A 5-year-old, healthy English Springer Spaniel died suddenly 4 months after delivering a litter of 7 puppies. Within 4 months of the dam's death, 3 offspring also died suddenly. Abnormal cardiac repolarization, caused by an inherited long QT syndrome, is thought to be responsible for arrhythmias leading to sudden death in this family. Four remaining dogs from the affected litter and 11 related dogs. Physical examination and resting ECG were done on the littermates and 9 related dogs. Additional tests on some or all littermates included echocardiogram with Doppler, Holter monitoring, and routine serum biochemistry. Blood for DNA sequencing was obtained from all 15 dogs. Three of 4 littermates examined, but no other dogs, had prolonged QT intervals with unique T-wave morphology. DNA sequencing of the KCNQ1 gene identified a heterozygous single base pair mutation, unique to these 3 dogs, which changes a conserved amino acid from threonine to lysine and is predicted to change protein structure. This family represents the first documentation in dogs of spontaneous familial QT prolongation, which was associated with a KCNQ1 gene mutation and sudden death. Although the final rhythm could not be documented in these dogs, their phenotypic manifestations of QT interval prolongation and abnormal ECG restitution suggested increased risk for sudden arrhythmic death. The KCNQ1 gene mutation identified is speculated to impair the cardiac repolarizing current IKs, similar to KCNQ1 mutations causing long QT syndrome 1 in humans. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
Siebrands, Cornelia C; Binder, Stephan; Eckhoff, Ulrike
BACKGROUND: Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study...... was to investigate whether the LQT1 mutation A344V in the S6 region of KCNQ1, at a position corresponding to the local anesthetic binding site in HERG, may render drug insensitive KCNQ1 channels into a toxicologically relevant target of these pharmacologic agents. This may suggest that LQTS constitutes not only...... a nonspecific but also a specific pharmacogenetic risk factor for anesthesia. METHODS: The authors examined electrophysiologic and pharmacologic properties of wild-type and mutant KCNQ1 channels. The effects of bupivacaine, ropivacaine, and mepivacaine were investigated using two-electrode voltage clamp...
Jons, Christian; Moss, Arthur J; Lopes, Coeli M
BACKGROUND: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events....... METHODS AND RESULTS: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino......-blocker therapy. CONCLUSIONS: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy Udgivelsesdato: 2009/8...
Dvir, Meidan; Strulovich, Roi; Sachyani, Dana; Ben-Tal Cohen, Inbal; Haitin, Yoni; Dessauer, Carmen; Pongs, Olaf; Kass, Robert; Hirsch, Joel A; Attali, Bernard
KCNQ1 and KCNE1 co-assembly generates the I(KS) K(+) current, which is crucial to the cardiac action potential repolarization. Mutations in their corresponding genes cause long QT syndrome (LQT) and atrial fibrillation. The A-kinase anchor protein, yotiao (also known as AKAP9), brings the I(KS) channel complex together with signaling proteins to achieve regulation upon β1-adrenergic stimulation. Recently, we have shown that KCNQ1 helix C interacts with the KCNE1 distal C-terminus. We postulated that this interface is crucial for I(KS) channel modulation. Here, we examined the yet unknown molecular mechanisms of LQT mutations located at this intracellular intersubunit interface. All LQT mutations disrupted the internal KCNQ1-KCNE1 intersubunit interaction. LQT mutants in KCNQ1 helix C led to a decreased current density and a depolarizing shift of channel activation, mainly arising from impaired phosphatidylinositol-4,5-bisphosphate (PIP2) modulation. In the KCNE1 distal C-terminus, the LQT mutation P127T suppressed yotiao-dependent cAMP-mediated upregulation of the I(KS) current, which was caused by reduced KCNQ1 phosphorylation at S27. Thus, KCNQ1 helix C is important for channel modulation by PIP2, whereas the KCNE1 distal C-terminus appears essential for the regulation of IKS by yotiao-mediated PKA phosphorylation. © 2014. Published by The Company of Biologists Ltd.
Dabrowska-Zamojcin, E; Tarnowski, M; Szydlowski, M; Romanowski, M; Dziedziejko, V; Safranow, K; Domanski, L; Pawlik, A
Post-transplant diabetes mellitus (PTDM) is a metabolic disorder occurring after solid organ transplantation during the therapy with calcineurin inhibitors. ATP-sensitive potassium channels KCNJ11 and KCNQ1 play an important role in the regulation of insulin secretion by β cells and development of diabetes mellitus. Numerous studies have confirmed the association between KCNJ11 and KCNQ1 gene polymorphisms and type 2 diabetes. The aim of this study was to examine the association between KCNJ11 and KCNQ1 gene polymorphisms and posttransplant diabetes mellitus in kidney allograft recipients treated with tacrolimus. The study included 201 patients who received kidney transplants. The patients were subdivided into two subgroups: patients with PTDM (N = 35) and patients without PTDM (N = 166). The association between KCNJ11 and KCNQ1 gene polymorphisms and post-transplant diabetes was studied in three models of univariate Cox regression analysis, i.e., additive, dominant and recessive. In these three models there were no statistically significant associations between KCNJ11 and KCNQ1 gene polymorphisms and PTDM. The results of this study suggest lack of association between KCNJ11 and KCNQ1 gene polymorphisms and post-transplant diabetes mellitus in kidney allograft recipients treated with tacrolimus in the Polish population.
Fabien C Coyan
Full Text Available Phosphatidylinositol-4,5-bisphosphate (PIP2 is a cofactor necessary for the activity of KCNQ1 channels. Some Long QT mutations of KCNQ1, including R243H, R539W and R555C have been shown to decrease KCNQ1 interaction with PIP2. A previous study suggested that R539W is paradoxically less sensitive to intracellular magnesium inhibition than the WT channel, despite a decreased interaction with PIP2. In the present study, we confirm this peculiar behavior of R539W and suggest a molecular mechanism underlying it.COS-7 cells were transfected with WT or mutated KCNE1-KCNQ1 channel, and patch-clamp recordings were performed in giant-patch, permeabilized-patch or ruptured-patch configuration. Similar to other channels with a decreased PIP2 affinity, we observed that the R243H and R555C mutations lead to an accelerated current rundown when membrane PIP2 levels are decreasing. As opposed to R243H and R555C mutants, R539W is not more but rather less sensitive to PIP2 decrease than the WT channel. A molecular model of a fragment of the KCNQ1 C-terminus and the membrane bilayer suggested that a potential novel interaction of R539W with cholesterol stabilizes the channel opening and hence prevents rundown upon PIP2 depletion. We then carried out the same rundown experiments under cholesterol depletion and observed an accelerated R539W rundown that is consistent with this model.We show for the first time that a mutation may shift the channel interaction with PIP2 to a preference for cholesterol. This de novo interaction wanes the sensitivity to PIP2 variations, showing that a mutated channel with a decreased affinity to PIP2 could paradoxically present a slowed current rundown compared to the WT channel. This suggests that caution is required when using measurements of current rundown as an indicator to compare WT and mutant channel PIP2 sensitivity.
Coyan, Fabien C; Abderemane-Ali, Fayal; Amarouch, Mohamed Yassine; Piron, Julien; Mordel, Jérôme; Nicolas, Céline S; Steenman, Marja; Mérot, Jean; Marionneau, Céline; Thomas, Annick; Brasseur, Robert; Baró, Isabelle; Loussouarn, Gildas
Phosphatidylinositol-4,5-bisphosphate (PIP2) is a cofactor necessary for the activity of KCNQ1 channels. Some Long QT mutations of KCNQ1, including R243H, R539W and R555C have been shown to decrease KCNQ1 interaction with PIP2. A previous study suggested that R539W is paradoxically less sensitive to intracellular magnesium inhibition than the WT channel, despite a decreased interaction with PIP2. In the present study, we confirm this peculiar behavior of R539W and suggest a molecular mechanism underlying it. COS-7 cells were transfected with WT or mutated KCNE1-KCNQ1 channel, and patch-clamp recordings were performed in giant-patch, permeabilized-patch or ruptured-patch configuration. Similar to other channels with a decreased PIP2 affinity, we observed that the R243H and R555C mutations lead to an accelerated current rundown when membrane PIP2 levels are decreasing. As opposed to R243H and R555C mutants, R539W is not more but rather less sensitive to PIP2 decrease than the WT channel. A molecular model of a fragment of the KCNQ1 C-terminus and the membrane bilayer suggested that a potential novel interaction of R539W with cholesterol stabilizes the channel opening and hence prevents rundown upon PIP2 depletion. We then carried out the same rundown experiments under cholesterol depletion and observed an accelerated R539W rundown that is consistent with this model. We show for the first time that a mutation may shift the channel interaction with PIP2 to a preference for cholesterol. This de novo interaction wanes the sensitivity to PIP2 variations, showing that a mutated channel with a decreased affinity to PIP2 could paradoxically present a slowed current rundown compared to the WT channel. This suggests that caution is required when using measurements of current rundown as an indicator to compare WT and mutant channel PIP2 sensitivity.
Lee, Hsiang-Chun; Rudy, Yoram; Liang, Hongwu; Chen, Chih-Chieh; Luo, Ching-Hsing; Sheu, Sheng-Hsiung; Cui, Jianmin
Gain-of-function mutations in the pore-forming subunit of I Ks channels, KCNQ1, lead to short QT syndrome (SQTS) and lethal arrhythmias. However, how mutant I Ks channels cause SQTS and the possibility of I Ks -specific pharmacological treatment remain unclear. V141M KCNQ1 is a SQTS associated mutation. We studied its effect on I Ks gating properties and changes in the action potentials (AP) of human ventricular myocytes. Xenopus oocytes were used to study the gating mechanisms of expressed V141M KCNQ1/KCNE1 channels. Computational models were used to simulate human APs in endocardial, mid-myocardial, and epicardial ventricular myocytes with and without β-adrenergic stimulation. V141M KCNQ1 caused a gain-of-function in I Ks characterized by increased current density, faster activation, and slower deactivation leading to I Ks accumulation. V141M KCNQ1 also caused a leftward shift of the conductance-voltage curve compared to wild type (WT) I Ks (V 1/2 = 33.6 ± 4.0 mV for WT, and 24.0 ± 1.3 mV for heterozygous V141M). A Markov model of heterozygous V141M mutant I Ks was developed and incorporated into the O'Hara-Rudy model. Compared to the WT, AP simulations demonstrated marked rate-dependent shortening of AP duration (APD) for V141M, predicting a SQTS phenotype. Transmural electrical heterogeneity was enhanced in heterozygous V141M AP simulations, especially under β-adrenergic stimulation. Computational simulations identified specific I K1 blockade as a beneficial pharmacologic target for reducing the transmural APD heterogeneity associated with V141M KCNQ1 mutation. V141M KCNQ1 mutation shortens ventricular APs and enhances transmural APD heterogeneity under β-adrenergic stimulation. Computational simulations identified I K1 blockers as a potential antiarrhythmic drug of choice for SQTS.
Jana V van Vliet-Ostaptchouk
Full Text Available BACKGROUND: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. METHODOLOGY: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. PRINCIPAL FINDINGS: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002. The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively. In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively. We found no evidence for an association of KCNQ1 with diabetic complications. CONCLUSIONS: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.
Alice A Royal
Full Text Available The slow delayed-rectifier potassium current (IKs is crucial for human cardiac action potential repolarization. The formation of IKs requires co-assembly of the KCNQ1 α-subunit and KCNE1 β-subunit, and mutations in either of these subunits can lead to hereditary long QT syndrome types 1 and 5, respectively. It is widely recognised that the KCNQ1/KCNE1 (Q1/E1 channel requires phosphatidylinositol-4,5-bisphosphate (PIP2 binding for function. We previously identified a cluster of basic residues in the proximal C-terminus of KCNQ1 that form a PIP2/phosphoinositide binding site. Upon charge neutralisation of these residues we found that the channel became more retained in the endoplasmic reticulum, which raised the possibility that channel-phosphoinositide interactions could play a role in channel trafficking. To explore this further we used a chemically induced dimerization (CID system to selectively deplete PIP2 and/or phosphatidylinositol-4-phosphate (PI(4P at the plasma membrane (PM or Golgi, and we subsequently monitored the effects on both channel trafficking and function. The depletion of PIP2 and/or PI(4P at either the PM or Golgi did not alter channel cell-surface expression levels. However, channel function was extremely sensitive to the depletion of PIP2 at the PM, which is in contrast to the response of other cardiac potassium channels tested (Kir2.1 and Kv11.1. Surprisingly, when using the CID system IKs was dramatically reduced even before dimerization was induced, highlighting limitations regarding the utility of this system when studying processes highly sensitive to PIP2 depletion. In conclusion, we identify that the Q1/E1 channel does not require PIP2 or PI(4P for anterograde trafficking, but is heavily reliant on PIP2 for channel function once at the PM.
Maha S. Al-Shammari
Full Text Available Abstract Genome-wide association studies have identified several loci associated with an increased risk for cardiovascular disease (CVD and type 2 diabetes (T2D. Polymorphisms within the KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1 gene are consistently associated with T2D in a number of populations. The current study was undertaken to evaluate the association of 3 polymorphisms of KCNQ1 (rs2237892, rs151290 and rs2237895 with T2D and/or CVD. Patients diagnosed with either T2D (320 patients, CVD (250 patients or both (60 patients and 516 healthy controls were genotyped by TaqMan assay run on a real time PCR thermocycler. A statistically significant association was found for SNPs rs151290 (OR = 1.76; 95%CI = 1.02-3.05; p = 0.0435 and rs2237895 (OR = 2.49; 95%CI = 1.72-3.61; p < 0.0001 with CVD. SNP rs151290 (OR = 7.43; 95%CI = 1.00-55.22; p = 0.0499 showed a strong association in patients with both T2D and CVD. None of the SNPs showed any significant association with T2D. Haploview analysis showed that the ACC (rs151290, rs2237892 and rs2237895 haplotype is the most significant risk allele combination for CVD, while CCA is the most significant risk haplotype for co-morbidity with T2D. KCNQ1 polymorphism at SNPs rs151290 and rs2237895 is strongly associated with CVD in this population, but presented no association with T2D.
Royal, Alice A; Tinker, Andrew; Harmer, Stephen C
The slow delayed-rectifier potassium current (IKs) is crucial for human cardiac action potential repolarization. The formation of IKs requires co-assembly of the KCNQ1 α-subunit and KCNE1 β-subunit, and mutations in either of these subunits can lead to hereditary long QT syndrome types 1 and 5, respectively. It is widely recognised that the KCNQ1/KCNE1 (Q1/E1) channel requires phosphatidylinositol-4,5-bisphosphate (PIP2) binding for function. We previously identified a cluster of basic residues in the proximal C-terminus of KCNQ1 that form a PIP2/phosphoinositide binding site. Upon charge neutralisation of these residues we found that the channel became more retained in the endoplasmic reticulum, which raised the possibility that channel-phosphoinositide interactions could play a role in channel trafficking. To explore this further we used a chemically induced dimerization (CID) system to selectively deplete PIP2 and/or phosphatidylinositol-4-phosphate (PI(4)P) at the plasma membrane (PM) or Golgi, and we subsequently monitored the effects on both channel trafficking and function. The depletion of PIP2 and/or PI(4)P at either the PM or Golgi did not alter channel cell-surface expression levels. However, channel function was extremely sensitive to the depletion of PIP2 at the PM, which is in contrast to the response of other cardiac potassium channels tested (Kir2.1 and Kv11.1). Surprisingly, when using the CID system IKs was dramatically reduced even before dimerization was induced, highlighting limitations regarding the utility of this system when studying processes highly sensitive to PIP2 depletion. In conclusion, we identify that the Q1/E1 channel does not require PIP2 or PI(4)P for anterograde trafficking, but is heavily reliant on PIP2 for channel function once at the PM.
Marcos De Donato
Full Text Available KCNQ1OT1 is located in the region with the highest number of genes showing genomic imprinting, but the mechanisms controlling the genes under its influence have not been fully elucidated. Therefore, we conducted a comparative analysis of the KCNQ1/KCNQ1OT1-CDKN1C region to study its conservation across the best assembled eutherian mammalian genomes sequenced to date and analyzed potential elements that may be implicated in the control of genomic imprinting in this region. The genomic features in these regions from human, mouse, cattle, and dog show a higher number of genes and CpG islands (detected using cpgplot from EMBOSS, but lower number of repetitive elements (including short interspersed nuclear elements and long interspersed nuclear elements, compared with their whole chromosomes (detected by RepeatMasker. The KCNQ1OT1-CDKN1C region contains the highest number of conserved noncoding sequences (CNS among mammals, where we found 16 regions containing about 38 different highly conserved repetitive elements (using mVista, such as LINE1 elements: L1M4, L1MB7, HAL1, L1M4a, L1Med, and an LTR element: MLT1H. From these elements, we found 74 CNS showing high sequence identity (>70% between human, cattle, and mouse, from which we identified 13 motifs (using Multiple Em for Motif Elicitation/Motif Alignment and Search Tool with a significant probability of occurrence, 3 of which were the most frequent and were used to find transcription factor–binding sites. We detected several transcription factors (using JASPAR suite from the families SOX, FOX, and GATA. A phylogenetic analysis of these CNS from human, marmoset, mouse, rat, cattle, dog, horse, and elephant shows branches with high levels of support and very similar phylogenetic relationships among these groups, confirming previous reports. Our results suggest that functional DNA elements identified by comparative genomics in a region densely populated with imprinted mammalian genes may be
Zulfa, Indana; Shim, Eun Bo; Song, Kwang-Soup; Lim, Ki Moo
Atrial fibrillation (AF) is related to mutations at the genetic level. This includes mutations in genes that encode KCNQ1, a subunit of the I Ks channel. Here, we investigate the mechanism of gain-of-function in I Ks towards the occurrence of AF. We used the Courtemanche-Ramirez-Nattel (CRN) human atrial cell model (Am J Physiol Heart Circ Physiol 275:H301-H321, 1998) and applied the modification proposed by Hasegawa et al. (Heart Rhythm 11:67-75, 2014) to fit the behavior of I Ks due to the G229D mutation in KCNQ1 under a heterozygous mutant form. This was incorporated into two-(2D) and three-dimensional (3D) tissue models, where the mutation sustained a reentrant wave. However, under the wild-type condition, the reentrant wave terminated before the end of our simulations (in 2D, the spiral wave terminated before 10 s, while in 3D, the spiral wave terminated before 13 s). Sustained reentry under the mutation conditions also resulted in a spiral wave breakup in the 3D model, which was sustained until the end of the simulation (20 s), indicating AF.
Cordeiro, Jonathan M; Perez, Guillermo J; Schmitt, Nicole
Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2...... borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed.......15 mV for K897T and WT, respectively; p KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest...
Li, Li; Shen, Chao; Yao, Zhaohui; Liang, Jinjun; Huang, Congxin
Atrial fibrillation (AF) is a common type of cardiac arrhythmia and is a major healthcare burden. Around 20% of patients show no obvious clinical manifestations; this can lead to a delay of AF diagnosis and prevention. Genetic mutations are one of the important risk factors for AF. This study aimed to assess the associations between polymorphisms on KCNE1, KCNQ1, and KCNH2 with the risk of AF in a Chinese population. A case-control study comprised of 438 AF patients and 450 controls. The tag single-nucleotide polymorphisms (SNPs) were retrieved in the International HapMap database and Haploview software was used to capture all the polymorphisms on KCNE1, KCNQ1, and KCNH2. DNA was extracted from blood and polymerase chain reaction-based assays were used to genotype polymorphisms of the KCNE1, KCNQ1, and KCNH2 genes. Chi-square test and student t-tests were used to evaluate the differences in the clinical characteristics between AF cases and controls. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated to assess the association between genetic variants of KCNQ1, KCNH2, KCNE1, and AF risk. Among the nine tag SNPs, three were significantly associated with the risk of AF: the rs1805127*G allele on KCNE1, and the rs2283228*C and rs1057128*A alleles on KCNQ1. In contrast, rs1805120*T variant was correlated with lower risk of AF. However, the other five genetic variants (rs2237892, rs2237895, rs2237897, rs2070357, and rs2070356) showed no significant association with AF risk (all p>0.05). Our study suggested that the rs1805127*G allele of KCNE1, and the rs2283228*C and rs1057128*A alleles on KCNQ1 are risk factors for AF, while the rs1805120*T allele on KCNH2 may serve as a protective factor for AF.
Organ-Darling, Louise E.; Vernon, Amanda N.; Giovanniello, Jacqueline R.; Lu, Yichun; Moshal, Karni; Roder, Karim; Li, Weiyan
KCNQ1 and hERG encode the voltage-gated potassium channel α-subunits of the cardiac repolarizing currents IKs and IKr, respectively. These currents function in vivo with some redundancy to maintain appropriate action potential durations (APDs), and loss-of-function mutations in these channels manifest clinically as long QT syndrome, characterized by the prolongation of the QT interval, polymorphic ventricular tachycardia, and sudden cardiac death. Previous cellular electrophysiology experiments in transgenic rabbit cardiomyocytes and heterologous cell lines demonstrated functional downregulation of complementary repolarizing currents. Biochemical assays indicated direct, protein-protein interactions between KCNQ1 and hERG may underlie the interplay between IKs and IKr. Our objective was to investigate hERG-KCNQ1 interactions in the intact cellular environment primarily through acceptor photobleach FRET (apFRET) experiments. We quantitatively assessed the extent of interactions based on fluorophore location and the potential regulation of interactions by physiologically relevant signals. apFRET experiments established specific hERG-KCNQ1 associations in both heterologous and primary cardiomyocytes. The largest FRET efficiency (Ef; 12.0 ± 5.2%) was seen between ion channels with GFP variants fused to the COOH termini. Acute treatment with forskolin + IBMX or a membrane-permeable cAMP analog significantly and specifically reduced the extent of hERG-KCNQ1 interactions (by 41 and 38%, respectively). Our results demonstrate direct interactions between KCNQ1 and hERG occur in both intact heterologous cells and primary cardiomyocytes and are mediated by their COOH termini. Furthermore, this interplay between channel proteins is regulated by intracellular cAMP. PMID:23241319
Ao, Deng; Wang, Hai-Jun; Wang, Li-Fang; Song, Jie-Yun; Yang, Hui-Xia; Wang, Yan
Recent genetic studies have shown that potassium voltage-gated channel, KQT-like subfamily, member1 (KCNQ1) gene is related to gestational diabetes mellitus (GDM). However, studies for the rs2237892 polymorphism in KCNQ1 and GDM remain conflicting in Asians. Furthermore, associations of this polymorphism with glucose levels during oral glucose tolerance test (OGTT) have not been described in Chinese pregnant women. The present study aimed to provide evidence for the associations of rs2237892 in KCNQ1 with GDM and glucose levels, and to systematically evaluate the effect of rs2237892 on GDM in Asians. A case-control study on 562 women with GDM and 453 controls was conducted in Beijing, China. The association of rs2237892 with risk of GDM was analyzed using logistic regression. The associations with quantitative glucose levels were assessed using linear regression models. A meta-analysis including the present case-control study and four previously published reports in Asians was conducted. The rs2237892 polymorphism in KCNQ1 was associated with GDM (OR (95%CI) =1.99(1.26-3.15)). Additionally, the polymorphism was associated with levels of 1h and 2h glucose during OGTT. The pre-pregnancy BMI, age and genotypes of KCNQ1 polymorphism were independent risk factors of GDM. Subsequently, we performed a meta-analysis in Asians. In total, C-allele carriers of rs2237892 polymorphism had a 50% higher risk for GDM (OR (95%CI) =1.50(1.15-1.78)). The study demonstrated for the first time that the KCNQ1 rs2237892 polymorphism was associated with GDM and glucose levels in Chinese women. The study provides systematic evidence for the association between this polymorphism and GDM in Asians.
Julio-Kalajzić, Francisca; Villanueva, Sandra; Burgos, Johanna; Ojeda, Margarita; Cid, L Pablo; Jentsch, Thomas J; Sepúlveda, Francisco V
K + channels are important in intestinal epithelium as they ensure the ionic homeostasis and electrical potential of epithelial cells during anion and fluid secretion. Intestinal epithelium cAMP-activated anion secretion depends on the activity of the (also cAMP dependent) KCNQ1-KCNE3 K + channel, but the secretory process survives after genetic inactivation of the K + channel in the mouse. Here we use double mutant mice to investigate which alternative K + channels come into action to compensate for the absence of KCNQ1-KCNE3 K + channels. Our data establish that whilst Ca 2+ -activated K Ca 3.1 channels are not involved, K 2P two-pore domain TASK-2 K + channels are major players providing an alternative conductance to sustain the intestinal secretory process. Work with double mutant mice lacking both TASK-2 and KCNQ1-KCNE3 channels nevertheless points to yet-unidentified K + channels that contribute to the robustness of the cAMP-activated anion secretion process. Anion and fluid secretion across the intestinal epithelium, a process altered in cystic fibrosis and secretory diarrhoea, is mediated by cAMP-activated CFTR Cl - channels and requires the simultaneous activity of basolateral K + channels to maintain cellular ionic homeostasis and membrane potential. This function is fulfilled by the cAMP-activated K + channel formed by the association of pore-forming KCNQ1 with its obligatory KCNE3 β-subunit. Studies using mice show sizeable cAMP-activated intestinal anion secretion in the absence of either KCNQ1 or KCNE3 suggesting that an alternative K + conductance must compensate for the loss of KCNQ1-KCNE3 activity. We used double mutant mouse and pharmacological approaches to identify such a conductance. Ca 2+ -dependent anion secretion can also be supported by Ca 2+ -dependent K Ca 3.1 channels after independent CFTR activation, but cAMP-dependent anion secretion is not further decreased in the combined absence of K Ca 3.1 and KCNQ1-KCNE3 K + channel activity. We
Murray, Christopher I; Westhoff, Maartje; Eldstrom, Jodene; Thompson, Emely; Emes, Robert; Fedida, David
Cardiac repolarization is determined in part by the slow delayed rectifier current (IKs), through the tetrameric voltage-gated ion channel, KCNQ1, and its β-subunit, KCNE1. The stoichiometry between α and β-subunits has been controversial with studies reporting either a strict 2 KCNE1:4 KCNQ1 or a variable ratio up to 4:4. We used IKs fusion proteins linking KCNE1 to one (EQ), two (EQQ) or four (EQQQQ) KCNQ1 subunits, to reproduce compulsory 4:4, 2:4 or 1:4 stoichiometries. Whole cell and single-channel recordings showed EQQ and EQQQQ to have increasingly hyperpolarized activation, reduced conductance, and shorter first latency of opening compared to EQ - all abolished by the addition of KCNE1. As well, using a UV-crosslinking unnatural amino acid in KCNE1, we found EQQQQ and EQQ crosslinking rates to be progressively slowed compared to KCNQ1, which demonstrates that no intrinsic mechanism limits the association of up to four β-subunits within the IKs complex.
Li, Qing; Tang, Ting-Ting; Jiang, Feng; Zhang, Rong; Chen, Miao; Yin, Jun; Bao, Yu-Qian; Cheng, Xiang; Hu, Cheng; Jia, Wei-Ping
KCNQ1 channel is a member of the voltage-gated potassium channel KQT-like subfamily. The KCNQ1 gene has recently been identified as a susceptibility locus for type 2 diabetes mellitus (T2DM). In the present study, we examined the effects of KCNQ1 variants on the therapeutic response to modified-release gliclazide (gliclazide MR) treatment in Chinese patients newly diagnosed with T2DM. A total of 100 newly diagnosed T2DM patients without a history of any anti-diabetic medications were treated with gliclazide MR for 16 weeks, but 91 patients completed the entire study. The anthropometric parameters were determined at baseline and at the final visit, while clinical laboratory tests were performed at baseline and on weeks 2, 4, 6, 12, 16. Two SNPs, rs2237892 and rs2237895, in the region of the KCNQ1 gene were genotyped in all the participants. All calculations and statistical analyses were conducted using SPSS. The rs2237892 TT homozygotes exhibited significantly higher 2-h glucose levels at baseline (PKCNQ1 polymorphisms are associated with gliclazide MR efficacy in Chinese patients with type 2 diabetes.
Bhuiyan, Zahurul A.; Momenah, Tarek S.; Amin, Ahmad S.; Al-Khadra, Ayman S.; Alders, Marielle; Wilde, Arthur A. M.; Mannens, Marcel M. A. M.
Romano-Ward syndrome (RWs) and Jervell and Lange-Nielsen Syndrome (JLNs) are two inherited arrhythmia disorders caused by monoallelic or bi-allelic mutations, respectively, in the KCNQ1 or KCNE1 genes. Both disorders could cause Long QT syndrome either without deafness (RWs), or with deafness
Li, Yan-yan; Wang, Xiang-ming; Lu, Xin-zheng
The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta-analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random-effect or fixed-effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240-1.480; P KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM. © 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Full Text Available Mutations in imprinted genes or their imprint control regions (ICRs produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte-derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5-E15.5. To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs that overlap known ICRs using EpiTYPER-mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.
Accili Eric A
Full Text Available Abstract Background Mutations in HERG and KCNQ1 potassium channels have been associated with Long QT syndrome and atrial fibrillation, and more recently with sudden infant death syndrome and sudden unexplained death. In other proteins, disease-associated amino acid mutations have been analyzed according to the chemical severity of the changes and the locations of the altered amino acids according to their conservation over metazoan evolution. Here, we present the first such analysis of arrhythmia-associated mutations (AAMs in the HERG and KCNQ1 potassium channels. Results Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains. Non-synonymous single nucleotide polymorphisms (nsSNPs are under-represented at evolutionarily conserved sites in HERG, but distribute randomly in KCNQ1. AAMs are chemically more severe, according to Grantham's Scale, than changes observed in evolution and their severity correlates with the expected chemical severity of the involved codon. Expected chemical severity of a given amino acid also correlates with its relative contribution to arrhythmias. At evolutionarily variable sites, the chemical severity of the changes is also correlated with the expected chemical severity of the involved codon. Conclusion Unlike nsSNPs, AAMs preferentially locate to evolutionarily conserved, and functionally important, sites and regions within HERG and KCNQ1, and are chemically more severe than changes which occur in evolution. Expected chemical severity may contribute to the overrepresentation of certain residues in AAMs, as well as to evolutionary change.
Nishimura, Motoi; Ueda, Marehiko; Ebata, Ryota; Utsuno, Emi; Ishii, Takuma; Matsushita, Kazuyuki; Ohara, Osamu; Shimojo, Naoki; Kobayashi, Yoshio; Nomura, Fumio
According to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel. Here, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants. To the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants.
Aston Christopher E
Full Text Available Abstract Background Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1 gene have been associated with type II diabetes (T2D in Japanese genome-wide association studies (GWAS. More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US. Methods We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US. Results Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362 with T2D showing an allelic odds ratio (OR of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036 and combined cohorts (meta-analysis OR 1.14; p = 0.018. Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008 as well as in combined cohort in meta-analysis (p = 0.009. Conclusions Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.
Jennifer M Frost
Full Text Available Genomic imprinting of the largest known cluster, the Kcnq1/KCNQ1 domain on mChr7/hChr11, displays significant differences between mouse and man. Of the fourteen transcripts in this cluster, imprinting of six is ubiquitous in mice and humans, however, imprinted expression of the other eight transcripts is only found in the mouse placenta. The human orthologues of the latter eight transcripts are biallelically expressed, at least from the first trimester onwards. However, as early development is less divergent between species, placental specific imprinting may be present in very early gestation in both mice and humans.Human embryonic stem (hES cells can be differentiated to embryoid bodies and then to trophoblast stem (EB-TS cells. Using EB-TS cells as a model of post-implantation invading cytotrophoblast, we analysed allelic expression of two telomeric transcripts whose imprinting is placental specific in the mouse, as well as the ncRNA KCNQ1OT1, whose imprinted expression is ubiquitous in early human and mouse development. KCNQ1OT1 expression was monoallelic in all samples but OSBPL5 and NAP1L4 expression was biallelic in EB-TS cells, as well as undifferentiated hES cells and first trimester human fetal placenta. DCN on hChr12, another gene imprinted in the mouse placenta only, was also biallelically expressed in EB-TS cells. The germline maternal methylation imprint at the KvDMR was maintained in both undifferentiated hES cells and EB-TS cells.The question of placental specific imprinting in the human has not been answered fully. Using a model of human trophoblast very early in gestation we show a lack of imprinting of two telomeric genes in the KCNQ1 region and of DCN, whose imprinted expression is placental specific in mice, providing further evidence to suggest that humans do not exhibit placental specific imprinting. The maintenance of both differential methylation of the KvDMR and monoallelic expression of KCNQ1OT1 indicates that the
Viadero, M Teresa; Rubín, Esther; Amigo, Teresa; González-Lamuño, Domingo
This report describes a three-generation family with a severe phenotype of long-QT syndrome-1 (LQTS-1) caused by a single nucleotide mutation in the KQT-like, voltage-gated potassium channel-1 gene (KCNQ1; MIM 607542). Two members of the family died suddenly in their childhood, and all eight surviving members with prolonged QT have a heterozygous missense mutation resulting in a glycine-to-glutamate amino acid substitution at position 316 of the potassium channel. In this family, the newly reported mutation, guanine-to-adenosine at position 947 in the KCNQ1 gene, exhibits a dominant trait of LQTS with complete penetrance, in contrast to the relatively reduced clinical penetrance found in most LQTS cases.
Winkel, Bo Gregers; Larsen, Maiken Kudahl; Berge, Knut Erik
setting. METHODS: DNA for genetic testing was available for 44 cases of sudden unexplained death in Denmark in the period 2000-2006 (equaling 33% of all cases of sudden unexplained death in the age group). KCNQ1, KCNH2, and SCN5A were sequenced and in vitro electrophysiological studies were performed...... on novel mutations. RESULTS: In total, 5 of 44 cases (11%) carried a mutation in 1 of the 3 genes corresponding to 11% of all investigated cases (R190W KCNQ1, F29L KCNH2 (2 cases), P297S KCNH2 and P1177L SCN5A). P1177L SCN5A has not been reported before. In vitro electrophysiological studies of P1177L SCN5...
Liu, Xin; Chen, Zhiyu; Zhao, Xiaoying; Huang, Mingzhu; Wang, Chenchen; Peng, Wei; Yin, Jiliang; Li, Jin; He, Guang; Li, Xin; Zhu, Xiaodong
The present study analyzed Type 2 diabetes mellitus (T2D)-related gene polymorphisms and their impacts on chemotherapeutic response and survival in patients with metastatic gastric cancer (MGC). This retrospective study enrolled 108 MGC patients treated with first-line EOF chemotherapy (epirubicin, oxaliplatin and 5-fluorouracil combination chemotherapy). Eleven single nucleotide polymorphisms of five T2D-related genes were determined. Among the 11 single nucleotide polymorphisms, three (IGF2BP2 rs4402960, IGF2BP2 rs6769511 and KCNQ1 rs163182) were significantly associated with disease control rate and two (GCKR rs780093 and rs780094) were significantly associated with progression-free and overall survival. Our results suggest IGF2BP2 and KCNQ1 polymorphisms might be independent predictors of chemotherapeutic response, while GCKR polymorphisms might be independent predictors of survival in MGC patients treated with first-line EOF chemotherapy. Original submitted 30 June 2014; revision submitted 15 April 2015.
Conclusion: In conclusion, human amniotic fluid mesenchymal stem cells contain a unique epigenetic signature during in vitro cell culture. H19 and KCNQ1OT1 possessed a substantial degree of hypermethylation status, and variable DNA methylation patterns of SNRPN was observed during in vitro cell culture of human amniotic fluid mesenchymal stem cells. Our results urge further understanding of epigenetic status of human amniotic fluid mesenchymal stem cells before it is applied in cell replacement therapy.
Full Text Available KCNQ1 has been identified as a susceptibility gene of type 2 diabetes mellitus (T2DM in Asian populations through genome-wide association studies. However, studies on the association between gene polymorphism of KCNQ1 and T2DM complications remain unclear. To further analyze the association between different alleles at the single nucleotide polymorphism (SNP rs2237892 within KCNQ1 and TD2M and its complications, we conducted a case-control study in a Chinese Han population. The C allele of rs2237892 variant contributed to susceptibility to T2DM (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20–1.75. Genotypes CT (OR, 1.97; 95% CI, 1.24–3.15 and CC (OR, 2.49; 95% CI, 1.57–3.95 were associated with an increased risk of T2DM. Multivariate regression analysis was performed with adjustment of age, gender, and body mass index. We found that systolic blood pressure (P = 0.015, prevalence of hypertension (P = 0.037, and risk of macrovascular disease (OR, 2.10; CI, 1.00–4.45 were significantly higher in subjects with the CC genotype than in the combined population with genotype either CT or TT. Therefore, our data support that KCNQ1 is associated with an increased risk for T2DM and might contribute to the higher incidence of hypertension and macrovascular complications in patients with T2DM carrying the risk allele C though it needs further to be confirmed in a larger population.
Eldstrom, Jodene; Wang, Zhuren; Werry, Daniel; Wong, Nathan; Fedida, David
The slowly activating delayed rectifier current IKs participates in cardiac repolarization, particularly at high heart rates, and mutations in this K(+) channel complex underlie long QT syndrome (LQTS) types 1 and 5. The purpose of this study was to determine biophysical mechanisms of LQT1 through single-channel kinetic analysis of IKs carrying LQT1 mutations in the S3 transmembrane region of the pore-forming subunit KCNQ1. We analyzed cell-attached recordings from mammalian cells in which a single active KCNQ1 (wild type or mutant) and KCNE1 complex could be detected. The S3 mutants of KCNQ1 studied (D202H, I204F, V205M, and S209F), with the exception of S209F, all led to a reduction in channel activity through distinct kinetic mechanisms. D202H, I204F, and V205M showed decreased open probability (Po) compared with wild type (0.07, 0.04, and 0.12 vs 0.2); increased first latency from 1.66 to >2 seconds at +60 mV (I204F, V205M); variable-to-severe reductions in open dwell times (≥50% in V205M); stabilization of closed states (D202H); and an inability of channels to reach full conductance levels (V205M, I204F). S209F is a kinetic gain-of-function mutation with a high Po (0.40) and long open-state dwell times. S3 mutations in KCNQ1 cause diverse kinetic defects in I(Ks), affecting opening and closing properties, and can account for LQT1 phenotypes. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Crotti, Lia; Lahtinen, Annukka M; Spazzolini, Carla; Mastantuono, Elisa; Monti, Maria Cristina; Morassutto, Caterina; Parati, Gianfranco; Heradien, Marshall; Goosen, Althea; Lichtner, Peter; Meitinger, Thomas; Brink, Paul A; Kontula, Kimmo; Swan, Heikki; Schwartz, Peter J
Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers. The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate-corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (P<0.05) and a reduced occurrence of cardiac events (P<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident. 3' Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers. © 2016 American Heart Association, Inc.
Frank S Choveau
Full Text Available Voltage-gated potassium (Kv channels are tetramers, each subunit presenting six transmembrane segments (S1-S6, with each S1-S4 segments forming a voltage-sensing domain (VSD and the four S5-S6 forming both the conduction pathway and its gate. S4 segments control the opening of the intracellular activation gate in response to changes in membrane potential. Crystal structures of several voltage-gated ion channels in combination with biophysical and mutagenesis studies highlighted the critical role of the S4-S5 linker (S4S5L and of the S6 C-terminal part (S6T in the coupling between the VSD and the activation gate. Several mechanisms have been proposed to describe the coupling at a molecular scale. This review summarizes the mechanisms suggested for various voltage-gated ion channels, including a mechanism that we described for KCNQ1, in which S4S5L is acting like a ligand binding to S6T to stabilize the channel in a closed state. As discussed in this review, this mechanism may explain the reverse response to depolarization in HCN-like channels. As opposed to S4S5L, the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2, stabilizes KCNQ1 channel in an open state. Many other ion channels (not only voltage-gated require PIP2 to function properly, confirming its crucial importance as an ion channel co-factor. This is highlighted in cases in which an altered regulation of ion channels by PIP2 leads to channelopathies, as observed for KCNQ1. This review summarizes the state of the art on the two regulatory mechanisms that are critical for KCNQ1 and other voltage-gated channels function (PIP2 and S4-S5L, and assesses their potential physiological and pathophysiological roles.
Zhang, Wanlin; Wang, Hailing; Guan, Xiaomin; Niu, Qing; Li, Wei
KCNQ1 has been identified as a susceptibility gene of type 2 diabetes mellitus (T2DM) in Asian populations through genome-wide association studies. However, studies on the association between gene polymorphism of KCNQ1 and T2DM complications remain unclear. To further analyze the association between different alleles at the single nucleotide polymorphism (SNP) rs2237892 within KCNQ1 and TD2M and its complications, we conducted a case-control study in a Chinese Han population. The C allele of rs2237892 variant contributed to susceptibility to T2DM (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20-1.75). Genotypes CT (OR, 1.97; 95% CI, 1.24-3.15) and CC (OR, 2.49; 95% CI, 1.57-3.95) were associated with an increased risk of T2DM. Multivariate regression analysis was performed with adjustment of age, gender, and body mass index. We found that systolic blood pressure (P=0.015), prevalence of hypertension (P=0.037), and risk of macrovascular disease (OR, 2.10; CI, 1.00-4.45) were significantly higher in subjects with the CC genotype than in the combined population with genotype either CT or TT. Therefore, our data support that KCNQ1 is associated with an increased risk for T2DM and might contribute to the higher incidence of hypertension and macrovascular complications in patients with T2DM carrying the risk allele C though it needs further to be confirmed in a larger population. Copyright © 2015 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.
Chen, Jing; Zhang, Chuangeng; Yang, Weishan; Cao, Zhijian; Li, Wenxin; Chen, Zongyun; Wu, Yingliang
Peptides with Ascaris-type fold are a new kind of toxins founded from venomous animals recently. Functionally, these unique toxin peptides had been identified as potent protease inhibitors, which was similar to other known Ascaris-type peptides from non-venomous animals. Whether Ascaris-type peptides from venom animals have neurotoxin activities remains unclear. Here, a scorpion toxin SjAPI-2 with Ascaris-type fold was characterized to have a neurotoxin activity, which can selectively inhibit KCNQ1 potassium channel. SjAPI-2 had 62 amino acid residues, including 10 cysteine residues. Charged residue analyses showed that two acidic residues of SjAPI-2 were regionally distributed, and 10 basic residues were distributed widely throughout the whole peptide, which was similar to classical potassium channel toxins. Pharmacological studies confirmed that SjAPI-2 was a selective KCNQ1 potassium channel inhibitor with weak effects on other potassium channels, such as Kv1.1, Kv1.2, Kv1.3, SKCa2, SKCa3, and IKCa channels. Concentration-dependent studies showed that SjAPI-2 inhibited the KCNQ1 potassium channel with an IC50 of 771.5±169.9 nM. To the best of our knowledge, SjAPI-2 is the first neurotoxin with a unique Ascaris-type fold, providing novel insights into the divergent evolution of neurotoxins from venomous animals. Copyright © 2015 Elsevier B.V. All rights reserved.
Kapplinger, Jamie D; Erickson, Anders; Asuri, Sirisha; Tester, David J; McIntosh, Sarah; Kerr, Charles R; Morrison, Julie; Tang, Anthony; Sanatani, Shubhayan; Arbour, Laura; Ackerman, Michael J
Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1 -encoded Kv7.1. 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier ( KCNH2- p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Berberine is a plant alkaloid with multiple pharmacological actions, including antidiarrhoeal activity and has been shown to inhibit Cl(-) secretion in distal colon. The aims of this study were to determine the molecular signaling mechanisms of action of berberine on Cl(-) secretion and the ion transporter targets. Monolayers of T84 human colonic carcinoma cells grown in permeable supports were placed in Ussing chambers and short-circuit current measured in response to secretagogues and berberine. Whole-cell current recordings were performed in T84 cells using the patch-clamp technique. Berberine decreased forskolin-induced short-circuit current in a concentration-dependent manner (IC(50) 80 +\\/- 8 muM). In apically permeabilized monolayers and whole-cell current recordings, berberine inhibited a cAMP-dependent and chromanol 293B-sensitive basolateral membrane K(+) current by 88%, suggesting inhibition of KCNQ1 K(+) channels. Berberine did not affect either apical Cl(-) conductance or basolateral Na(+)-K(+)-ATPase activity. Berberine stimulated p38 MAPK, PKCalpha and PKA, but had no effect on p42\\/p44 MAPK and PKCdelta. However, berberine pre-treatment prevented stimulation of p42\\/p44 MAPK by epidermal growth factor. The inhibitory effect of berberine on Cl(-) secretion was partially blocked by HBDDE ( approximately 65%), an inhibitor of PKCalpha and to a smaller extent by inhibition of p38 MAPK with SB202190 ( approximately 15%). Berberine treatment induced an increase in association between PKCalpha and PKA with KCNQ1 and produced phosphorylation of the channel. We conclude that berberine exerts its inhibitory effect on colonic Cl(-) secretion through inhibition of basolateral KCNQ1 channels responsible for K(+) recycling via a PKCalpha-dependent pathway.
Berberine is a plant alkaloid with multiple pharmacological actions, including antidiarrhoeal activity and has been shown to inhibit Cl(-) secretion in distal colon. The aims of this study were to determine the molecular signaling mechanisms of action of berberine on Cl(-) secretion and the ion transporter targets. Monolayers of T84 human colonic carcinoma cells grown in permeable supports were placed in Ussing chambers and short-circuit current measured in response to secretagogues and berberine. Whole-cell current recordings were performed in T84 cells using the patch-clamp technique. Berberine decreased forskolin-induced short-circuit current in a concentration-dependent manner (IC(50) 80 ± 8 μM). In apically permeabilized monolayers and whole-cell current recordings, berberine inhibited a cAMP-dependent and chromanol 293B-sensitive basolateral membrane K(+) current by 88%, suggesting inhibition of KCNQ1 K(+) channels. Berberine did not affect either apical Cl(-) conductance or basolateral Na(+)-K(+)-ATPase activity. Berberine stimulated p38 MAPK, PKCα and PKA, but had no effect on p42\\/p44 MAPK and PKCδ. However, berberine pre-treatment prevented stimulation of p42\\/p44 MAPK by epidermal growth factor. The inhibitory effect of berberine on Cl(-) secretion was partially blocked by HBDDE (∼65%), an inhibitor of PKCα and to a smaller extent by inhibition of p38 MAPK with SB202190 (∼15%). Berberine treatment induced an increase in association between PKCα and PKA with KCNQ1 and produced phosphorylation of the channel. We conclude that berberine exerts its inhibitory effect on colonic Cl(-) secretion through inhibition of basolateral KCNQ1 channels responsible for K(+) recycling via a PKCα-dependent pathway.
Shao, Hong; Zhang, Yanmin; Liu, Liwen; Ma, Zhiling; Zuo, Lei; Ye, Chuang; Wei, Xiaomei; Sun, Chao; Tao, Ling
To explore the relationship between electrocardiographic (ECG) and genetic mutations of patients with hypertrophic cardiomyopathy (HCM), and early ECG changes in HCM patients. Clinical, 12-lead ECG and echocardiographic examination as well as genetic examinations were made in a three-generation Chinses HCM pedigree with 8 family members (4 males). The clinical characterization and ECG parameters were analyzed and their relationship with genotypes in the family was explored. Four missense mutations (MYH7-H1717Q, MYLK2-K324E, KCNQ1-R190W, TMEM70-I147T) were detected in this pedigree. The proband carried all 4 mutations and 5 members carried 2 mutations. Corrected QTc interval of KCNQ1-H1717Q carriers was significantly prolonged and was consistent with the ECG characterization of long QT syndrome. MYLK2-K324E and KCNQ1-R190W carriers presented with Q wave and(or) depressed ST segment, as well as flatted or reversed T waves in leads from anterolateral and inferior ventricular walls. ECG results showed ST segment depression, flat and inverted T wave in the gene mutation carriers with normal echocardiographic examination results. ECG and echocardiographic results were normal in TMEM70-I147T mutation carrier. The combined mutations of the genes associated with cardiac ion channels and HCM are linked with the ECG phenotype changes in this HCM pedigree. The variations in ECG parameters due to the genetic mutation appear earlier than the echocardiography and clinical manifestations. Variation in ECG may become one of the indexes for early diagnostic screening and disease progression of the HCM gene mutation carriers.
Full Text Available Berberine is a plant alkaloid with multiple pharmacological actions, including antidiarrhoeal activity and has been shown to inhibit Cl- secretion in distal colon. The aims of this study were to determine the molecular signalling mechanisms of action of berberine on Cl- secretion and the ion transporter targets. Monolayers of T84 human colonic carcinoma cells grown in permeable supports were placed in Ussing chambers and short-circuit current measured in response to secretagogues and berberine. Whole-cell current recordings were performed in T84 cells using the patch-clamp technique. Berberine decreased forskolin-induced short-circuit current in a concentration-dependent manner (IC50 80 8 M. In apically permeabilized monolayers and whole-cell current recordings, berberine inhibited a cAMP-dependent and chromanol 293B-sensitive basolateral membrane K+ current by 88%, suggesting inhibition of KCNQ1 K+ channels. Berberine did not affect either apical Cl- conductance or basolateral Na+-K+-ATPase activity. Berberine stimulated p38 MAPK, PKC and PKA, but had no effect on p42/p44 MAPK and PKC. However, berberine pre-treatment prevented stimulation of p42/p44 MAPK by epidermal growth factor. The inhibitory effect of berberine on Cl- secretion was partially blocked by HBDDE (65 %, an inhibitor of PKC and to a smaller extent by inhibition of p38 MAPK with SB202190 (15 %. Berberine treatment induced an increase in association between PKC and PKA with KCNQ1 and produced phosphorylation of the channel. We conclude that berberine exerts its inhibitory effect on colonic Cl- secretion through inhibition of basolateral KCNQ1 channels responsible for K+ recycling via a PKC-dependent pathway.
Qian, Yun; Dong, Meihua; Lu, Feng; Li, Huizhang; Jin, Guangfu; Hu, Zhibin; Shen, Chong; Shen, Hongbing
Genome-wide association studies (GWAS) in populations of European ancestry have identified nine single nuclear polymorphisms (SNP) on chromosome 11 related to type 2 diabetes (T2D) susceptibility. Herein, we further evaluate the association of these SNPs and T2D in a Chinese Han population. We performed a case-control study of 2925 T2D cases and 3281 controls to evaluate the association of five SNPs of KCNJ11, MTNR1B, CENTD2 and LOC387761 and T2D in addition to the previously reported four SNPs of KCNQ1. Multiple logistic regression was used to evaluate SNP's effect by adjustment for confounding factor age, sex and BMI. In the first stage, SNPs rs1552224 at CENTD2 were significantly associated with T2D and the association was statistically significant in the whole study population (P = 0.001) although it was not replicated in the second stage. rs1552224 and rs2237897 of KCNQ1 showed significant joint effect on T2D and there was a significant decreased risk of T2D with the number increase of risk alleles (P for trend = 3.81 × 10(-17)). Compared to those without carrying any risk allele, individuals carrying one, two, and three or four risk alleles had a 30.7%, 44.8% and 62.0% decreased risk for developing T2D, respectively. Our finding suggests that genetic variant rs1552224 of CENTD2 on chromosome 11 contributes to an independent effect as well as joint cumulative effect with rs2237897 of KCNQ1 on the risk of T2D in Chinese Han population, and further functional research would be warranted. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Kienitz, Marie-Cécile; Vladimirova, Dilyana
Cardiac KCNQ1/KCNE1 channels (IKs) are dependent on the concentration of membrane phosphatidylinositol-4,5-bisphosphate (PIP2) and on cytosolic ATP by two distinct mechanisms. In this study we measured IKs and FRET between PH-PLCδ-based fluorescent PIP2 sensors in a stable KCNQ1/KCNE1 CHO cell line. Effects of activating either a muscarinic M3 receptor or the switchable phosphatase Ci-VSP on IKs were analyzed. Recovery of IKs from inhibition induced by muscarinic stimulation was incomplete despite full PIP2 resynthesis. Recovery of IKs was completely suppressed under ATP-free conditions, but partially restored by the ATP analog AMP-PCP, providing evidence that depletion of intracellular ATP inhibits IKs independent of PIP2-depletion. Simultaneous patch-clamp and FRET measurements in cells co-expressing Ci-VSP and the PIP2-FRET sensor revealed a component of IKs inhibition directly related to dynamic PIP2-depletion. A second component of inhibition was independent of acute changes in PIP2 and could be mimicked by ATP-free pipette solution, suggesting that it results from intracellular ATP-depletion. The reduction of intracellular ATP upon Ci-VSP activation appears to be independent of its activity as a phosphoinositide phosphatase. Our data demonstrate that ATP-depletion slowed IKs activation but had no short-term effect on PIP2 regeneration, suggesting that impaired PIP2-resynthesis cannot account for the rapid IKs inhibition by ATP-depletion. Furthermore, the second component of IKs inhibition by Ci-VSP was reduced by AMP-PCP in the pipette filling solution, indicating that direct binding of ATP to the KCNQ1/KCNE1 complex is required for voltage activation of IKs. We suggest that fluctuations of the cellular metabolic state regulate IKs in parallel with Gq-coupled PLC activation and PIP2-depletion. Copyright © 2015 Elsevier Inc. All rights reserved.
Full Text Available Abstract Background KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS, an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype. Methods In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis. Results LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P Conclusion Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.
Hasegawa, Kanae; Ohno, Seiko; Ashihara, Takashi; Itoh, Hideki; Ding, Wei-Guang; Toyoda, Futoshi; Makiyama, Takeru; Aoki, Hisaaki; Nakamura, Yoshihide; Delisle, Brian P; Matsuura, Hiroshi; Horie, Minoru
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. In some patients, the disease is inheritable; however, hereditary aspects of AF remain not fully elucidated. The purpose of this study was to identify genetic backgrounds that contribute to juvenile-onset AF and to define the mechanism. In 30 consecutive juvenile-onset AF patients (onset age KCNQ1, KCNH2, KCNE1-3, KCNE5, KCNJ2, SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations. Among the juvenile-onset AF patients, we identified three mutations (10%): SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Because KCNQ1 variant (G229D) identified in a 16-year-old boy was novel, we focused on the proband. The G229D-IKs was found to induce a large instantaneous activating component without deactivation after repolarization to -50 mV. In addition, wild-type (WT)/G229D-IKs (WT and mutant coexpression) displayed both instantaneous and time-dependent activating currents. Compared to WT-IKs, the tail current densities in WT/G229D-IKs were larger at test potentials between -130 and -40 mV but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-IKs resulted in a negative voltage shift for current activation (-35.2 mV) and slower deactivation. WT/G229D-IKs conducted a large outward current induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-IKs results revealed that the mutation shortened atrial but not ventricular action potential. A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF. © 2013 Heart Rhythm Society Published by Heart Rhythm Society All rights reserved.
Wu, Jie; Mizusawa, Yuka; Ohno, Seiko; Ding, Wei-Guang; Higaki, Takashi; Wang, Qi; Kohjitani, Hirohiko; Makiyama, Takeru; Itoh, Hideki; Toyoda, Futoshi; James, Andrew F; Hancox, Jules C; Matsuura, Hiroshi; Horie, Minoru
Congenital long QT syndrome (LQTS) caused by compound mutations is usually associated with more severe clinical phenotypes. We identified a LQTS family harboring three compound mutations in different genes (KCNQ1-R174C, hERG-E1039X and SCN5A-E428K). KCNQ1-R174C, hERG-E1039X and SCN5A-E428K mutations and/or relevant wild-type (WT) cDNAs were respectively expressed in mammalian cells. I Ks -like, I Kr -like, I Na -like currents and the functional interaction between KCNQ1-R174C and hERG-E1039X channels were studied using patch-clamp and immunocytochemistry techniques. (1) Expression of KCNQ1-R174C alone showed no I Ks . Co-expression of KCNQ1-WT + KCNQ1-R174C caused a loss-of-function in I Ks and blunted the activation of I Ks in response to isoproterenol. (2) Expression of hERG-E1039X alone and co-expression of hERG-WT + hERG-E1039X negatively shifted inactivation curves and decelerated the recovery time from inactivation. (3) Expression of SCN5A-E428K increased peak I Na , but had no effect on late I Na . (4) I Ks and I Kr interact, and hERG-E1039X caused a loss-of-function in I Ks . (5) Immunocytochemical studies indicated that KCNQ1-R174C is trafficking defective and hERG-E1039X is defective in biosynthesis/degradation, but the abnormities were rescued by co-expression with WT. Thus, KCNQ1-R174C and hERG-E1039X disrupted I Ks and I Kr functions, respectively. The synergistic lesion, caused by KCNQ1-R174C and hERG-E1039X in I Ks , is very likely why patients showed more severe phenotypes in the compound mutation case.
Tzimas, Iliana; Zingraf, Jana-Christin; Bajanowski, Thomas; Poetsch, Micaela
Drowning is one of the most frequent causes of accidental deaths worldwide, and still it remains a diagnosis of exclusion. Moreover, sudden cardiac deaths (SCD) or, if no actual cardiac alterations can be found, sudden unexplained deaths (SUD) represent a major group within mortality statistics as well. This leads to the assumption that there might be a general underlying cause for at least some cases of drowning, SCD, or SUD, for example, genetic aberrations in arrhythmia-associated genes. In the present study, blood samples of 171 corpses found in water (drowning, death after almost drowning, and unclear deaths) were analyzed in 19 known variants of the genes KCNQ1, KCNH2, KCNE1, SCN5A, and NOS1AP by minisequencing. In three variants of NOS1AP, significant differences of allele and/or genotype frequencies could be demonstrated between victims of drowning and published controls as well as own controls. Moreover, similar differences were found comparing unexplained deaths in water and controls. Regarding the other genes, especially one single nucleotide polymorphism (SNP) of KCNQ1 could be associated with drowning. These results propose that performing a molecular autopsy analyzing known variants of arrhythmia-associated genes, in particular NOS1AP, may assist in establishing a cause of death for bodies found in water without clear drowning signs.
Full Text Available BACKGROUND: Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1 have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897 on estimates of glucose stimulated insulin release. METHODOLOGY/PRINCIPAL FINDINGS: Genotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses. Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC 277+/-160 vs. (AC 280+/-164 vs. (AA 299+/-200 pmol/l, p = 0.008 after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007, incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02 among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228. CONCLUSION: The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.
Characterization of a novel KCNQ1 mutation for type 1 long QT syndrome and assessment of the therapeutic potential of a novel IKs activator using patient-specific induced pluripotent stem cell-derived cardiomyocytes.
Ma, Dongrui; Wei, Heming; Lu, Jun; Huang, Dou; Liu, Zhenfeng; Loh, Li Jun; Islam, Omedul; Liew, Reginald; Shim, Winston; Cook, Stuart A
Type 1 long QT syndrome (LQT1) is a common type of cardiac channelopathy associated with loss-of-function mutations of KCNQ1. Currently there is a lack of drugs that target the defected slowly activating delayed rectifier potassium channel (IKs). With LQT1 patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs), we tested the effects of a selective IKs activator ML277 on reversing the disease phenotypes. A LQT1 family with a novel heterozygous exon 7 deletion in the KCNQ1 gene was identified. Dermal fibroblasts from the proband and her healthy father were reprogrammed to hiPSCs and subsequently differentiated into hiPSC-CMs. Compared with the control, LQT1 patient hiPSC-CMs showed reduced levels of wild type KCNQ1 mRNA accompanied by multiple exon skipping mRNAs and a ~50% reduction of the full length Kv7.1 protein. Patient hiPSC-CMs showed reduced IKs current (tail current density at 30 mV: 0.33±0.02 vs. 0.92±0.21, PKCNQ1, we generated hiPSC-CMs that faithfully recapitulated the LQT1 phenotypes that are likely associated with haploinsufficiency and trafficking defect of KCNQ1/Kv7.1. The small molecule ML277 restored IKs function in hiPSC-CMs and could have therapeutic value for LQT1 patients.
Vyas, Bijal; Puri, Ratna D; Namboodiri, Narayanan; Nair, Mohan; Sharma, Deepak; Movva, Sireesha; Saxena, Renu; Bohora, Shomu; Aggarwal, Neeraj; Vora, Amit; Kumar, Jatinder; Singh, Tarandeep; Verma, Ishwar C
Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Full Text Available Abstract Background Long QT syndrome (LQTS is a cardiac disorder characterized by prolonged QT intervals on electrocardiograms (ECG, ventricular arrhythmias, and sudden death. Clinically, two inherited forms of LQTS have been defined: autosomal dominant LQTS or Romano-Ward syndrome (RWS not associated with deafness and autosomal recessive LQTS or Jervell and Lange-Nielsen syndrome (JLNS associated with deafness. Methods A Chinese family with both RWS and JLNS was identified. Family members were diagnosed based on the presence of a prolonged QT interval as seen on a 12-lead ECG and a medical history of syncope, palpitation, and deafness. Mutational studies in the KCNQ1 potassium channel gene were performed using direct DNA sequence analysis and restriction length polymorphism analysis. Results The proband in the Chinese family and her brother had previously been diagnosed with JLNS, and two other members were affected with RWS. The proband was also affected with atrial fibrillation. A single nucleotide substitution of C to T at nucleotide 965 of KCNQ1 was identified, and the mutation resulted in the substitution of a threonine residue at codon 322 by a methionine residue (T322M. The novel heterozygous T322M mutation was identified in two patients with RWS, one member with borderline QTc, and two normal family members. The two JLNS patients in the family carried the homozygous T322M mutation. The T322M mutation was not found in 200 Chinese normal controls. Conclusion Our results suggest that T322M is a novel mutation that caused RWS with high intrafamilial variability in the heterozygous carriers and typical JLNS in the homozygous carriers within this Chinese family. The T322M mutation is the first mutation identified for JLNS in the Chinese population.
Gao, Kaiping; Wang, Jinjin; Li, Linlin; Zhai, Yujia; Ren, Yongcheng; You, Haifei; Wang, Bingyuan; Wu, Xuli; Li, Jianna; Liu, Zichen; Li, Xiong; Huang, Yaxin; Luo, Xin-Ping; Hu, Dongsheng; Ohno, Kinji; Wang, Chongjian
Genetic variants at KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963 have been associated with type 2 diabetes mellitus (T2DM), but the results are contradictory in Chinese populations. The aim of the present study was to investigate the association of these four SNPs with T2DM in a large population of Han Chinese at Henan province, China. Seven-hundred-thirty-six patients with T2DM (cases) and Seven-hundred-sixty-eight healthy glucose-tolerant controls were genotyped for KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963. The association of genetic variants in these four genes with T2DM was analyzed using multivariate logistic regression. Genotypes and allele distributions of KCNQ1 rs151290 were significantly different between the cases and controls (p KCNQ1 were associated with increases risk of T2DM before (OR = 1.482, 95% CI = 1.062-2.069; p = 0.021; OR = 1.544, 95% CI = 1.097-2.172, p = 0.013; and OR = 1.509, 95% CI = 1.097-2.077, p = 0.011, respectively) and after (OR = 1.539, 95% CI = 1.015-2.332, p = 0.042; OR = 1.641, 95% CI = 1.070-2.516, p = 0.023; and OR = 1.582, 95% CI = 1.061-2.358, p = 0.024; respectively) adjustment for sex, age, anthropometric measurements, biochemical indexes, smoking and alcohol consumption. Consistent with results of genotype analysis, the C allele of rs151290 in KCNQ1 was also associated with increased risk of T2DM (OR = 1.166, 95% CI = 1.004-1.355, p = 0.045). No associations between genetic variants of KLF14 rs972283, GCKR rs780094 or MTNR1B rs10830963 and T2DM were detected. The AC and CC genotypes and the C allele of rs151290 in KCNQ1 may be risk factors for T2DM in Han Chinese in Henan province.
Antúnez-Argüelles, Erika; Rojo-Domínguez, Arturo; Arregui-Mena, Ana Leticia; Jacobo-Albavera, Leonor; Márquez, Manlio Fabio; Iturralde-Torres, Pedro; Villarreal-Molina, María Teresa
Sudden death in a child is a devastating event with important medical implications for surviving relatives. Because it may be the first manifestation of unknown inherited cardiac disease, molecular autopsy can be helpful to determine the cause of death and identify at risk family members. The aim of the study was to perform a molecular autopsy in a seven year-old girl with sudden unexplained death, to find evidence supporting the possible pathogenicity of mutations identified in inherited cardiac disease genes, and to clinically and genetically assess first-degree relatives. DNA from the index case was extracted from umbilical cord cells stored at birth, and DNA of first-degree relatives from blood samples. Targeted sequencing was performed using a Haloplex design including 81 cardiogenes. Possible functional consequences of the mutations were analyzed using protein modeling and structural mobility analyses. The child was compound heterozygous for KCNQ1 variants p.Ala300Thr and p.Pro535Thr. Ala300Thr is known to cause long QT syndrome in the homozygous state, while Pro535Thr is novel and of unknown clinical significance. The father and sibling were Ala300Thr heterozygous, and had normal QTc intervals at rest and during exercise. The asymptomatic mother was heterozygous for Pro535Thr, and showed borderline QTc at rest, but prolonged QTc during exercise. Protein modeling predicted that Ala300Thr alters the mobility profile of the Kv7.1 tetramer and Thr535 disrupts a calmodulin-binding site, probably causing co-assembly or trafficking defects of the mutant monomer. Altogether, the evidence strongly suggests that this child was affected with a recessive form of Romano Ward syndrome. Copyright © 2017. Published by Elsevier B.V.
Kienitz, Marie-Cécile; Vladimirova, Dilyana; Müller, Christian; Pott, Lutz; Rinne, Andreas
Activation of G q protein-coupled receptors (G q PCRs) might induce divergent cellular responses, related to receptor-specific activation of different branches of the G q signaling pathway. Receptor-specific desensitization provides a mechanism of effector modulation by restricting the spatiotemporal activation of signaling components downstream of G q We quantified signaling events downstream of G q PCR activation with FRET-based biosensors in CHO and HEK 293 cells. KCNQ1/KCNE1 channels (I Ks ) were measured as a functional readout of receptor-specific activation. Activation of muscarinic M 1 receptors (M 1 -Rs) caused robust and reversible inhibition of I Ks. In contrast, activation of α 1B -adrenergic receptors (α 1B -ARs) induced transient inhibition of I Ks , which turned into delayed facilitation after agonist withdrawal. As a novel finding, we demonstrate that G q PCR-specific kinetics of I Ks modulation are determined by receptor-specific desensitization, evident at the level of Gα q activation, phosphatidylinositol 4,5-bisphosphate (PIP 2 ) depletion, and diacylglycerol production. Sustained I Ks inhibition during M 1 -R stimulation is attributed to robust membrane PIP 2 depletion, whereas the rapid desensitization of α 1B -AR delimits PIP 2 reduction and augments current activation by protein kinase C (PKC). Overexpression of Ca 2+ -independent PKCδ did not affect the time course of α 1B -AR-induced diacylglycerol formation, excluding a contribution of PKCδ to α 1B -AR desensitization. Pharmacological inhibition of Ca 2+ -dependent PKC isoforms abolished fast α 1B receptor desensitization and augmented I Ks reduction, but did not affect I Ks facilitation. These data indicate a contribution of Ca 2+ -dependent PKCs to α 1B -AR desensitization, whereas I Ks facilitation is induced by Ca 2+ -independent PKC isoforms. In contrast, neither inhibition of Ca 2+ -dependent/Ca 2+ -independent isoforms nor overexpression of PKCδ induced M 1 receptor
Hayashi, Mikio; Wang, Jing; Hede, Susanne Edeling
the molecular basis of functional K(+) channels in rodent and human pancreatic ducts (Capan-1, PANC-1, and CFPAC-1) using molecular and electrophysiological techniques. RT-PCR analysis revealed mRNAs for KCNQ1, KCNH2, KCNH5, KCNT1, and KCNT2, as well as KCNN4 coding for the following channels: KVLQT1; HERG; EAG...
Struijk, Johannes J.; Kanters, Jørgen K.; Andersen, M P
been shown to be useful discriminators, but no single ECG parameter has been sufficient to solve the diagnostic problem. In this study we present a method for discrimination among persons with a normal genotype and those with mutations in the KCNQ1 (KvLQT1 or LQT1) and KCNH2 (HERG or LQT2) genes...
Wang, Lifeng; Zuo, Lei; Hu, Jing; Shao, Hong; Lei, Changhui; Qi, Wei; Liu, Ying; Miao, Yunbo; Ma, Xuan; Huang, Christopher L-H; Wang, Bo; Zhou, Xiaodong; Zhang, Yanmin; Liu, Liwen
Hypertrophic cardiomyopathy (HCM) mainly results from autosomal-dominant inherited single heterozygous mutations in cardiac sarcomere genes. Contributions of multiple gene mutations to disease heterogeneity in a three-generation family were investigated. Clinical, electrocardiographic (ECG), and echocardiographic examination in members of a three-generation Chinese family was followed by exon and boarding intron analysis of 96 genes in the proband using second-generation sequencing. The identified mutations were confirmed by bi-directional Sanger sequencing in all family members and 300 healthy controls. Four missense mutations were detected in the family. These were two novel MYH7-H1717Q and MYLK2-K324E mutations accompanied by the KCNQ1-R190W and TMEM70-I147T mutations. The proband carried all four mutations and showed overlapping HCM and LQT1 phenotypes. Five family members each carried two mutations. Subject II-2 only carried TMEM70-I147T. MYH7-H1717Q and TMEM70-I147T came from the paternal side, whereas KCNQ1-R190W and MYLK2-K324E came from the maternal side. Left ventricle mass indices in MYH7-H1717Q carriers were significantly higher than in non-H1717Q carriers (90.05 ± 7.33 g/m(2), 63.20 ± 4.53 g/m(2), respectively, P KCNQ1-R190W carriers showed QTc intervals that were significantly more prolonged than those in non-R190W carriers (472.25 ± 16.18 and 408.50 ± 7.66 ms, respectively, P < 0.05). All MYLK2-K324E carriers showed inverted ECG T waves. The subject with only a TMEM70-I147T mutation showed normal ECG and echocardiographs, suggesting that this had less pathological effects at least in this family. We demonstrate dual LQT1 and HCM phenotypes in this multiple LQT1- and HCM-related gene mutation carrier family for the first time and suggest that LQT-related gene mutations associate with QT interval prolongation and/or arrhythmia in HCM patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For
Full Text Available Abstract Background Recently, several genome-wide and candidate gene association studies have identified many novel genetic loci for type 2 diabetes (T2D; among these genes, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 are the most important. We aimed to determine the effects of these genetic loci associated with T2D in the Chinese Han population of China. Methods Single-nucleotide polymorphisms (SNPs in or near CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 genes were genotyped in a case-control Chinese Han sample living in Beijing, China involving 1024 patients with T2D and 1005 control subjects. Results In Chinese Han, we replicated the associations between 7 genetic loci and T2D, with risk allele-specific odds ratios (ORs as follows: 1.27 (95% CI, 1.11-1.45; p = 0.0008 for CDKAL1-rs10946398, 1.26 (95% CI, 1.08-1.47; p = 0.003 for IGF2BP2-rs4402960, 1.19 (95% CI, 1.04-1.37; p = 0.009 for SLC30A8-rs13266634, 1.22 (95% CI, 1.06-1.41; p = 0.005 for CDKN2A/B-rs10811661, 1.20 (95% CI, 1.01-1.42; p = 0.03 for HHEX-rs5015480, 1.37 (95% CI, 1.19-1.69; p = 1.0 × 10-4 for KCNQ1-rs2237892, and 1.24 (95% CI, 1.01-1.52; p = 0.046 for FTO-rs8050136 after adjustment for age, gender, and body mass index. Not only did an association between WFS1-rs6446482 and early-onset T2D exist in the subgroup analysis, but TCF2-rs7501939 and WFS1-rs6446482 were also confirmed to confer risk for T2D in this meta-analysis. Moreover, the relationship between FTO-rs8050136 and body mass index, together with the effect of CDKAL1-rs10946398 on beta cell function, was also observed in the control individuals. Conclusions Our findings support the important contribution of these genetic loci to susceptibility for T2D in the Chinese Han population in Beijing of China.
Full Text Available Abstract Background Beckwith-Wiedemann syndrome (BWS is a loss-of-imprinting pediatric overgrowth syndrome. The primary features of BWS include macrosomia, macroglossia, and abdominal wall defects. Secondary features that are frequently observed in BWS patients are hypoglycemia, nevus flammeus, polyhydramnios, visceromegaly, hemihyperplasia, cardiac malformations, and difficulty breathing. BWS is speculated to occur primarily as the result of the misregulation of imprinted genes associated with two clusters on chromosome 11p15.5, namely the KvDMR1 and H19/IGF2. A similar overgrowth phenotype is observed in bovine and ovine as a result of embryo culture. In ruminants this syndrome is known as large offspring syndrome (LOS. The phenotypes associated with LOS are increased birth weight, visceromegaly, skeletal defects, hypoglycemia, polyhydramnios, and breathing difficulties. Even though phenotypic similarities exist between the two syndromes, whether the two syndromes are epigenetically similar is unknown. In this study we use control Bos taurus indicus X Bos taurus taurus F1 hybrid bovine concepti to characterize baseline imprinted gene expression and DNA methylation status of imprinted domains known to be misregulated in BWS. This work is intended to be the first step in a series of experiments aimed at determining if LOS will serve as an appropriate animal model to study BWS. Results The use of F1 B. t. indicus x B. t. taurus tissues provided us with a tool to unequivocally determine imprinted status of the regions of interest in our study. We found that imprinting is conserved between the bovine and human in imprinted genes known to be associated with BWS. KCNQ1OT1 and PLAGL1 were paternally-expressed while CDKN1C and H19 were maternally-expressed in B. t. indicus x B. t. taurus F1 concepti. We also show that in bovids, differential methylation exists at the KvDMR1 and H19/IGF2 ICRs. Conclusions Based on these findings we conclude that the
U.S. Department of Health & Human Services — GenBank is the NIH genetic sequence database, an annotated collection of all publicly available DNA sequences. GenBank is designed to provide and encourage access...
Ince Ayu Khairani Kadriah
menggunakan isolat bakteri yang diisolasi dari budidaya udang windu di berbagai daerah di Sulawesi Selatan dan Jawa. Pada penelitian ini digunakan primer spesifik untuk mendeteksi gen-gen virulen toxR gene, hemolysin (vvh gene, dan GyrB gene dengan metode PCR. Dari 35 isolat yang diisolasi, 20 isolat terdeteksi memiliki gen virulensi dan 8 di antaranya memiliki dua gen virulen. Spesies bakteri yang memiliki gen virulen adalah: V.harveyi, V. parahaemolyticus, V. mimicus, dan V. campbelli
v 1. Overview of TrafficGen Application 1 2. Modules 2 3. User Interface 3 3.1 Top-Level MVC Classes 3 3.1.1 TrafficGenView 3 3.1.2...for download on the ARL public web site.4 2. Modules Fig. 2 depicts the various modules that constitute this application. It shows its internal...release; distribution unlimited. 3 A key design concept in use here is the model-view-controller ( MVC ) pattern. In general, the MVC design pattern
Previous studies from our laboratory demonstrated that 17beta-estradiol (E2) rapidly inhibits Cl(-) secretion in rat and human distal colonic epithelium. The inhibition has been shown to occur via targeting of a basolateral K(+) channel identified as the KCNQ1 (KvLQT1) channel. E2 indirectly modulates the channel activity via a cascade of second messengers which are rapidly phosphorylated in response to E2. The anti-secretory mechanism may be the manner by which E2 induces fluid retention in the intestine during periods of high circulating plasma E2. Here we review the sex-dependent and estrous cycle regulation of this novel rapid response to E2. The inhibition of KCNQ1 channel activity and Cl(-) secretion will be of interest in the future in the investigation of the retentive effects of estrogen in female tissue and also in the study of secretory disorders and drugable targets of the intestine.
Previous studies from our laboratory demonstrated that 17beta-estradiol (E2) rapidly inhibits Cl(-) secretion in rat and human distal colonic epithelium. The inhibition has been shown to occur via targeting of a basolateral K(+) channel identified as the KCNQ1 (KvLQT1) channel. E2 indirectly modulates the channel activity via a cascade of second messengers which are rapidly phosphorylated in response to E2. The anti-secretory mechanism may be the manner by which E2 induces fluid retention in the intestine during periods of high circulating plasma E2. Here we review the sex-dependent and estrous cycle regulation of this novel rapid response to E2. The inhibition of KCNQ1 channel activity and Cl(-) secretion will be of interest in the future in the investigation of the retentive effects of estrogen in female tissue and also in the study of secretory disorders and drugable targets of the intestine.
Cabe, Jim; Elliott, Mike
This report summarizes the comprehensive siting, permitting, engineering, design, and costing activities completed by the FutureGen Industrial Alliance, the Department of Energy, and associated supporting subcontractors to develop a first of a kind near zero emissions integrated gasification combined cycle power plant and carbon capture and storage project (IGCC-CCS). With the goal to design, build, and reliably operate the first IGCC-CCS facility, FutureGen would have been the lowest emitting pulverized coal power plant in the world, while providing a timely and relevant basis for coal combustion power plants deploying carbon capture in the future. The content of this report summarizes key findings and results of applicable project evaluations; modeling, design, and engineering assessments; cost estimate reports; and schedule and risk mitigation from initiation of the FutureGen project through final flow sheet analyses including capital and operating reports completed under DOE award DE-FE0000587. This project report necessarily builds upon previously completed siting, design, and development work executed under DOE award DE-FC26- 06NT4207 which included the siting process; environmental permitting, compliance, and mitigation under the National Environmental Policy Act; and development of conceptual and design basis documentation for the FutureGen plant. For completeness, the report includes as attachments the siting and design basis documents, as well as the source documentation for the following: • Site evaluation and selection process and environmental characterization • Underground Injection Control (UIC) Permit Application including well design and subsurface modeling • FutureGen IGCC-CCS Design Basis Document • Process evaluations and technology selection via Illinois Clean Coal Review Board Technical Report • Process flow diagrams and heat/material balance for slurry-fed gasifier configuration • Process flow diagrams and heat/material balance
Wilde, Arthur A.M.; Jongbloed, Rosalie J.E.; Doevendans, Pieter A.; Düren, Donald R.; Hauer, Richard N.W.; Van Langen, Irene M.; Van Tintelen, J. Peter; Smeets, Hubert J.M.; Meyer, Henk; Geelen, Jan L.M.C.
OBJECTIVE: This study was performed to identify a possible relationship between genotype and phenotype in the congenital familial long QT syndrome (cLQTS). BACKGROUND: The cLQTS, which occurs as an autosomal dominant or recessive trait, is characterized by QT-interval prolongation on the
Wilde, A. A.; Jongbloed, R. J.; Doevendans, P. A.; Düren, D. R.; Hauer, R. N.; van Langen, I. M.; van Tintelen, J. P.; Smeets, H. J.; Meyer, H.; Geelen, J. L.
This study was performed to identify a possible relationship between genotype and phenotype in the congenital familial long QT syndrome (cLQTS). The cLQTS, which occurs as an autosomal dominant or recessive trait, is characterized by QT-interval prolongation on the electrocardiogram and torsade de
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GenLab es el nombre que tiene el software diseñado por nosotros, en el cual se modela el proceso meiótico y la fecundación en organismos diploides. El objetivo de esta aplicación es ilustrar el resultado de un cruce determinado, tratando de ser lo más ajustados a la realidad. La modelación de la reproducción sexual se realiza internamente y el GenLab se limita a presentar los resultados según el número de descendencia seleccionado para un cruce específico, esto significa que se puede escoger una gran cantidad de características para los parentales y se puede estudiar la frecuencia de estos en la descendencia. El modelo cuenta con base de datos donde están almacenados algunos de los locus de Drosophila melanogaster junto con su ubicación en centimorgans 1. EI propósito de este modelo es servir como herramienta pedagógica y didáctica tanto en universidades como en colegios, facilitando el aprendizaje de algunos principios básicos de la genética, por lo cual puede ser usado si se cuenta con una conexión a Internet y un navegador visitando http://biologia.unal.edu.co/fidel.
Zemke, Ron; Raines, Claire; Filipczak, Bob
.... With their micromanaged childhoods and tech addictions, Gen Yers require constant feedback-frustrating for the Me Generation that can't let go of the spotlight, and annoying for Gen Xers, sandwiched between the two...
José Jesús Martínez Páez
Full Text Available Esta técnica se basa en el concepto de evolución a través de selección de los mejores individuos, y de los operadores genéticos de selección, reproducción y mutación. Se trata entonces, de definir un espacio de soluciones para el problema que se quiere solucionar, en una cadena de bits. A esto se le conoce como la codificación del cromosoma, donde cada bit, denominado gen tiene cierto significado especial. Inicialmente el algoritmo genera al azar muchas de estas cadenas o seres, es decir, una población, que luego confronta can un ambiente, que es el problema solucionar o función que se quiere optimizar. De esta confrontación o evaluación a que se somete cada ser. Se obtiene información sobre cómo se comporto cada uno. A través de métodos aleatorios, pero con probabilidad de selección proporcional a su comportamiento, es decir, a mejor comportamiento mayor probabilidad, se selecciona una nueva población de seres supuestamente mejores que la generación anterior.
Robert Cailliau (centre), with Geneva's Mayor Alain Vaissade (left) and Jean Erhardt, Secretary General of the Administrative Council of Geneva (right). Geneva recognised the contribution of two CERN people to the reputation of the city last Tuesday when Mayor Alain Vaissade presented the Genève Reconaissante Medal to Tim Berners-Lee and Robert Cailliau. Berners-Lee, who was not able to be present in person, invented the World Wide Web at CERN just over a decade ago, while Cailliau was his first collaborator. Quoting Cailliau, Vaissade said that whilst there is no doubt that something like the Web would have appeared sooner or later, the fact that it happened at CERN, in Geneva, was no accident. Both the Laboratory and the city are places where people from around the world meet and work in harmony.
... has helped advance scientific discoveries worldwide Since its origin 25 years ago, the database of nucleic acid ... by those who conduct the sequencing, mostly individual labs and large-scale sequencing projects. GenBank exchanges data ...
Leahy, Bart D.; Hidalgo, Loretta; Kloberdanz, Cassie
Space advocates need to engage Generation Y (born 1977-1999).This outreach is necessary to recruit the next generation of scientists and engineers to explore Mars. Space advocates in the non-profit, private, and government sectors need to use a combination of technical communication, marketing, and politics, to develop messages that resonate with Gen Y. Until now, space messages have been generated by and for college-educated white males; Gen Y is much more diverse, including as much as one third minorities. Young women, too, need to be reached. My research has shown that messages emphasizing technology, fun, humor, and opportunity are the best means of reaching the Gen Y audience of 60 million (US population is 300 million). The important things space advocates must avoid are talking down to this generation, making false promises, or expecting them to "wait their turn" before they can participate. This is the MTV generation! We need to find ways of engaging Gen Y now to build a future where human beings can live and work on the planet Mars. In addition to the messages themselves, advocates need to keep up with Gen Y' s social networking and use of iPods, cell phones, and the Internet. NASA and space advocacy groups can use these tools for "viral marketing," where young people share targeted space-related information via cell phones or the Internet because they like it. Overall, Gen Y is a socially dynamic and media-savvy group; advocates' space messages need to be sincere, creative, and placed in locations where Gen Y lives. Mars messages must be memorable!
Bolaños Salvatierra, Silvio
En este documento se rebaten críticas hechas por Raventós y Jensen al artículo “Genética y comportamiento”. Cuatro temas fueron seleccionados: 1) se determina que los antipsicóticos aparecieron veinte años después de la concepción hereditaria de la esquizofrenia; 2) se considera que la discusión es altamente pertinente, para nada bizantina o irrelevante, debido que persisten prácticas epistémicas riesgosas en los investigadores genético-conductuales; 3) aunque ninguna conducta humana está exe...
Padullés i Riu, Josep Ma; Terrados, Nicolás; Rodas, Gil; Campos, Narciso
Los últimos avances en el estudio del genoma humano están afectando a diversas áreas de las ciencias relacionadas con el deporte. En los últimos años se ha observado que el número de artículos aparecidos en las revistas científicas relacionados con la genética y el deporte ha sufrido un incremento exponencial. Este hecho pone de manifiesto una inquietud creciente en el mundo científico por el conocimiento y las posibilidades que la genética aplicada a distintas áreas del deporte. Paralelament...
Full Text Available Bekanntlich ist die got. Endung -ē eine Besonderheit, der in den übrigen germ. Sprachen nichts Vergleichbares gegenübersteht. Man nimmt wohl -allgemein an, dass es sich um eine innergot. Neuschöpfung handelt; auch ist eine idg. Endung des Gen. Pl. -ēm; linbelegt. Folgender Erklärungsversuch geht von der Annahme aus, dass die Triebkraft für dfese Neuschöpfupg in der Neigung zur Differenzierung des Maskulinums vom Femininum auf -ō (gibō : dagē zu suchen ist. Diese Neigung ist besonders im Nom. und Gen. bemerkbar.
Riyanti, Eny Ida
Harga minyak mentah dunia yang berfluktuasi dan cadangan minyak yang makin menipis telah mendorongpenggunaan biofuel sebagai bahan bakar alternatif dan mengintensifkan penelitian bioetanol dengan menggunakanmikroba. Identifikasi dan karakterisasi gen-gen yang bertanggung jawab dalam produksi bioetanol (etanologen) danekspresinya pada beberapa inang telah dilakukan untuk meningkatkan produksi bioetanol oleh mikroba. Tulisan inimengulas sumber-sumber gen bioetanol (pdc dan adh) dan ekspresinya ...
R. C. Veloso
Full Text Available RESUMOObjetivou-se com este trabalho verificar a divergência genética entre sete genótipos de frangos tipo caipira da linhagem Redbro utilizando as características de desempenho por meio de técnicas de análise multivariada. Foram utilizados 840 pintos de um dia, machos, distribuídos em delineamento inteiramente ao acaso, dos seguintes genótipos: Caboclo, Carijó, Colorpak, Gigante Negro, Pesadão Vermelho, Pescoço Pelado e Tricolor. Após a consistência dos dados, foram avaliadas as seguintes variáveis: ganho em peso médio diário, consumo de ração médio diário e conversão alimentar, para os períodos: 1 a 28, 1 a 56, 1 a 70 e 1 a 84 dias de idade; peso corporal ao nascimento, aos 28, 56, 70 e aos 84 dias de idade. O desempenho dos genótipos foi avaliado por meio da análise de variância multivariada e da função discriminante linear de Fisher, usando os testes do maior autovalor de Roy e da união-interseção de Roy para as comparações múltiplas. O estudo da divergência genética foi feito por meio da análise por variáveis canônicas e pelo método de otimização de Tocher. Os genótipos Caboclo e Gigante Negro apresentaram médias canônicas diferentes dos demais genótipos. As duas primeiras variáveis canônicas explicaram 97,41% da variação entre os genótipos. A divergência genética entre os genótipos avaliados permitiu a formação de quatro grupos com os seguintes genótipos: grupo 1 - Colorpak; grupo 2 - Pesadão Vermelho e Pescoço Pelado; grupo 3 - Carijó e Tricolor; e grupo 4 - Caboclo e Gigante Negro.
Bueno i Torrens, David, 1965-
Fa unes setmanes un grup suec va relacionar la funció d'un gen anomenat receptor de la vasopressina amb el comportament monògam dels humans. La seva funció és que determinades neurones rebin un senyal neuroquímic, la vasopressina, molt més abundant en cervells masculins [...].
Bidartondo, M.I.; Bruns, T. D.; Blackwell, M.
GenBank, the public repository for nucleotide and protein sequences, is a critical resource for molecular biology, evolutionary biology, and ecology. While some attention has been drawn to sequence errors (1), common annotation errors also reduce the value of this database. In fact, for organisms...
Information Systems Agency for Teleport Gen 3 CAC Subject: CN=SCHENCK.ALFRED.A.1057426639,OU=DISA,OU= PKI ,OU=DoD,O=U.S. Government,C=US Date: 3/7/2014 01:54...SATCOM - Satellite Communications SIPRNET - Secret Internet Protocol Router Network SSC - Small Scale Contingence TRANSEC - Transmission Security UHF
Cross, E. V., III; Perera, J. S.; Hanson, A. M.; English, K.; Vu, L.; Amonette, W.
Each exercise device on the International Space Station (ISS) has a unique, customized software system interface with unique layouts / hierarchy, and operational principles that require significant crew training. Furthermore, the software programs are not adaptable and provide no real-time feedback or motivation to enhance the exercise experience and/or prevent injuries. Additionally, the graphical user interfaces (GUI) of these systems present information through multiple layers resulting in difficulty navigating to the desired screens and functions. These limitations of current exercise device GUI's lead to increased crew time spent on initiating, loading, performing exercises, logging data and exiting the system. To address these limitations a Next Generation One Portal (NextGen One Portal) Crew Countermeasure System (CMS) was developed, which utilizes the latest industry guidelines in GUI designs to provide an intuitive ease of use approach (i.e., 80% of the functionality gained within 5-10 minutes of initial use without/limited formal training required). This is accomplished by providing a consistent interface using common software to reduce crew training, increase efficiency & user satisfaction while also reducing development & maintenance costs. Results from the usability evaluations showed the NextGen One Portal UI having greater efficiency, learnability, memorability, usability and overall user experience than the current Advanced Resistive Exercise Device (ARED) UI used by astronauts on ISS. Specifically, the design of the One-Portal UI as an app interface similar to those found on the Apple and Google's App Store, assisted many of the participants in grasping the concepts of the interface with minimum training. Although the NextGen One-Portal UI was shown to be an overall better interface, observations by the test facilitators noted specific exercise tasks appeared to have a significant impact on the NextGen One-Portal UI efficiency. Future updates to
Rittenhouse, P.; Ren, W.
A Gen IV Materials Handbook is being developed to provide an authoritative single source of highly qualified structural materials information and materials properties data for use in design and analyses of all Generation IV Reactor Systems. The Handbook will be responsive to the needs expressed by all of the principal government, national laboratory, and private company stakeholders of Gen IV Reactor Systems. The Gen IV Materials Handbook Implementation Plan provided here addresses the purpose, rationale, attributes, and benefits of the Handbook and will detail its content, format, quality assurance, applicability, and access. Structural materials, both metallic and ceramic, for all Gen IV reactor types currently supported by the Department of Energy (DOE) will be included in the Gen IV Materials Handbook. However, initial emphasis will be on materials for the Very High Temperature Reactor (VHTR). Descriptive information (e.g., chemical composition and applicable technical specifications and codes) will be provided for each material along with an extensive presentation of mechanical and physical property data including consideration of temperature, irradiation, environment, etc. effects on properties. Access to the Gen IV Materials Handbook will be internet-based with appropriate levels of control. Information and data in the Handbook will be configured to allow search by material classes, specific materials, specific information or property class, specific property, data parameters, and individual data points identified with materials parameters, test conditions, and data source. Details on all of these as well as proposed applicability and consideration of data quality classes are provided in the Implementation Plan. Website development for the Handbook is divided into six phases including (1) detailed product analysis and specification, (2) simulation and design, (3) implementation and testing, (4) product release, (5) project/product evaluation, and (6) product
Full Text Available In the past few years, contributions of molecular biology assays to the investigation of sudden juvenile death have permitted to clarify some of the pathogenetic aspects of sudden arrhythmic death, opening the way to preventive action on victims’ relatives. We reviewed literature on the genetics of sudden juvenile death, and on molecular biology assays performed on autoptic samples. Biological investigation permits the detection of genetic mutations underlying the susceptibility to sudden cardiac death of individuals with rare inherited forms of arrhythmia (Long QT Syndrome, Brugada Syndrome, Lev’s disease etc. through the analysis of critical sequences codifying for ion channel subunits (HERG, KvLQT1, MinK, Mirp1, SCN5A, KCNQ1, KCNH2, KCNE1, KCNE2. The main objective of post-mortem investigation in sudden juvenile death is the detection of treatable monogenic inherited disorders, in order to prevent further deaths among the relatives of the deceased patient.
Full Text Available Equinoxe , revue genevoise de sciences humaines, consacre son dernier numéro à l’émergence et au développement des contre-cultures à Genève depuis la fin des années 1960. Celui-ci se présente comme « une réflexion critique sur trois décennies de pratiques culturelles et sur la manière dont celles-ci sont parvenues non sans heurts à se faire une place dans la cité ». L’intérêt de la démarche réside dans le fait qu’à Genève, contrairement à Berlin, Paris, Barcelone ...
Diesel Gen-Sets are hardly romantic instruments, yet they do save lives. Humming away in the corner for back-up power or emergency generation, this compact form of power supply, keeps hospital lights on, computers going and often proves a vital, if unnoticed addition to festivals and outdoor events. And as many master engine builders have discovered, this is a rapidly growing market. (author)
Nunes Martínez, Virginia
La cistinuria es una aminoaciduria que se transmite de forma autosómica rececesiva. Clínicamente se distinguen 3 formas de cistinuria, tipos I, II y III. Inicialmente identificamos un gen, implicado en el transporte de cistina y aminoácidos básicos, rBAT como responsable de esta enfermedad. Hasta la fecha se han identificado 22 mutaciotles en rBAT responsables de cistinuria. Mediante estudios de mutaciones y ligamiento genético en familias con cistinuria hemos podido demostrar que la enfermed...
Araya-Valverde, Emanuel; Instituto Tecnológico de Costa Rica, Escuela de Ingeniería Forestal; Cartago, Costa Rica; Murillo-Gamboa, Olman; Instituto Tecnológico de Costa Rica, Escuela de Ingeniería Forestal; Cartago, Costa Rica; Aguilar, Gabriel; Universidad de Costa Rica; Rocha, Oscar; Universidad de Costa Rica
Como parte del proyecto Mejoramiento Genético Forestal Asistido por Marcadores Genéticos (Instituto Tecnológico de Costa Rica y Universidad de Costa Rica, financiado por la Fundación CRUSA), se han desarrollado aplicaciones en el programa de mejoramiento genético de especies forestales como teca, melina y pilón. Con la utilización de diez microsatélites se ha podido generar una huella genética para cada uno de los clones de teca de la colección del Instituto Tecnológico de Costa Rica y FUNDEC...
João Monteiro de Pina-Neto
Full Text Available OBJETIVO: Esta revisão sobre aconselhamento genético (AG teve o objetivo de mostrar os conceitos atuais e os princípios filosóficos e éticos aceitos na grande maioria dos países e recomendados pela Organização Mundial da Saúde, as fases do processo, seus resultados e o impacto psicológico de uma doença genética em uma família. FONTES DOS DADOS: Os conceitos apresentados são baseados em uma síntese histórica da literatura sobre AG desde a década de 1930 até o momento atual, sendo que os artigos citados representam os principais trabalhos publicados e que hoje fundamentam a teoria e a prática do AG. SÍNTESE DOS DADOS: O AG modernamente é definido como um processo de comunicação que trata dos problemas humanos relacionados à ocorrência de uma doença genética em uma família. É fundamental que os profissionais da saúde conheçam os aspectos psicológicos desencadeados pela doença genética e como estes aspectos podem ser manejados. Vivemos ainda na genética humana e médica uma fase de predomínio dos aspectos técnicos e científicos e de pouca ênfase no estudo das reações emocionais e dos processos de adaptação das pessoas a estas doenças, o que leva ao baixo entendimento dos clientes sobre os fatos ocorridos, com conseqüências negativas sobre a vida familiar e para a sociedade. CONCLUSÕES: Conclui-se pela necessidade de que as famílias com doenças genéticas sejam encaminhadas para AG e que os profissionais desta área invistam mais na humanização do atendimento, desenvolvendo mais as técnicas do AG psicológico não-diretivo.OBJECTIVE: The objective of this review of genetic counseling (GC is to describe the current concepts and philosophical and ethical principles accepted by the great majority of countries and recommended by the World Health Organization, the stages of the process, its results and the psychological impact that a genetic disease has on a family. SOURCES: The concepts presented are
Sauer, Christopher R. [President & CEO; McEntee, Jarlath [VP Engineering & CTO
ORPC Maine, LLC, a wholly-owned subsidiary of Ocean Renewable Power Company, LLC (collectively ORPC), submits this Final Technical Report for the TidGen® Power System Commercialization Project (Project), partially funded by the U.S. Department of Energy (DE-EE0003647). The Project was built and operated in compliance with the Federal Energy Regulatory Commission (FERC) pilot project license (P-12711) and other permits and approvals needed for the Project. This report documents the methodologies, activities and results of the various phases of the Project, including design, engineering, procurement, assembly, installation, operation, licensing, environmental monitoring, retrieval, maintenance and repair. The Project represents a significant achievement for the renewable energy portfolio of the U.S. in general, and for the U.S. marine hydrokinetic (MHK) industry in particular. The stated Project goal was to advance, demonstrate and accelerate deployment and commercialization of ORPC’s tidal-current based hydrokinetic power generation system, including the energy extraction and conversion technology, associated power electronics, and interconnection equipment capable of reliably delivering electricity to the domestic power grid. ORPC achieved this goal by designing, building and operating the TidGen® Power System in 2012 and becoming the first federally licensed hydrokinetic tidal energy project to deliver electricity to a power grid under a power purchase agreement in North America. Located in Cobscook Bay between Eastport and Lubec, Maine, the TidGen® Power System was connected to the Bangor Hydro Electric utility grid at an on-shore station in North Lubec on September 13, 2012. ORPC obtained a FERC pilot project license for the Project on February 12, 2012 and the first Maine Department of Environmental Protection General Permit issued for a tidal energy project on January 31, 2012. In addition, ORPC entered into a 20-year agreement with Bangor Hydro Electric
Ren, Weiju [ORNL
This document is prepared for navigation and operation of the Gen IV Materials Handbook, with architecture description and new user access initiation instructions. Development rationale and history of the Handbook is summarized. The major development aspects, architecture, and design principles of the Handbook are briefly introduced to provide an overview of its past evolution and future prospects. Detailed instructions are given with examples for navigating the constructed Handbook components and using the main functionalities. Procedures are provided in a step-by-step fashion for Data Upload Managers to upload reports and data files, as well as for new users to initiate Handbook access.
Abha R Gupta
Full Text Available O autismo é um transtorno fortemente genético, com uma herdabilidade estimada de mais de 90%. Uma combinação de heterogeneidade fenotípica e o provável envolvimento de múltiplos loci que interagem entre si dificultam os esforços de descobertas de genes. Conseqüentemente, a etiologia genética dos transtornos relacionados ao autismo permanece, em grande parte, desconhecida. Nos últimos anos, a convergência entre tecnologias genômicas em rápido avanço, a finalização do projeto genoma humano e os crescentes e exitosos esforços em colaboração para aumentar o número de pacientes disponíveis para estudo conduziram às primeiras pistas sólidas sobre as origens biológicas desses transtornos. Este artigo revisará a literatura até nossos dias, resumindo os resultados de estudos de ligação genética, citogenéticos e de genes candidatos com um foco no progresso recente. Além disso, são consideradas as vias promissoras para pesquisas futuras.Autism is a strongly genetic disorder, with an estimated heritability of greater than 90%. A combination of phenotypic heterogeneity and the likely involvement of multiple interacting loci have hampered efforts at gene discovery. As a consequence, the genetic etiology of the spectrum of autism related disorders remains largely unknown. Over the past several years, the convergence of rapidly advancing genomic technologies, the completion of the human genome project, and increasingly successful collaborative efforts to increase the number of patients available for study have led to the first solid clues to the biological origins of these disorders. This paper will review the literature to date summarizing the results of linkage, cytogenetic, and candidate gene studies with a focus on recent progress. In addition, promising avenues for future research are considered.
Madsen, Claus Krogh; Dionisio, Giuseppe; Brinch-Pedersen, Henrik
Den nyeste forskning i kornarternes fytaser viser, hvordan en gen-duplikation for 32-54 mio. år siden påvirker foderkvaliteten i dag.......Den nyeste forskning i kornarternes fytaser viser, hvordan en gen-duplikation for 32-54 mio. år siden påvirker foderkvaliteten i dag....
... Recommendations for Submission to FAA Executive Level NextGen Implementation Metrics--an executive-level set of metrics that capture an overall status of NextGen implementation Other Business/Anticipated Issues for NAC... to the interested public but limited to space availability. With the approval of the chairman...
Full Text Available El alcoholismo es una patología psiquiátrica compleja y de origen multifactorial en la que el factor genético explica alrededor del 50 % del fenómeno. Son numerosos los genes que se han asociado a esta enfermedad, pero su aporte individual es mínimo y contradictorio. Estos genes operan a través de características intermedias como la impulsividad y la sensibilidad al alcohol, lo que hace compleja la definición del fenotipo del alcoholismo. Los estudios de asociación de SNPs, de asociación a todo el genoma, de expresión y epigenéticos han identificado una amplia gama de variantes genéticas y epigenéticas, blancos para los estudios de susceptibilidad, diagnóstico y tratamiento farmacológico. Actualmente se comprenden mucho más estas relaciones y el desarrollo rápido de nuevas metodologías de estudio promete continuar este proceso, así como la generación de algoritmos de diagnóstico, prevención y tratamientos más acertados y confiables.
Bervald, Clauber Mateus Priebe
O uso de seqüências de DNA tem sido à base da genômica comparativa para estudos evolucionários e a transferência de informações de espécies modelo para espécies agrícolas tem revolucionado a genética molecular e estratégias de melhoramento das culturas. A combinação de métodos clássicos de genética e melhoramento com tecnologias moleculares de análise genômica abre uma nova perspectiva para a ampliação do conhecimento das bases genéticas e aceleração de programas de melhoram...
To determine the glycemic index of Gen-Premium. Ten healthy volunteers were included for testing glycemic index of Gen-Premium. After the overnight fast, the subjects consumed 50 grams of glucose (reference food) within five minutes. The blood samples were collected at 0, 30, 60, 90, and 120 minutes for measuring of plasma glucose. One day later the same subjects consumed 50 grams of carbohydrate from Gen-Premium (test food) within five minutes. After complete the data, the glycemic index was calculated by the standard method. The glycemic index of Gen-Premium was 27.29, which classify in low GI food. According to the methodology of glycemic index determination, the glycemic index of Gen-Premium is 27.29, which is considered to be favorably low.
Skidmore, Zachary L; Wagner, Alex H; Lesurf, Robert; Campbell, Katie M; Kunisaki, Jason; Griffith, Obi L; Griffith, Malachi
Visualizing and summarizing data from genomic studies continues to be a challenge. Here, we introduce the GenVisR package to addresses this challenge by providing highly customizable, publication-quality graphics focused on cohort level genome analyses. GenVisR provides a rapid and easy-to-use suite of genomic visualization tools, while maintaining a high degree of flexibility by leveraging the abilities of ggplot2 and Bioconductor. GenVisR is an R package available via Bioconductor (https://bioconductor.org/packages/GenVisR) under GPLv3. Support is available via GitHub (https://github.com/griffithlab/GenVisR/issues) and the Bioconductor support website. email@example.com or firstname.lastname@example.org Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.
Si de nombreux journaux d’écrivains sont à juste titre considérés comme « atelier » d’écriture et « laboratoire » de l’œuvre littéraire, il existe, à côté de la forme bien délimitée des carnets, des journaux (constitués d’entrées datées) dont l’objet principal est de réfléchir à la genèse d’une œuvre en particulier, de témoigner des interrogations, des doutes, des conflits intérieurs, des choix qui président à la phase rédactionnelle, et parfois l’accompagnent. Seront brièvement examinés quat...
Ancel, Ersin; Gheorghe, Adrian; Jones, Sharon Monica
The successful implementation of the next generation infrastructure systems requires solid understanding of their technical, social, political and economic aspects along with their interactions. The lack of historical data that relate to the long-term planning of complex systems introduces unique challenges for decision makers and involved stakeholders which in turn result in unsustainable systems. Also, the need to understand the infrastructure at the societal level and capture the interaction between multiple stakeholders becomes important. This paper proposes a methodology in order to develop a holistic approach aiming to provide an alternative subject-matter expert (SME) elicitation and data collection method for future sociotechnical systems. The methodology is adapted to Next Generation Air Transportation System (NextGen) decision making environment in order to demonstrate the benefits of this holistic approach.
Novi Silvia Hardiany
Full Text Available Kemajuan ilmu biologi molekuler memberikan manfaat dalam bidang kedokteran untuk mengembangkanterapi gen. Tujuan terapi gen adalah untuk memperbaiki kerusakan gen atau mengganti gen yang rusakdengan gen yang normal. Pemindahan gen dilakukan dengan teknik transfeksi. Transfeksi merupakanproses pemindahan asam nukleat baik menggunakan vektor virus (transduksi atau menggunakan metodenonviral yaitu zat kimia, lipid dan metode fisik. Vektor virus yang digunakan pada transduksi adalahretrovirus, adenovirus, adeno-associated virus (AAV dan herpes simplex virus (HSV. Keberhasilantransfeksi ditentukan oleh berbagai faktor yang dapat dapat dinilai dengan menggunakan reporter sepertigreen fluorescence protein (GFP. Kata Kunci: terapi gen, transfeksi non viral, transduksi, vektor virus Methods of Nucleic Acid Transfer as Basic Gene Therapy Abstract The advancement of molecular biology provides benefit in the field of medicine to develop genetherapy. The aim of gene therapy is to repair the genetic damage or to replace damaged gene with thenormal gene. Delivery of gene is carried out by transfection technique, a technique to transfer nucleic acidinto eukaryote cells either using viral vectors (known as transduction, and also using non viral methodsuch as chemical substance, lipid and physical method. Some of the viral vectors used in the transductionare retrovirus, adenovirus, Adeno-associated virus (AAV and Herpes Simplex Virus (HSV. The success oftransfection is determined by various factors which can be assessed using several reporters such as GreenFluorescence Protein (GFP. Key words: gene therapy, non viral transfection, transduction, viral vector. Normal 0 false false false IN X-NONE X-NONE
RxGen is a prescription generator for JPL's in-house optical modeling software package called MACOS (Modeling and Analysis for Controlled Optical Systems), which is an expert optical analysis software package focusing on modeling optics on dynamic structures, deformable optics, and controlled optics. The objectives of RxGen are to simplify and automate MACOS prescription generations, reducing errors associated with creating such optical prescriptions, and improving user efficiency without requiring MACOS proficiency. RxGen uses MATLAB (a high-level language and interactive environment developed by MathWorks) as the development and deployment platform, but RxGen can easily be ported to another optical modeling/analysis platform. Running RxGen within the modeling environment has the huge benefit that variations in optical models can be made an integral part of the modeling state. For instance, optical prescription parameters determined as external functional dependencies, optical variations by controlling the in-/exclusion of optical components like sub-systems, and/or controlling the state of all components. Combining the mentioned capabilities and flexibilities with RxGen's optical abstraction layer completely eliminates the hindering aspects for requiring proficiency in writing/editing MACOS prescriptions, allowing users to focus on the modeling aspects of optical systems, i.e., increasing productivity and efficiency. RxGen provides significant enhancements to MACOS and delivers a framework for fast prototyping as well as for developing very complex controlled optical systems.
Kadek Pramesti Dewi
Full Text Available Karsinoma sel basal (KSB merupakan keganasan kulit non-melanotik tersering dan mempunyai kaitan erat dengan paparan sinar ultra violet (UV. Keganasan ini berasal dari sel-sel pluripotensial stratum basalis epidermis maupun selubung akar folikel rambut. Gambaran klinis dan histopatologis terdiri dari KSB tipe klasik (noduler dan KSB varian (tipe superfisial, fibroepithelial, KSB dengan diferensiasi adneksal, basoskuamous, infiltrating, morpheaform.Kanker pada tubuh manusia muncul karena adanya mutasi genetik pada gen-gen yang terlibat dalamkontrol pertumbuhan sel, seperti onkogen, tumor suppressor gene, gen apoptosis, dan DNA repair gene.Pada kebanyakan kasus KSB, gen yang tersering mengalami mutasi adalah tumor suppressor genep53. Mutasi ini timbul akibat paparan langsung sinar UV, bergantung pada dosis, durasi dan intensitas paparan.Gen p53 dikenal dengan sebutan guardian of the genome, karena fungsinya sebagai sensor terhadapterjadinya kerusakan DNA. Adanya kerusakan DNA menginduksi aktivasi p53 untuk menghentikan siklus sel saat memasuki fase G1, sehingga memberikan kesempatan kepada DNA repair proteinbekerja memperbaiki kerusakan DNA. Lebih dari itu, p53 juga mengaktivasi gen GADD45 (growth arrest and DNA damage untuk membantu perbaikan DNA. Jika perbaikan gagal, p53 akanmengarahkan sel dengan DNA yang rusak ke mesin apoptosis.Pada sel-sel basal terpapar UV, gen p53 mengalami mutasi dan inaktivasi. Karena itu, sel-sel dengan DNA yang mengalami kerusakan non-lethal akan mengalami ekspansi klonal sehingga tumbuh menjadilesi pra kanker dan akhirnya kanker (KSB. [MEDICINA 2014;45:38-42
Nates Parra, Guiomar
El concepto de que el comportamiento de los animales esta determinado genéticamente no es nuevo si se considera que ya Darwin en su famosa obra El origen del hombre, en 1871 mencionaba que… “los rasgos del temperamento de los animales son heredados”. Pero solo hasta hace casi 50 años fue que la genética del comportamiento surgió como una especialidad importante dentro de la Genética; desde esa época muchos son los avances que refuerzan la idea generalmente aceptada de que todos los patrones c...
Full Text Available List Contact us GenLibi Database Description General information of database Database name GenLibi Alternati...sculus Taxonomy ID: 10090 Taxonomy Name: Rattus norvegicus Taxonomy ID: 10116 Database description GenLibi (...bout This Database Database Description Download License Update History of This Database Site Policy | Contact Us Database Description - GenLibi | LSDB Archive ...
Psychrophilic sulfate-reducing bacteria isolated from permanently cold Arctic marine sediments: description of Desulfofrigrus oceanense gen. nov., sp nov., Desulfofrigus fragile sp nov., Desulfofaba gelida gen. nov., sp nov., Desulfotalea psychrophila gen. nov., sp nov and Desulfotalea arctica sp
Knoblauch, C.; Sahm, K.; Jørgensen, BB
known sulfate reducers. Due to the phylogenetic and phenotypic differences between the new isolates and their closest relatives, establishment of the new genera Desulfotalea gen. nov., Desulfofaba gen. nov. and Desulfofrigus gen. nov. is proposed, with strain ASv26(T) as the type strain of the type...
Bellocq, Chloé; van Ginneken, Antoni C. G.; Bezzina, Connie R.; Alders, Mariel; Escande, Denis; Mannens, Marcel M. A. M.; Baró, Isabelle; Wilde, Arthur A. M.
Background - The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2. The present study demonstrates that this
Schmitt, Nicole; Calloe, Kirstine; Nielsen, Nathalie Hélix
The long QT-syndrome is characterized by a prolongation of the QT-interval and tachyarrhythmias causing syncopes and sudden death. We identified the missense mutation M520R in the calmodulin binding domain of the Kv7.1 channel from a German family with long QT-syndrome. Heterologous expression of...
Jongbloed, Rosalie J.E.; Wilde, AAM; Geelen, JLMC; Doevendans, P; Schaap, C; Van Langen, [No Value; van Tintelen, JP; Cobben, JM; Beaufort-Krol, GCM; Geraedts, JPM; Smeets, HJM
Congenital long RT syndrome (cLQTS) is electrocardiographically characterized by a prolonged RT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant
Al-Aama, J. Y.; Al-Ghamdi, S.; Bdier, A. Y.; Wilde, A. A. M.; Bhuiyan, Zahurul A.
Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive disorder, clinically characterized by severe cardiac arrhythmias [due to prolonged QTc interval in electrocardiogram (ECG)] and bilateral sensory neural deafness. Molecular defects causal to JLNS are either homozygous or compound
Jongbloed, R. J.; Wilde, A. A.; Geelen, J. L.; Doevendans, P.; Schaap, C.; van Langen, I.; van Tintelen, J. P.; Cobben, J. M.; Beaufort-Krol, G. C.; Geraedts, J. P.; Smeets, H. J.
Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant
Peinado, Alberto; Munilla, Jorge; Fúster-Sabater, Amparo
This paper analyzes the cryptographic security of J3Gen, a promising pseudo random number generator for low-cost passive Radio Frequency Identification (RFID) tags. Although J3Gen has been shown to fulfill the randomness criteria set by the EPCglobal Gen2 standard and is intended for security applications, we describe here two cryptanalytic attacks that question its security claims: (i) a probabilistic attack based on solving linear equation systems; and (ii) a deterministic attack based on the decimation of the output sequence. Numerical results, supported by simulations, show that for the specific recommended values of the configurable parameters, a low number of intercepted output bits are enough to break J3Gen. We then make some recommendations that address these issues.
Full Text Available This paper analyzes the cryptographic security of J3Gen, a promising pseudo random number generator for low-cost passive Radio Frequency Identification (RFID tags. Although J3Gen has been shown to fulfill the randomness criteria set by the EPCglobal Gen2 standard and is intended for security applications, we describe here two cryptanalytic attacks that question its security claims: (i a probabilistic attack based on solving linear equation systems; and (ii a deterministic attack based on the decimation of the output sequence. Numerical results, supported by simulations, show that for the specific recommended values of the configurable parameters, a low number of intercepted output bits are enough to break J3Gen. We then make some recommendations that address these issues.
Cruz Rico, Alejandra
Fundamentos de la vida - Continuidad de la vida. Examen sobre las bases genéticas de la herencia, la estructura química del ARN y del ADN, el modelo de la doble hélice propuesto por Watson y Crick y cómo funciona un gen a través de los procesos de transcripción y traducción.
A Comparison of the Single-sided (Gen II) and Double-sided (Gen I) Combat Arms Earplugs (CAE): Acoustic Properties, Human Performance, and...and Double-sided (Gen I) Combat Arms Earplugs (CAE): Acoustic Properties, Human Performance, and User Acceptance Mary Binseel, Kara Cave, Joel...Double-sided (Gen I) Combat Arms Earplugs (CAE): Acoustic Properties, Human Performance, and User Acceptance 5a. CONTRACT NUMBER 5b. GRANT
Scotch, Matthew; Sarkar, Indra Neil; Mei, Changjiang; Leaman, Robert; Cheung, Kei-Hoi; Ortiz, Pierina; Singraur, Ashutosh; Gonzalez, Graciela
Phylogeography is a field that focuses on the geographical lineages of species such as vertebrates or viruses. Here, geographical data, such as location of a species or viral host is as important as the sequence information extracted from the species. Together, this information can help illustrate the migration of the species over time within a geographical area, the impact of geography over the evolutionary history, or the expected population of the species within the area. Molecular sequence data from NCBI, specifically GenBank, provide an abundance of available sequence data for phylogeography. However, geographical data is inconsistently represented and sparse across GenBank entries. This can impede analysis and in situations where the geographical information is inferred, and potentially lead to erroneous results. In this paper, we describe the current state of geographical data in GenBank, and illustrate how automated processing techniques such as named entity recognition, can enhance the geographical data available for phylogeographic studies. PMID:21723960
Full Text Available AbstrakPenyakit Campak disebabkan oleh virus campak yang termasuk genus Morbilivirus dan Family Paramyxoviridae. Penyakit campak masih menjadi masalah kesehatan karena masih ditemukan Kejadian Luar Biasa (KLB di Indonesia. Salah satu penyebab terjadinya KLB tersebut diduga sebagaiakibat perbedaan antigenesitas antara strain vaksin yang digunakan dengan strain virus campak liar yang beredar di Indonesia. Penelitian ini bertujuan mendapatkan gambaran tentang karakteristik genetik gen Haemagglutinin virus campak liar yang ada di Indonesia. Spesimen yang digunakan sebanyak 27 isolat virus penyebab KLB dari 17 propinsi selama periode tahun 2003-2010. Isolat virus dilakukan pemeriksaan secara RT-PCR dan sekuensing dengan metode Sanger. Hasil sekuensing dianalisis dengan menggunakan perangkat lunak Bioedit 7.0 dan MEGA 4.0. Hasil penelitian didapatkan perbedaan 10 asam amino antara virus campak strain vaksin CAM-70 dan virus campak liar pada posisi D416N; K424T; V451M; N455T; V466I; I473T; F476L; Y481S atau Y481N; H495N; G505D. Kesimpulan penelitian ini adalah terdapat perbedaan karakteristik genetik antara virus campak liar di Indonesia berbeda dengan strain virus vaksin CAM-70.Kata kunci : Campak, Analisis Molekuler, Hemagglutinin, CD46AbstractMeasles is caused by virus belonging to the genus Morbilivirus and Family Paramyxoviridae. Measles is still a public health problem because outbreak of measles still found in Indonesia. Outbreak is suspected as a result of differences in antigenicity between vaccine strains used with wild-type measles virus strains circulating in Indonesia. This study aims to get genetic characteristics of wild-type measles virus haemagglutinin gene in Indonesia. The specimens were used 27 viral isolates from 17 provinces period 2003-2010. Viral isolates examined by RT-PCR and sequencing with Sanger method. Sequencing analysis were conducted using Bioedit 7.0 and MEGA 4.0 software. The results showed 10 amino acid differences
Full Text Available Las poblaciones centroamericanas no han sido objeto de muchos estudios genéticos con la excepción de análisis esporádicos de la variación entre y dentro de los grupos amerindios y de origen africano ubicados en el área. No obstante, en los últimos 15 años se efectuaron investigaciones sistemáticas en este sentido incluyendo poblaciones mestizas, particularmente las de Costa Rica y Panamá. En los amerindios se efectuaron estudios detallados de su estructura genética y las relaciones filogenéticas entre poblaciones en un contexto regional y continental. De manera general estos grupos mantienen una baja diversidad genética. Por otra parte, estimativas de la mezcla génica en la población mestiza muestran diferencias dentro y entre los distintos países del área. Al Valle Central de Costa Rica se le atribuye la condición de aislado con una supuesta constitución genética homogénea favorable para los estudios de desequilibrio de ligamiento y asociaciones con algunas enfermedades hereditarias; sin embargo, los resultados obtenidos con relación el flujo génico direccional, la amalgama de etnias y otros componentes de su estructura como la variación temporal y espacial de la consanguinidad y la migración indican una mayor heterogeneidad. Se muestran los resultados y conclusiones obtenidas y se plantean las perspectivas y tendencias al mediano plazo que vinculan los enfoques y métodos de la epidemiología y la antropología genética y el estudio genético de poblaciones.
Rodriguez, Rosalva; Guerrero, David; Rivas, Yoyna; Lacruz, Andrea; Flores, Yris
.... MH ha sido asociada con mutaciones en las proteinas del sarcomero, siendo la beta miosina cardiaca, codificada por el gen MYH7 y la proteina de union a miosina C, codificada por el gen MYBPC3, las...
Tenn, Joseph S.
The Astronomy Genealogy Project (AstroGen), a project of the Historical Astronomy Division of the American Astronomical Society (AAS), will soon appear on the AAS website. Ultimately, it will list the world's astronomers with their highest degrees, theses for those who wrote them, academic advisors (supervisors), universities, and links to the astronomers or their obituaries, their theses when online, and more. At present the AstroGen team is working on those who earned doctorates with astronomy-related theses. We show what can be learned already, with just ten countries essentially completed.
the nourished beach and the natural beach berm height are identical. GenCade requires the modeler to input a beach fill as an added berm width...step in the simulation. A graphic of the volume of each shoal through time can be viewed by going to Display->Plot Wizard and selecting GenCade Inlet...Station. Kraus, N. C. 2002. Reservoir model for calculating natural sand bypassing and change in volume of ebb-tidal shoals, part I: Description. ERDC
Kim, Seong O; Kim Se Yun; Kim, Seok Hoon; Eoh, Jae Hyuk; Lee, Hyeong Yeon; Choi, Byung Seon
The R and D items performed in this study were selected from the R and D task of ' Reliability improvement of Steam Generator' of GEN-IV SFR Component Design and BOP. Since this project deals with one of the most important issues for a GEN-IV SFR system, it needs to enhance the domestic technical backgrounds associated with the corresponding R and D items even for a very short period by 2005. This study provides the R and D results for i) Development of assessment methodology for dissimilar metal weld and ii) Development of multi-dimensional simulation methodology for a SWR event in a SFR steam generator.
Walter Carlos Pereira
Full Text Available É relatada a ocorrência de formas clínicas diversas de craniostenose em gêmeos de sexo diferente. A menina apresentava obliteração completa da sutura coronaria e dos dois terços anteriores da sutura sagital; no menino a sutura sagital era a única afetada. O estudo genético mostrou que a craniostenose independe de aberrações cromossômicas, indicando ser transmitida por gens recessivos raros de natureza autossômica.
Rizwan-uddin; Nick Karancevic; Stefano Markidis; Joel Dixon; Cheng Luo; Jared Reynolds
many GEN-IV candidate designs are currently under investigation. Technical issues related to material, safety and economics are being addressed at research laboratories, industry and in academia. After safety, economic feasibility is likely to be the most important crterion in the success of GEN-IV design(s). Lessons learned from the designers and operators of GEN-II (and GEN-III) reactors must play a vital role in achieving both safety and economic feasibility goals.
Sigrin, Benjamin [National Renewable Energy Lab. (NREL), Golden, CO (United States); Gleason, Michael [National Renewable Energy Lab. (NREL), Golden, CO (United States); Preus, Robert [National Renewable Energy Lab. (NREL), Golden, CO (United States); Baring-Gould, Ian [National Renewable Energy Lab. (NREL), Golden, CO (United States); Margolis, Robert [National Renewable Energy Lab. (NREL), Golden, CO (United States)
The Distributed Generation Market Demand model (dGen) is a geospatially rich, bottom-up, market-penetration model that simulates the potential adoption of distributed energy resources (DERs) for residential, commercial, and industrial entities in the continental United States through 2050. The National Renewable Energy Laboratory (NREL) developed dGen to analyze the key factors that will affect future market demand for distributed solar, wind, storage, and other DER technologies in the United States. The new model builds off, extends, and replaces NREL's SolarDS model (Denholm et al. 2009a), which simulates the market penetration of distributed PV only. Unlike the SolarDS model, dGen can model various DER technologies under one platform--it currently can simulate the adoption of distributed solar (the dSolar module) and distributed wind (the dWind module) and link with the ReEDS capacity expansion model (Appendix C). The underlying algorithms and datasets in dGen, which improve the representation of customer decision making as well as the spatial resolution of analyses (Figure ES-1), also are improvements over SolarDS.
Describes characteristics of the "new" college student, who may be an adult learner from the Baby Boomer era, a high school member of the "Millennial" generation, or a "Gen-Xer." Explores the learning styles of each type of student and discusses the importance of technology to each group. (SLD)
Full Text Available e for comparative gene identification transcript 94 (CGI-94), complete sequence. PRI 1e-114 1 ... ...3A3 gene for 60kDa splicing factor 3a subunit 3, the FHL3 gene for four and a half LIM domains 3 and the gen
Full Text Available e for comparative gene identification transcript 94 (CGI-94), complete sequence. PRI 5e-40 1 ... ...3A3 gene for 60kDa splicing factor 3a subunit 3, the FHL3 gene for four and a half LIM domains 3 and the gen
Full Text Available ome 1p34.2-36.11 Contains the 3' end of the KPNA6 gene for karyopherin alpha 6 (importin alpha 7), a novel g...ene (DKFZp451J0118), a novel gene (MGC1203) a novel gene, a novel gene (FLJ10547), a novel gene, a novel gen
Full Text Available ome 1p34.2-36.11 Contains the 3' end of the KPNA6 gene for karyopherin alpha 6 (importin alpha 7), a novel g...ene (DKFZp451J0118), a novel gene (MGC1203) a novel gene, a novel gene (FLJ10547), a novel gene, a novel gen
Slowly but surely, Generation Xers have been taking over from Baby Boomers as the majority of parents in elementary and secondary education. In the early 1990s, Gen Xers began joining parent-teacher associations in the nation's elementary schools. Around 2005, they became the majority of middle school parents. By the fall of 2008, they took over…
Pan, Paul Y [Los Alamos National Laboratory
An overview of key issues relevant to safeguards by design (SBD) for GEN III/IV nuclear reactors is provided. Lessons learned from construction of typical GEN III+ water reactors with respect to SBD are highlighted. Details of SBD for safeguards guidance development for GEN III/III+ light water reactors are developed and reported. This paper also identifies technical challenges to extend SBD including proliferation resistance methodologies to other GEN III/III+ reactors (except HWRs) and GEN IV reactors because of their immaturity in designs.
Maria Graciela De Ortuzar
Full Text Available Las expectativas puestas en el conocimiento genético exceden el ámbito de la medicina tradiciona, debido a que la intervención directa en la lotería natural demandaría el replanteamiento de conceptos centrales de justicia en salud: necesidades médicas, enfermedad, normalidad, e igualdad de oportunidades en el acceso a la salud. El punto en debate es sí el replanteo de dichos conceptos conlleva un cambio radical en las teorías de justicia (libertariana y/o liberal, mostrando su obsolescencia, o sí simplemente se requiere ampliar dichos conceptos claves por fallas estructurales en las mismas teorías. Como hipótesis general considero que los supuestos cuestionamientos, lejos de socavar las bases de las teorías de justicia, sólo ponen en evidencia sus viejos problemas estructurales. Por razones expositivas, dividiré la presentación tres partes. En la Primera parte, analizo la teoría libertariana, estudiando las contradicciones del modelo a través del impacto de la información genética en el seguro privado de salud. En la Segunda Parte, desarrollo la propuesta alternativa liberal rawlsianadanielsiana del modelo de seguro público, evaluando las implicaciones de la genética a partir de la crítica de su concepto biológico de enfermedad y su restricción al acceso a la salud por necesidades naturales. En la Tercera parte presento un modelo integral de necesidades y capacidades básicas, comprendiendo la prevención, el tratamiento y el mejoramiento moralmente permisible (genético y no genético.Mi aporte principal consiste en la elaboración de este modelo normativo integral de necesidades y capacidades para la regulación conjunta de la información y terapia genética con los restantes problemas de salud.
Nakatani,Andreia K.; Lopes,Ricardo; Camargo,Luis E.A.
A mancha bacteriana, causada por Xanthomonas axonopodis pv. passiflorae, é uma das mais importantes doenças do maracujazeiro, podendo limitar a produção dessa frutífera em algumas regiões do País. O uso de resistência genética e controle químico, juntamente com o emprego de medidas de exclusão, são as práticas de controle da doença mais recomendadas. Para o desenvolvimento de variedades resistentes é necessário conhecer tanto a variabilidade genética do hospedeiro quanto do patógeno. Nesse tr...
Juan Rincon F.
Full Text Available Objetivo. Determinar las frecuencias alélicas y genotípicas del polimorfismo del intrón 3 del gen bGH y estimar algunos parámetros de estructura poblacional en ganado Holstein. Materiales y métodos. El estudio se realizó con 1366 vacas Holstein en 120 hatos de 11 municipios del departamento de Antioquia. Se extrajo DNA por el método de Salting out y la genotipificación se realizó usando la técnica de PCR-RFLPs. La diversidad genética se determinó mediante la comparación de las heterocigosidades, El equilibrio de Hardy-Weinberg (HW y la diferenciación genética entre las poblaciones se realizó usando el software Arlequín 2.0 Las frecuencias alélicas y genotípicas se evaluaron mediante el paquete estadístico SAS®. Resultados. Las frecuencias genotípicas encontradas fueron 0.764 (+/+, 0.223 (+/- y 0.013 (-/- y las frecuencias alélicas 0.876 (+ y 0.124 (-. No se encontraron desviaciones del Equilibrio de Hardy Weinberg en ninguna de las subpoblaciones. La diversidad genética determinada mediante la comparación de las heterocigosidades fue relativamente baja entre poblaciones pero al interior de estas no. El valor de FST de toda la población fue de 0.0068 y significativo (p<0.05, algunos FST pareados también lo fueron, tomando valores desde 0.0 a 0.13. Los estadísticos FIT y FIS no fueron significativos. Conclusiones. El gen bGH es un candidato interesante para evaluar características de importancia económica ya que no parece haber sido sometido a selección directa, presenta una variabilidad media en las poblaciones, observándose diferenciación genética significativa entre distintos municipios, producto de los diferentes sistemas de producción y acceso a las biotecnologías.
Boekhout, Teun; Theelen, Bart; Houbraken, Jos; Robert, Vincent; Scorzetti, Gloria; Gafni, Aviva; Gerson, Uri; Sztejnberg, Abraham
Three novel mite-associated basidiomycetous species are described in two new anamorph genera as Meira geulakonigii gen. nov., sp. nov. (type CBS 110052(T)=NRRL Y-27483(T)=AS 004(T)), Meira argovae sp. nov. (type CBS 110053(T)=NRRL Y-27482(T)=AS 005(T)) and Acaromyces ingoldii gen. nov., sp. nov.
Suyanto, Putri Y; Utomo, Ahmad R; Sandra, Ferry
Farmakogenetik dalam terapi kanker adalah pemberian terapi kepada pasien berdasarkan status atau profil genetik dari sel kanker. Dengan demikian, pemberian kemoterapi diharapkan bisa lebih efektif dan meningkatkan kualitas hidup pasien dengan menghindari terapi yang diketahui secara genetik tidak memberikan keuntungan klinis. Pemeriksaan DNA gen p53 sebagai salah satu tumor suppresor gene yang termutasi pada hampir sebagian besar tumor diharapkan mampu menjadi faktor prediktif ketika dilakuka...
Karssen, Lennart C; van Duijn, Cornelia M; Aulchenko, Yurii S
Development of free/libre open source software is usually done by a community of people with an interest in the tool. For scientific software, however, this is less often the case. Most scientific software is written by only a few authors, often a student working on a thesis. Once the paper describing the tool has been published, the tool is no longer developed further and is left to its own device. Here we describe the broad, multidisciplinary community we formed around a set of tools for statistical genomics. The GenABEL project for statistical omics actively promotes open interdisciplinary development of statistical methodology and its implementation in efficient and user-friendly software under an open source licence. The software tools developed withing the project collectively make up the GenABEL suite, which currently consists of eleven tools. The open framework of the project actively encourages involvement of the community in all stages, from formulation of methodological ideas to application of software to specific data sets. A web forum is used to channel user questions and discussions, further promoting the use of the GenABEL suite. Developer discussions take place on a dedicated mailing list, and development is further supported by robust development practices including use of public version control, code review and continuous integration. Use of this open science model attracts contributions from users and developers outside the "core team", facilitating agile statistical omics methodology development and fast dissemination.
Alicia D. Burghardt
Full Text Available Prosopis ferox (Mimosaceae es una especie arbustiva o arbórea espinosa que se distribuye desde el Sur de Bolivia hasta el noroeste de la Argentina. En la provincia de Jujuy se encuentra a grandes alturas (entre los 2400 y los 3700 m s.m.. Existe una gran variabilidad morfológica, especialmente en cuanto a las dimensiones del fruto y la cantidad de semillas por fruto, ambas características importantes debido al uso de esta planta como forraje. Con el objeto de verificar si existe además variabilidad genética, se realizó un estudio electroforético de proteínas seminales de árboles procedentes de distintas localidades de la provincia de Jujuy. Los patrones polipeptídicos obtenidos por SDS-PAGE presentaron en total 26 bandas. Cada población se caracterizó por sus patrones de presencia-ausencia de bandas, habiéndose encontrado variabilidad intrapoblacional (polimorfismo en algunas de ellas, siendo otras genéticamente homogéneas. Los índices polimórficos en poblaciones de P. ferox son comparables a los obtenidos previamente en P. ruscifolia. La variabilidad genética interpoblacional hallada por medio del estudio electroforético de las proteínas seminales hace suponer la existencia de ecotipos
R. C. Veloso
Full Text Available RESUMOObjetivou-se com este trabalho comparar o padrão de crescimento, mediante ajustes das respectivas curvas de crescimento por modelos não lineares, bem como estudar o desenvolvimento de cortes de carcaça em relação ao peso da carcaça em diferentes genótipos de frangos tipo caipira. Foram utilizados 840 pintos de um dia, machos, distribuídos em delineamento inteiramente ao acaso, dos seguintes genótipos da linhagem Redbro: Caboclo, Carijó, Colorpak, Gigante Negro, Pesadão Vermelho, Pescoço Pelado e Tricolor. As aves foram alojadas em 28 boxes, sendo 30 aves/boxe, em galpão de alvenaria com acesso a um piquete de 45m², com quatro repetições. O peso corporal individual dos frangos foi medido ao nascer, aos 14, 28, 42, 56, 70 e 84 dias de idade. Para a determinação das curvas de crescimento do peso corporal das aves, os dados coletados foram avaliados por meio dos modelos não lineares: Brody, Gompertz, Logístico, Richards e von Bertalanffy. Foi empregado o PROC NLIN do SAS, utilizando-se o método interativo de Gauss-Newton. Os critérios usados para escolha do modelo de melhor ajuste da curva de crescimento foram o coeficiente de determinação, o desvio padrão assintótico, o desvio médio absoluto dos resíduos e o índice assintótico. As análises para obtenção dos coeficientes alométricos foram realizadas por meio do PROC GLM do SAS para os genótipos Carijó, Colorpak, Pesadão Vermelho, Pescoço Pelado e Tricolor. Foram avaliados os pesos da carcaça, do peito, das coxas, das sobrecoxas, das pernas e das asas das aves abatidas aos 85 dias de idade. Apenas as equações propostas por Gompertz, von Bertalanffy e Logístico atingiram a convergência, e o modelo proposto por von Bertalanffy foi o mais adequado para descrever o crescimento dos genótipos de frangos caipiras. Todos os cortes avaliados apresentaram crescimento tardio em relação ao peso da carcaça em genótipos de frangos tipo caipira.
Full Text Available Pseudorandom number generation (PRNG is the main security tool in low-cost passive radio-frequency identification (RFID technologies, such as EPC Gen2. We present a lightweight PRNG design for low-cost passive RFID tags, named J3Gen. J3Gen is based on a linear feedback shift register (LFSR configured with multiple feedback polynomials. The polynomials are alternated during the generation of sequences via a physical source of randomness. J3Gen successfully handles the inherent linearity of LFSR based PRNGs and satisfies the statistical requirements imposed by the EPC Gen2 standard. A hardware implementation of J3Gen is presented and evaluated with regard to different design parameters, defining the key-equivalence security and nonlinearity of the design. The results of a SPICE simulation confirm the power-consumption suitability of the proposal.
Melià-Seguí, Joan; Garcia-Alfaro, Joaquin; Herrera-Joancomartí, Jordi
Pseudorandom number generation (PRNG) is the main security tool in low-cost passive radio-frequency identification (RFID) technologies, such as EPC Gen2. We present a lightweight PRNG design for low-cost passive RFID tags, named J3Gen. J3Gen is based on a linear feedback shift register (LFSR) configured with multiple feedback polynomials. The polynomials are alternated during the generation of sequences via a physical source of randomness. J3Gen successfully handles the inherent linearity of LFSR based PRNGs and satisfies the statistical requirements imposed by the EPC Gen2 standard. A hardware implementation of J3Gen is presented and evaluated with regard to different design parameters, defining the key-equivalence security and nonlinearity of the design. The results of a SPICE simulation confirm the power-consumption suitability of the proposal.
Baguñà Monjo, Jaume
D'ençà que Darwin (i Wallace) van formular la teoria de l'evolució per selecció natural, les relacions entre el desenvolupament embrionari i l'evolució morfològica han estat, llevat d'un breu període inicial, de mútua i absoluta ignorància. D'ençà de la dècada dels setanta, la biologia molecular i, molt especialment, la genètica del desenvolupament, la genòmica comparada i l'evo-devo (evolució i desenvolupament) han capgirat completament el panorama. Els gens controlen el desen...
Pires Aldrin Vieira
Full Text Available Foram utilizados dados de peso da leitegada ao nascimento (PLN, peso da leitegada aos 21 dias (PL21, tamanho de leitegada ao nascimento (TLN, tamanho de leitegada ao desmame (TLD e taxa de mortalidade (TM, para avaliar a tendência genética atribuída aos efeitos genéticos aditivos diretos e maternos, em suínos Duroc, Landrace e Large White. As estimativas dos componentes de (covariância foram obtidas pelo método da máxima verossimilhança restrita (REML. As tendências genéticas dos efeitos genéticos direto e materno foram calculadas pela regressão das médias dos valores genéticos preditos das características, em relação ao ano de nascimento das porcas. As estimativas de tendências genéticas dos efeitos diretos mostraram que pouco ou praticamente nenhum progresso ocorreu nas características de leitegada, havendo tendências genéticas negativas (-0,0382 a 0,0756 kg no PLN, -0,1119 a 0,1118 kg no PL21, -0,0031 a 0,0509 leitões no TLN, -0,0217 a 0,0084 leitões no TLD e 0,0997 a --0,0059% na TM, evidenciando a dificuldade de se obterem ganhos genéticos expressivos nas características reprodutivas. Estes resultados destacam a importância de se utilizar a informação de parentes no melhoramento genético destas características, para otimizar os ganhos por seleção. As estimativas de tendência genética dos efeitos genéticos materno apresentaram-se, em geral, negativas, possivelmente em função das correlações genéticas negativas entre os efeitos genéticos aditivos direto e materno.
Full Text Available Peinado et al. analyzed the security of the J3Gen pseudorandom number generator proposed by Melià-Seguí et al., and claimed weaknesses regarding its security properties. They also presented a deterministic attack based on the decimation of the J3Gen output sequences. We show that the assumptions made by Peinado et al. are not correct and that the proposed deterministic attack against J3Gen does not hold in practice.
Cross, Ismael; Rebordinos, Laureana
El archivo es un ejercicio desarrollado con JCross en Hotpotatoes para que los alumnos prueben e identifiquen su nivel con respecto a cuestiones de Genética, conceptos, técnicas, características del ADN, etc. El ejercicio permite obtener pistas para completar el crucigrama y de esta manera finalizar el mismo habiendo asimilado o aprendido conceptos ya sabidos o nuevos de Genética. El crucigrama contiene cerca de 40 definiciones de Genética.
Foster, Jennifer; Andersen, Øistein E.
This paper explores the issue of automatically generated ungrammatical data and its use in error detection, with a focus on the task of classifying a sentence as grammatical or ungrammatical. We present an error generation tool called GenERRate and show how GenERRate can be used to improve the performance of a classifier on learner data. We describe initial attempts to replicate Cambridge Learner Corpus errors using GenERRate.
Petkovski, Trajan K; Scharf, Burkhard; Keyser, Dietmar
Material from Spitsbergen (Norway) collected by Spitzenberger (1996) was reinvestigated. A new genus Arctocypris and a new species Arctocypris. fuhrmanni n. gen. n. sp. are described in the present paper. A key to the genera of the subfamily Eucypridinae is provided. At the moment Arctocypris n. gen. comprises four species: Arctocypris arctica (Olofsson, 1918) comb. nov.; A. dulcifons (Diebel & Pietrzeniuk, 1969) comb. nov.; A. foveata (Delorme, 1968) comb. nov. and Arctocypris fuhrmanni n. gen., n. sp.
Pérez Triviño, José Luis
El aumento genético en el rendimiento deportivo parece inevitable y por lo tanto, es necesario establecer criterios racionales sobre el dopaje genético. Una estrategia para establecer estos parámetros normativos es atender a dos criterios: la extensión de los efectos del tratamiento y el tipo de intervención genética. Habiendo examinado estas posibilidades de modificación genética en relación con el deporte se pueden sugerir algunas conclusiones: 1) Mejora somática Intervenciones: su aplic...
Full Text Available switchLanguage; BLAST Search Image Search Home About Archive Update History Data ...List Contact us GenLibi Update History of This Database Date Update contents 2014/03/25 GenLibi English archi...base Description Download License Update History of This Database Site Policy | Contact Us Update History of This Database - GenLibi | LSDB Archive ... ...ve site is opened. 2007/03/01 GenLibi ( http://gene.biosciencedbc.jp/ ) is opened. About This Database Data
Gao, M.; Danielsen, Jannie Michaela Rendtlew; Wei, L.-Z.
The maintenance of genomic stability requires accurate genome replication, repair of DNA damage, and the precise segregation of chromosomes in mitosis. GEN1 possesses Holliday junction resolvase activity in vitro and presumably functions in homology driven repair of DNA double strand breaks...... but not catalytic activity of GEN1 is required for preventing centrosome hyper-amplification, formation of multiple mitotic spindles, and multi-nucleation. Our findings provide novel insight into the biological functions of GEN1 by uncovering an important role of GEN1 in the regulation of centrosome integrity....
Full Text Available La mayor parte de los trabajos realizados en nuestro país sobre polimorfismos hematológicos, abordan la necesaria descripción de las poblaciones. Se pone de relieve la importancia de encarar estudios, en base a la valiosa información publicada, que vinculen los grupos con técnicas que permitan realizar nuevas inferencias sobre sus relaciones. Conocidas en gran medida en cuanto a sus manifestaciones culturales, pueden aportar desde lo genético a la comprensión de los procesos microevolutivos ocurridos en una región. Para el NOA, se ha considerado la presencia de comunidades aborígenes incluídas en cuatro familias lingüísticas. Se tendrán en cuenta estos complejos como representativos de afinidades que se establecen a partir de estrechas relaciones entre las etnias, no sólo por la lengua, sino también por las características de sus sistemas productivos, religiosidad y organización. En base a las frecuencias génicas publicadas correspondientes a los siguientes alelos: I*A, I*B, I*O; M, N, S, s; Dia , Dib; P1, P2; C, c; D, d, E, e; Le, le; Fya, Fyb; Jka, Jkb; K y k se construyeron tablas de frecuencias. Se estimaron los coeficientes de distancias genéticas que fueron analizados y posteriormente incluídos en la construcción de un fenograma de los grupos de estudio, mediante agrupaciones (Sahn Cluster secuenciales, aglomerativas, jerárquicas y anidadas. De acuerdo a la información recopilada de las frecuencias de los 25 alelos estudiados en trece poblaciones de aborígenes del NOA y Paraguay, las distancias genéticas obtenidas reflejan los caracteres lingüístico-culturales.
d OME lrlrtst!UCI!n .,.tJ)$.8()V1’ (NMIIItrH’Nt~lt) o/(~MJtl·~ +8«Jwp Stw ... -.nc. .fdt:<)’Mid,.rY*~~:~nS~U-~I)Ot o¢chbtl*• .Aw T tlffoc...communications, when paired with active flight following allows automation and dispatch resources to harness the maximum of FAA NextGen...meet dynamic requirements while working with limited internal resources (limited aircraft, man power, gate/ramp space, fuel, and ground equipment
García González, Jaime
Se definen los términos relacionados directamente con la temática del artículo para luego citar algunas de las contradicciones de los promotores de este tipo de alimentos. Posteriormente, se mencionan los principales riesgos y preocupaciones existentes en torno al consumo de los alimentos genéticamente alterados. Además, se destacan las principales incertidumbres y cuestionamientos señalados y reconocidos por parte de diversos autores y organizaciones de profesionales en la salud, entre ellas...
We present a framework, called TrayGen, to generate tray designs for the exhibition and packaging of a collection of objects. Based on principles from shape perception and visual merchandising, we abstract a number of design guidelines on how to organize the objects on the tray for the exhibition of their individual features and mutual relationships. Our framework realizes these guidelines by analyzing geometric shapes of the objects and optimizing their arrangement. We demonstrate that the resultant tray designs not only save space, but also highlight the characteristic of each object and the inter-relations between objects. © 2013 The Eurographics Association and John Wiley & Sons Ltd.
Antonia Gutiérrez M.; Fernando Santacruz R.; José L. Cabrera P.; Benjamín Rodríguez G.
El mejoramiento genético de plantas es una de las hazañas más antiguas del hombre, que inició con la domesticación de las mismas bajo condiciones controladas y la selección de aquellas capaces de proporcionar una mejor fuente de alimentos. Esto marcó una de las fases más importantes en el progreso de la humanidad, al permitirle transitar de una vida nómada e individualista a una sociedad organizada y cooperativista. Dicho mejoramiento fue fortuito y lento y permaneció como un arte y ...
Matsumoto, Masakazu; Yagasaki, Takuma; Tanaka, Hideki
GenIce is an efficient and user-friendly tool to generate hydrogen-disordered ice structures. It makes ice and clathrate hydrate structures in various file formats. More than 100 kinds of structures are preset. Users can install their own crystal structures, guest molecules, and file formats as plugins. The algorithm certifies that the generated structures are completely randomized hydrogen-disordered networks obeying the ice rule with zero net polarization. © 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. © 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
Gutiérrez Vásquez, Ramiro; Facultad de Psicología, Universidad Peruana Cayetano Heredia.
Para recrear las ideas de Jean Piaget sobre su epistemología genética se ha visto por conveniente abordar el trabajo desde varios aspectos: abordar el problema de su significado y de lo que estudia; fundamentar su estatus de ciencia, característica central que la diferencia de otras posturas epistemológicas; probar que la psicología juega un rol importante al momento de analizar la ciencia. Del mismo modo, se estudia los métodos y procedimientos originales con los que Piaget abordó los temas ...
International Journal of Engineering, Science and Technology. Vol. 2, No. ... Accordingly, the proposed approach could be a beneficial decision-making tool for a GenCo in energy trading. ... This paper proposes an optimal trading strategy for a GenCo in multi-market environment including day-ahead LMP-based and.
... Recommendations for Submission to FAA. NextGen Implementation Performance Measurement Criteria. Review and Approve... Vice President, Operations and Administration, National Business Aviation Association and Tom Hendricks... Incentives to Equip for NextGen. Review and Approve Recommendations for Submission to FAA. Business Case Gap...
... Review and Approve Recommendation for Submission to FAA NextGen Implementation Metrics--a recommendation for Key city pairs evaluation of Transcon/Regional City Pairs that can be used for NextGen metrics..., 2013 Other Business Adjourn Attendance is open to the interested public but limited to space...
.... Huerta 10:00-10:45 Review and Approve Recommendation for Submission to FAA NextGen Implementation Metrics--a recommendation for an executive-level set of metrics that capture an overall status of NextGen... Business 3:00 Adjourn Attendance is open to the interested public but limited to space availability. With...
Lígia Regina Lima Gouvêa
Full Text Available The objective of this work was to estimate the genetic variability and divergence among 22 superior rubber tree (Hevea sp. genotypes of the IAC 400 series. Univariate and multivariate analyses were performed using eight quantitative traits (descriptors, including yield. In the univariate analyses, the estimated parameters were: genetic and environmental variances; genetic and environmental coefficients of variation; and the variation index. The Mahalanobis generalized distance, the Tocher agglomerative method and canonical variables were used for the multivariate analyses. In the univariate analyses, variability was verified among the genotypes for all the variables evaluated. The Tocher method grouped the genotypes into 11 clusters of dissimilarity. The first four canonical variables explained 87.93% of the cumulative variation. The highest genetic variability was found in rubber yield-related traits, which contributed the most to the genetic divergence. The most divergent pairs of genotypes are suggested for crossbreeding. The genotypes evaluated are suitable for breeding and may be used to continue the IAC rubber tree breeding program.O objetivo deste trabalho foi estimar a divergência e a variabilidade genética entre 22 genótipos superiores de seringueira (Hevea sp. da série IAC 400. Análises univariadas e multivariadas foram realizadas com oito caracteres quantitativos (descritores, incluindo produtividade. Na análise univariada, os parâmetros estimados foram: variâncias genética e ambiental, coeficientes de variação genética e ambiental, e índice de variação. A distância generalizada de Mahalanobis, o método aglomerativo de Tocher e variáveis canônicas foram utilizados nas análises multivariadas. Nas análises univariadas, verificou-se variabilidade entre os genótipos para todas as variáveis avaliadas. O método de Tocher agrupou os genótipos em 11 grupos de dissimilaridade. As quatro primeiras variáveis can
Full Text Available Fatores genéticos, neurobiológicos e ambientais participam da gênese das depressões. Esta breve revisão visa enfatizar os estudos sobre os aspectos genéticos, neuroquímicos e neuroanatômicos na etiologia e fisiopatologia das depressões e suas implicações no desenvolvimento de novos tratamentos. Procura-se enfatizar as limitaç��es encontradas até o momento na tentativa do estabelecimento de uma etiopatogenia comum às depressões, principalmente em função da dificuldade no diagnóstico e da heterogeneidade na fenomenologia do episódio agudo e no curso longitudinal. Perspectivas para futuras pesquisas também são apresentadas.Genetic, neurobiological and environmental factors play a role in the pathogenesis of depressive disorders. This brief review points to the major studies on the genetics, neurochemistry and neuroanatomy of depressive disorders as well as their implications on the development of new treatments. The limitations found by several groups in establishing a common etiopathogenesis are emphasised in light of the difficulty in establishing a reliable diagnosis and of the clinical heterogeneity found in the phenomenology of acute episodes and long-term outcome. Future research perspectives are also presented.
Full Text Available Las enfermedades mitocondriales son un grupo de trastornos que están producidos por un fallo en el sistema de fosforilación oxidativa (sistema Oxphos, la ruta final del metabolismo energético mitocondrial, con la consiguiente deficiencia en la biosíntesis del trifosfato de adenosina (ATP, por sus siglas en inglés. Parte de los polipéptidos que componen este sistema están codificados en el ácido desoxirribonucleico (DNA mitocondrial y, en los últimos años, se han descrito mutaciones que se han asociado con síndromes clínicos bien definidos. Las características genéticas del DNA mitocondrial, herencia materna, poliplasmia y segregación mitótica, confieren a estas enfermedades propiedades muy particulares. Las manifestaciones clínicas de estas enfermedades son muy heterogéneas y afectan a distintos órganos y tejidos por lo que su correcto diagnóstico implica la obtención de datos clínicos, morfológicos, bioquímicos y genéticos. El texto completo en inglés de este artículo está disponible en: http://www.insp.mx/salud/index.html
Full Text Available Glutation merupakan antioksidan yang berperan dalam fungsi imun, dan diekspresikan secara genetik oleh urutan gen yang membentuk protein enzim Glutation Peroxidase (GPx1. Bila ekspresi gen berubah maka terjadi perubahan fungsi glutation dan kerentanan terhadap stress oksidatif. Metode yang digunakan adalah Kasus-kontrol. Sampel yang digunakan adalah sampel darah. Kelompok kasus adalah sampel darah pasien tuberkulosis paru sedangkan kelompok kontrol adalah sampel darah orang sehat. Pemeriksaan gen Glutation peroxidase (GPx1 menggunakan metode Polymerase Chain Reaction (PCR untuk melihat pita DNA pada pasien tuberkulosis par serta elektroforesis produk PCR-RFLP gen GPx1 kelompok sampel tuberkulosis. Hasil penelitian menunjukkan bahwa tidak terdapat hubungan yang bermakna antara polimorfisme gen GPx1 (p=0,365 pasein tuberkulois dengan individu sehat, sehingga tidak dapat digunakan sebagai alat deteksi kerentanan terhadap stress oksidatif pada pasien tuberkulosis. Perlu penelitian lanjutan yang menggunakan sampel lebih besar dan populasi etnik yang berbeda.
Martinez, Ricardo; Pasquier, Nicolas; Pasquier, Claude
GenMiner is an implementation of association rule discovery dedicated to the analysis of genomic data. It allows the analysis of datasets integrating multiple sources of biological data represented as both discrete values, such as gene annotations, and continuous values, such as gene expression measures. GenMiner implements the new NorDi (normal discretization) algorithm for normalizing and discretizing continuous values and takes advantage of the Close algorithm to efficiently generate minimal non-redundant association rules. Experiments show that execution time and memory usage of GenMiner are significantly smaller than those of the standard Apriori-based approach, as well as the number of extracted association rules. The GenMiner software and supplementary materials are available at http://bioinfo.unice.fr/publications/genminer_article/ and http://keia.i3s.unice.fr/?Implementations:GenMiner Supplementary data are available at Bioinformatics online.
Cruz Renata Pereira da
Full Text Available A ferrugem-da-folha (Puccinia coronata f. sp. avenae é a principal doença da cultura da aveia (Avena sativa L., e o uso de cultivares resistentes é o método de controle mais importante. Este trabalho teve por objetivo determinar o controle genético da resistência à ferrugem-da-folha em aveia e identificar fontes de genes diferentes para resistência a esta doença. Foram utilizados três genótipos resistentes (UFRGS 15, UFRGS 881920 e UFRGS 86A1194-2, três genótipos suscetíveis (UFRGS 7, UFRGS 8 e UFRGS 14 e a geração segregante F3 proveniente dos cruzamentos entre estes genótipos. As plantas foram avaliadas individualmente quanto à presença ou ausência da ferrugem-da-folha, sendo os dados destas leituras utilizados numa análise genética em que a hipótese de um ou dois genes de resistência foi testada pelo qui-quadrado. Os resultados evidenciaram um gene dominante de resistência no genótipo UFRGS 881920 e dois genes complementares no genótipo UFRGS 15 quando estes foram cruzados com os suscetíveis. A análise genética feita não permitiu determinar se estes dois genótipos são ou não a mesma fonte genética de resistência.
... Energy Regulatory Commission Green Borders Geothermal, LLC, Complainant, v. Terra-Gen Dixie Valley, LLC... Geothermal, LLC (Green Borders) filed a formal complaint against Terra-Gen Dixie Valley, LLC (f/k/a Caithness Dixie Valley, LLC) (Terra-Gen) pursuant to section 206 of the Federal Power Act, and 18 CFR 385.206...
Oliveira Alvarenga, Danillo; Rigonato, Janaina; Henrique Zanini Branco, Luis; Soares Melo, Itamar; Fatima Fiore, Marli
Cyanobacteria dwelling on the salt-excreting leaves of the mangrove tree Avicennia schaueriana were isolated and characterized by ecological, morphological and genetic approaches. Leaves were collected in a mangrove with a history of oil contamination on the coastline of São Paulo state, Brazil, and isolation was achieved by smearing leaves on the surface of solid media or by submerging leaves in liquid media. Twenty-nine isolated strains were shown to belong to five cyanobacterial orders (thirteen to Synechococcales, seven to Nostocales, seven to Pleurocapsales, one to Chroococcales, and one to Oscillatoriales) according to morphological and 16S rRNA gene sequence evaluations. More detailed investigations pointed six Rivulariacean and four Xenococcacean strains as novel taxa. These strains were classified as Phyllonema gen. nov. (type species Phyllonema aviceniicola sp. nov. with type strain CENA341T) and Foliisarcina gen. nov. (type species Foliisarcina bertiogensis sp. nov. with type strain CENA333T), according to the International Code of Nomenclature for Algae, Fungi, and Plants. This investigation shows some of the unique cyanobacteria inhabiting the phyllosphere of Avicennia schaueriana can be retrieved by culturing techniques, improving current taxonomy and providing new insights into the evolution, ecology, and biogeography of this phylum.
Barsheshet, Alon; Goldenberg, Ilan; O-Uchi, Jin
β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location....
Connaissez-vous le Festival du rire de Genève ? La deuxième édition aura lieu du 25 au 28 mars 2015 au Casino-Théâtre à Carouge. Côté programmation, Marc Donnet-Monay ouvre les festivités avant trois autres soirées de folie et d’humour que nous vous laissons le soin de découvrir dans le programme : http://www.rire-geneve.ch/#programme. Réduction de 30% sur l’achat de places pour les membres du personnel du CERN. Pour cela, il suffit de se rendre sur la billetterie en ligne de notre site : www.rire-geneve.ch et d’utiliser le code promotionnel. Contacter le secrétariat de l’Association du personnel (Staff.Association@cern.ch) pour connaitre ce code promotionnel.
Pradip, Prashant Kaliram
Stirling engine based cogeneration systems have potential to reduce energy consumption and greenhouse gas emission, due to their high cogeneration efficiency and emission control due to steady external combustion. To date, most studies on this unit have focused on performance based on both experimentation and computer models, and lack experimental data for diversified operating ranges. This thesis starts with the commissioning of a WhisperGen Stirling engine with components and instrumentation to evaluate power and thermal performance of the system. Next, a parametric study on primary engine variables, including air, diesel, and coolant flowrate and temperature were carried out to further understand their effect on engine power and efficiency. Then, this trend was validated with the thermodynamic model developed for the energy analysis of a Stirling cycle. Finally, the energy balance of the Stirling engine was compared without and with heat recovery from the engine block and the combustion chamber exhaust.
Gustavo A. Charria-Ortiz
Full Text Available En años recientes se ha podido definir con gran exactitud la existencia de alteraciones genéticas específicas en una gran variedad de síndromes epilépticos tradicionales. Es decir, por vez primera se ha podido relacionar de manera contundente y predecible la presencia de alteraciones genómicas y/o proteómicas con síndromes epilépticos antes considerados como "idiopáticos". La gran mayoría de dichos defectos han sido encontrados en genes codificadores para canales iónicos y/o receptores de membrana, lo cual en cierto modo confirma la ya antes postulada relevancia que estas estructuras tienen en la actividad electroquímica espontánea neuronal cuyo desajuste conllevaría a ciertas formas de epilepsia. Esta revisión se centra en los aspectos genéticos y clínicos de dichas condiciones y alteraciones. También se revisarán brevemente los estudios más relevantes de la literatura médica según los cuales -aun a pesar de no haberse definido con la misma exactitud el tipo de anomalías etiológicas- puede tranquilamente inferirse el gran componente genético que parece subyacer a la etiología de las epilepsias. Por ultimo se enfatizará en que a pesar de dichos descubrimientos, su aplicación en la práctica clínica diaria aun es muy limitada, no solo por la relativa rareza de algunos de tales síndromes neurológicos sino también por la poca relevancia que hasta ahora ellos han tenido en el manejo médico rutinario de la mayoría de los pacientes. Las posibilidades inmediatas de tales avances -incluida la farmacogenómica-, así como los posibles conflictos éticos en que se podría incurrir serán también brevemente discutidos.In the last few years, the presence of specific genetic abnormalities leading to some of the classical epileptic syndromes has been clearly elucidated. This means that for the first time, it has become possible to create a strong relationship between the presence of specific genomic and/or proteomic
Korning, Peter G.; Hebsgaard, Stefan M.; Rouze, Pierre
Data driven computational biology relies on the large quantities of genomic data stored in international sequence data banks. However, the possibilities are drastically impaired if the stored data is unreliable. During a project aiming to predict splice sites in the dicot Arabidopsis thaliana, we...... extracted a data set from the A. thaliana entries in GenBank. A number of simple `sanity' checks, based on the nature of the data, revealed an alarmingly high error rate. More than 15% of the most important entries extracted did contain erroneous information. In addition, a number of entries had directly...... common. It is proposed that the level of error correction should be increased and that gene structure sanity checks should be incorporated - also at the submitter level - to avoid or reduce the problem in the future. A non-redundant and error corrected subset of the data for A. thaliana is made available...
Tenn, Joseph S.
"Astrogen", the Astronomy Genealogy Project, is in the development stage. Patterned after the Mathematics Genealogy Project at http://genealogy.math.ndsu.nodak.edu, it will eventually include most of the world's astronomers, past and present, and provide information about their years of life, highest degrees, universities, and thesis titles. There will also be links to online theses, home pages, and obituaries when these are available. Although a few details remain to be worked out before it becomes public, it is possible to make some use of what has already been compiled. I will give an example, comparing graduates of Harvard University, the University of California at Berkeley, and the University of Chicago from different decades, with information about their professional careers and publication records. The author welcomes queries about AstroGen and is seeking more participants.
Thalmann, Nadia; Bhaaskaran, V
This book is a collection of keynote lectures from international experts presented at International Conference on NextGen Electronic Technologies (ICNETS2-2016). ICNETS2 encompasses six symposia covering all aspects of electronics and communications domains, including relevant nano/micro materials and devices . This volume comprises of recent research in areas like computational signal processing analysis, intelligent embedded systems, nanoelectronic materials and devices, optical and microwave technologies, VLSI design: circuits systems and application, and wireless communication networks, and the internet of things. The contents of this book will be useful to researchers, professionals, and students working in the core areas of electronics and their applications, especially to signal processing, embedded systems, and networking.
Full Text Available Penelitian ini bertujuan untuk mengetahui prevalensi Vibrio parahaemolyticus patogenik pada udang vaname yang berasal dari tambak tradisional dan intensif berdasarkan keberadaan gen tdh dan trh. Isolasi dan konfirmasi Vibrio parahaemolyticus mengacu pada BAM (2004, yang dilanjutkan dengan konfirmasi gen tdh dan trh Vibrio parahaemolyticus menggunakan metode PCR. Hasil identifikasi menunjukkan bahwa sebanyak 16/32(50% dan 6/32 (18,8% udang dari tambak tradisional dan intensif positif Vibrio parahaemolyticus. Berdasarkan gen tdh, ditemukan Vibrio parahaemolyticus patogenik pada udang tambak tradisional dan intensif berturut-turut adalah 81% (13/16 dan 50% (3/6. Sementara itu, jika didasarkan pada gen trh, Vibrio parahaemolyticus patogenik pada udang tambak tradisional dan intensif berturut-turut adalah 15/16 (93,8% dan 4/6 (66,7%. Secara keseluruhan prevalensi udang vaname yang positif gen tdh adalah sebesar 72,2% (16/22 gen trh sebesar 86,4% (19/22 dan yang memiliki kedua gen adalah sebanyak 63,6% (14/22.
Full Text Available IceCube-Gen2 is the planned next generation neutrino telescope at the South Pole incorporating a high-energy array for neutrino astronomy and a dense array (PINGU aimed at the determination of the neutrino mass hierarchy. Here, we present alternative designs to IceCube-Gen2's single-PMT baseline optical module which are currently being developed. These designs feature up to 24 smaller photomultipliers and use glass and gel with enhanced UV transparency to increase the number of detected photons and provide additional information. Thereby, they have the potential to significantly enhance the performance of IceCube-Gen2.
Chaverri Esquivel, Laura; Jiménez Alfaro, Esteban; Camacho Cascante, María Isabel
El proyecto se desarrolló en la Estación Experimental Finca Santa Lucía, ubicada en el distrito Santa Lucía, Barva, Heredia.El objetivo general fue desarrollar y operar un programa de mejoramiento genético mediante reproducción asistida en rumiantes menores. Los objetivos específicos se agruparon en tres áreas: genética, reproductiva y transferencia tecnológica.En el área de genética se evaluaron caracteres productivos de importancia económica en ovinos y se estableció la metodología de evalu...
Barros Fernández, Paula
El presente trabajo trata la controversia del tema de los organismos modificados genéticamente (OMG). Se mencionan los beneficios que aporta la ingeniería genética y también los principales riesgos y preocupaciones existentes en torno al consumo de los alimentos modificados genéticamente, reportando casos de estudios que así lo constatan.Se tratan temas como seguridad alimentaria, legislación y normativas de etiquetado de estos nuevos alimentos, señalando su relación con la salud. Además, se ...
Barreta Pinto, Julia
El estudio de los camélidos sudamericanos es de gran interés en los países andinoscomo Perú, Bolivia, Chile, Argentina, debido a su importante valor económico y suimportancia en el mantenimiento y desarrollo de las poblaciones rurales en dichos países. Dada la falta de estudios genéticos centrados en las poblaciones de camélidos quehabitan en Bolivia, y la necesidad de realizar una valoración de la diversidad genética deestas poblaciones, la presente Tesis doctoral ha abordado el estudio gené...
Delgado de la Torre, Rosario
La genética de poblaciones estudia la distribución de los genes en las poblaciones, así como los factores que mantienen o cambian la constitución genética de las mismas, de una generación a otra. Una población se define como un conjunto de individuos capaces de reproducirse entre sí, que coexisten geográfica y temporalmente, y constituyen una unidad evolutiva. El estudio de la genética de poblaciones es muy importante desde el punto de vista sanitario, ya que la mayoría de las enfermedades ti...
Fumiyoshi Watanabe; Michelle Robles; José A. García
Existen ciertas evidencias experimentales que sugieren un mundo primitivo en el que la molécula de ácido ribonucleico (RNA) era la molécula responsable de codificar la información genética y de catalizar un número limitado de reacciones. En este "mundo de RNA" pudo darse el origen del código genético actual. En este manuscrito se presenta una breve discusión sobre las principales teorías que se han propuesto sobre el origen del código genético.
Elizabeth T. Arias-Bohart
Full Text Available Sharon gen. nov. is here described to include Asaphes? amoenus Philippi, 1861 comb. nov. from Chile. A redescription of the species is based on the female holotype and material from different geographic locations. Candèze (1891 placed Asaphes amoenus and Parasaphes elegans in the suprageneric group Asaphites. We discuss differences between Sharon gen. nov. and Hemicrepidius Germar, 1839, where Asaphes amoenus was later placed by Blackwelder (1944. Based on morphological characters, Sharon gen. nov. appears to be related to Parasaphes Candèze, 1881, Wynarka Calder, 1986, and Tasmanelater Calder, 1996, all from Australia, suggesting Gondwanan relationships.
Faria, Ivo Frederico Barbedo da Costa
Trabalho Complementar apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de licenciado em Ciências da Nutrição A dieta Mediterrânica é um dos padrões alimentares mais saudáveis do mundo. Pelo facto de ser uma dieta muito rica em nutrientes essenciais e substâncias com atividade antioxidante e anti-inflamatória, ela tem sido implicada na manutenção da estabilidade genómica, incluindo o DNA telomérico. A disfunção telomérica tem sido associada à senesc...
Full Text Available En este documento se rebaten críticas hechas por Raventós y Jensen al artículo “Genética y comportamiento”. Cuatro temas fueron seleccionados: 1 se determina que los antipsicóticos aparecieron veinte años después de la concepción hereditaria de la esquizofrenia; 2 se considera que la discusión es altamente pertinente, para nada bizantina o irrelevante, debido que persisten prácticas epistémicas riesgosas en los investigadores genético-conductuales; 3 aunque ninguna conducta humana está exenta de influencia constitucional, el enfoque biologicista se ha propasado al pretender explicar genéticamente casi todo, desconfirmando solapadamente la importancia de la historia personal; y, 4 se plantea que la investigación biológica sobrevalora el peso de las anomalías genéticas frente a la historia social, por lo que solo aparenta cautela. Se propone investigar genéticamente la esperanza con el objetivo de saturar a la humanidad con ese tipo de explicaciones, para alcanzar más rápido una convivencia basada en la tolerancia y el respeto.
Nancy Rodríguez C.
Full Text Available Objetivo. Estimar algunos parámetros de estructura poblacional en una población Holstein del departamento de Antioquia. Materiales y métodos. El estudio se realizó con 427 vacas de la raza Holstein pertenecientes a 5 municipios del departamento de Antioquia. La genotipificación se llevó a cabo usando la técnica de PCR-PFLPs. La Heterocigocidad observada (Ho y Heterocigocidad esperada (He, la prueba de Hardy-Weinberg (HW y la estructura y diferenciación genética entre las poblaciones se calculó mediante los parámetros F de Wright, evaluados mediante el software GENEPOP. Las frecuencias alélicas y genotípicas se evaluaron con el método descrito por Hartl. Resultados. Las frecuencias genotípicas encontradas fueron 0.61, 0.34 y 0.05 para los genotipos AA, AB y BB respectivamente y las frecuencias de los alelos fueron 0.78 y 0.22 para A y B, encontrándose la población en equilibrio de HW. La heterocigocidad fue media entre poblaciones (Ho=0.368. Los valores FIS, FST y FIT de la población total fueron -0.0717, 0.0099 y -0.0611. Conclusiones. No fue posible asumir endogamia, ni exogamia en los municipios analizados, exceptuando el municipio de San Pedro de los Milagros, en cuyo caso se percibe de manera más fuerte el efecto del mejoramiento genético y la disminución de la heterocigocidad.
Full Text Available switchLanguage; BLAST Search Image Search Home About Archive Update History Data ...access [here]. About This Database Database Description Download License Update History of This Database Site Policy | Contact Us Download - GenLibi | LSDB Archive ...
National Aeronautics and Space Administration — The Next Generation Air Transportation System (NextGen) brings significant advancements to the current management of the National Airspace (NAS). These fundamental...
Milena Paneque; Martina C Cornel; Vaclava Curtisova; Elisa Houwink; Leigh Jackson; Alastair Kent; Peter Lunt; Milan Macek; Vigdis Stefansdottir; Daniela Turchetti; Heather Skirton
.... Education that can be accessed by practitioners without cost or travel is essential. The Gen-Equip project was formed to provide effective education in genetics for primary healthcare in Europe and so improve patient care...
Marlon Altoé Biazatti
Full Text Available RESUMO: Este trabalho teve por objetivo avaliar a resistência de genótipos de P. cattleyanum a M. enterolobii. O experimento foi conduzido em DIC, com seis tratamentos, constituídospor cinco genótipos de P. cattleyanum, pela goiabeira 'Paluma' (testemunha e oito repetições constituídas por clones desses genótipos. A classificação quanto à resistência foi determinada de acordo com o fator de reprodução (FR, avaliado aos 135 dias após inoculação com o nematoide. Os genótipos de P. cattleyanum avaliados foram resistentes a M. enterolobii com FR iguais ou inferiores a 0,2.
Data Comma digital, text-based controller-pilot communication systemis critical to many NextGen improvements. With Data Comm, communication becomes a visual task. Although Data Comm brings many advantages, interacting with a visual display may ...
Full Text Available Kepadatan tulang tubuh ditentukan oleh gen CYP19 aromatase, hormon estrogen dan androgen. Pada periodontitis agresif terjadi perkembangan cepat kerusakan tulang alveolar, dan kerusakan tulang alveoler tersebut tidak diimbangioleh regenerasi tulang. Tujuan penelitian ini adalah menunjukkan ekspresi gen CYP19 aromatase, estrogen, androgen pada penderita periodontitis agresif agar dapat untuk menjadi pertimbangan pada saat melakukan perawatan periodontal. Metode penelitian, pemeriksaan ekspresi gen aromatse CYP19 berasal dari spesimen tulang alveolar menggunakan imunohistokimia, pengukuran hormon estrogen dan androgen dari serum menggunakan Vidas: Elfa. Hasil penelitian ekspresi gene CYP19 aromatase pada periodontitis agresif menunjukkan gambaran lebih rendah densitasnya dibandingkan pada nonperiodontitis. Estrogen dan androgen pad aperiodontitis agresif ada kecenderungan lebih rendah dibandingkan pada nonperiodontitis. Kesimpulan regenerasi tulang alveoler pad a periodontitis agresif terhambat karena sedikitnya gen CYP19 aromatase dan hormon estrogen dan androgen yang berperan pada pembentukan tulang alveoler kurang memadai.
Evizal Evizal; Tharek Abd Rahman; Sharul Kamal Abdul Rahim; Sri Listia Rosa
.... This paper explore and develop the use of RFID EPC Class1 Gen2 tag for multipurpose access system for identification and access control, such as personal identity identification, door access control...
GenCo) in multi-market environment including day-ahead spot and long term bilateral contract markets using self-organising hierarchical ... The Monte Carlo method is employed to simulate other bidders' behaviour in competitive environment.
Tahsin, Tasnia; Weissenbacher, Davy; O'Connor, Karen; Magge, Arjun; Scotch, Matthew; Gonzalez-Hernandez, Graciela
GeoBoost is a command-line software package developed to address sparse or incomplete metadata in GenBank sequence records that relate to the location of the infected host (LOIH) of viruses. Given a set of GenBank accession numbers corresponding to virus GenBank records, GeoBoost extracts, integrates, and normalizes geographic information reflecting the LOIH of the viruses using integrated information from GenBank metadata and related full-text publications. In addition, to facilitate probabilistic geospatial modeling, GeoBoost assigns probability scores for each possible LOIH. Binaries and resources required for running GeoBoost are packed into a single zipped file and freely available for download at https://tinyurl.com/geoboost. A video tutorial is included to help users quickly and easily install and run the software. The software is implemented in Java 1.8, and supported on MS Windows and Linux platforms. email@example.com.
... developed by the Business Case and Performance Metrics Work Group. Recommendation for NextGen Activity... public but limited to space availability. With the approval of the chairman, members of the public may...
... to track and analyze the impacts of NextGen developed by the Business Case and Performance Metrics... limited to space availability. With the approval of the chairman, members of the public may present oral...
... Recommendations to be Considered for Submission to FAA, NextGen Performance Metrics. Preliminary Reports on Key.... Adjourn. Attendance is open to the interested public but limited to space availability. With the approval...
Full Text Available Transgenesis pada ikan merupakan sebuah teknik modern yang berpotensi besar dalam menghasilkan organisme yang memiliki karakter lebih baik melalui rekombinan DNA gen target termasuk gen anti virus dalam peningkatan resistensi pada udang. Gen anti virus PmAV (Penaeus monodon Anti Viral gene merupakan salah satu gen pengkode anti virus yang berasal dari spesies krustase. Penelitian ini dilakukan untuk mengetahui karakteristik gen anti virus yang diisolasi dari udang windu, Penaeus monodon. Isolasi gen anti virus menggunakan metode Polymerase Chain Reaction (PCR dan selanjutnya dipurifikasi untuk sekuensing. Data yang dihasilkan dianalisis dengan program Genetyx Versi 7 dan basic local alignment search tool (BLAST. Hasil penelitian menunjukkan bahwa gen anti virus PmAV yang berhasil diisolasi dari cDNA udang windu dengan panjang sekuen 520 bp yang mengkodekan 170 asam amino. BLAST-N menunjukkan tingkat similaritas yang sangat tinggi (100% dengan gen anti virus yang ada di GeneBank. Komposisi asam amino penyusun gen anti virus yang paling besar adalah serin (10,00%, sedangkan yang terkecil adalah asam amino prolin dan lisin masing-masing 1,76%. Analisis sekuen gen dan deduksi asam amino (BLAST-P memperlihatkan adanya C-type lectin-like domain (CTLD yang memiliki kemiripan dengan gen C-type lectin yang diisolasi dari beberapa spesies krustase. Transgenic fish technology is a potential modern technique in producing better character organism through DNA recombinant of target genes including anti viral gene for improvement of shrimp immunity. PmAV (Penaeus monodon Anti Viral gene is one of anti viral genes isolated from crustacean species. The research was conducted to analyze the characteristics anti viral gene isolated from tiger prawn, Penaeus monodon. Anti viral gene was isolated using Polymerase Chain Reaction (PCR technique and then purified for sequencing. Data obtained were analyzed using Genetyx Version 7 software and basic local alignment
Full Text Available Teknologi transgenesis khususnya rekayasa genetik untuk menghasilkan udang windu resisten penyakit merupakan salah satu strategi yang dapat dilakukan dalam upaya pemecahan masalah penyakit yang menimpa budidaya udang windu. Teknologi transgenesis khususnya transfer gen antivirus pada udang windu telah berhasil dilakukan melalui teknik transfeksi. Meskipun demikian optimalisasi komponen teknologi tersebut masih perlu dilakukan. Konsentrasi DNA gen merupakan salah satu komponen teknologi transgenesis yang harus dioptimalkan untuk mendapatkan efisiensi dalam transfer gen. Penelitian bertujuan untuk mengetahui konsentrasi DNA gen antivirus yang optimal sebagai bahan transfer gen ke embrio menggunakan metode transfeksi. Embrio udang windu yang diperoleh dari hasil pemijahan induk asal Aceh, dikoleksi 5-10 menit setelah memijah dengan kepadatan 625 telur/2 mL. Transfeksi dilakukan dengan menggunakan media larutan transfeksi jetPEI dengan konsentrasi DNA gen antivirus sebagai perlakuan, yakni: 5, 10, dan 15 µg serta kontrol positif (tanpa plasmid DNA dan negatif (tanpa plasmid DNA dan larutan transfeksi, masing-masing 3 ulangan. Embrio hasil transfeksi ditetaskan pada stoples berisi air laut sebanyak 2 L yang diletakkan pada waterbath. Hasil penelitian menunjukkan bahwa gen antivirus telah berhasil diintroduksi ke embrio udang windu. Hasil analisis ragam menunjukkan bahwa perbedaan konsentrasi DNA (5-15 µg tidak berpengaruh nyata (P>0,05 terhadap daya tetas embrio udang windu. Analisis ekspresi gen pada larva udang windu juga menunjukkan adanya aktivitas ekspresi gen antivirus pada semua perlakuan konsentrasi DNA, di mana ekspresi gen antivirus pada larva transgenik lebih tinggi dibandingkan dengan kontrol (tanpa transfeksi. Sintasan pasca-larva PL-1 yang didapatkan pada penelitian ini adalah 12,0%; 10,0%; 10,6%; 12,3%; dan 14,2% masing-masing untuk perlakuan konsentrasi plasmid DNA 5 µg, 10 µg, 15 µg, kontrol positif dan negatif, di mana
Juan Castro Gómez
Full Text Available Myrciaria dubia “camu-camu” es un frutal amazónico caracterizado por su amplia variación de vitamina C. Pero los estudios genético moleculares que puedan explicar esta variación son limitados. Por ello nuestro objetivo fue realizar la clonación y filogenia molecular de un segmento del gen codante de la actina de M. dubia. Las muestras fueron obtenidas de la colección de germoplasma del INIA. Luego, el ARN fue purificado y mediante RT-PCR con cebadores degenerados se amplificó un segmento del gen. En base a la secuencia obtenida se diseñaron cebadores específicos para PCR en tiempo real. Los resultados muestran que se ha aislado, clonado y secuenciado un segmento del gen codante de actina de M. dubia y detectado su expresión en hojas, pulpa y cáscara de M. dubia. Así, con el soporte de herramientas bioinformáticas y uso de técnicas de biología molecular hemos aislado, clonado y secuenciado un segmento del gen codante de la actina de M. dubia. Asimismo, los análisis realizados muestran que el gen se expresa y presenta niveles similares de expresión en hojas, pulpa y cáscara de M. dubia. Sin embargo, es necesario realizar más experimentos a fin de verificar su estabilidad de expresión.
Full Text Available acquisition method The results of GenBank homology searches were used for GO term classifications. Data ana...lysis method The GO term classifications were done based on the results of blastx searches...ed on GenBank homology searches Data file File name: kome_go_classification_genbank.zip File URL: ftp://ftp....lsdba.nbdc00120-023 Description of data contents Results of GO (Gene Ontology) term classifications done bas
Cross, Ismael; Rebordinos, Laureana
El archivo es un ejercicio desarrollado con JCross en Hotpotatoes para que los alumnos prueben e identifiquen su nivel de base con respecto a cuestiones básicas de Genética, conceptos, técnicas, características del ADN, etc. El ejercicio permite obtener pistas para completar el crucigrama y de esta manera finalizar el mismo habiendo asimilado o aprendido conceptos ya sabidos o nuevos de Genética.
CERN Video Productions
Questions : Qu'est-ce-que le LHC? Quelle est la fonction du LHC? Qu'est-ce-que le CERN? D'après vous, les recherches engendrées pour le LHC peuvent-elles ?tre bénéfiques, utiles pour la société? Où a été inventé le Web? Lieux : Forum Meyrin Université de Genève Genève Centre
Tomas Mas, Carmen; Børsting, Claus; Morling, Niels
SNPs are being increasingly used by forensic laboratories. Different platforms have been developed for SNP typing. We describe the GenPlex™ HID system protocol, a new SNP-typing platform developed by Applied Biosystems where 48 of the 52 SNPforID SNPs and amelogenin are included. The GenPlex™ HID...... system protocol has been successfully tested by a number of forensic laboratories using both ordinary and forensic samples....
Full Text Available A obesidade definida como a acumulação excessiva de gordura corporal deriva de um desequilíbrio crônico entre a energia ingerida e a energia gasta. Neste desequilíbrio podem estar implicados diversos fatores relacionados com o estilo de vida (dieta e exercício físico, alterações neuro-endócrinas, juntamente com um componente hereditário. O componente genético constitui um fator determinante de algumas doenças congênitas e um elemento de risco para diversas doenças crônicas como diabetes, osteoporose, hipertensão, câncer, obesidade, entre outras. O aumento da prevalência da obesidade em quase todos os países durante os últimos anos, parece indicar que existe uma predisposição ou susceptibilidade genética para a obesidade, sobre a qual atuam os fatores ambientais relacionados com os estilos de vida, em que se incluem principalmente os hábitos alimentares e a atividade física. A utilização de modelos animais de obesidade, a transferência génica e os estudos de associação e ligamento, permitiram a identificação de vários genes implicados na obesidade.Obesity, defined as an excessive body fat accumulation, is caused by a chronic imbalance between energy intake and energy expenditure. Several factors have been associated with this energy imbalance, such as life style (diet and physical activity, neuroendocrine disorders, together with the genetic background. The genetic background is a major determinant factor of some congenital diseases and a risk factor for some chronic disorders, such as diabetes, osteoporosis, hypertension, cancer, obesity, and others. The increased prevalence of obesity in most countries during the last years, seems to indicate that there is a genetic predisposition or susceptibility to be obese which is increased by environmental and life style factors, mainly by food habits and physical in activity. The use of obesity animal models, genetic transfer and the association and linkage studies
En este documento se rebaten críticas hechas por Raventós y Jensen al artículo “Genética y comportamiento”. Cuatro temas fueron seleccionados: 1) se determina que los antipsicóticos aparecieron veinte años después de la concepción hereditaria de la esquizofrenia; 2) se considera que la discusión es altamente pertinente, para nada bizantina o irrelevante, debido que persisten prácticas epistémicas riesgosas en los investigadores genético-conductuales; 3) aunque ninguna conducta humana está exe...
Ecole de physique - Département de physique nucléaire et corspusculaire 24, quai Ernest-Ansermet - 1211 GENÈVE 4 Tél: (022) 379 62 73 - Fax: (022) 379 69 92 Lundi 1er décembre 2008 PARTICLE PHYSICS SEMINAR at 17.00 hrs – Stückelberg Auditorium Superconducting Interfaces between Insulating Oxide Prof. Jean-Marc TRISCONE / Université de Genève At interfaces between complex oxides, electronic systems with unusual properties can be generated. A striking example is the interface between LaAlO3 and SrTiO3, two good insulating perovskite oxides, which was found in 2004 to be conducting with a high mobility. We recently discovered that the ground state of this system is a superconducting condensate, with a critical temperature of about 200 mK. The characteristics observed for the superconducting transitions are consistent with a two-dimensional superconducting sheet as thin as a few nanometers. Recent field effect experiments revealed the sensitivity of the normal and superconducting states to the carrier ...
Eduardo Geraldo Alves Coelho
Full Text Available Nos últimos anos a equideocultura deu um salto qualitativo, havendo hoje, no mercado, animais de alto valor e geneticamente superiores. Isso é possível, em grande parte, devido aos avanços na área da genética animal, os quais permitem identificar, não apenas anomalias, mas também diversos genes de interesse econômico. Com o auxílio da citogenética pode-se identificar indivíduos com alterações no número ou na estrutura dos cromossomos, o que em muitos casos afeta principalmente a reprodução. Também a confirmação de genealogia, anteriormente feita por tipagem sangüínea e atualmente por testes de DNA, tem papel extremamente importante, não apenas por garantir a ascendência dos animais, mas também porque um pedigree confiável pode permitir ao criador identificar a origem de problemas genéticos em seu rebanho e reduzi-los ou mesmo, eliminá-los. Ainda com as ferramentas da biologia molecular, podemos hoje, identificar indivíduos que apresentam genes desejáveis ou indesejáveis, o que nos permite selecioná-los precocemente, reduzindo assim, os custos do produtor e aumentando o valor agregado dos animais. Entre tais genes podemos destacar os que identificam portadores ou afetados por mutações genéticas indesejáveis como: SCID (Síndrome da Imunodeficiência Combinada, HYPP (Parilisa Hipercalêmica, HERDA (Astenia Dérmica Regional Hereditária Eqüina, etc. Também a identificação dos genes que determinam a cor ou padrão da pelagem já pode ser feita direta ou indiretamente (por meio de marcadores genéticos, como é o caso dos genes para as pelagens Overo, Tobiano, etc. Com os avanços no estudo do genoma eqüino muito mais estará disponível em breve, o que certamente só trará maiores contribuições à equideocultura mundial.In the last few years the horse breeding industry is achieving significant progresses producing animals of high commercial value and genetically superior. It was possible, mainly due to
Ecole de physique - Département de physique nucléaire et corspusculaire 24, quai Ernest-Ansermet 1211 GENÈVE 4 Tél: (022) 379 62 73 - Fax: (022) 379 69 92 Lundi 1er décembre 2008 PARTICLE PHYSICS SEMINAR at 17.00 hrs – Stückelberg Auditorium Superconducting Interfaces between Insulating Oxide Prof. Jean-Marc TRISCONE / Université de Genève At interfaces between complex oxides, electronic systems with unusual properties can be generated. A striking example is the interface between LaAlO3 and SrTiO3, two good insulating perovskite oxides, which was found in 2004 to be conducting with a high mobility. We recently discovered that the ground state of this system is a superconducting condensate, with a critical temperature of about 200 mK. The characteristics observed for the superconducting transitions are consistent with a two-dimensional superconducting sheet as thin as a few nanometers. Recent field effect experiments revealed the sensitivity of the normal and superconducting states to the carrier d...
Ana Heloísa Costa Lemos
Full Text Available Despite the attention that Generation Y has received in recent times, studies that map the attitudes related to work of these individuals has devoted little attention to understanding the differences that gender can produce in the same generational group. However, we believe that gender differences should be better understood, because, according to the IBGE (2012, women represent 45.4% of the current Brazilian labor force. The growing importance of women in the labor market brings the challenge for organizations to attract and retain that portion of the workforce, whose demands are not necessarily equal those of men. The scarcity of studies on the expectations related to career of Gen Y women motivated the present work, which sought to understand the desires of young professionals with regard to the construction of their professional careers. To answer these questions we carried out a qualitative research, interviewing young women born between 1980 and 2000. We tried to understand what these professionals expect from its insertion in the labor market. The results confirm the analysis of the descriptions of the recent literature on Yrs, because the interviewees proved eager for success, professional recognition and attractive remuneration, but also highlight differences and indicate some specifics aspects related to the gender considerations, as expressed by these young woman, which expect to lower their work dedication when they become mothers and wives.
Full Text Available The technological changes along with the psychological and structural changes of the young generation (Gen Z require adjustment of the educational methods. In this regard, the paper presents a way of explaining uncertainty of measurements by the use of experimental subject-spotting. The method consists in splitting – subject-spotting – a complex subject into small parts that require lower sustained attention and are easier to be understood and memorized. Each subject-spot uses the link between theory and practice, allowing multi-tasking behaviours. The focus is on obtaining quick results. The practical application of experimental subject-spotting of uncertainty is based on the measurement of the water flow through a pipe by the method of time volume collection. The flow rate measurement represents the grounding for developing several experimental subject-spots that explain the uncertainty of analogue and digital readings, of repeated measurements, the level of confidence, expanded uncertainty and the propagation of uncertainty. The mathematical model and program, some final considerations and further reading suggestions open other directions of studying uncertainty, eventually covered by other subject-spots.
Full Text Available Should we say that selective abortion is a “powerful message that we seek to eliminate future persons”? When deaf parents want to have a deaf children, Are they crazy? Are they advocates of a culture –the Deaf culture? If genetic engineering can give us health, intelligent, and athletic childrens, why say not to this advantages? The aim of this article is not to deal with all objections that could be urged against these options; the purpose is developing a clear understanding of the central values at stake.
¿Estamos eliminando una cultura, la de los sordos, cuando tratamos de evitar que nazcan niños sordos? El aborto terapéutico, ¿significa que, por ejemplo, creemos que las vidas de los afectados por síndrome de Down son vidas de menor valor que las vidas “normales”? Si se permitiera la manipulación genética de los embriones ¿sería poco ético encargar hijos guapos y altos? Este artículo no aporta respuestas a estas preguntas, pero sí que plantea los términos para dar cuenta de ellas y eleva acta de lo difícil que es dar una respuesta concluyente.
Tiago Vieira Bomtempo
La ingeniería genética trajo posibilidades antes inimaginables, en la que no hace mucho tiempo era visto sólo en las películas. De la terapia génica, dirigida hacia una corrección o cura de una enfermedad, pasa a la posibilidad del mejoramiento genético, actualmente vislumbrado en el mundo del deporte con el doping genético. ¿Pero, el doping genético no estaría violando el derecho al patrimonio genético no modificado? Aunque la intervención genética no se transmita a los descendentes, habría ...
Bosch i Tubert, Fàtima
Gen quimérico para el desarrollo de aproximaciones terapéuticas a la intolerancia hereditaria a la fructosa. Comprende un promotor unido al gen o al ADNc de la fructoquinasa. Dicho gen quimérico se inserta en una célula hepática, permitiendo la expresión de fructoquinasa. También se refiere a un animal transgénico cuyo genoma comprende dicho gen quimérico y desarrollando, dicho animal transgénico, alteraciones asociadas a la intolerancia hereditaria a la fructosa tras la administración de fru...
Nora Alejandra Zuluaga
Full Text Available La preeclampsia es considerada un problema de salud pública debido a su alta prevalencia. Muchas investigaciones coinciden en que su origen se relaciona con la interacción entre factores genéticos y ambientales. Por esta razón, múltiples estudios han explorado tales factores genéticos tratando de identificar regiones cromosómicas y genes candidatos cuyas variantes se relacionen con una mayor susceptibilidad a la enfermedad. Diversos estudios de asociación han identificado algunos genes de susceptibilidad a la preeclampsia, pero los resultados no se han replicado consistentemente en todas las poblaciones, quizá por su complejidad clínica y genética. El levantamiento de mapas de genes y regiones cromosómicas basado en análisis de ligamiento ha mostrado resultados interesantes con algunos marcadores en los cromosomas 2 y 4. En este sentido, hay muchas expectativas con respecto a los genes localizados en tales regiones candidatas, debido a que la identificación de los factores de riesgo genético podría ayudar al entendimiento de esta condición y en proveer claves para su prevención y tratamiento.
Elibett Carcasés Carcasés
Full Text Available La estimación de la prevalencia de las enfermedades genéticas se dificulta, entre otras causas, por su rareza. Se realizó un estudio descriptivo retrospectivo, para identificar las enfermedades genéticas de mayor prevalencia en pacientes atendidos por este programa en el Centro Provincial de Genética Médica de Las Tunas, Cuba; desde el año 1989 hasta julio de 2014. Se revisaron todas las historias clínicas. Predominó el origen monogénico (69 %, siendo los síndromes dismórficos los más numerosos y diversos, entre ellos los neurocutáneos, que representaron el 35 %. La enfermedad genética monogénica con mayor número de casos fue la Neurofibromatosis I con el 14,4 % y el 22,2 % de las enfermedades eran de origen monogénico y dismórfico. La Trisomía 21 representó el 77 % de la causa cromosómica. En el origen multifactorial prevalecieron los defectos congénitos mayores, entre ellos los defectos reductivos de miembros (27 %
Kottow Miguel H
Full Text Available La investigación genética ha tenido una enorme expansión en recientes décadas, con repercusiones terapéuticas aún inciertas. El análisis bioético tradicional de las complejas prácticas genéticas ha sido insuficiente por sostenerse en la ética de la investigación y en la bioética de corte principialista. Los problemas éticos más importantes de la genética son de orden colectivo y deben ser abordados por una reflexión ético-social cuyo enfoque es más amplio que la agenda interpersonal del principialismo. Temas como exploraciones genéticas, cuestiones patrimoniales, manipulación génica y asignación de recursos, deben todos ser sometidos a un pensamiento inspirado en los requerimientos de la ciudadanía, en el bien común y en la definición del rol del Estado en fiscalizar actividades genéticas y en proteger a la población. El objetivo del estudio es mostrar cómo el amplio campo de la ética y de la genética tiene una mayor relevancia en el campo social que en el clínico. El objetivo del trabajo es señalar que la bioética principialista ha enfatizado los problemas éticos individuales que nacen con la intervención genética, a costa de marginar sus importantes repercusiones sociales.
Miguel H Kottow
Full Text Available La investigación genética ha tenido una enorme expansión en recientes décadas, con repercusiones terapéuticas aún inciertas. El análisis bioético tradicional de las complejas prácticas genéticas ha sido insuficiente por sostenerse en la ética de la investigación y en la bioética de corte principialista. Los problemas éticos más importantes de la genética son de orden colectivo y deben ser abordados por una reflexión ético-social cuyo enfoque es más amplio que la agenda interpersonal del principialismo. Temas como exploraciones genéticas, cuestiones patrimoniales, manipulación génica y asignación de recursos, deben todos ser sometidos a un pensamiento inspirado en los requerimientos de la ciudadanía, en el bien común y en la definición del rol del Estado en fiscalizar actividades genéticas y en proteger a la población. El objetivo del estudio es mostrar cómo el amplio campo de la ética y de la genética tiene una mayor relevancia en el campo social que en el clínico. El objetivo del trabajo es señalar que la bioética principialista ha enfatizado los problemas éticos individuales que nacen con la intervención genética, a costa de marginar sus importantes repercusiones sociales.
Pinheiro Andréa Poyastro
Full Text Available OBJETIVO: Revisar a literatura atual concernente à pesquisa genética em transtornos do comportamento alimentar e discutir questões relevantes ao desenvolvimento de um projeto de pesquisa genética nessa área no Brasil. MÉTODO: A revisão realizada utilizou a base de dados Medline, no período de 1984 a maio de 2005, com os seguintes termos de busca: "anorexia nervosa", "bulimia nervosa", "eating disorders", "binge eating disorder", "family studies", "twin studies", "molecular genetics studies". RESULTADOS: Os dados atuais apontam para uma contribuição relevante dos fatores genéticos na suscetibilidade à anorexia e à bulimia nervosa. A pesquisa genética com populações miscigenadas deve levar em consideração o tamanho da amostra, a densidade de genotipagem e a estratificação populacional. Através de "admixture mapping" é possível estimar a estrutura genética destas populações e localizar genes relacionados à variação étnica de doenças ou traços de interesse. CONCLUSÕES: O desenvolvimento de uma grande iniciativa de colaboração em genética de transtornos alimentares no Brasil e na América Latina viabilizará estudar os fatores genéticos em transtornos do comportamento alimentar no contexto de grupos inter-étnicos, e integrar uma nova perspectiva biológica à etiologia destes distúrbios.
Caro, M; Marian, J; Martinez, E; Erhart, P
Within the LDRD on 'Critical Issues on Materials for Gen-IV Reactors' basic thermodynamics of the Fe-Cr alloy and accurate atomistic modeling were used to help develop the capability to predict hardening, swelling and embrittlement using the paradigm of Multiscale Materials Modeling. Approaches at atomistic and mesoscale levels were linked to build-up the first steps in an integrated modeling platform that seeks to relate in a near-term effort dislocation dynamics to polycrystal plasticity. The requirements originated in the reactor systems under consideration today for future sources of nuclear energy. These requirements are beyond the present day performance of nuclear materials and calls for the development of new, high temperature, radiation resistant materials. Fe-Cr alloys with 9-12% Cr content are the base matrix of advanced ferritic/martensitic (FM) steels envisaged as fuel cladding and structural components of Gen-IV reactors. Predictive tools are needed to calculate structural and mechanical properties of these steels. This project represents a contribution in that direction. The synergy between the continuous progress of parallel computing and the spectacular advances in the theoretical framework that describes materials have lead to a significant advance in our comprehension of materials properties and their mechanical behavior. We took this progress to our advantage and within this LDRD were able to provide a detailed physical understanding of iron-chromium alloys microstructural behavior. By combining ab-initio simulations, many-body interatomic potential development, and mesoscale dislocation dynamics we were able to describe their microstructure evolution. For the first time in the case of Fe-Cr alloys, atomistic and mesoscale were merged and the first steps taken towards incorporating ordering and precipitation effects into dislocation dynamics (DD) simulations. Molecular dynamics (MD) studies of the transport of self
Antonia Gutiérrez M.
Full Text Available El mejoramiento genético de plantas es una de las hazañas más antiguas del hombre, que inició con la domesticación de las mismas bajo condiciones controladas y la selección de aquellas capaces de proporcionar una mejor fuente de alimentos. Esto marcó una de las fases más importantes en el progreso de la humanidad, al permitirle transitar de una vida nómada e individualista a una sociedad organizada y cooperativista. Dicho mejoramiento fue fortuito y lento y permaneció como un arte y no como una ciencia hasta principios del siglo XX, luego de que las llamadas leyes de Mendel, pioneras en la explicación de los procesos de la herencia, obtuvieron reconocimiento (Briggs y Knowles, 1967. El proceso que emplea fitomejoradores ha creado un sinnúmero de variedades de plantas con el objeto de incrementar su producción, resistencia a plagas y enfermedades, y la adaptación a ambientes específicos, regiones y usos, mediante la selección de variedades cultivadas localmente, cruzadas entre sí o con las de otras áreas, o también con plantas silvestres que tengan los genes deseados. Sin embargo, obtener plantas mejoradas por estos medios resulta difícil en ocasiones por lo que se recurre a otros métodos para producir variantes útiles, tales como la selección celular, la variación somaclonal y las mutaciones inducidas, entre otros
Lucimara Ribeiro Venial
Full Text Available Genótipos de Theobroma cacao L. devem ser melhor estudados, para se identificar aqueles que produzem sementes mais desenvolvidas e viáveis após o armazenamento. Objetivou-se com este trabalho estudar a biometria e dois tempos de armazenamento de sementes de genótipos de cacaueiro. A biometria foi avaliada em oito genótipos de cacaueiro (tratamentos. Foram instalados testes de germinação em delineamento inteiramente ao acaso, no esquema fatorial 8 x 2 (genótipos: CCN51, PH16, CEPEC2002, Ipiranga, SJ02, PS1319, TSH1188 e Comum x dois períodos de armazenamento: 0 e dois dias. O genótipo TSH1188 apresentou maior comprimento, relação comprimento/largura, espessura e massa de 100 sementes. A absorção de água das sementes recém-colhidas dos genótipos é lenta, justificada pelos altos teores de água, o que não caracteriza padrão-trifásico. Os teores de água reduziram em média 2,3 vezes nas sementes armazenadas em relação às recém-colhidas. A germinação das sementes recém-colhidas dos genótipos foi de 100%. Após o armazenamento, as sementes do PS1319 apresentaram a menor redução da germinação (39%, enquanto as dos PH16, CEPEC2002 e SJ02 reduziram 96%. A velocidade de germinação foi maior e o tempo médio menor que dois dias nas sementes recém-colhidas do PS1319, indicando serem mais tolerante à dessecação. Sugere-se o uso dos genótipos TSH1188 e PS1319 em programas de melhoramento genético.
Manuel Santos Alcántara
Full Text Available El gran avance que ha tenido la Genética en los últimos años y, particularmente, aquello relacionado con el desciframiento del genoma humano, ha traído a la discusión pública la posibilidad concreta de manipular genéticamente a los seres humanos. El mejoramiento o perfeccionamiento genético de los seres humanos, denominado eugenesia, actualmente se ha convertido técnicamente en una realidad, motivando una profunda reflexión de tipo ético. La pregunta básica es la siguiente: aquello que es técnicamente posible de realizar ¿es ético hacerlo? ¿Tienen derecho los padres a acceder a la tecnología genética para mejorar las características de sus hijos? En este artículo se revisan las bases científicas del mejoramiento genético de los seres humanos, y se plantean los cuestionamientos éticos más relevantes derivados de esta manipulación.
Xu, Xidong; Ulrey, Mike L.; Brown, John A.; Mast, James; Lapis, Mary B.
NextGen is a complex socio-technical system and, in many ways, it is expected to be more complex than the current system. It is vital to assess the safety impact of the NextGen elements (technologies, systems, and procedures) in a rigorous and systematic way and to ensure that they do not compromise safety. In this study, the NextGen elements in the form of Operational Improvements (OIs), Enablers, Research Activities, Development Activities, and Policy Issues were identified. The overall hazard situation in NextGen was outlined; a high-level hazard analysis was conducted with respect to multiple elements in a representative NextGen OI known as OI-0349 (Automation Support for Separation Management); and the hazards resulting from the highly dynamic complexity involved in an OI-0349 scenario were illustrated. A selected but representative set of the existing safety methods, tools, processes, and regulations was then reviewed and analyzed regarding whether they are sufficient to assess safety in the elements of that OI and ensure that safety will not be compromised and whether they might incur intolerably high costs.
Full Text Available Abstract Background The integration of genomic information with quantitative experimental data is a key component of systems biology. An increasing number of microbial genomes are being sequenced, leading to an increasing amount of data from post-genomics technologies. The genomes of prokaryotes contain many structures of interest, such as operons, pathogenicity islands and prophage sequences, whose behaviour is of interest during infection and disease. There is a need for simple and novel tools to display and analyse data from these integrated datasets, and we have developed ProGenExpress as a tool for visualising arbitrarily complex numerical data in the context of prokaryotic genomes. Results Here we describe ProGenExpress, an R package that allows researchers to easily and quickly visualize quantitative measurements, such as those produced by microarray experiments, in the context of the genome organization of sequenced prokaryotes. Data from microarrays, proteomics or other whole-genome technologies can be accurately displayed on the genome. ProGenExpress can also search for novel regions of interest that consist of groups of adjacent genes that show similar patterns across the experimental data set. We demonstrate ProGenExpress with microarray data from a time-course experiment involving Salmonella typhimurium. Conclusion ProGenExpress can be used to visualize quantitative data from complex experiments in the context of the genome of sequenced prokaryotes, and to find novel regions of interest.
Lohr, Gary; Lee, Jonathan; Poage, James L.; Tobias, Leonard
The NextGen-Airportal Project is organized into three research focus areas: Safe and Efficient Surface Operations, Coordinated Arrival/Departure Operations Management, and Airportal Transition and Integration Management. The content in this document was derived from an examination of constraints and problems at airports for accommodating future increases in air traffic, and from an examination of capabilities envisioned for NextGen. The concepts are organized around categories of constraints and problems and therefore do not precisely match, but generally reflect, the research focus areas. The concepts provide a framework for defining and coordinating research activities that are, and will be, conducted by the NextGen-Airportal Project. The concepts will help the research activities function as an integrated set focused on future needs for airport operations and will aid aligning the research activities with NextGen key capabilities. The concepts are presented as concept elements with more detailed sub-elements under each concept element. For each concept element, the following topics are discussed: constraints and problems being addressed, benefit descriptions, required technology and infrastructure, and an initial list of potential research topics. Concept content will be updated and more detail added as the research progresses. The concepts are focused on enhancing airportal capacity and efficiency in a timeframe 20 to 25 years in the future, which is similar to NextGen's timeframe.
Dahlquist Kam D
Full Text Available Abstract Background Microarray technologies have evolved rapidly, enabling biologists to quantify genome-wide levels of gene expression, alternative splicing, and sequence variations for a variety of species. Analyzing and displaying these data present a significant challenge. Pathway-based approaches for analyzing microarray data have proven useful for presenting data and for generating testable hypotheses. Results To address the growing needs of the microarray community we have released version 2 of Gene Map Annotator and Pathway Profiler (GenMAPP, a new GenMAPP database schema, and integrated resources for pathway analysis. We have redesigned the GenMAPP database to support multiple gene annotations and species as well as custom species database creation for a potentially unlimited number of species. We have expanded our pathway resources by utilizing homology information to translate pathway content between species and extending existing pathways with data derived from conserved protein interactions and coexpression. We have implemented a new mode of data visualization to support analysis of complex data, including time-course, single nucleotide polymorphism (SNP, and splicing. GenMAPP version 2 also offers innovative ways to display and share data by incorporating HTML export of analyses for entire sets of pathways as organized web pages. Conclusion GenMAPP version 2 provides a means to rapidly interrogate complex experimental data for pathway-level changes in a diverse range of organisms.
Full Text Available El autismo, hoy en día definido como trastornos del espectro autista, fue descrito inicialmente en 1943. Se caracteriza por alteraciones en la comunicación, la interacción social y un espectro restringido de intereses del paciente. Generalmente se identifica en etapas tempranas del desarrollo a partir de los 18 meses de edad. Actualmente el autismo se considera un desorden neurológico con un espectro que abarca diferentes grados que se asocian con factores genéticos, no genéticos y del medio ambiente. Dentro de los factores genéticos se han referido diversos síndromes relacionados con este trastorno. Asimismo, el autismo se ha estudiado a nivel genético, neuroﬁsiológico, neuroquímico y neuropatológico. Las técnicas de neuroimagen han mostrado múltiples anormalidades estructurales en estos pacientes. También se han observado alteraciones relacionadas en los sistemas serotoninérgico, GABAérgico, catecolaminérgico y colinérgico. En este trabajo se presenta una actualización de la información de los aspectos genéticos y neuroendocrinos del trastorno del espectro autista.
Crystianne Bentes Barbosa Ferreira
Full Text Available O objetivo deste trabalho foi avaliar a diversidade genética, entre e dentro de progênies de dendezeiro tipo dura, de origem Deli. A caracterização genética foi feita com uso de marcadores microssatélites em 24 progênies usadas na produção comercial de sementes, sendo 22 provenientes de autofecundação e duas de cruzamentos entre irmãos completos. Foi realizada análise de variância molecular entre e dentro das progênies, com posterior construção de um dendrograma. Observou-se baixa variabilidade genética nas progênies, com média de 1,32 alelos por loco e variância genética total igual a 0,3241. A maior parte da variação ocorreu entre progênies. A menor variabilidade genética dentro das progênies pode ser explorada nos cruzamentos com progênies endogâmicas de outras origens, o que facilitaria o alcance de heterose para o desenvolvimento de novas variedades.
Full Text Available Pola pigmen merupakan faktor utama yang menentukan tingginya kualitas ikan hias. Pada benih-benih F1 populasi budidaya ikan badut hitam (Amphiprion percula diketahui mengalami degeneratif pola pigmen yang menyimpang dibandingkan dengan populasi di alam. Pola pigmen merupakan salah satu karakter fenotip yang diturunkan di mana ekspresinya bergantung pada interaksi genetik dengan faktor eksternal yaitu lingkungan. Tujuan dari penelitian ini adalah untuk mengkaji peran gen yaitu Aim1 yang mengontrol sintesis melanin dan kondisi lingkungan dalam menginduksi pola pigmen hitam ikan badut hitam (Amphiprion percula. Analisis gen Aim1 dilakukan dengan menggunakan program speedy PCR dilanjutkan dengan SSCP (single strand confirmation polymorphism untuk mengidentifikasi variasi genetik dari gen Aim1. Analisis SDS Page dilakukan untuk mengetahui peranan lingkungan terhadap profil protein yang disintesis. Berdasarkan hasil penelitian diketahui bahwa primer Aim1 memiliki sisi pengenalan pada whole genom ikan badut hitam (Amphiprion percula pada target sequence 45 bp. Berdasarkan analisis SSCP profil fragmentasi amplicon primer Aim1 pada masing-masing tingkatan pada populasi budidaya homolog dengan populasi alam, sehingga gen Aim1 bukan merupakan gen yang mengontrol fenomena degeneratif pola pigmen ikan badut hitam (Amphiprion percula. Peran lingkungan yaitu cahaya memberikan pengaruh positif dalam menginduksi pola pigmen melalui stimulus pada sistem neuron dan migrasi melanophore.
Jesús H. Córdova
Full Text Available Objetivos: Avanzar en el conocimiento del origen de las poblaciones peruanas estudiadas en un contexto filogeográfico. Diseño: Estudio genético poblacional. Instituciones: Laboratorio de Genética Humana, Facultad de Ciencias Biológicas, Universidad Nacional Mayor de San Marcos, e Instituto de Genética y Biología Molecular, Facultad de Medicina, Universidad San Martín de Porras, Lima, Perú. Participantes: Siete poblaciones peruanas. Metodología: Análisis comparativo de los resultados a partir del estudio del mtDNA y el gen nuclear MBL de siete poblaciones peruanas, procesados de manera separada y luego combinados, utilizando el programa PHYLYP 3.65, para obtener valores FST de diferenciación genética y la construcción de árboles de distancias por aplicación del algorritmo UPGMA y el análisis subsecuente de los agrupamientos (clusters generados. Principales medidas de resultados: Árboles genéticos generados. Resultados: De manera separada, los árboles generados para cada marcador genético tuvieron topologías propias y diferentes entre sí. Procesados de manera combinada, el árbol resultante demostró que los mayores valores de diferenciación genética se hallaron en las Islas del Lago Titicaca (Puno, Perú conocidas -Taquile, Amantani y Anapia-, que fue calificada como muy alta, porque mostró valores de FST de 0.3113, 0.2949 y 0.3348 respecto de las poblaciones estudiadas, tanto fuera del Departamento de Puno -como Chachapoyas, Pucallpa y Chiclayo, respectivamente-, así como a la de los Uro del mismo Puno y del mismo Lago Titicaca (0.2837. Fuera de Puno, el par de poblaciones Chachapoyas-Pucallpa fue el menos divergente, al alcanzar entre ellas un valor de FST de 0.0108, calificándosele de pequeña. Conclusiones: El árbol obtenido del procesamiento de los marcadores vía una matriz combinada demostró que las poblaciones que habitan las islas de Taquile, Amantani y Anapia, divergen notablemente de las restantes cuatro
Alberto M Galaburda
Full Text Available La dislexia del desarrollo es un trastorno que se caracteriza por dificultades en el aprendizaje de la lectura. Recientemente se ha podido vincular la dislexia a cuatro distintos genes candidatos de riesgo: DYX1C1, KIAA0319, DCDC2 y ROBO1. Estos cuatro genes participan en el desarrollo cerebral, y anomalías de dicho desarrollo constituyen los elementos conocidos del cuadro biológico que subyace a la dislexia. En animales experimentales, la inducción de anomalías del desarrollo cerebral similares produce problemas en el procesamiento de ciertos sonidos. En humanos, problemas de procesamiento de sonidos semejantes se asocian a un trastorno de aprendizaje de la lectura. Por consiguiente, es posible por primera vez, trazar una trayectoria tentativa entre una característica genética, variaciones del desarrollo del cerebro, y trastornos conductuales y cognitivos asociados a la dislexia.Developmental dyslexia is a disorder characterized by difficulties in reading acquisition. Recently, dyslexia has been related to four different genes which are prone-risk candidates: DYX1C1, KIAA0319, DCDC2, and ROBO1. These four genes participate in brain development, and anomalies in that development comprise the known elements of the biological constellation underlying dyslexia. The induction of similar brain development anomalies in experimental animals produces problems in the processing of certain sounds. In humans, similar sound processing problems are related to a reading acquisition disorder. Consequently, for the first time it is possible to delineate a tentative path between a genetic characteristic, brain development variations, and behavioral and cognitive disorders related to dyslexia.
Sirgo, G; Rello, J; Bodí, M; Diaz, E; Pérez vela, J.L; Hernández, G; Waterer, G
... genético en el paciente crítico respecto a la inflamación y la sepsis. En la presente Revisión se discute la importancia de los aspectos genéticos en relación con la coagulación y el síndrome...
Marta Alvarez; Regla M. Lara; Rodríguez, J.; Fernández, R.; Cuartero, J.
Frente a los nematodos del género Meloidogyne es la resistencia genética, junto a métodos de lucha integrada, la opción más recomendada para el tomate, por lo que los cultivares e híbridos modernos portan, en su mayoría, el gen Mi, que confiere resistencia no completa a varias especies del género Meloidogyne. El Instituto Nacional de Ciencias Agrícolas (INCA), con la colaboración de la Estación Experimental La Mayora-CSIC, España, ha desarrollado un programa de mejora genética, con el objetiv...
Naim, Mohammad Faraz; Lenka, Usha
The present study is aimed at investigating the impact of mentoring on intention to stay of Gen Y employees working in Indian IT industry. Also, the mediating roles of perceived organization support and affective commitment are examined. Primary data were collected from a sample of 314 Gen Y employees (born between 1980-2000) from IT industry in Delhi, NCR India. Data analysis was carried out using AMOS and SPSS to test sequential mediation. Findings reveal that mentoring has a direct influence on intention to stay of Gen Y employees and perceived organization support and affective commitment sequentially mediate the relationship between the two. This study contributes to the literature on mentoring, perceived organization support, affective commitment, and intention to stay. PMID:28580029
Li, Nein-Yi; Collins, Doug; Jatar, Shashank; Lavrova, Olga; Helms, Chris; Luo, Wenlin; Liu, Linlin; Liu, Chiyu; Qiu, Mei; Roff, Kent; Wang, Charlie; Yang, Chia-Chun; Chiou, Hwann-Kaeo
In this paper, we present the design and manufacturing of next-generation 850 nm 10 Gb/s vertical-cavity surface-emitting lasers (GenX VCSELs). They were developed to provide a 10 Gb/s solution that meets Class-1 eye safety limits, IEEE 802.3ae standards, 10G Fiber Channel standards, and corresponding multisource agreement requirements for emerging low-cost, high-volume, and high-performance data communication applications in local and storage area networks (LANs and SANs). The paper covers GenX device designs, manufacturing processes, DC and AC characteristics, equivalent circuit models, recommended operating conditions, as well as reliability studies. As a simple drop-in replacement, we have successfully demonstrated that GenX VCSELs work well with all existing Emcore 10G transmitter optical sub-assembly (TOSA) products.
Gladys Casas Cardoso; Robersy Sánchez Rodríguez; Deborah Galpert Cañizares; Maria del Carmen Chávez; Ricardo Grau Ábalo; Eberto Morgado Morales
Las estructuras boolenas del código genético constituyen modelos matemáticos minimales y muy simplificados que nos ayudan a comprender mejor la lógica subyacente del código genético. Más específicamente, estas estructuras reflejan una fuerte conexión entre los órdenes del código genético y las propiedades físico-químicas de los aminoácidos. En este artículo presentamos dos aplicaciones de esta estructura algebraica en problemas típicos de Bioinformática. El primer es el de la clasificación de...
VaxGen is developing prophylactic vaccines against HIV-1 consisting of two recombinant gp120 surface proteins from different HIV-1 strains.This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. The bivalent vaccines [AIDSVAX B/B and AIDSVAX B/E] are being evaluated in two phase III trials. The first multicentre phase III trial of AIDSVAX B/B, was conducted principally in Canada and the US but also at some sites in the Netherlands and Puerto Rico. The trial was completed at the end of 2002. The second phase III trial is being conducted in Thailand with the AIDSVAX B/E vaccine. VaxGen announced in July 2002 that it would be delaying its Biologics License Application (BLA) for AIDSVAX until 2004 to enable the company to fulfil pre-approval manufacturing requirements. AIDSVAX is based on an earlier monovalent gp120 vaccine developed by Genentech that was shown to be safe in humans. VaxGen (formerly Genenvax) was formed as a spin-off company from Genentech with the sole purpose of developing the gp120 vaccine. VaxGen announced in July 2002 that the original License and Supply agreement with Genentech, signed in May 1997, had been amended. Under the revised agreement, Genentech maintains its right to market and sell AIDSVAX in North America, but has relinquished its options to commercialise the vaccine candidate in the rest of the world. Genentech's earlier decision to waive its option to manufacture AIDSVAX has also been formalised in this agreement. Additionally, VaxGen's royalty payments to Genentech for sales to the WHO or UN for underdeveloped nations have also been reduced by up to 50% and Genentech has extended the milestone date associated with VaxGen submitting an NDA. A $US120 million joint venture (Celltrion) has been formed between VaxGen and South Korean investors to manufacture more than 200 million doses of AIDSVAX a year. Celltrion will build and operate two biotechnology manufacturing
A human-in-the-loop simulation conducted in the Airspace Operations Laboratory (AOL) at NASA Ames Research Center explored the feasibility of a Next Generation Air Transportation System (NextGen) solution to address airspace and airport capacity limitations in and around the New York metropolitan area. A week-long study explored the feasibility of a new Optimal Profile Descent (OPD) arrival into the airspace as well as a novel application of a Terminal Area Precision Scheduling and Spacing (TAPSS) enhancement to the Traffic Management Advisor (TMA) arrival scheduling tool to coordinate high volume arrival traffic to intersecting runways. In the simulation, four en route sector controllers and four terminal radar approach control (TRACON) controllers managed traffic inbound to Newark International Airport's primary runway, 22L, and its intersecting overflow runway, 11. TAPSS was used to generate independent arrival schedules for each runway and a traffic management coordinator participant adjusted the arrival schedule for each runway 11 aircraft to follow one of the 22L aircraft. TAPSS also provided controller-managed spacing tools (slot markers with speed advisories and timelines) to assist the TRACON controllers in managing the arrivals that were descending on OPDs. Results showed that the tools significantly decreased the occurrence of runway violations (potential go-arounds) when compared with a Baseline condition with no tools. Further, the combined use of the tools with the new OPD produced a peak arrival rate of over 65 aircraft per hour using instrument flight rules (IFR), exceeding the current maximum arrival rate at Newark Liberty International Airport (EWR) of 52 per hour under visual flight rules (VFR). Although the participants rated the workload as relatively low and acceptable both with and without the tools, they rated the tools as reducing their workload further. Safety and coordination were rated by most participants as acceptable in both
Full Text Available Apolitical sociology of food must look into the processes whereby regulatory decisions on food are made, and also into the democratic potential of their alternatives. Five "experiments in democracy" are described, in which a promising deliberative device has been used: citizens' juries. Indian and Brazilian peasants, on the one hand, and British consumers in the other took part in them, and they focused on Genetically Modified Organisms. These processes, whose defining trait is granting jurors access to expert witnesses presented by all stakeholders in the controversy, show the impressive ability of ordinary citizens to articulate their analysis of complex issues, a reassessment of risks, and a recontextualization of the use of GMOs. At any rate, deliberative democracy is not a magic bullet for the epistemic and political crisis that underlies food crisis; instead, it points at a paradigm change towards an experimental democratic polity in which the instances of representation of the public and publics are multiplied.
Una sociología política de la alimentación debe analizar los procesos a través de los cuales se alcanzan las decisiones de regulación y control alimentario y examinar el potencial de sus alternativas. Se describen aquí cinco experimentos democráticos en los que se ha empleado uno de los dispositivos deliberativos más prometedores en condiciones de alta complejidad cognitiva, los llamados jurados ciudadanos, con la participación de campesinos hindúes y brasileños y consumidores británicos, y centrados en los Organismos Genéticamente Modificados. Estos procesos, caracterizados por el acceso de los miembros del jurado a testigos expertos presentados por los distintos participantes en la controversia, muestran la enorme capacidad de los ciudadanos "de a pie" para articular el análisis de un problema complejo, reevaluar sus riesgos y recontextualizar el uso de los OGM. En todo caso, la democracia deliberativa no es
Hardin C Timothy
Full Text Available Abstract Background Detection of short, subtle conserved motif regions within a set of related DNA or amino acid sequences can lead to discoveries about important regulatory domains such as transcription factor and DNA binding sites as well as conserved protein domains. In order to help assess motif detection algorithms on motifs with varying properties and levels of conservation, we have developed a computational tool, rMotifGen, with the sole purpose of generating a number of random DNA or protein sequences containing short sequence motifs. Each motif consensus can be user-defined, randomly generated, or created from a position-specific scoring matrix (PSSM. Insertions and mutations within these motifs are created according to user-defined parameters and substitution matrices. The resulting sequences can be helpful in mutational simulations and in testing the limits of motif detection algorithms. Results Two implementations of rMotifGen have been created, one providing a graphical user interface (GUI for random motif construction, and the other serving as a command line interface. The second implementation has the added advantages of platform independence and being able to be called in a batch mode. rMotifGen was used to construct sample sets of sequences containing DNA motifs and amino acid motifs that were then tested against the Gibbs sampler and MEME packages. Conclusion rMotifGen provides an efficient and convenient method for creating random DNA or amino acid sequences with a variable number of motifs, where the instance of each motif can be incorporated using a position-specific scoring matrix (PSSM or by creating an instance mutated from its corresponding consensus using an evolutionary model based on substitution matrices. rMotifGen is freely available at: http://bioinformatics.louisville.edu/brg/rMotifGen/.
Ballesteros Diana carolina
Full Text Available Phytophthora infestans causa la gota, que es la enfermedad en la papa de mayor importancia económica a nivel mundial. La obtención de cultivares resistentes al patógeno es una estrategia necesaria para su control, por lo cual la identificación de genes de resistencia a P. infestans (Rpi es fundamental para apoyar los programas de mejoramiento. La introgresión de Rpi desde especies silvestres o nativas dentro de cultivares es una vía para desarrollar cultivares con resistencia. S. phureja tiene notables características culinarias y nutricionales, e igualmente ha sido identificada como una fuente de resistencia a la gota, lo cual la sitúa en una posición de interés desde el punto de vista de recurso genético con fines de mejoramiento. Se caracterizaron genotípicamente 88 accesiones de S. phureja con marcadores moleculares tipo SCAR, el gen R1 de resistencia a P. infestans, el gen candidato StAOS2 y un marcador tipo CAPS ligados a loci para resistencia a P. infestans en Solanum tuberosum. Se presentó polimorfismo en los marcadores Prp1 y R1. La amplificación del marcador R1 mostró el alelo de 1.400 pb, característico del gen R1 en 17 accesiones de la colección de S. phureja, lo cual sugiere que estas accesiones posiblemente podrían tener un gen homólogo al gen R1 identificado en S. demissum.
Feitosa Mary F.
Full Text Available A epidemiologia genética evoluiu de um enfoque em estudos sobre doenças mendelianas raras para a análise genética de características complexas. Com o advento de informações sobre a completa seqüência de genes ao longo do genoma humano e de outros organismos, o interesse da epidemiologia genética em desvendar a natureza dos fatores que influenciam essas características se tornou primordial. São apresentados os principais métodos empregados no estudo de doenças complexas bem como suas principais vantagens e desvantagens. Discute-se a importância na determinação da amostra e o uso de fenótipos e marcadores genéticos apropriados. Como exemplo das estratégias citadas tomamos o estudo de índice de massa corporal (BMI para ilustrar um fator genético principal localizado no cromossomo 7. Em uma discussão sobre tendências no estudo de ligação, embora reconhecendo que famílias e genealogias continuarão sendo o foco principal das amostras, discute-se alguns novos e eficientes tipos de amostragem (como por exemplo, controles não-relacionados em que amostras de conjunto de DNA serão universalmente empregadas. O reconhecimento da heterogeneidade genética entre estudos e sua interpretação será uma das mais importantes características no futuro das análises de características complexas.
Ana María Sifuentes Rincón
Full Text Available Se determinaron las frecuencias alélicas y genotípicas de ocho marcadores localizados en los genes calpaína (CAPN, 4 751 y 316, calpastatina (CASTT1 y tiroglobulina (TG5, asociados a calidad de carne, y en los genes, m iost atina (MSTN, Q204X, arginino succinato sintasa (ASS, monofosfato sintasa (UMPS y miofosforilasa (PYGM, asocia dos a enfermedade s genéticas de ganado bovino. Se muestrearon 493 animales Charolais de registro de dos hatos ubicado s en Sonora (n=157 y tres en Nuevo León (n=336. No se encontraron portadores de los alelos T-ASS y T-UM PS, pero sí portadores del alelo Q204X del gen MSTN en frecuencias de 1 % en las poblaciones de Sonora y de 8.6 a 14.4 % en las de Nuevo León. Además, se identificaron portadores del marcador del gen PYGM, en frecuencias del 6.5 y de 1.0 % para un hato de Sonora y otro de Nuevo León, respectivamente. El análisis de diferenciación génica p areado entre las poblaciones y con los cuatro loci mostró que hay diferencias altamente significativas dentro de pobl aciones del noroeste ( P <0.0001 y entre éstas y las del noreste ( P <0.001, la cual es explicada principalmente por los loci CAPN-316 y TG5. De acuerdo a los resultados obtenidos se recomienda el monitoreo del marcador del gen PYGM y del ale lo Q204X del gen MSTN, así como también implementar estrategias para confirmar la utilidad de los marcadores asociado s a calidad y productividad como herramienta para complementar los progra mas de mejoramiento genético.
Sonia Castro Guzmán
Full Text Available Jatrophacurcas L.es una especie nativa de América tropical; en nuestro país se ha venido utilizando principalmente como medicinal y alimenticia desde la época prehispánica. Actualmente el aceite extraído de sus semillas ha adquirido importancia internacional ya que puede ser transformado a biodiesel. El conocimiento que existe sobre la variabilidad genética de la especie es escaso. Un gen utilizado con éxito para el estudio de patrones de variación y origen de la yuca (ManihotesculentaL. y del caco (Theobromacacao L. es el gen nuclearG3pdh(Gliceraldehído3 fosfato deshidrogenasa involucrado en la fotosíntesis. Con base en ello, en este trabajo se exploró la variabilidad del gen G3pdh en individuos deJ. curcasprovenientes de 15 poblaciones de los estados de Veracruz, Campeche, Yucatán y Quintana Roo. Para obtener el gen G3pdh completo de alrededor de 1000 pares de bases, se amplificó utilizando losprimersdiseñados porStrandet al. (1997 y los dosprimersinternos reverse diseñados porOlsenySchaal(1999 para obtener segmentos más cortos, de 600 y 800 pares de bases aproximadamente. Por primera vez se amplificaron aproximadamente 500pby los resultados demuestran que el gen G3pdh es útil para analizar la variabilidad deJ. curcas, y con un importante potencial para evaluar la distribución y evolución de sus poblaciones en México, conocer las relaciones ancestro descendiente a nivel poblacional y explicar las causas de la distribución de los distintoshaplotipos.
Vanderlei Sebastiao de Souza
Full Text Available Aborda o contexto de criação do Museu da Genética, em 2011 no Departamento de Genética na Universidade Federal do Rio Grande do Sul, em Porto Alegre, e apresenta sua estrutura e conteúdo. Argumenta-se que os materiais disponibilizados no Museu da Genética constituem uma rica fonte para pesquisas sobre a história da genética no Brasil (e da genética de populações humanas em particular a partir da segunda metade do século XX, tema ainda pouco investigado, apesar da proeminência dessa área do conhecimento no Brasil.
... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission GenOn Marsh Landing, LLC; Supplemental Notice That Initial Market-Based Rate...-referenced proceeding, of GenOn Marsh Landing, LLC's application for market-based rate authority, with an...
Fattah, Yusuf R; Kamu, Vanda S; Runtuwene, Max R. J; Momuat, Lidya I
Gedi (Abelmoschus L.) merupakan tumbuhan tropis. Tumbuhan ini memilki efek farmakologis. Masyarakat Minahasa mengkonsumsi daun gedi yang direbus tanpa diberi bumbu sebagai obat tradisional untuk menurunkan kadar kolesterol, antihipertensi dan antidiabetes. Suatu metode baru untuk mengidentifikasi dan menganalisis keanekaragaman genetika spesies telah dikembangkan dengan menggunakan potongan gen standar yang dikenal dengan teknik DNA barcoding. Salah satu gen yang terdapat pada tumbuhan yaitu ...
Tomas Mas, Carmen; Stangegaard, Michael; Børsting, Claus
, Somalia and Greenland were investigated with GenPlex using a Biomek 3000 (Beckman Coulter) robot. The results were compared to results obtained with an ISO 17025 accredited SNP typing assay based on single base extension (SBE). With the GenPlex SNP genotyping system, full SNP profiles were obtained in 97...
... [Federal Register Volume 75, Number 5 (Friday, January 8, 2010)] [Notices] [Page 1052] [FR Doc No: 2010-62] DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. EL10-29-000] Terra-Gen... 30, 2009. Take notice that on December 24, 2009, Terra-Gen Dixie Valley, LLC, TGP Dixie Development...
Fàbregas i Batlle, Pere Jordi
Consultable des del TDX Títol obtingut de la portada digitalitzada Introducció El treball "Detecció i estudi de gens implicats en el desenvolupament prenatal de la rata" parteix de la hipòtesi de treball de què la carcinogènesi i el desenvolupament són processos que comparteixen mecanismes de funcionament com són l'elevat índex de proliferació, la capacitat de migració cel·lular o l'angiogènesi sostinguda i que, per tant, deuen compartir els gens que els regulen. Amb aquest plantejament...
Demarchi, Darío Alfredo
Full Text Available En este trabajo se investigaron las relaciones genéticas entre 17 poblaciones nativas sudamericanas en relación a 15 microsatélites (STRs autosómicos, utilizando 3 distancias genéticas- DST, DAy (δu2-que se ajustan a diferentes postulados teóricos. A través de diferentes técnicas de análisis (escalamiento multidimensional, correlación y correlación parcial de matrices se puso a prueba si las distancias genéticas reflejaban las relaciones interpoblacionales esperadas a partir de la distribución geográfica o de relaciones lingüísticas entre las poblaciones. Además, se estimó en que grado las distintas medidas de distancias genéticas eran influenciadas por la diversidad (He de cada población. Los mapas genéticos muestran, principalmente para DST y DA, que las poblaciones aisladas y con bajo tamaño efectivo (Ne aparecen como outliers, mientras que las poblaciones con alto Ne y mayor flujo génico ocupan una posición central a bajos valores de distancia unas de otras y sin un patrón definido de agrupamiento. La falta de asociación entre distancias genéticas y lingüísticas o geográficas y por otra parte, la alta correlación negativa entre He y distancias génicas promedio por población confiman ese patrón, demostrando que la mayor parte de la variación interpoblacional puede ser explicada en función del grado de diversidad intrapoblacional. Es decir, las distancias genéticas no reflejan relaciones filogenéticas, lingüísticas o geográficas, sino más bien eventos demográficos recientes tales como cuellos de botella genético, efecto fundador o migración externa masiva. Este hecho puede ser comprobado por medio de otra metodología analítica, el modelo de Harpending y Ward.
Full Text Available Melostelis gen. nov., espécies novas e notas complementares sobre Anthidiini (Hymenoptera, Apidae. Melostelis gen. nov. é proposto para um novo Anthidiini cleptoparasita. São descritas e ilustradas duas espécies novas: Melostelis amazonensis sp. nov. de Manaus, Amazonas e Larocanthidium chacoense sp. nov. de Porto Murtinho, Mato Grosso do Sul. São dados a conhecer os machos de Epanthidium bolivianum Urban, 1995 e Epanthidium araranguense Urban, 2006 e, registrados pela primeira vez no Brasil, na sub-região do chaco, Ketianthidium zanolae Urban, 2000 e Epanthidium bolivianum.
Lee, Young June
A new cicada genus, Galgoria gen. nov., is described with Tanna herzbergi Schmidt, 1932 (from southern China) as its type species, which is placed in the subtribe Leptopsaltriina Moulton, 1923 of the tribe Leptopsaltriini Moulton, 1923 in the subfamily Cicadinae Latreille, 1802 (Hemiptera: Cicadidae). Tanna herzbergi Schmidt, 1932 is transferred from Tanna Distant, 1905 to Galgoria gen. nov. to become Galgoria herzbergi (Schmidt, 1932) comb. nov. Tanna apicalis Chen, 1940 syn. nov. and Tanna pseudocalis Lei & Chou, 1997 syn. nov. are synonymized here with Galgoria herzbergi (Schmidt, 1932) comb. nov.
Salamanca Ortiz, Daysi Natalia; Vergara Vergara, Jorge Yamit; Escobar Córdoba, Franklin; Rodríguez Gama, Álvaro; Caminos Pinzón, Jorge Eduardo
Actualmente, con el aumento de la disponibilidad de técnicas para la realización de estudios genéticos, han aparecido nuevas áreas del conocimiento como la epigenética y la farmacogenética. Estas nuevas áreas han permitido esclarecer las bases genéticas implicadas en la aparición de las enfermedades que afectan al ser humano. Dada su aplicación global, la psiquiatría no ha sido ajena al alcance de estas nuevas disciplinas, lo cual se refleja en el gran número de estudios realizados a nivel mu...
Full Text Available Introducción. Las enzimas carbapenemasas de tipo KPC tienen gran capacidad de diseminación, son causantes de epidemias y se asocian a mayor mortalidad y estancia hospitalaria. En Colombia se han venido reportando cada vez más desde 2007, pero se desconoce la prevalencia hospitalaria. Objetivo. Estimar la prevalencia hospitalaria del gen blaKPC. Materiales y métodos. Se evaluó la presencia del gen blaKPC y su ‘clonalidad’ en aislamientos de enterobacterias y Pseudomonas aeruginosa de pacientes hospitalizados. Resultados. De los 424 aislamientos evaluados durante el periodo de estudio, 273 cumplieron con criterios de elegibilidad, 31,1 % fue positivo para el gen blaKPC y, al ajustar por ‘clonalidad’, la positividad fue de 12,8 %. El gen blaKPC se encontró con mayor frecuencia en Klebsiella pneumoniae seguido de P. aeruginosa y otras enterobacterias. A pesar de que la unidad de cuidados intensivos aportó el mayor número de aislamientos, no se encontró un patrón más prevalente del gen blaKPC en las ellas que en las otras salas. El aparato respiratorio fue el sitio anatómico de origen con la mayor prevalencia. No se presentó estacionalidad en la frecuencia de los aislamientos portadores del gen blaKPC. Conclusión. Este estudio reveló la alta prevalencia del gen blaKPC en diferentes microorganismos aislados en varias instituciones hospitalarias del país. La extraordinaria capacidad de propagación del gen blaKPC, las dificultades del diagnóstico y la limitada disponibilidad de antibióticos plantean la apremiante necesidad de fortalecer los sistemas de vigilancia epidemiológica y ajustar oportunamente las políticas institucionales de uso racional de antibióticos con el fin de contener su diseminación a otras instituciones de salud del país.
Corredor Otavo, Daniel
La computación evolutiva y muy especialmente los algoritmos genéticos son cada vez más empleados en las organizaciones para resolver sus problemas de gestión y toma de decisiones (Apoteker & Barthelemy, 2000). La literatura al respecto es creciente y algunos estados del arte han sido publicados. A pesar de esto, no hay un trabajo explícito que evalúe de forma sistemática el uso de los algoritmos genéticos en problemas específicos de los negocios internacionales (ejemplos de ell...
Villagra, Andrea; San Pedro, María Eugenia de; Lasso, Marta Graciela; Pandolfi, Daniel
En este trabajo se exploran dos implementaciones computacionales diferentes basadas en la teoría biológica del Gen egoísta propuesta por Richard Dawkins en 1976. Este enfoque computacional fue propuesto inicialmente por Corno et al en problemas de optimización y llamado Algoritmo del Gen Egoísta. Las modificaciones discutidas aquí tienen como objetivo mejorar la velocidad de convergencia del algoritmo introduciendo modificaciones en la estructura de la población virtual de genes y la aplicaci...
Santos, Alisson Moura
Com o objetivo de estudar a variabilidade genética, estimar os parâmetros genéticos e avaliar o desempenho inicial dos indivíduos no teste clonal e teste de procedência/progênie instalou-se dois experimentos em Campo Belo, MG. Por meio do teste de procedência/progênie de Toona ciliata avaliou-se 78 progênies de polinização aberta, provenientes de 16 procedências distintas da Austrália. O experimento foi instalado em janeiro de 2008 no delineamento de blocos ao acaso, com 3 repetições e 16 pla...
Amador, Carmen; Toro Ibañez, Miguel Angel; Fernandez, J.
La pérdida de diversidad genética, que conlleva descensos en eficacia biológica y pérdida de adaptabilidad, suele considerarse un fenómeno a evitar. Sin embargo determinadas poblaciones requieren la preservación del fondo genético diferenciado de otros grupos: han de ser mantenidas en pureza. El motivo puede ser económico: razas que proporcionan productos de interés (como los cerdos ibéricos o bovinos de raza Reggiana; Dalvit et al., 2007) razas, como en perros, que no se cruzan por mot...
Zaava Ravid; Sofía Duque; Adriana Arévalo; Rubén Santiago Nicholls; Moisés Wasserman
Introducción. Giardia intestinalis es un parásito protozoario que causa la infección gastrointestinal conocida como giardiosis, la cual se transmite principalmente a través de la contaminación fecal-oral. Estudios genéticos de aislamientos de Giardia cultivados axénicamente han identificado dos grupos genéticos principales distribuidos en el mundo. En el presente estudio se analizaron 24 cepas nativas del parásito por medio de la técnica RAPD (ADN polimórfico amplificado aleatoriamente). O...
Full Text Available BACKGROUND: Gentisate (2,5-dihydroxybenzoate is a key ring-cleavage substrate involved in various aromatic compounds degradation. Corynebacterium glutamicum ATCC13032 is capable of growing on gentisate and genK was proposed to encode a transporter involved in this utilization by its disruption in the restriction-deficient mutant RES167. Its biochemical characterization by uptake assay using [(14C]-labeled gentisate has not been previously reported. METHODOLOGY/PRINCIPAL FINDINGS: In this study, biochemical characterization of GenK by uptake assays with [(14C]-labeled substrates demonstrated that it specifically transported gentisate into the cells with V(max and K(m of 3.06 ± 0.16 nmol/min/mg of dry weight and 10.71 ± 0.11 µM respectively, and no activity was detected for either benzoate or 3-hydoxybenzoate. When GenK was absent in strain RES167 ΔgenK, it retained 85% of its original transport activity at pH 6.5 compared to that of strain RES167. However, it lost 79% and 88% activity at pH 7.5 and 8.0, respectively. A number of competing substrates, including 3-hydroxybenzoate, benzoate, protocatechuate and catechol, significantly inhibited gentisate uptake by more than 40%. Through site-directed mutagenesis, eight amino acid residues of GenK, Asp-54, Asp-57 and Arg-386 in the hydrophobic transmembrane regions and Arg-103, Trp-309, Asp-312, Arg-313 and Ile-317 in the hydrophilic cytoplasmic loops were shown to be important for gentisate transport. When conserved residues Asp-54 and Asp-57 respectively were changed to glutamate, both mutants retained approximately 50% activity and were able to partially complement the ability of strain RES167 ΔgenK to grow on gentisate. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that GenK is an active gentisate transporter in Corynebacterium glutamicum ATCC13032. The GenK-mediated gentisate transport was also shown to be a limiting step for the gentisate utilization by this strain. This enhances our
Stangegaard, Michael; Tomas, Carmen; Hansen, Anders J.
Single nucleotide polymorphism genotyping provides a supplement for conventional short tandem repeats-based kits currently used for human identification. GenPlex (Applied Biosystems (AB), Foster City, CA) is an SNP-genotyping kit based on a multiplex of 48 informative, autosomal SNPs from...... of both partial and full plates. A total of 286 samples were analyzed in duplicates with the GenPlex reaction using the Biomek-3000. The results were compared with those obtained from the same samples using the SNaPshot(AB) single-base extension system. Full concordance of the results was obtained in all...
Muñoz Domínguez, Carlos
La Fibrosis Quística (FQ) es una enfermedad autosómica recesiva producida por mutaciones en el gen CFTR. Dicho gen produce una proteína (CFTR) implicada en el transporte de iones Cl- a través de la membrana plasmática. La alteración ... La consecuencia de estas secreciones afecta principalmente a pulmones, páncreas exocrino, aparato reproductor masculino y glándulas sudoríparas, provocando un cuadro clínico muy variable de unos pacientes a otros. Tanto la elevada concentración iónica en el su...
Fernández Isasi, Leonor
El presente trabajo trata de ahondar en la controversia de un tema tan amplio y polémico como es el uso de los organismos genéticamente modificados (OGMs) o derivados de los mismos en la generación de los alimentos transgénicos. A lo largo de este documento se introduce la situación actual en la que se encuentran a nivel mundial, europeo y nacional. Se ejemplifican las diferentes aplicaciones de la ingeniería genética en los diferentes tipos de OGMs (animales, vegetales y microorganismos), as...
Oviedo, Norma; Manuel-Apolinar, Leticia; De la Chesnaye, Elsa; Guerra-Araiza, Christian
El autismo, hoy en día definido como trastornos del espectro autista, fue descrito inicialmente en 1943. Se caracteriza por alteraciones en la comunicación, la interacción social y un espectro restringido de intereses del paciente. Generalmente se identifica en etapas tempranas del desarrollo a partir de los 18 meses de edad. Actualmente el autismo se considera un desorden neurológico con un espectro que abarca diferentes grados que se asocian con factores genéticos, no genéticos y del medio ...
Esta tese realiza uma análise econômica do impacto da entrada de medicamentos genéricos no mercado farmacêutico brasileiro, em particular sobre os preços dos seus respectivos medicamentos de marca de referência. Analisa, também, as características dos medicamentos de marca que atraíram os medicamentos genéricos aos seus mercados, bem como, busca avaliar o comportamento dos consumidores com base numa estimação de demanda de medicamentos. A análise das condições institucionais específicas do ...
Cirne, Adriana Damasceno Pereira Pinto
As concepções alternativas são ideias dos estudantes sobre conhecimentos específicos, constituindo-se em uma causa importante que pode levar a erros conceituais, dificultando a aprendizagem significativa de conceitos científicos, especialmente aqueles com alto grau de abstração, como biologia celular e genética. Objetivou-se, com este trabalho, avaliar as dificuldades de aprendizagem de estudantes de ensino fundamental sobre conceitos de genética, em uma escola da rede pública no Estado do RN...
Full Text Available Determinar variabilidad y estimar los niveles de mestizaje en las razas de GCC mediante laevaluación de marcadores polimórficos en ADN mitocondrial y cromosoma Y y analizar filo-genéticamente el origen del GCC.Las siete razas de GCC han sufrido procesos de adaptación a las condiciones tropicales y hanacumulado características genéticas únicas y de gran valor, principalmente de tipo reproductivoe inmunológico.
Menezes, Mariney de
A qualidade fisiológica de sementes de soja é uma característica a ser considerada nos programas de melhoramento. Dessa forma há necessidade de se conhecer o controle genético para essa característica assim como associar as características do tegumento de sementes com a qualidade fisiológica das mesmas. Em uma primeira etapa foi avaliada a variabilidade genética para a qualidade fisiológica de sementes entre diferentes cultivares de soja por meio de testes de germinação e vigor. Em outra etap...
Fernando Martins Antoneli Junior
Neste trabalho resolvemos o problema da classicação dos possíveis esquemas de quebra de simetria que reproduzem as degenerescências do código genético na categoria dos grupos finitos simples, contribuindo assim para a busca de modelos algébricos para a evolução do código genético, iniciada por Hornos & Hornos. In this work we solve the problem of classifying the possible symmetry breaking schemes based on simple finite groups that reproduce the degeneracies of the genetic code, ...
O artigo organiza o debate sobre a medicina genética corretiva (as intervenções genéticas em seres humanos) e analisa as principais objeções contra ela: (1) a acusação de eugenia e (2) a possibilidade do aumento da discriminação e da desigualdade social. A primeira objeção é respondida através da distinção entre eugenia liberal e eugenia autoritária e da crítica à distinção entre terapia e melhoramento. À segunda objeção é oferecida a resposta liberal através da discussão de seus princípios d...
Costa Roberto Alexandre; Rodrigues Rosana; Sudré Cláudia Pombo
A mancha-bacteriana, principal doença bacteriana do pimentão causa desfolha intensa quando em condições favoráveis, deixando os frutos expostos ao sol, depreciando-os e diminuindo a produção. Para estimar, nas condições de Campos dos Goytacazes, os efeitos genéticos da reação do hospedeiro ao patógeno, tanto em folhas como em frutos, foram obtidos híbridos F1, sem recíprocos, a partir de cruzamentos dialélicos entre cinco genótipos de pimentão, sendo três suscetíveis ('UENF 1420', 'UENF 1421'...
Full Text Available The increasing demand for raw material for multiple uses of forest products and by-products has attracted the interest for fast growing species, such as the Australian Cedar (Toona ciliata, which presents high productive and economic potential. The present work aimed at estimating genetic diversity by DNA markers and morphological traits supported for the mixed models. The following traits were measured and genotypes were sampled randomly in different areas: diameter at breast height, height, cylindrical volume, diameter, distance between nodes and crown diameter. Twelve RAPD primers were used and generated a total of 91 marks, 82 of which were polymorphic. The high percentage of polymorphic markers, 90.10%, demonstrated that discrimination in this species is efficient, but it yet little studied, for this case we can find the extent of the genetic basis for the application of technical improvement. The assessment of genetic diversity by the UPGMA method using the binary and morphological data provided the expression of genetic dissimilarities among the accessions evaluated, optimizing the perception of this divergence. The use of mixed models was efficient to assess combined genetic diversity to optimize the selection of genotypes with divergent genetic values for diameter at breast height.A crescente demanda por matéria-prima para múltiplos usos dos produtos florestais e subprodutos tem despertado o interesse para espécies de crescimento rápido, como o cedro australiano (Toona ciliata, que apresenta potencial produtivo e econômico. Neste trabalho, objetivou-se estimar a diversidade genética por marcadores de DNA e caracteres morfológicos com o uso dos modelos mistos. Os seguintes caracteres foram medidos e os genótipos foram amostrados aleatoriamente em diferentes áreas de plantio: diâmetro à altura do peito, altura, volume cilíndrico, distância entre nós e diâmetro de copa. Doze primers RAPD foram utilizados e geraram um total
Wyszynski Diego F.
Full Text Available La epidemiología genética es una disciplina relativamente reciente que estudia la interacción entre los factores genéticos y ambientales que dan origen a las enfermedades del ser humano. Valiéndose de marcadores genéticos desarrollados a través de la biología molecular, de complejos algoritmos almacenados en computadoras y de amplias bases de datos, la epidemiología genética se ha desarrollado notablemente durante los últimos 10 años. El presente artículo describe los objetivos de la epidemiología genética y su metodología, empleando ejemplos concretos tomados de la literatura científica reciente.
Gloria Jiménez Marín; Rodrigo Elías Zambrano
... clave: automóviles, cine, discurso, intertextualidad, publicidad, semiótica. Jiménez Marín, G. Elias Zambrano, R. (2013): Cine y publicidad. La intertextualidad en las campañas de Volkswägen. Arte, Individuo y Sociedad, 25(1) 153-167 Abstract This article is a reflexion about cinema's influence on commercial advertising, specifically the cine-...
Leonardo A. Pinto
Full Text Available OBJETIVO: Apresentar os resultados dos estudos mais importantes e recentes sobre a genética da asma. Estes dados devem auxiliar os clínicos gerais a compreender o impacto da genética sobre este distúrbio complexo e como os genes e polimorfismos influenciam a asma e a atopia. FONTES DOS DADOS: Os dados foram coletados do banco de dados MEDLINE. Os estudos de associação genética foram selecionados do Genetic Association Database, um repositório de estudos de associação genética de doenças e distúrbios complexos organizado pelo National Institutes of Health. SÍNTESE DOS DADOS: Considerando os dados de diversos importantes estudos de gêmeos sobre a genética da asma, a heritabilidade, que mensura a contribuição dos fatores genéticos para a variância da asma, pode ser estimada entre 0,48 e 0,79. Uma grande quantidade de estudos de associação genética tentou identificar genes de susceptibilidade à asma. Os resultados mais replicados nos estudos de associação genética envolvem as cinco regiões do genoma humano a seguir: 5q31-32, 6p21, 11q12-13, 16p11-12, e 20p13. Recentemente, outro gene de susceptibilidade à asma (ORMDL3, considerado determinante crítico para a asma infantil, foi identificado por um estudo genômico de associação. CONCLUSÕES: É possível estimar que a contribuição genética à asma varia entre 48 e 79%. Diversos loci parecem influenciar a susceptibilidade à asma. Os genes localizados no cromossomo 5q (ADRB2, IL13 e IL4 e o gene ORMDL3, no cromossomo 17, identificado recentemente, parecem ser determinantes para a asma infantil. O diagnóstico e a farmacogenética podem ser as primeiras implicações clínicas de estudos extensivos sobre a genética da asma.OBJECTIVE: To present the most important and recent results of studies on asthma genetics. These data may help general physicians understand the impact of genetics on this complex disorder and how genes and polymorphisms influence asthma and atopy
Full Text Available El presente artículo revisa la evidencia científica que muestra la heredabilidad de la esquizofrenia, su forma de herencia compleja y la posible heterogeneidad genética y ambiental. Se presentan las regiones cromosómicas que han sido ligadas a la enfermedad y algunos de los genes candidatos. El objetivo es presentar los resultados más importantes en el campo de la investigación genética de la enfermedad. Aunque se acepta que factores ambientales deben estar presentes en la etiopatogenia de la enfermedad, no se profundiza en ellos. Finalmente, se comenta el modelo lamarquiano sugerido por el Prof.. Bolaños. El fin es transmitir que en la actualidad no hay contradicción entre el modelo biologista o psicológico que explicaban esta enfermedad. La concepción moderna une ambos modelos: se considera una enfermedad del neurodesarrollo en la que participan factores genéticos, factores epigenéticos y noxas ambientales, incluyendo los factores psicosociales.
Henning Jensen Pennington
Full Text Available El artículo plantea la necesidad de no sobresimplificar fenómenos complejos como el de la esquizofrenia, pues su etiología implica la interacción de aspectos genéticos, biológicos y sociopsicológicos. Se plantea que el mismo conocimiento genético imposibilita la asunción de estas posiciones radicales, razón por la cual la investigación biológica actúa con cautela en la formulación de hipótesis causales. No obstante, se pone de manifiesto la interpretación inapropiada de los resultados de investigaciones genéticas y biológicas, cuando por un lado, se postula la complejidad del fenómeno, pero por otro lado y por un acto de simplificación cognoscitiva, se desatiende esa complejidad y se da el salto hacia explicaciones monocausales. La actividad investigativa en el campo de la esquizofrenia se enfrenta entonces a la responsabilidad histórica de dar a cada elemento el lugar que le corresponde en la intrincada red de elementos que influyen en la aparición y desarrollo de la esquizofrenia.
Rodrigo Gonçalves Dias
Full Text Available Atletas de elite são reconhecidos como fenômenos esportivos e o potencial para atingir níveis superiores de performance no esporte está parcialmente sob o controle de genes. A excelência atlética é essencialmente multifatorial e determinada por complexas interações entre fatores ambientais e genéticos. Existem aproximadamente 10 milhões de variantes genéticas dispersas por todo o genoma humano e uma parcela destas variantes têm demonstrado influenciar a responsividade ao treinamento físico. Os fenótipos de performance física humana parecem ser altamente poligênicos e alguns estudos têm comprovado a existência de raras combinações genotípicas em atletas. No entanto, os mecanismos pelos quais genes se interagem para amplificar a performance física são desconhecidos. O conhecimento sobre os genes que influenciam a treinabilidade somado ao potencial uso indevido dos avanços da terapia gênica, como a possível introdução de genes em células de atletas, fez surgir o termo doping genético, um novo e censurado método de amplificação da performance física, além dos limites fisiológicos. Aumentos na hipertrofia muscular esquelética e nos níveis de hematócrito estão sendo conseguidos através da manipulação da expressão de genes específicos, mas a grande parte das impressionáveis alterações foi obtida em experimentação com animais de laboratório. A compreensão dos resultados científicos envolvendo genética, performance física humana e doping genético é uma difícil tarefa. Com o propósito de evitar a contínua má interpretação e propagação de conceitos errôneos, esta revisão, intencionalmente, vem discutir as evidências científicas produzidas até o momento sobre o tema, permitindo a compreensão do atual "estado da arte"
Full Text Available Herein, we report the main characteristics of a new species named Pacaella massiliensis gen. nov., sp. nov., strain Marseille-P2670T (CSUR P2670 that was isolated from the gut microbiota of a 45-year-old French patient.
Eric P Xing
Full Text Available With the continuous improvement in genotyping and molecular phenotyping technology and the decreasing typing cost, it is expected that in a few years, more and more clinical studies of complex diseases will recruit thousands of individuals for pan-omic genetic association analyses. Hence, there is a great need for algorithms and software tools that could scale up to the whole omic level, integrate different omic data, leverage rich structure information, and be easily accessible to non-technical users. We present GenAMap, an interactive analytics software platform that 1 automates the execution of principled machine learning methods that detect genome- and phenome-wide associations among genotypes, gene expression data, and clinical or other macroscopic traits, and 2 provides new visualization tools specifically designed to aid in the exploration of association mapping results. Algorithmically, GenAMap is based on a new paradigm for GWAS and PheWAS analysis, termed structured association mapping, which leverages various structures in the omic data. We demonstrate the function of GenAMap via a case study of the Brem and Kruglyak yeast dataset, and then apply it on a comprehensive eQTL analysis of the NIH heterogeneous stock mice dataset and report some interesting findings. GenAMap is available from http://sailing.cs.cmu.edu/genamap.
Liu, Yijin; Freeman, Alasdair D J; Déclais, Anne-Cécile; Wilson, Timothy J; Gartner, Anton; Lilley, David M J
We present the crystal structure of the junction-resolving enzyme GEN1 bound to DNA at 2.5 Å resolution. The structure of the GEN1 protein reveals it to have an elaborated FEN-XPG family fold that is modified for its role in four-way junction resolution. The functional unit in the crystal is a monomer of active GEN1 bound to the product of resolution cleavage, with an extensive DNA binding interface for both helical arms. Within the crystal lattice, a GEN1 dimer interface juxtaposes two products, whereby they can be reconnected into a four-way junction, the structure of which agrees with that determined in solution. The reconnection requires some opening of the DNA structure at the center, in agreement with permanganate probing and 2-aminopurine fluorescence. The structure shows that a relaxation of the DNA structure accompanies cleavage, suggesting how second-strand cleavage is accelerated to ensure productive resolution of the junction. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Brucella suis. 21.10%. 47.40%. 40.60%. 26.70%. 26.70%. Supplementary Table 2 Classification of Genomic Islands (GIs) predicted by INDeGenIUS into 6 functional categories in each of the representative proteobacteria. GI in organisms. Property encoded in predicted GI. Predicted functional island. Alpha proteobacteria.
Full Text Available La deficiencia de la 21-Hidroxilasa 21(OH es la causa más frecuente de Hiperplasia SuprarenalCongénita. Aproximadamente 75% de los casos son causados por mutaciones puntuales y 25%son debidas a deleciones y grandes conversiones del gen. En el presente estudio se buscó evaluarla deleción del gen y 5 mutaciones puntuales en 19 individuos afectados por la forma clásica dela enfermedad (CL. Por medio de PCR se realizó la amplificación selectiva del gen CYP21 y luegomediante la aplicación de la metodología de ACRS (Amplication Created Restriction Sites seidentificaron las mutaciones. Se observó la deleción del gen en 2 de los alelos estudiados (5.26%.La mutación Q318Stop, que resulta de un cambio de C-T en el codón 318 se encontró en 13alelos (34.21%. La mutación empalme en el Intrón 2 que se produce por el cambio de A-Glo que altera el marco de lectura y produce un codón de parada prematuro, se halló en 10 ale-los (26.32%.
Data Comma text-based controller-pilot communication systemis expected to yield several NextGen safety and efficiency benefits. With Data Comm, communication becomes a visual task, and may potentially increase head-down time on the flight deck ...
Roig José L. Domingo
Full Text Available A lo largo de 1999, se ha venido intensificando el debate sobre la seguridad de los alimentos modificados genéticamente, una importante y compleja área de investigación científica, la cual demanda unos estándares rigurosos. Diversos grupos, incluyendo asociaciones de consumidores y Organizaciones no Gubernamentales (ONGs han sugerido que todos los alimentos modificados genéticamente deberían ser sometidos a estudios a largo plazo con animales antes de su aprobación para el consumo humano. El principal objetivo de la presente revisión ha sido conocer cual es el estado actual de la cuestión en lo referente a los potenciales efectos adversos sobre la salud de los alimentos modificados genéticamente. Dos bases de datos, Medline y Toxline, así como una serie de direcciones de internet, han sido empleadas para la obtención de bibliografía. Aunque son numerosos los comentarios, noticias generales y cartas al Editor aparecidos en prestigiosas revistas, los artículos referentes a estudios experimentales sobre la seguridad de los alimentos modificados genéticamente son, sorprendentemente, muy escasos. Si se han obtenido resultados procedentes de la evaluación toxicológica de estos alimentos, no han sido publicados en revistas científicas y, por lo tanto, no han podido ser debidamente juzgados o contrastados.
Full Text Available We present the crystal structure of the junction-resolving enzyme GEN1 bound to DNA at 2.5 Å resolution. The structure of the GEN1 protein reveals it to have an elaborated FEN-XPG family fold that is modified for its role in four-way junction resolution. The functional unit in the crystal is a monomer of active GEN1 bound to the product of resolution cleavage, with an extensive DNA binding interface for both helical arms. Within the crystal lattice, a GEN1 dimer interface juxtaposes two products, whereby they can be reconnected into a four-way junction, the structure of which agrees with that determined in solution. The reconnection requires some opening of the DNA structure at the center, in agreement with permanganate probing and 2-aminopurine fluorescence. The structure shows that a relaxation of the DNA structure accompanies cleavage, suggesting how second-strand cleavage is accelerated to ensure productive resolution of the junction.
Hill, C.R.; Wagner, R.H.; El-Khayal, A. A.
The marattialean fern Qasimia schyfsmae (Lemoigne) gen. et comb. nov. is described from the Late Permian plant bed at Unayzah in central Saudi Arabia. Although no organic matter is preserved, impregnation of the compressions by iron minerals at an early stage of diagenesis has partly mineralised the
Gore, Brian Francis; Hooey, Becky Lee; Mahlstedt, Eric; Foyle, David C.
To meet the expected increases in air traffic demands, NASA and FAA are researching and developing Next Generation Air Transportation System (NextGen) concepts. NextGen will require substantial increases in the data available to pilots on the flight deck (e.g., weather,wake, traffic trajectory predictions, etc.) to support more precise and closely coordinated operations (e.g., self-separation, RNAV/RNP, and closely spaced parallel operations, CSPOs). These NextGen procedures and operations, along with the pilot's roles and responsibilities, must be designed with consideration of the pilot's capabilities and limitations. Failure to do so will leave the pilots, and thus the entire aviation system, vulnerable to error. A validated Man-machine Integration and design Analysis System (MIDAS) v5 model was extended to evaluate anticipated changes to flight deck and controller roles and responsibilities in NextGen approach and Land operations. Compared to conditions when the controllers are responsible for separation on decent to land phase of flight, the output from these model predictions suggest that the flight deck response time to detect the lead aircraft blunder will decrease, pilot scans to the navigation display will increase, and workload will increase.
Valente, P.; Boekhout, T.; Landell, M.F.; Crestani, J.; Pagnocca, F.C.; Sette, L.D.; Passarini, M.R.Z.; Rosa, C.A.; Brandão, L.R.; Pimenta, R.S.; Ribeiro, J.R.A.; Garcia, K.M.; Lee, C.-F.; Suh, S.-O.; Péter, G.; Dlauchy, D.; Fell, J.W.; Scorzetti, G.; Theelen, B.; Vainstein, M.H.
Independent surveys across the globe led to the proposal of a new basidiomycetous yeast genus within the Bulleromyces clade of the Tremellales, Bandoniozyma gen. nov., with seven new species. The species were characterized by multiple methods, including the analysis of D1/D2 and ITS nucleotide
Improved N-mer based Detection of Genomic Islands Using Sequence-clustering (INDeGenIUS) for the identification of GIs. ... haemagglutinin; PAI, pathogenicity island; RI, resistance island; SyI, symbiotic island; SI, secretion island; TCA, tri carboxylic acid ..... incorrect signatures could result in wrong prediction of.
Qiu, Lu; Che, Yanli; Wang, Zongqing
Sinolatindia petila gen. n. and sp. n. (Blattodea: Corydiidae: Latindiinae) is reported from Yunnan Province, China. Description, illustrations and a distribution map of the new taxon are provided. Comparisons with the type genus Latindia Stål, 1860 and the genus Homopteroidea Shelford, 1906 are given.
Qiu, Lu; Che, Yanli; Wang, Zongqing
Sinolatindia petila gen. n. and sp. n. (Blattodea: Corydiidae: Latindiinae) is reported from Yunnan Province, China. Description, illustrations and a distribution map of the new taxon are provided. Comparisons with the type genus Latindia Stål, 1860 and the genus Homopteroidea Shelford, 1906 are given.
The proposed strategy is illustrated on the PJM 5-bus system and compared to the well-known stochastic search approaches, inertia weight approach particle swarm optimisation (IWAPSO) and GA. The rest of the paper is organised as follows: Section 2 expresses problem formulation including the GenCo's objective model.
Camposano, Susana W; Galaburda, Alberto D
..., o a través de proteínas funcionales que estos genes producen. La dislexia evolutiva representa un síndrome conductual complejo que ha comenzado a analizarse experimentalmente, logrando establecer un recorrido por lo menos aproximativo entre un gen especí?co y una función cognitiva puntual.
Warmerdam, Amanda; Lewis, Ioni; Banks, Tamara
Purpose: Using the Theory of Planned Behaviour (TPB) framework, the purpose of this paper is to explore whether the standard TPB constructs explained variance in Generation Y (Gen Y) individuals' intentions to join their ideal organisation. Design/methodology/approach: A mixed methods approach was used featuring qualitative and quantitative…
En esta revisión se proporciona una visión global de la genómica de la LLA, describiendo algunas estrategias que contribuyen a la identificación de biomarcadores con potencial utilidad en la práctica clínica.
information) dans les pays d'Afrique, des Caraïbes et du Pacifique - phase III. Les phases I et II de ce projet d'octroi de petites subventions ont été financées par les projets nos 101698 et 102900, respectivement. GenARDIS III apportera à 15 ...
Building America Builders Challenge fact sheet on the NextGen demo home built in Las Vegas. The home has a Home Energy Rating System (HERS) index score of 44 with R-40 spray foam attic insulation, R-40 insulated concrete walls, and a 4kW DC solar laminate
Full Text Available We introduce the graph transformation tool GrGen.NET (www.grgen.net by solving the Hello World Case of the Transformation Tool Contest 2011 which consists of a collection of small transformation tasks; for each task a section is given explaining our implementation.
Xing, Eric P.; Curtis, Ross E.; Schoenherr, Georg; Lee, Seunghak; Yin, Junming; Puniyani, Kriti; Wu, Wei; Kinnaird, Peter
With the continuous improvement in genotyping and molecular phenotyping technology and the decreasing typing cost, it is expected that in a few years, more and more clinical studies of complex diseases will recruit thousands of individuals for pan-omic genetic association analyses. Hence, there is a great need for algorithms and software tools that could scale up to the whole omic level, integrate different omic data, leverage rich structure information, and be easily accessible to non-technical users. We present GenAMap, an interactive analytics software platform that 1) automates the execution of principled machine learning methods that detect genome- and phenome-wide associations among genotypes, gene expression data, and clinical or other macroscopic traits, and 2) provides new visualization tools specifically designed to aid in the exploration of association mapping results. Algorithmically, GenAMap is based on a new paradigm for GWAS and PheWAS analysis, termed structured association mapping, which leverages various structures in the omic data. We demonstrate the function of GenAMap via a case study of the Brem and Kruglyak yeast dataset, and then apply it on a comprehensive eQTL analysis of the NIH heterogeneous stock mice dataset and report some interesting findings. GenAMap is available from http://sailing.cs.cmu.edu/genamap. PMID:24905018
Lobatolampea tetragona gen. nov. & spec. nov. was collected from coastal waters of Ise Bay, near Toba, Pacific coast of middle Japan. It assumes a medusoid bell-shape when floating, but is nearly discshaped when resting on the bottom. It is characterized by four C-shaped gonads present on the distal
Scatolini, D.; Penteado-Dias, A.M.; Achterberg, van C.
Pseudorhysipolis gen. nov. (type species: Pseudorhysipolis fenix spec. nov. from Brazil and Panama) is described and illustrated. A key to nine new species is added; one new subgenus is described (Pararhysipolis nov.; type species: Pseudorhysipolis mellinotum spec. nov.) and the first host record
Smit CE; MSP; VSP
Het is niet mogelijk om indicatieve waterkwaliteitsnormen te bepalen voor twee perfluorverbindingen die kunnen vrijkomen bij de productie van teflon met de zogeheten GenX-technologie. Er ontbreken gegevens over de mate waarin deze stoffen in vissen ophopen. Deze informatie is onmisbaar om te
Full Text Available Très peu de philosophes politiques se sont intéressés à l’oeuvre de Genlis, en partie parce que son oeuvre est communément réduite à un moralisme religieux insipide. Si Alice Laborde con-clut sa biographie en soulignant que Genlis « est moraliste avant tout », les travaux récents de Mary Trouille mettent tout autant l’accent sur le fait que la comtesse est « moralist to the core ». La visée du présent article est de nuancer cette lecture, non pas en niant le moralisme de Genlis, mais plutôt en montrant que celui-ci ne l’a pas empêchée de publier des textes à portée politique qui mériteraient notre attention aujourd’hui—particulièrement l’attention de ceux et celles qui se donnent pour tâche de penser l’accueil et le soin de l’Autre. A partir du Discours sur la sup-pression des convens et du Discours sur le luxe et l’hospitalité, nous indiquons non seulement l’actualité, mais aussi la surprenante radicalité des textes publiés par Genlis en période révolu-tionnaire.
Gilmore, Tyler; Bonneville, Alain; Sullivan, Charlotte; Kelley, Mark; Appriou, Delphine; Vermeul, Vince; White, Signe; Zhang, Fred; Bjornstad, Bruce; Cornet, Francois; Gerst, Jacqueline; Gupta, Neeraj; Hund, Gretchen; Horner, Jake; Last, George; Lanigan, Dave; Oostrom, Mart; McNeil, Caitlin; Moody, Mark; Rockhold, Mark; Elliott, Mike; Spane, Frank; Strickland, Chris; Swartz, Lucy; Thorne, Paul; Brown, Christopher; Hoffmann, Jeffrey; Humphreys, Kenneth
The objective of the FutureGen 2.0 Project was to demonstrate, at the commercial scale, the technical feasibility of implementing carbon capture and storage (CCS) in a deep saline formation in Illinois, USA. Over approximately 5 years, the FutureGen Alliance conducted a detailed site-selection process and identified a site for carbon sequestration storage in Morgan County, Illinois. The storage site was fully characterized, including the collection of seismic data and the drilling and characterization of a stratigraphic borehole. The characterization data provided critical input for developing a site-specific conceptual model and subsequent numerical modeling simulations. The modeling simulations, coupled with the upstream designs of the pipeline and power plant supported the development of a detailed 90 percent design that included the injection wells and associated control and monitoring infrastructure. Collectively, all these data were used by the FutureGen Alliance to develop the required documentation to support the applications for four underground injection control (UIC) permits (one for each proposed well). In August 2014, the U.S. Environmental Protection Agency issued four, first-of-their-kind, Class VI UIC permits for carbon sequestration in the United States to the FutureGen Alliance. The information and data generated under this project have been made publically available through reports and publications, including this journal and others.
Xing, Eric P; Curtis, Ross E; Schoenherr, Georg; Lee, Seunghak; Yin, Junming; Puniyani, Kriti; Wu, Wei; Kinnaird, Peter
With the continuous improvement in genotyping and molecular phenotyping technology and the decreasing typing cost, it is expected that in a few years, more and more clinical studies of complex diseases will recruit thousands of individuals for pan-omic genetic association analyses. Hence, there is a great need for algorithms and software tools that could scale up to the whole omic level, integrate different omic data, leverage rich structure information, and be easily accessible to non-technical users. We present GenAMap, an interactive analytics software platform that 1) automates the execution of principled machine learning methods that detect genome- and phenome-wide associations among genotypes, gene expression data, and clinical or other macroscopic traits, and 2) provides new visualization tools specifically designed to aid in the exploration of association mapping results. Algorithmically, GenAMap is based on a new paradigm for GWAS and PheWAS analysis, termed structured association mapping, which leverages various structures in the omic data. We demonstrate the function of GenAMap via a case study of the Brem and Kruglyak yeast dataset, and then apply it on a comprehensive eQTL analysis of the NIH heterogeneous stock mice dataset and report some interesting findings. GenAMap is available from http://sailing.cs.cmu.edu/genamap.
Roberto de A Melo
Full Text Available With the development of new cultivars, a precise genetic characterization is essential for improvement programs or for cultivar registration and protection. Molecular markers have been complementing the traditional morphological and agronomic characterization techniques because they are virtually unlimited, cover the whole genome and are not environmentally influenced. Genetic characterization constitutes the basis for studies involving estimates of genetic similarity. Therefore, the objective of the present study was to evaluate the genetic similarity between ten coriander genotypes (nine cultivars and one line using ISSR markers. The cultivars used were: Americano, Asteca, Palmeira, Português, Santo, Supéria, Tabocas, Tapacurá, Verdão and the experimental line HTV-9299. The genetic similarity between the cultivars was estimated using 227 banded regions of ISSR molecular markers. The UBC 897 oligonucleotide generated the highest number of fragments (16, resulting in a higher polymorphism. The results indicate that the twenty-nine oligonucleotides chosen were satisfactory for detecting polymorphism. Based on the grouping analysis determined from the similarity data, there were two groups and two sub-groups. The calculated similarity for the genotypes varied from 52 to 75%. The lowest similarity was observed between Português and Verdão, at 52%. The highest similarity was found between Português and Palmeira, at 75%. The ISSR is efficient for identifying DNA polymorphism in coriander.Com o surgimento de novas cultivares, uma caracterização genética precisa é essencial, visando à utilização em programas de melhoramento ou para fins de registros e ou proteção de cultivares. Marcadores moleculares vêm complementando a caracterização morfológica e agronômica tradicional, uma vez que são virtualmente ilimitados, cobrem todo o genoma e não são influenciados pelo ambiente. A caracterização genética constitui a base para
Full Text Available El polimorfismo -511 citosina/timina (-511 C/T en la región promotora del gen interleuquina 1 beta (IL1β estα implicado en la producciσn diferencial de la citoquina y por tanto puede estar asociado a la respuesta inmuno-inflamatoria en obesidad, dislipidemias, cardiopatías, cáncer, infecciones, y el tratamiento con nutrientes y fármacos. Objetivos: Establecer la distribución de frecuencias de los genotipos y alelos del polimorfismo -511 C/T del gen IL1β en diferentes subpoblaciones peruanas. Diseño: Estudio descriptivo, observacional, transversal. Instituciones: Centro de Investigación de Bioquímica y Nutrición e Instituto de Medicina Tropical D.A. Carrión, Facultad de Medicina, UNMSM y Centro de Genética y Biología Molecular, Facultad de Medicina, USMP, Lima, Perú. Participantes: Pobladores peruanos. Intervenciones: Extracción de ADN genómico a partir de muestras sanguíneas o epitelio bucal según metodología estándar, de 168 individuos de 9 grupos subpoblacionales: 23 mestizos de Lima, 33 amazónicos (20 de Pucallpa y 13 de Amazonas y 112 andinos (12 de Ancash, 10 de Cajamarca, 18 de Huarochirí-Lima, 25 de Puno-Taquile, 25 de Puno-Uros y 22 de Puno-Anapia. Análisis del polimorfismo -511 C/T mediante la técnica de PCR/RFLP, con primers específicos y digestión con la enzima de restricción AvaI, detectándose los fragmentos por electroforesis en geles de agarosa al 2% y tinción con bromuro de etidio. Principales medidas de resultados: Frecuencias genotípicas y alélicas del gen IL1β. Resultados: Se encontró las siguientes frecuencias genotípicas CC=0,024; CT=0,369 y TT=0,607, consistentes con el equilibrio de Hardy-Weinberg; y las frecuencias alélicas fueron alelo C=0,208 y aleloT= 0,792. La frecuencia del alelo T, considerado el mutante, fue muy alta en los Uros de Puno (0.940 y más baja en los mestizos de Lima (0.609. La comparación de las frecuencias genotípicas (TT versus CT+CC y alélicas (T versus C
Sarai S. Mendoza-Retana
Full Text Available La Comarca Lagunera es la cuenca lechera más importante de México. En la actualidad se están utilizando diversas técnicas que permiten evaluar genéticamente el animal a una edad temprana, permitiendo seleccionar futuros reproductores con características deseables. Entre los genes relacionados con la producción de leche, se encuentran el gen Ob también llamado gen Leptina el cual actúa sobre el sistema nervioso central y tejidos periféricos jugando un papel muy importante en la modulación regulación del apetito, ganancia de peso vivo, incremento del metabolismo energético y el anabolismo muscular. Este trabajo se realizó para determinar el polimorfismo de longitud del fragmento de restricción ACI I de gen leptina en el exón 2 y correlacionarlo con los parámetros de producción y calidad de leche. Se recolectaron 100 muestra de sangre de vacas en producción del establo “Lácteos Florida” de Francisco I. Madero municipio de Coahuila, México con tres esta tus de producción: altas, medias y bajas La extracción de ADN se realizó por el método modificado de Salting - Out. Se realizó PCR del gen leptina originando un fragmento de 272 bp de longitud y se realizó PCR - RFLP con la enzima de restricción ACI I y secue nciación, correlacionando los genotipos TT, CT Y CC con tres estatus de producción de leche: altas, medias, bajas. El análisis estadístico indicó que las vacas portadoras del genotipo homocigoto (TT tienen un efecto significativo (P<0.01 con respecto a l as características de producción y calidad de leche ya que tuvieron un mayor consumo de alimento, ganancia de peso, además de una elevada producción de leche en comparación a los genotipos heterocigoto (CT y homocigoto (CC. Los resultados obtenidos muest ran que l a identificación molecular de polimorfismos del gen Ob puede usarse como herramienta de selección genética en bovinos de raza Holstein.
Mobilicoccus pelagius gen. nov., sp. nov. and Piscicoccus intestinalis gen. nov., sp. nov., two new members of the family Dermatophilaceae, and reclassification of Dermatophilus chelonae (Masters et al. 1995) as Austwickia chelonae gen. nov., comb. nov.
Hamada, Moriyuki; Iino, Takao; Iwami, Takahiro; Harayama, Shigeaki; Tamura, Tomohiko; Suzuki, Ken-ichiro
Two Gram-positive bacteria, designated strains Aji5-31(T) and Ngc37-23(T), were isolated from the intestinal tracts of fishes. 16S rRNA gene sequence analysis indicated that both strains were related to the members of the family Dermatophilaceae, with 95.6-96.9% 16S rRNA gene sequence similarities. The family Dermatophilaceae contains 2 genera and 3 species: Dermatophilus congolensis, Dermatophilus chelonae and Kineosphaera limosa. However, it has been suggested that the taxonomic position of D. chelonae should be reinvestigated using a polyphasic approach, because the chemotaxonomic characteristics are not known (Stackebrandt, 2006; Stackebrandt and Schumann, 2000). Our present study revealed that strains Aji5-31(T), Ngc37-23(T) and D. chelonae NBRC 105200(T) should be separated from the other members of the family Dermatophilaceae on the basis of the following characteristics: the predominant menaquinone of strain Aji5-31(T) is MK-8(H(2)), strain Ngc37-23(T) possesses iso- branched fatty acids as major components, and the menaquinone composition of D. chelonae is MK-8(H(4)), MK-8 and MK-8(H(2)) (5 : 3 : 2, respectively). On the basis of these distinctive phenotypic characteristics and phylogenetic analysis results, it is proposed that strains Aji5-31(T) and Ngc37-23(T) be classified as two novel genera and species of the family Dermatophilaceae. The names are Mobilicoccus pelagius gen. nov., sp. nov. and Piscicoccus intestinalis gen. nov., sp. nov., and the type strains are Aji5-31(T) (=NBRC 104925(T) =DSM 22762(T)) and Ngc37-23(T) (=NBRC 104926(T) =DSM 22761(T)), respectively. In addition, D. chelonae should be reassigned to a new genus of the family Dermatophilaceae with the name Austwickia chelonae gen. nov., comb. nov.
Nascimento Filho Firmino José do
Full Text Available As técnicas multivariadas, para estimar a diversidade genética de um grupo de progenitores, têm sido utilizadas com freqüência pelos melhoristas de plantas. Os progenitores são utilizados em cruzamentos biparentais ou múltiplos, para formação de populações segregantes que tenham maior probabilidade de recuperação de genótipos superiores. Este trabalho foi realizado com o objetivo de identificar clones de guaranazeiro produtivos e divergentes que possam ser utilizados em um programa de cruzamentos para obter híbridos com alto valor heterótico e materiais para propagação vegetativa. Foram avaliados 148 clones de guaranazeiro atualmente em uso no programa de melhoramento genético da Embrapa-Centro de Pesquisa Agroflorestal da Amazônia Ocidental. Utilizou-se, para estimativa da divergência genética, a análise de agrupamento, em que a medida de dissimilaridade utilizada foi a distância euclidiana média padronizada e os métodos de agrupamento de otimização de Tocher e do vizinho mais próximo para construção do dendrograma entre grupos de clones. Houve a formação de sete grupos divergentes de clones. Concluiu-se que a divergência genética entre os clones não é grande, pois dois grupos foram formados com dois clones e três grupos foram formados somente com um único clone. Os clones CMU384 e CMU801 foram os mais próximos geneticamente e podem ser utilizados na formação de uma população com desenvolvimento vegetativo uniforme para uso em plantios comerciais.
Goldfinger, Judith Z; Preiss, Liliana R; Devereux, Richard B; Roman, Mary J; Hendershot, Tabitha P; Kroner, Barbara L; Eagle, Kim A
Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL. This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data. QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity. In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL. In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier
Carlos Yábar V
Full Text Available Objetivo: Determinar las variantes genéticas de aislamientos del virus peruano de la Fiebre Amarilla (FA. Materiales y métodos: la región carboxiterminal del gen de la envoltura (E de cinco aislamientos de FA obtenidas de pacientes provenientes de Ayacucho 1978 (PER1, Junín 1995 (PER2, Cerro de Pasco (PER3, Cusco (1998 y San Martín (1999 fue amplificada por PCR, secuenciada y analizada con programas software de ADN. Resultados: el índice de similaridad de la secuencia de nucleótidos entre los cinco aislamientos reveló valores oscilantes entre 94,3% y 99,3%, mientras que la secuencia de aminoácidos presentó valores entre 97,6% y 99,7% de similaridad. El análisis filogenético demostró una distancia genética entre 0,40 y 6,50 mediante la secuencia de nucleótidos y a través de la secuencia de aminoácidos se observó un rango de 0,30 y 4,29. Sin embargo, las secuencias correspondientes a los sitios de glicosilación y a los epítopes de reconocimiento humoral fueron conservadas entre los cinco aislamientos, con excepción de algunos aislamientos de referencia reportados por otros autores. Conclusiones: los virus de FA peruanos forman un grupo filogenético distinto a otros virus de FA sudamericanos, basados en el análisis genéticos del gen E.
Nilton César Mantovani
Full Text Available Este trabalho teve por objetivos avaliar a técnica de alporquia visando ao resgate vegetativo de genótipos de urucum (Bixa orellana L. e a obtenção de plantas fornecedoras de propágulos para processos de propagação clonal. Foram utilizadas dez plantas matrizes de urucum, com 12 anos de idade, obtidas partindo do cruzamento artificial entre os genótipos "Fruto Verde Piloso" X "Fruto Vermelho Liso". Os alporques foram realizados em ramos de 1 a 2 cm de diâmetro, utilizando-se como substrato uma mistura de vermiculita e musgo. Foi avaliado o efeito (1 do tipo de anelamento da casca dos ramos (total ou parcial, com 1 cm de comprimento, (2 do AIB (ácido indol-3-butírico a 0 e 4,92 mM aplicado em papel filtro e (3 do tipo de proteção dos alporques (filmes plásticos transparente ou preto ou tecido tencel, no enraizamento de alporque dos dez genótipos. A técnica de alporquia proporcionou o enraizamento de ramos dos dez genótipos avaliados, com eficiência variável de 20 a 100%, havendo efeito do genótipo sobre a frequência de enraizamento. A sobrevivência desses alporques foi de 100% após o plantio quando estes foram produzidos com anelamento total, tratados com AIB e protegidos com plástico transparente. Em casa de vegetação os alporques desenvolveram ramos partindo da brotação de gemas caulinares constituindo estoques de explantes apropriados para serem utilizados como estacas ou como fontes de segmentos nodais para a propagação in vitro desta espécie.
Donovan H Parks
Full Text Available GenGIS is free and open source software designed to integrate biodiversity data with a digital map and information about geography and habitat. While originally developed with microbial community analyses and phylogeography in mind, GenGIS has been applied to a wide range of datasets. A key feature of GenGIS is the ability to test geographic axes that can correspond to routes of migration or gradients that influence community similarity. Here we introduce GenGIS version 2, which extends the linear gradient tests introduced in the first version to allow comprehensive testing of all possible linear geographic axes. GenGIS v2 also includes a new plugin framework that supports the development and use of graphically driven analysis packages: initial plugins include implementations of linear regression and the Mantel test, calculations of alpha-diversity (e.g., Shannon Index for all samples, and geographic visualizations of dissimilarity matrices. We have also implemented a recently published method for biomonitoring reference condition analysis (RCA, which compares observed species richness and diversity to predicted values to determine whether a given site has been impacted. The newest version of GenGIS supports vector data in addition to raster files. We demonstrate the new features of GenGIS by performing a full gradient analysis of an Australian kangaroo apple data set, by using plugins and embedded statistical commands to analyze human microbiome sample data, and by applying RCA to a set of samples from Atlantic Canada. GenGIS release versions, tutorials and documentation are freely available at http://kiwi.cs.dal.ca/GenGIS, and source code is available at https://github.com/beiko-lab/gengis.
Binley, Katie; Widdowson, Peter; Loader, Julie; Kelleher, Michelle; Iqball, Sharifah; Ferrige, Georgina; de Belin, Jackie; Carlucci, Marie; Angell-Manning, Diana; Hurst, Felicity; Ellis, Scott; Miskin, James; Fernandes, Alcides; Wong, Paul; Allikmets, Rando; Bergstrom, Christopher; Aaberg, Thomas; Yan, Jiong; Kong, Jian; Gouras, Peter; Prefontaine, Annick; Vezina, Mark; Bussieres, Martin; Naylor, Stuart; Mitrophanous, Kyriacos A
StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed. Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery. Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment. In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.
Barajas-Martínez,Héctor; Hu, Dan; Antzelevitch, Charles
El síndrome de Brugada es una enfermedad hereditaria caracterizada por una anormalidad electrocardiográfica y un aumento del riesgo de muerte súbita cardiaca. El síndrome de Brugada puede ser causado por la presencia de mutaciones en el gen SCN5A en aproximadamente el 20% de los casos familiares. El gen SCN5A codifica la subunidad a del canal iónico de sodio en las células cardiacas. Estudios realizados durante la última década en genética molecular han permitido identificar 11 nuevos genes c...
Weinbach, Natalia L.; Chesñevar, Carlos Iván
La bioinformática constituye un área interdisciplinaria que ha tenido un fuerte desarrollo en los últimos años. Dentro de dicha área, el aprendizaje del código genético a través de modelos computacionales apropiados constituye una problemática de gran importancia. El objetivo de este trabajo es presentar un primer acercamiento al aprendizaje del código genético a través de redes neuronales utilizando la herramienta de software Weka. Dentro del aprendizaje del código genético, el problema c...
Villela Cortés, Fabiola; Linares Salgado, Jorge
Los avances en genética seguidos de las nuevas tecnologías en la detección temprana de afecciones genéticas conllevan dilemas bioéticos sobre el uso adecuado de estas técnicas, la información que se le da a la mujer embarazada y la decisión que ella tomará al recibirla. Detectar a tiempo anomalías genéticas permite, en algunas ocasiones, el inicio de un tratamiento adecuado que permita que el niño por nacer no desarrolle una enfermedad discapacitante, como el caso de la fenilcetonuria,...
Video-juego desarrollado con e-learning sobre Genética. El personaje principal llamado ADNito, es un niño con aspecto de super-héroe que quiere aprender Genética porque es muy importante para él. Para ello, anima al jugador a que le acompañe por una Isla donde hay diferentes puntos de referencia o “estaciones” donde tendrá encuentros con personajes y situaciones relacionados con los principales hitos en los descubrimientos de la Genética y la Evolución. Cuando el protagonista entra en un esc...
Guzmán Valencia, Stephanie
La identidad y estructura genética de poblaciones de Oligonychus punicae y O. perseae (Acari: Tetranychidae) fue estudiada en siete localidades productoras de aguacate Persea americana var. Hass. La identidad de los ácaros fue determinada morfológica y molecularmente mediante la secuenciación de una fracción del gen Citocromo Oxidasa subunidad I (COI). La variación genética intraespecífica de diferentes poblaciones de ambas especies de ácaros fue estudiada mediante la secuenciación de las reg...
Hiram Larangeira de Almeida Jr
Full Text Available O estudo das alterações moleculares das epidermólises bolhosas tem contribuído para que se compreenda melhor essas enfermidades. Na epidermólise bolhosa simples a maioria dos casos está associada com alteração nas citoqueratinas basais 5 (gen KRT5 e 14 (gen KRT14, o que modifica o citoesqueleto na camada basal da epiderme, levando à degeneração dessa camada, formando bolha intra-epidérmica. Mutações na plectina (gen PLEC1, componente da placa interna do hemidesmossoma, levam também à clivagem intra-epidérmica. Na epidermólise bolhosa juncional vários gens estão envolvidos, em decorrência da complexidade da zona da membrana basal, todos levando ao descolamento dos queratinócitos basais na lâmina lúcida, pela disfunção da aderência entre esses e a lâmina densa. Alterações na laminina 5 (gens LAMA3, LAMB3 e LAMC2, integrina alfa6beta4 (gens ITGA6 e ITGB4 e colágeno XVII (gen COL17A1 foram descritas. Por fim, na epidermólise bolhosa distrófica apenas um gen está mutado, alterando o colágeno VII (gen COL7A1, principal componente das fibrilas ancorantes, produzindo clivagem abaixo da lâmina densa, variando fenotipicamente de acordo com a conseqüência da mutação. Outra aplicação importante dessas informações refere-se ao diagnóstico pré-natal, com a perspectiva no futuro da terapia gênica.New data regarding the molecular aspects of the heterogeneous group of epidermolysis bullosa has brought some important information about its pathogenesis. In epidermolysis bullosa simplex the majority of mutations are localized in the genes of the basal cytokeratin 5 (gene KRT5 and 14 (gene KRT14, cytolysis at this layer with intraepidermal blister is seen under light microscopy. Mutations of plectin (gene PLEC1, a protein found in the inner hemidesmosomal plaque, leads also to intraepidermal blisters. In junctional epidermolysis bullosa many proteins from the basal membrane zone are involved, such as laminin 5 (genes
Cordiamyia globosa gen.n. e sp.n. (Diptera, Cecidomyiidae, Cecidomyiidi associado com Cordia Verbenacea DC. (Boraginaceae no Brasil Cordiamyia globosa gen.n. and sp.n. (Diptera, Cecidomyiidae associated with Cordia verbekacea DC. (Boraginaceae in Brazil
Valéria Cid Maia
Full Text Available Cordiamyia globosa gen.n., sp.n. (Diptera, Cecidomyiidae, Cecidomyiidi associated with Cordia verbenacea (Boraginaceae, in Brazil, is described and illustrated (larva, pupa, male, female and gall.
Taiane Alves Vieira
Introdução: Com o melhor controle das causas ambientais, as doenças genéticas e as malformações congênitas cada vez mais ganham destaque como fatores morbidade e mortalidade, assim como cada vez mais se reconhece a importância da base genética para as doenças comuns. Desta forma, é necessário desenvolver estratégias de prevenção e controle destas condições, assim como acesso aos cuidados de saúde para pessoas com ou em risco de desenvolver uma doença genética. A integração da genética na Aten...
Adriana Antonieta do Nascimento Rizzo
Full Text Available Estimou-se a divergência genética entre cinco genótipos de melão rendilhado (Cucumis melo var. reticulatus Naud. (JAB-20, JAB-21, JAB-22, JAB-23 e 'Bônus nº 2' e determinou-se qual a contribuição relativa das 16 características avaliadas [nº médio de flores masculinas, hermafroditas/planta; produção total de frutos/m², peso médio dos frutos comerciáveis; diâmetro médio transversal e longitudinal do fruto (DMTF e DMLF; diâmetro médio transversal da inserção do pedúculo (DMTP; espessura média do mesocarpo e epicarpo (EMM e EME; diâmetro médio longitudinal e transversal do lóculo (DMTL e DMLL; proporção da cavidade (PC; desprendimento de sementes (DS; teor de sólidos solúveis totais (SST, pH e acidez titulável (AT] na divergência gen��tica. Obtiveram-se dois grupos de similaridade: I- JAB-20, JAB-21 e 'Bônus nº2' e II- JAB-22 e JAB-23. As características DMLF, DMTP, DMLL, DS e SST foram as que mais contribuíram para a divergência genética entre os genótipos.The genetic divergence of five cultivars of muskmelon was estimated (Cucumis melo var. reticulatus Naud (JAB-20, JAB-21, JAB-22, JAB-23 and 'Bônus nº2' and the relative contribution of each 16 characteristics were determined (number of male flowers per plant; total production of fruit, weight of fruits; longitudinal and transversal diameters of fruits; thickness and color of flesh and skin; longitudinal and transversal loculos diameter of fruits; seed loosing; netting thickness; and % total solvers solids, pH and total acidity in genetic divergence. Two groups of similarity were formed between the genitors by the values of D², one of then was constituted of the JAB-20 and JAB-21 and 'Bônus nº 2' genotypes, and another of the JAB-22 and JAB-23. The characteristics of longitudinal loculos diameters, longitudinal diameter of fruits, transversal diameter of peduncle insertion, % total solvers solids and seed loosing contributed to for genetic
Sierra CH.; Au WW.; Cajas N.
La enzima metabólica hidrolasa epóxida microsomal (mHE) está involucrada en biotransforma-ción de carcinógenos del cigarrillo (ej., benzo-a-pireno). Este estudio investigó la susceptibilidad genética a desarrollar cáncer de pulmón asociada con los polimorfismos en los exones 3 y 4 delgen mHE, los cuales confieren reducida e incrementada actividad enzimática respectivamente. Además, se determinó su efecto en la frecuencia de aberraciones cromosómicas (AC) como unamedida adicional de riesgo. La...
Conclusión. Este trabajo demostró diferenciación genética entre las poblaciones de T. dimidiata de La Guajira, Cesar y Santander. Se sugiere una posible relación entre tal subdivisión y algunas características eco-epidemiológicas que posee T. dimidiata en el centro-oriente y en el norte de Colombia. Finalmente, este trabajo describe, por primera vez, la utilidad del ND4 como un marcador molecular para el estudio de poblaciones naturales de T. dimidiata.
Darwin Hernández H.
Full Text Available Objetivo. Caracterizar el polimorfismo del gen BoLA-DRB3.2* en las razas bovinas criollas y colombianas. Materiales y métodos. En 360 muestras de ADN de ocho razas bovinas criollas (Blanco Orejinegro, Casanareño, Costeño con Cuernos, Chino Santandereano, Caqueteño, Hartón del Valle, Romosinuano y San Martinero, dos razas sintéticas Colombianas (Lucerna y Velásquez y dos razas foráneas (Brahman y Holstein se evaluó el polimorfismo del gen BoLA-DRB3.2 mediante técnicas moleculares (PCR-RFLP; se calculó el número promedio de alelos (NPA, las frecuencias, la heterocigocidad esperada (He y observada (Ho, el equilibrio de Hardy-Weinberg, la estructura genética y los valores de FST y FIS. Resultados. El NPA fue 14.6 ± 3.8 siendo Caqueteño la raza con mayor NPA (25 y el menor el Chino Santandereano (10. Se encontraron 41 alelos BoLA-DRB3.2* los más frecuentes fueron *28, *37, *24, *23, *20, *27, *8, *16, *39 (0.17, 0.11, 0.10, 0.09, 0.09, 0.07, 0.07 y 0.06 respectivamente. Se encontró alta diversidad genética (He = 0.878 con mayor valor en Caqueteño (0.96 y menor en San Martinero (0.81. Todas las razas se encontraron en equilibrio de Hardy-Weinberg, se encontraron valores altamente significativos de diferenciación genética (FST= 0.044 y de coeficiente de endogamia (FIS = 0.249. Conclusiones. El ganado criollo colombiano posee alto polimorfismo del gen BoLA-DRB3.2* representado en los altos valores de NPA y diversidad génetica.
Laurito, Andres; The ATLAS collaboration
Simulation is an important tool to validate the performance impact of control decisions in Software Defined Networks (SDN). Yet, the manual modeling of complex topologies that may change often during a design process can be a tedious error-prone task. We present TopoGen, a general purpose architecture and tool for systematic translation and generation of network topologies. TopoGen can be used to generate network simulation models automatically by querying information available at diverse sources, notably SDN controllers. The DEVS modeling and simulation framework facilitates a systematic translation of structured knowledge about a network topology into a formal modular and hierarchical coupling of preexisting or new models of network entities (physical or logical). TopoGen can be flexibly extended with new parsers and generators to grow its scope of applicability. This permits to design arbitrary workflows of topology transformations. We tested TopoGen in a network engineering project for the ATLAS detector ...
Laurito, Andres; The ATLAS collaboration
Simulation is an important tool to validate the performance impact of control decisions in Software Defined Networks (SDN). Yet, the manual modeling of complex topologies that may change often during a design process can be a tedious error-prone task. We present TopoGen, a general purpose architecture and tool for systematic translation and generation of network topologies. TopoGen can be used to generate network simulation models automatically by querying information available at diverse sources, notably SDN controllers. The DEVS modeling and simulation framework facilitates a systematic translation of structured knowledge about a network topology into a formal modular and hierarchical coupling of preexisting or new models of network entities (physical or logical). TopoGen can be flexibly extended with new parsers and generators to grow its scope of applicability. This permits to design arbitrary workflows of topology transformations. We tested TopoGen in a network engineering project for the ATLAS detector ...
Hermilo Sánchez Sánchez
Full Text Available La evolución de la interacciónparásito-hospedero es un proceso dinámicoque implica cambios en la composicióngenética de las especies involucradas. Loscambios pueden observarse en los genes delos individuos mediante el modelo gen porgen, o en la estructura genética de lapoblación mediante el modelo del mosaicogeográfico.
Schreuders, ZC; Ardern, L
Computer security students benefit from having hands-on experience with hacking tools and with access to vulnerable systems that they can attack and defend. However, vulnerable VMs are static; once they have been exploited by a student there is no repeatable challenge as the vulnerable boxes never change. A new novel solution, SecGen, has been created and deployed. SecGen solves the issue by creating vulnerable machines with randomised vulnerabilities and services, with constraints that ensur...
Full Text Available El cáncer colorrectal es el tercer cáncer más frecuente en hombres y el segundo más frecuente en mujeres, con una incidencia mundial aproximada de 1.2 millones de casos nuevos por año. Nuestro objetivo primario fue estudiar la relación existente entre las características clínico-histológicas en individuos con cáncer colorrectal y el estado mutacional de los codones 12 y 13 del gen KRAS (7 mutaciones validadas, con el fin de hallar un marcador histopatológico para los tumores mutados. El objetivo secundario fue determinar cuántos pacientes tenían mutaciones adicionales en los codones 15 y 61 del gen KRAS y 600 del gen BRAF que podrían modificar el fenotipo tumoral. Fueron seleccionados 60 individuos con cáncer colorrectal (30 wild-type y 30 con mutaciones validadas en los codones 12 y 13 del gen KRAS. Se amplificaron y secuenciaron del gen KRAS los exones 2 y 3, y del gen BRAF el exón 15. La información recolectada se examinó mediante un análisis descriptivo, análisis univariado y/o análisis multivariado, según correspondiese. En conclusión, no se encontró relación entre las características clínico-histológicas de los tumores de individuos con diagnóstico de cáncer colorrectal y el estado mutacional de los codones 12 y 13 del gen KRAS. No hallamos un marcador histopatológico para los tumores mutados. En pacientes con adenocarcinomas colorrectales avanzados y KRAS wild-type resulta de interés considerar el estudio del codón 600 del gen BRAF.
Paiva, Leonardo Silveira
Mestrado em Engenharia Electrotécnica e de Computadores Este trabalho visa propor um método de sintonia, através da aplicação de Algoritmos Genéticos, para controladores do tipo proporcional, integral e derivativo (PID). Os Algoritmos Genéticos (AGs) são uma técnica de busca estocástica, onde a procura do óptimo global é baseada no processo de evolução natural. Vários são os casos de sucesso da aplicação dos AGs em problemas de alto grau de complexidade e que apresentam regiões de grande d...
Valentin Ekiaka Nzai
Full Text Available This paper explored Net Gen Bilingual pre-service teachers’ perspectives future digital native classrooms based on the National Education Technology Plan (2010 postulates. Participants were Seven Net Gen bilingual future teachers enrolled at a semester – long laboratory of practices project for Literacy Development for English Language Learners. Data were collected using Ginsburg’s (1989 narrative strategy, which consisted of analyzing information from participants’ life stories produced during two audiotaped focus group conversations. Findings showed that pre-service teachers had positive perceptions and beliefs toward the laboratory of practices built upon the experimental cyberlearning workstation frame designed by the authors. The hands-on experiences helped them enhance their digital native-like citizenship in order to meet future students’ individual abilities and learning styles, and stimulate teaching with digital technologies. Some recommendations and limitations are also addressed.
Saad, Sara Teresinha O.
As causas genéticas de deficiência de ferro, real ou funcional, ocorrem por defeitos em muitas proteínas envolvidas na absorção e metabolismo de ferro. Neste capítulo descreveremos sucintamente causas genéticas de carência de ferro para a síntese de hemoglobina, que cursa então com anemia microcítica e hipocrômica. Ressalto que estas são alterações raras, com poucas descrições na literatura. Em alguns casos, o ferro funcional não está disponível para os eritroblastos sintetizarem hemoglobina,...
Anjang Bangun Prasetio
dan 3:1 dengan jumlah ulangan masing-masing sebanyak enam kali. Sebagai kontrol, ditambahkan juga perlakuan non transfeksi (non transgenik yaitu tanpa penyisipan gen GFP maupun RFP. Pengamatan dilakukan sejak perkembangan zigot mulai dari penghitungan derajat penetasan (HR dan sintasan larva (SR. Hasil penelitian menunjukkan bahwa setelah dilakukan transfeksi tidak memperlihatkan pola yang jelas dari setiap perlakuan, namun secara umum tidak berbeda signifikan dengan kontrol non transgenik. PCR pada embrio dan larva menunjukkan hasil positif di mana DNA teramplifikasi pada ukuran sekitar 0,6 kb untuk beberapa ulangan. Dari hasil yang diperoleh ini dapat ditarik kesimpulan bahwa metode transfeksi efektif digunakan untuk transfer gen ikan cupang alam, wild betta (Betta imbellis.
Gorzoni,Milton Luiz; Fabbri,Renato Moraes Alves; Pires,Sueli Luciano
OBJETIVO: Determinar a prevalência de fármacos potencialmente inapropriados para idosos em medicamentos genéricos brasileiros pelos critérios de Beers-Fick. MÉTODOS: Análise da lista de medicamentos genéricos publicada no Diário Oficial da União de 12 de julho de 2004 e copiada da página da Agência Nacional de Vigilância Sanitária (ANVISA) - www.anvisa.gov.br, utilizando-se os critérios de Beers-Fick. RESULTADOS: Contendo 299 produtos e/ou apresentações, a lista analisada apresentava 20 deles...
Full Text Available This letter is the reply to: Remarks on Peinado et al.’s Analysis of J3Gen by J. Garcia-Alfaro, J. Herrera-Joancomartí and J. Melià-Seguí published in Sensors 2015, 15, 6217–6220. Peinado et al. cryptanalyzed the pseudorandom number generator proposed by Melià-Seguí et al., describing two possible attacks. Later, Garcia-Alfaro claimed that one of this attack did not hold in practice because the assumptions made by Peinado et al. were not correct. This letter reviews those remarks, showing that J3Gen is anyway flawed and that, without further information, the interpretation made by Peinado et al. seems to be correct.
Keller, J.; Blarigan, P. Van [Sandia National Labs., Livermore, CA (United States)
In this manuscript the authors report on two projects each of which the goal is to produce cost effective hydrogen utilization technologies. These projects are: (1) the development of an electrical generation system using a conventional four-stroke spark-ignited internal combustion engine generator combination (SI-GenSet) optimized for maximum efficiency and minimum emissions, and (2) the development of a novel internal combustion engine concept. The SI-GenSet will be optimized to run on either hydrogen or hydrogen-blends. The novel concept seeks to develop an engine that optimizes the Otto cycle in a free piston configuration while minimizing all emissions. To this end the authors are developing a rapid combustion homogeneous charge compression ignition (HCCI) engine using a linear alternator for both power take-off and engine control. Targeted applications include stationary electrical power generation, stationary shaft power generation, hybrid vehicles, and nearly any other application now being accomplished with internal combustion engines.
López, Mariana P.; Ghiglione, Hernán Oscar; Linares Figueroa, María Alejandra; Curá, José Alfredo
p.11-18 Un sistema muy utilizado en la transformación genética de plantas se basa en el uso de Agrobacterium, que posee un plásmido denominado Ti. El ADN-T de dicho plásmido es transferido a la planta huésped donde se integra al genoma de la misma. El objetivo de este trabajo fue la obtención de callos de arroz derivados de escutelo modificados genéticamente. Para tal técnica de transferencia génica se utilizaron las cepas GV3101 y AGLI de Agrobacterium tumefaciens llevando el plásmido pCR...
Rogers, William H.; Waldron, Timothy P.; Stroiney, Steven R.
The goal of this work was to analytically identify and quantify the issues, challenges, technical hurdles, and pilot-vehicle interface issues associated with conflict detection and resolution (CD&R)in emerging operational concepts for a NextGen terminal aneuvering area, including surface operations. To this end, the work entailed analytical and trade studies focused on modeling the achievable safety benefits of different CD&R strategies and concepts in the current and future airport environment. In addition, crew-vehicle interface and pilot performance enhancements and potential issues were analyzed based on review of envisioned NextGen operations, expected equipage advances, and human factors expertise. The results of perturbation analysis, which quantify the high-level performance impact of changes to key parameters such as median response time and surveillance position error, show that the analytical model developed could be useful in making technology investment decisions.
Harris, Leonard A; Hogg, Justin S; Tapia, José-Juan; Sekar, John A P; Gupta, Sanjana; Korsunsky, Ilya; Arora, Arshi; Barua, Dipak; Sheehan, Robert P; Faeder, James R
: BioNetGen is an open-source software package for rule-based modeling of complex biochemical systems. Version 2.2 of the software introduces numerous new features for both model specification and simulation. Here, we report on these additions, discussing how they facilitate the construction, simulation and analysis of larger and more complex models than previously possible. Stable BioNetGen releases (Linux, Mac OS/X and Windows), with documentation, are available at http://bionetgen.org Source code is available at http://github.com/RuleWorld/bionetgen CONTACT: firstname.lastname@example.orgSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: email@example.com.
Raúl Francisco Sebastián Solanes
Full Text Available En el presente texto proponemos una reflexión sobre uso de tecnologías genéticas que aumentan el rendimiento deportivo como futuro campo de investigación de una Neuroética social. Este problema, que se ha dado en llamar “dopaje genético”, congrega a su alrededor un debate entre los partidarios del Bioconservadurismo y del Transhumanismo. Expondremos la concepción de dos importantes representantes del Transhumanismo (J. Savulescu y C. Tamburrini y de dos conocidos partidarios del Bioconservadurismo (M. Sandel y R. L. Simon, a fin de subrayar la importancia de este debate y las futuras implicaciones en la mejora del rendimiento físico, cognitivo y educacional a las que se deberá hacer frente desde el nivel socio-cultural de la Neuroética.
Arney, L. D.; Sandquist, D. L.; Forsyth, D. W.; Lidstone, G. L.; Long-Davis, Mary Jo (Technical Monitor)
Testing of the HSCT Generation 2.0 nozzle model hardware was conducted at the Boeing Low Speed Aeroacoustic Facility, LSAF. Concurrent measurements of noise and thrust were made at critical takeoff design conditions for a variety of mixer/ejector model hardware. Design variables such as suppressor area ratio, mixer area ratio, liner type and thickness, ejector length, lobe penetration, and mixer chute shape were tested. Parallel testing was conducted at G.E.'s Cell 41 acoustic free jet facility to augment the LSAF test. The results from the Gen 2.0 testing are being used to help shape the current nozzle baseline configuration and guide the efforts in the upcoming Generation 2.5 and 3.0 nozzle tests. The Gen 2.0 results have been included in the total airplane system studies conducted at MDC and Boeing to provide updated noise and thrust performance estimates.
Ristanti Frinra Daud
ekonomis penting. Ice-ice merupakan penyakit yang paling umum menyerang rumput laut dan menyebabkan menurunnya produksi rumput laut. Penyakit ini disebabkan oleh perubahan salinitas, suhu, dan pencemaran logam berat. Asam sitrat digunakan sebagai pengkelat logam berat. Introduksi gen sitrat sintase ke dalam genom tanaman diketahui dapat mengurangi cekaman oksidatif. Penelitian ini bertujuan untuk mengintroduksi gen sitrat sintase ke dalam genom K. alvarezii menggunakan perantara Agrobacterium tumefaciens. Berdasarkan eksplan yang tahan pada media seleksi higromisin, efisiensi transformasi pada K. alvarezii sebesar 7,5%. Efisiensi regenerasi tunas transgenik putatif sebesar 100%, efisiensi tunas non transgenik sebesar 100%. Analisis molekular menggunakan teknik PCR, satu dari lima K. alvarezii transgenik putatif mengandung transgen PaCS di bawah kendali promoter 35S CaMV.
João Costa Filho
Full Text Available ResumoThis review aims at addressing the main issues related to genetic improvement applied to fish species with zootechnical potential, such as selection, genetic parameters and use of biotechnology as well as address the importance of this area of study for the expansion of aquaculture and its development trend. Fish breeding is one of the most important areas of study for fish production development. Important techniques are applied in order to advance genetic progress in fish breeding (e.g., individual selection, genetic parameters estimation and the use of biotechnology. Traditional breeding in fish farming has been conducted mainly through biometric analysis, which helps in choosing selection criteria and in the assessment of genetic parameters such as heritability and correlations between interesting traits. The use of biotechnology in fish breeding has been successful; it is an important strategy that allows breeding results to be achieved faster, although at a greater cost than traditional breeding. Fish breeding in Brazil is currently in its initial stages; however, it is a field with great growth expectations, and there is still significant research to be conducted in this area.AbstractEsta revisão tem como objetivo a abordagem dos principais aspectos relacionados ao melhoramento genético aplicado em espécies de peixes com potencial zootécnico, tais como seleção, parâmetros genéticos e utilização da biotecnologia, bem como abordar a importância desta área de estudos para a ampliação da aquicultura e sua tendência de desenvolvimento. O melhoramento genético é uma das áreas prioritárias de estudo para o desenvolvimento da produção de peixes. Assim, importantes técnicas são aplicadas visando à obtenção de progresso genético no melhoramento de peixes, como por exemplo, a seleção individual, a estimativa de parâmetros genéticos e o uso da biotecnologia. O melhoramento genético tradicional na piscicultura tem
Lemieux Perreault, Louis-Philippe; Provost, Sylvie; Legault, Marc-André; Barhdadi, Amina; Dubé, Marie-Pierre
Genetic association studies making use of high-throughput genotyping arrays need to process large amounts of data in the order of millions of markers per experiment. The first step of any analysis with genotyping arrays is typically the conduct of a thorough data clean up and quality control to remove poor quality genotypes and generate metrics to inform and select individuals for downstream statistical analysis. We have developed pyGenClean, a bioinformatics tool to facilitate and standardize the genetic data clean up pipeline with genotyping array data. In conjunction with a source batch-queuing system, the tool minimizes data manipulation errors, accelerates the completion of the data clean up process and provides informative plots and metrics to guide decision making for statistical analysis. pyGenClean is an open source Python 2.7 software and is freely available, along with documentation and examples, from http://www.statgen.org.
Full Text Available A new genus, Pentatomiana, and a new species, P. beckerae, are described, based on specimens from Rio de Janeiro and Santa Catarina States, Brazil. Brachyptery is present in the males of the new species. Pentatomiana gen. nov. is compared with Lojus McDonald, 1982, which also presents brachyptery in one of the species, but in females. Illustrations of male and female external genitalia are provided.Um novo gênero, Pentatomiana, e uma nova espécie, P. beckerae, são descritos, com base em espécimes do Rio de Janeiro e de Santa Catarina, Brasil. Machos da nova espécie apresentam braquipteria. Pentatomiana gen. nov. é comparado com Lojus McDonald, 1982, o qual também apresenta braquipteria em uma das espécies, mas em fêmeas. São fornecidas ilustrações da genitália externa masculina e feminina.
Hansmann, Tim; Auffenberg, Jan; Haack, Christian; Hansmann, Bengt; Kemp, Julian; Konietz, Richard; Leuner, Jakob; Raedel, Leif; Stahlberg, Martin; Schoenen, Sebastian; Wiebusch, Christopher [III. Physikalisches Institut B, RWTH Aachen University (Germany); Collaboration: IceCube-Collaboration
IceCube is a neutrino observatory located at the geographic South Pole. The main backgrounds for IceCube's primary goal, the measurement of astrophysical neutrinos, are muons and neutrinos from cosmic-ray air showers in the Earth's atmosphere. Strong supression of these backgrounds from the Southern hemisphere has been demonstrated by coincident detection of these air showers with the IceTop surface detector. For an extended instrument, IceCube-Gen2, it is considered to build an enlarged surface array, IceVeto, that will improve the detection capabilities of coincident air showers. We will present simulation studies to estimate the IceVeto capabilities to optimize the IceCube-Gen2 design.
Full Text Available Earlier phylogenetic analyses of the marine Rhodobacteraceae (class Alphaproteobacteria genera Leisingera and Phaeobacter indicated that neither genus might be monophyletic. We here used phylogenetic reconstruction from genome-scale data, MALDI-TOF mass-spectrometry analysis and a re-assessment of the phenotypic data from the literature to settle this matter, aiming at a reclassification of the two genera. Neither Phaeobacter nor Leisingera formed a clade in any of the phylogenetic analyses conducted. Rather, smaller monophyletic assemblages emerged, which were phenotypically more homogeneous, too. We thus propose the reclassification of Leisingera nanhaiensis as the type species of a new genus as Sedimentitalea nanhaiensis gen. nov., comb. nov., the reclassification of Phaeobacter arcticus and Phaeobacter leonis as Pseudophaeobacter arcticus gen. nov., comb. nov. and Pseudophaeobacter leonis comb. nov., and the reclassification of Phaeobacter aquaemixtae, Phaeobacter caeruleus and Phaeobacter daeponensis as Leisingera aquaemixtae comb. nov., Leisingera caerulea comb. nov. and Leisingera daeponensis comb. nov. The genera Phaeobacter and Leisingera are accordingly emended.
La diffusion des rapports de recherche et des constatations sera assurée par une diversité de moyens, électroniques et classiques. Le projet devrait stimuler le réseautage entre les chercheurs de GenARDIS et favoriser le respect des sexospécificités dans l'application des TIC au développement agricole et rural.
Patrícia Santana Correia
Full Text Available O objetivo deste trabalho foi estudar o conhecimento, as crenças e opiniões sobre Genética em um grupo de médicos residentes. Foi utilizada a técnica de grupos focais com 12 residentes de Pediatria em seu primeiro mês de curso, divididos em quatro grupos. Para a análise do material, foi escolhida a técnica da leitura isotópica. Os participantes demonstraram pouco interesse pelo assunto, mas tinham um grau razoável de conhecimento. Este conhecimento, entretanto, era pouco vinculado à prática clínica, sugerindo a necessidade de reformulação da formação médica. Os grupos mostraram consciência da alta prevalência e da grande morbidade das doenças genéticas, sinalizando que a nova geração de médicos pode ser mais sensível à questão da inserção da Genética na saúde pública. O Brasil está passando por um momento de transição epidemiológica, com o aumento proporcional das doenças de etiologia genética como causas de morbi-mortalidade, tornando necessária a inclusão dessas condições no planejamento para a gestão da saúde pública.
Sumampow, Thalita C. P
Copepoda merupakan zooplankton kaya manfaat dengan diversitas yang sangat tinggi dan terdiri dari banyak spesies kriptik. Identifikasi cepat, akurat, dan hemat dapat dilakukan dengan menggunakan teknik DNA Barcoding. Kesuksesan teknik tersebut sangat dipengaruhi oleh penggunaan primer yang tepat. Tujuan penelitian ini adalah untuk menguji kemampuan dua pasang primer universal, yakni LCO1490-HCO2198 dan FF2d-FR1d, mengamplifikasi gen COI Copepoda. Dalam penelitian ini, pasangan primer LCO1490-...
Arrago, J P; Rain, J D; Brocheriou, C; Rocher, F
Scintigraphy of the salivary glands with technetium-sodium pertechnetate (99mTc) was undertaken on 320 patients with oral dryness or connective tissue disease using a computer assisted method that gave quantitative results about the major salivary gland function. Compared with clinical and histological data, scintigraphy provides a sensitive method, even though it is not specific, for detecting minimal injuries to salivary glands in patients suspected of having Sjögen's syndrome. Moreover, it...
Morales-Montero, Fernando; Cuenca-Berger, Patricia
Artículo científico -- Universidad de Costa Rica, Instituto de Investigaciones en Salud-- 1999 Mvotonic Dystrophy is a multisystemic illness which affects several tissues such as the muscle, the brain and some endocrine tissues. It presents a dominant of autosomic inheritance with incomplete penetrance and variable expression. The molecular defect turned out to be an expansion of the trinucleotide CTG present in the 3 ' mon-codifying region of the gen DMPK. There is a positive correlation ...
Die vorliegende Arbeit befaßt sich mit der Kontrolle des Expressionsmusters des UNUSUAL FLORAL ORGANS (UFO) Gens von Arabidopsis thaliana. UFO wird im Sproß- und Blütenmeristemen aller Entwicklungsstadien der Pflanze exprimiert. In Blütenmeristemen agiert UFO als Kofaktor von LEAFY (LFY) bei der Aktivierung der Organidentitätsgene des zweiten und dritten Wirtels. UFO stellt also einen generellen Faktor der Musterbildung in Meristemen dar. Um regulatorische Gene, die die Expression von UFO bee...
A densely scaled small mushroom in Baltic amber is described as Gerontomyces lepidotus gen. et sp. nov. and is characterized by a convex pileus 1.0 mm in diameter, distant to subdistant lamellae with smooth margins and a centrally inserted cylindrical, solid stipe. Its taxonomic placement is uncertain. This is the first mushroom described from Baltic amber. Copyright © 2016 British Mycological Society. Published by Elsevier Ltd. All rights reserved.
Hidayani, Andi Aliah; Carman, Odang; Alimuddin,
Salah satu pertimbangan penting dalam teknologi transgenesis adalah pemilihan promoter pengatur ekspresi gen pengkode protein yang berhubungan dengan suatu karakter. Penelitian ini dilakukan untuk membandingkan tingkat efektivitas promoter homolog dan heterolog pada ikan mas sebagai model dengan menggunakan promoter ??-aktin dari ikan mas (Cyprinus carpio): ccBA (Cyprinus carpio ??-aktin) , ikan nila (Oreochromis niloticus): tiBA (tilapia ??-aktin), dan ikan medaka (Oryzias latipes): mkBA (me...
Científicamente nombrada como “osteogénesis imperfecta” y popularmente conocida como “huesos de cristal” esta patología consiste en una malformación de los huesos desencadenada por la mutación de un gen encargado de producir el colágeno una proteína esencial responsable de dar rigidez a los huesos.