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Sample records for leho kiv simmo

  1. Basic principles of the KIV model and its application to the navigation problem.

    PubMed

    Kozma, Robert; Freeman, Walter J

    2003-06-01

    EEG measurements indicate the presence of common-mode, coherent oscillations shared by multiple cortical areas. In previous studies the KIII model has been introduced, which interprets the experimental observations as nonlinear, spatially distributed dynamical oscillations of locally coupled neural populations. KIII can account for the fast and robust classification and pattern recognition in sensory cortices. In order to describe selection of action, planning, and spatial orientation functions, in this paper we expand KIII into the KIV model. KIV approximates the operation of the corticostriatal-hippocampal system. KIV consists of three KI, eight KII and three KIII components, including sensory and cortical systems, as well as the hippocampus, amygdala, and the septum. KIV implements various types of dynamic neural activities. The neural activity patterns determine the emergence of global spatial encoding to implement the orientation function of a simulated animal. Our results indicate the mechanisms, which we believe support the generation of cognitive maps in the hippocampus based on the sensory input-based destabilization of cortical spatio-temporal patterns. In this paper, we describe the conceptual design of the KIV model. We outline the biological background and motivation of the basic principles that are applied to design the KIV computational model. We use the KIV model to explain how the hippocampal neural circuitry functions are constructed and controlled by the corticostriatal-hippocampal loops, supplemented with specific subcortical units. In the second part, we implement these principles using the example of the hippocampal formation as a KIII unit. We demonstrate the learning and navigation principles using the Evolving Multi-module Mobile Agent (EMMA) in 2D software environment.

  2. Luminous exothermic hollow optical elements for enhancement of biofilm growth and activity.

    PubMed

    Zhong, Nianbing; Zhao, Mingfu; Zhong, Lianchao; Li, Shan; Luo, Binbin; Tang, Bin; Song, Tao; Shi, Shenghui; Hu, Xinyu; Xin, Xin; Wu, Ruohua; Cen, Yanyan; Wang, Zhengkun

    2017-03-20

    In this work, we present a luminous-exothermic hollow optical element (LEHOE) that performs spectral beam splitting in the visible spectral range for the enhancement of biofilm growth and activity. The LEHOE is composed of a four-layer structure with a fiber core (air), cladding (SiO2), coating I (LaB6 film), and coating II (SiO2-Agarose-Medium film). To clarify the physical, optical and photothermal conversion properties of the LEHOE, we determined the surface morphology and composition of the coating materials, and examined the luminous intensity and heating rate at the LEHOE surface. The biofilm activity on the biocompatible LEHOE is far greater than that of commercial fibers, and the biofilm weight on the LEHOE is 4.5 × that of the uncoated hollow optical element.

  3. Nuclear magnetic resonance (NMR) solution structure, dynamics, and binding properties of the kringle IV type 8 module of apolipoprotein(a).

    PubMed

    Chitayat, Seth; Kanelis, Voula; Koschinsky, Marlys L; Smith, Steven P

    2007-02-20

    The plasma lipoprotein lipoprotein(a) [Lp(a)] comprises a low-density lipoprotein (LDL)-like particle covalently attached to the glycoprotein apolipoprotein(a) [apo(a)]. Apo(a) consists of multiple tandem repeating kringle modules, similar to plasminogen kringle IV (designated KIV1-KIV10), followed by modules homologous to the kringle V module and protease domain of plasminogen. The apo(a) KIV modules have been classified on the basis of their binding affinity for lysine and lysine analogues. The strong lysine-binding apo(a) KIV10 module mediates lysine-dependent interactions with fibrin and cell-surface receptors. Weak lysine-binding apo(a) KIV7 and KIV8 modules display a 2-3-fold difference in lysine affinity and play a direct role in the noncovalent step in Lp(a) assembly through binding to unique lysine-containing sequences in apolipoproteinB-100 (apoB-100). The present study describes the nuclear magnetic resonance solution structure of apo(a) KIV8 and its solution dynamics properties, the first for an apo(a) kringle module, and compares the effects of epsilon-aminocaproic acid (epsilon-ACA) binding on the backbone and side-chain conformation of KIV7 and KIV8 on a per residue basis. Apo(a) KIV8 adopts a well-ordered structure that shares the general tri-loop kringle topology with apo(a) KIV6, KIV7, and KIV10. Mapping of epsilon-ACA-induced chemical-shift changes on KIV7 and KIV8 indicate that the same residues are affected, despite a 2-3-fold difference in epsilon-ACA affinity. A unique loop conformation within KIV8, involving hydrophobic interactions with Tyr40, affects the positioning of Arg35 relative to the lysine-binding site (LBS). A difference in the orientation of the aromatic side chains comprising the hydrophobic center of the LBS in KIV8 decreases the size of the hydrophobic cleft compared to other apo(a) KIV modules. An exposed hydrophobic patch contiguous with the LBS in KIV8 and not conserved in other weak lysine-binding apo(a) kringle modules

  4. Lipoprotein(a) and risk of myocardial infarction--genetic epidemiologic evidence of causality.

    PubMed

    Kamstrup, Pia R; Tybjærg-Hansen, Anne; Nordestgaard, Børge G

    2011-04-01

    Elevated levels of lipoprotein(a) are associated with an increased risk of myocardial infarction. Our study aimed to test whether genetic data are consistent with this association being causal. Accordingly, we developed a high-throughput realtime PCR assay to genotype for the lipoprotein(a) kringle IV type 2 (KIV-2) repeat polymorphism in the LPA gene in > 40,000 individuals. The LPA KIV-2 genotype associated with plasma levels of lipoprotein(a) (trend p < 0.001), and the LPA KIV-2 genotype associated with risk of myocardial infarction (trend p < 0.001 to 0.03) in a manner consistent with its effect on plasma levels of lipoprotein(a). The association of LPA KIV-2 genotypes raising plasma levels of lipoprotein(a) with increased risk of myocardial infarction strongly supports a causal association of lipoprotein(a) with risk of myocardial infarction.

  5. Apolipoprotein(a) inhibits hepatitis C virus entry through interaction with infectious particles.

    PubMed

    Oliveira, Catarina; Fournier, Carole; Descamps, Véronique; Morel, Virginie; Scipione, Corey A; Romagnuolo, Rocco; Koschinsky, Marlys L; Boullier, Agnès; Marcelo, Paulo; Domon, Jean-Marc; Brochot, Etienne; Duverlie, Gilles; Francois, Catherine; Castelain, Sandrine; Helle, Francois

    2017-06-01

    The development of different cell culture models has greatly contributed to increased understanding of the hepatitis C virus (HCV) life cycle. However, it is still challenging to grow HCV clinical isolates in cell culture. If overcome, this would open new perspectives to study HCV biology, including drug-resistant variants emerging with new antiviral therapies. In this study we hypothesized that this hurdle could be due to the presence of inhibitory factors in patient serum. Combining polyethylene glycol precipitation, iodixanol gradient, and size-exclusion chromatography, we obtained from HCV-seronegative sera a purified fraction enriched in inhibitory factors. Mass spectrometric analysis identified apolipoprotein(a) (apo[a]) as a potential inhibitor of HCV entry. Apo(a) consists of 10 kringle IV domains (KIVs), one kringle V domain, and an inactive protease domain. The 10 KIVs are present in a single copy with the exception of KIV type 2 (KIV2 ), which is encoded in a variable number of tandemly repeated copies, giving rise to numerous apo(a) size isoforms. In addition, apo(a) covalently links to the apolipoprotein B component of a low-density lipoprotein through a disulfide bridge to form lipoprotein(a). Using a recombinant virus derived from the JFH1 strain, we confirmed that plasma-derived and recombinant lipoprotein(a) as well as purified recombinant apo(a) variants were able to specifically inhibit HCV by interacting with infectious particles. Our results also suggest that small isoforms are less inhibitory than the large ones. Finally, we observed that the lipoprotein moiety of HCV lipoviroparticles was essential for inhibition, whereas functional lysine-binding sites in KIV7 , KIV8 , and KIV10 were not required. Our results identify apo(a) as an additional component of the lipid metabolism modulating HCV infection. (Hepatology 2017;65:1851-1864). © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for

  6. Apolipoprotein(a) Kringle-IV Type 2 Copy Number Variation Is Associated with Venous Thromboembolism

    PubMed Central

    Sticchi, Elena; Magi, Alberto; Kamstrup, Pia R.; Marcucci, Rossella; Prisco, Domenico; Martinelli, Ida; Mannucci, Pier Mannuccio; Abbate, Rosanna; Giusti, Betti

    2016-01-01

    In addition to the established association between high lipoprotein(a) [Lp(a)] concentrations and coronary artery disease, an association between Lp(a) and venous thromboembolism (VTE) has also been described. Lp(a) is controlled by genetic variants in LPA gene, coding for apolipoprotein(a), including the kringle-IV type 2 (KIV-2) size polymorphism. Aim of the study was to investigate the role of LPA gene KIV-2 size polymorphism and single nucleotide polymorphisms (SNPs) (rs1853021, rs1800769, rs3798220, rs10455872) in modulating VTE susceptibility. Five hundred and sixteen patients with VTE without hereditary and acquired thrombophilia and 1117 healthy control subjects, comparable for age and sex, were investigated. LPA KIV-2 polymorphism, rs3798220 and rs10455872 SNPs were genotyped by TaqMan technology. Concerning rs1853021 and rs1800769 SNPs, PCR-RFLP assay was used. LPA KIV-2 repeat number was significantly lower in patients than in controls [median (interquartile range) 11(6–17) vs 15(9–25), p<0.0001]. A significantly higher prevalence of KIV-2 repeat number ≤7 was observed in patients than in controls (33.5% vs 15.5%, p<0.0001). KIV-2 repeat number was independently associated with VTE (p = 4.36 x10-9), as evidenced by the general linear model analysis adjusted for transient risk factors. No significant difference in allele frequency for all SNPs investigated was observed. Haplotype analysis showed that LPA haplotypes rather than individual SNPs influenced disease susceptibility. Receiver operating characteristic curves analysis showed that a combined risk prediction model, including KIV-2 size polymorphism and clinical variables, had a higher performance in identifying subjects at VTE risk than a clinical-only model, also separately in men and women. PMID:26900838

  7. Apolipoprotein(a) Kringle-IV Type 2 Copy Number Variation Is Associated with Venous Thromboembolism.

    PubMed

    Sticchi, Elena; Magi, Alberto; Kamstrup, Pia R; Marcucci, Rossella; Prisco, Domenico; Martinelli, Ida; Mannucci, Pier Mannuccio; Abbate, Rosanna; Giusti, Betti

    2016-01-01

    In addition to the established association between high lipoprotein(a) [Lp(a)] concentrations and coronary artery disease, an association between Lp(a) and venous thromboembolism (VTE) has also been described. Lp(a) is controlled by genetic variants in LPA gene, coding for apolipoprotein(a), including the kringle-IV type 2 (KIV-2) size polymorphism. Aim of the study was to investigate the role of LPA gene KIV-2 size polymorphism and single nucleotide polymorphisms (SNPs) (rs1853021, rs1800769, rs3798220, rs10455872) in modulating VTE susceptibility. Five hundred and sixteen patients with VTE without hereditary and acquired thrombophilia and 1117 healthy control subjects, comparable for age and sex, were investigated. LPA KIV-2 polymorphism, rs3798220 and rs10455872 SNPs were genotyped by TaqMan technology. Concerning rs1853021 and rs1800769 SNPs, PCR-RFLP assay was used. LPA KIV-2 repeat number was significantly lower in patients than in controls [median (interquartile range) 11(6-17) vs 15(9-25), p<0.0001]. A significantly higher prevalence of KIV-2 repeat number ≤7 was observed in patients than in controls (33.5% vs 15.5%, p<0.0001). KIV-2 repeat number was independently associated with VTE (p = 4.36 x10-9), as evidenced by the general linear model analysis adjusted for transient risk factors. No significant difference in allele frequency for all SNPs investigated was observed. Haplotype analysis showed that LPA haplotypes rather than individual SNPs influenced disease susceptibility. Receiver operating characteristic curves analysis showed that a combined risk prediction model, including KIV-2 size polymorphism and clinical variables, had a higher performance in identifying subjects at VTE risk than a clinical-only model, also separately in men and women.

  8. Microvascular Materials for Mass and Energy Transport

    DTIC Science & Technology

    2012-08-01

    2D vs. 3D : Visualizing Reacivity! 2D 3D Nguyen, Leho, Esser-Kahn Lab Chip 2012 2.96 ± .35 mol/m2 hr 1.66 ± .17 mol/m2 hr Mass...Celery! Lithography Big Mac Assembly Celery Assembly 3D Techniques HRL AMS Fibers Can be Woven Into Composite Materials! Channel extends over...Structures Mammal Fish 3D Gas Exchange Unit Just how efficient are natural structures?! Merck – Lung Guide! Breathing Capacity of Lung 3 million

  9. [Advances in the Association between Apolipoprotein (a) Gene Polymorphisms and Coronary Heart Disease].

    PubMed

    Zhu, Li; L, Zhan; Song, Yong-yan

    2015-08-01

    Human apolipoprotein (a) (LPA) gene is highly polymorphic, and the polymorphic loci on this gene include the Kringle 4 subtype 2(KIV-2) repeat polymorphism, the pentanucleotide repeat (TTTTA)n polymorphism, and a number of single nucleotide polymorphisms. KIV-2 repeat polymorphism was found to be significantly associated with coronary heart disease(CHD), and the reducing number of KIV-2 repeats is a risk factor for CHD. Both the increase and decrease of the pentanucleotide repeat(TTTTA)n polymorphism repeats are possibly associated with CHD risk. In single nucleotide polymorphisms loci, the rs10455872 and rs3798220 loci were widely reported to be associated with CHD, while other loci were less reported. The association between LPA polymorphisms and CHD may be mediated by either the elevation of plasma LPA level or the change of LPA subtypes. This article reviews the association between the LPA polymorphisms and CHD and the underlying mechanisms.

  10. Impact of lipoprotein(a) levels and apolipoprotein(a) isoform size on risk of coronary heart disease.

    PubMed

    Hopewell, J C; Seedorf, U; Farrall, M; Parish, S; Kyriakou, T; Goel, A; Hamsten, A; Collins, R; Watkins, H; Clarke, R

    2014-09-01

    Observational and genetic studies have shown that lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] isoform size are both associated with coronary heart disease (CHD) risk, but the relative independence of these risk factors remains unclear. Clarification of this uncertainty is relevant to the potential of future Lp(a)-lowering therapies for the prevention of CHD. Plasma Lp(a) levels and apo(a) isoform size, estimated by the number of kringle IV (KIV) repeats, were measured in 995 patients with CHD and 998 control subjects. The associations between CHD risk and fifths of Lp(a) levels were assessed before and after adjustment for KIV repeats and, conversely, the associations between CHD risk and fifths of KIV repeats were assessed before and after adjustment for Lp(a) levels. Individuals in the top fifth of Lp(a) levels had more than a twofold higher risk of CHD compared with those in the bottom fifth, and this association was materially unaltered after adjustment for KIV repeats [odds ratio (OR) 2.05, 95% confidence interval (CI) 1.38-3.04, P < 0.001]. Furthermore, almost all of the excess risk was restricted to the two-fifths of the population with the highest Lp(a) levels. Individuals in the bottom fifth of KIV repeats had about a twofold higher risk of CHD compared with those in the top fifth, but this association was no longer significant after adjustment for Lp(a) levels (OR 1.13, 95% CI 0.77-1.66, P = 0.94). The effect of KIV repeats on CHD risk is mediated through their impact on Lp(a) levels, suggesting that absolute levels of Lp(a), rather than apo(a) isoform size, are the main determinant of CHD risk. © 2013 The Association for the Publication of the Journal of Internal Medicine.

  11. Acetolactate synthase from Bacillus subtilis serves as a 2-ketoisovalerate decarboxylase for isobutanol biosynthesis in Escherichia coli.

    PubMed

    Atsumi, Shota; Li, Zhen; Liao, James C

    2009-10-01

    A pathway toward isobutanol production previously constructed in Escherichia coli involves 2-ketoacid decarboxylase (Kdc) from Lactococcus lactis that decarboxylates 2-ketoisovalerate (KIV) to isobutyraldehyde. Here, we showed that a strain lacking Kdc is still capable of producing isobutanol. We found that acetolactate synthase from Bacillus subtilis (AlsS), which originally catalyzes the condensation of two molecules of pyruvate to form 2-acetolactate, is able to catalyze the decarboxylation of KIV like Kdc both in vivo and in vitro. Mutational studies revealed that the replacement of Q487 with amino acids with small side chains (Ala, Ser, and Gly) diminished only the decarboxylase activity but maintained the synthase activity.

  12. Acetolactate Synthase from Bacillus subtilis Serves as a 2-Ketoisovalerate Decarboxylase for Isobutanol Biosynthesis in Escherichia coli▿

    PubMed Central

    Atsumi, Shota; Li, Zhen; Liao, James C.

    2009-01-01

    A pathway toward isobutanol production previously constructed in Escherichia coli involves 2-ketoacid decarboxylase (Kdc) from Lactococcus lactis that decarboxylates 2-ketoisovalerate (KIV) to isobutyraldehyde. Here, we showed that a strain lacking Kdc is still capable of producing isobutanol. We found that acetolactate synthase from Bacillus subtilis (AlsS), which originally catalyzes the condensation of two molecules of pyruvate to form 2-acetolactate, is able to catalyze the decarboxylation of KIV like Kdc both in vivo and in vitro. Mutational studies revealed that the replacement of Q487 with amino acids with small side chains (Ala, Ser, and Gly) diminished only the decarboxylase activity but maintained the synthase activity. PMID:19684168

  13. Risk factors for adult interpersonal violence in suicide attempters

    PubMed Central

    2014-01-01

    Background Suicidal and violent behaviours are interlinked and share common biological underpinnings. In the present study we analysed the association between violent behaviour as a child, childhood trauma, adult psychiatric illness, and substance abuse in relation to interpersonal violence as an adult in suicide attempters with mood disorders. Methods A total of 161 suicide attempters were diagnosed with Structured Clinical Interviews and assessed with the Karolinska Interpersonal Violence Scale (KIVS) measuring exposure to violence and expressed violent behaviour in childhood (between 6-14 years of age) and during adult life (15 years or older). Ninety five healthy volunteers were used as a comparison group. A logistic regression analysis was conducted with the two KIVS subscales, expressed violent behaviour as a child and exposure to violence in childhood together with substance abuse, personality disorder diagnoses and age as possible predictors of adult interpersonal violence in suicide attempters. Results Violent behaviour as a child, age and substance abuse were significant predictors of adult interpersonal violence. ROC analysis for the prediction model for adult violence with the KIVS subscale expressed violence as a child gave an AUC of 0.79. Using two predictors: violent behaviour as a child and substance abuse diagnosis gave an AUC of 0.84. The optimal cut-off for the KIVS subscale expressed violence as a child was higher for male suicide attempters. Conclusions Violent behaviour in childhood and substance abuse are important risk factors for adult interpersonal violent behaviour in suicide attempters. PMID:25001499

  14. Genetic variation in LPAL2, LPA, and PLG predicts plasma lipoprotein(a) level and carotid artery disease risk

    PubMed Central

    Ronald, James; Rajagopalan, Ramakrishnan; Cerrato, Felecia; Nord, Alex S.; Hatsukami, Thomas; Kohler, Ted; Marcovina, Santica; Heagerty, Patrick; Jarvik, Gail P.

    2010-01-01

    Background and Purpose Lipoprotein(a) level (Lp(a)) is an established risk factor for coronary artery disease and has been implicated in carotid artery disease (CAAD). The relationship between genetic variation in the LPA gene region and CAAD risk remains unknown. Methods We genotyped single nucleotide polymorphisms (SNPs) in the LPAL2, LPA, and PLG region in 530 individuals with severe CAAD and 770 controls and kringle IV type 2 (KIV2) repeat length in a subset of 90 individuals. Results Nine SNPs collectively accounted for 30% of the variance in Lp(a) level. Six SNPs were associated with Lp(a) level after accounting for KIV2 copy number, and the dominant KIV2 allele combined with these markers explained 60% of the variance in Lp(a) level. Five SNPs, including rs10455872, which had an odds ratio of 2.1 per minor allele, and haplotypes formed by rs10455872, rs6919346, and rs3123629 were significant predictors of CAAD. After accounting for Lp(a) level, all evidence of CAAD-genotype association in the LPA region was eliminated. Conclusions LPA region SNPs capture some but not all of the effect of KIV2 repeat length on Lp(a) level. There are associations between LPA region SNPs and CAAD which appear to be due to effects on Lp(a) level. PMID:21127300

  15. Thiamin-responsive maple-syrup-urine disease: decreased affinity of the mutant branched-chain alpha-keto acid dehydrogenase for alpha-ketoisovalerate and thiamin pyrophosphate.

    PubMed Central

    Chuang, D T; Ku, L S; Cox, R P

    1982-01-01

    The biochemical basis for the therapeutic effects of thiamin in thiamin-responsive maple-syrup-urine disease (MSUD) was investigated in intact and disrupted fibroblast cultures from normals and patients with various forms of MSUD. Decarboxylation of alpha-keto[1-14C]isovalerate (KIV) by intact cells from a thiamin-responsive MSUD patient was at 30-40% of the normal rate with or without thiamin in the incubation medium. Under similar conditions, intact classical MSUD fibroblasts failed to decarboxylate KIV. Branched-chain alpha-keto acid (BCKA) dehydrogenase activity measured in disrupted cells from the thiamin-responsive subject showed sigmoidal kinetics in the absence of thiamin pyrophosphate (TPP), with an increased concentration of substrate needed for half-maximal velocity (K0.5 for KIV = 7 mM vs. 0.05 mM in normal cells). When assayed with 0.2 mM TPP present, the mutant enzyme showed (i) a shift in kinetics to near Michaelis-Menten type as observed with the normal BCKA dehydrogenase and (ii) a lower K0.5 value of 4 mM for KIV, suggesting a TPP-mediated increase in the mutant enzyme's affinity for substrate. By contrast, TPP increased only the Vmax and was without effect on the apparent Km for KIV of the BCKA dehydrogenase from cells of normals and patients with classical MSUD and variant thiamin-responsive MSUD (grade 3). Measurement of the apparent Km for TPP of the BCKA dehydrogenase from thiamin-responsive mutant MSUd cells showed a 16-fold increase in the constant to 25 microM compared to enzymes from normal or classical MSUD cells. These findings demonstrate that the primary defect in the thiamin-responsive MSUD patient is a reduced affinity of the mutant BCKA dehydrogenase for TPP that results in impaired oxidative decarboxylation of BCKA. PMID:6954481

  16. Metabolism of branched-chain keto acids in neonatal rat liver perfusions.

    PubMed

    Frost, S C; Wells, M A

    1983-10-15

    The ability of the neonatal rat to oxidize the branched-chain amino acids leucine and valine and their corresponding keto acids was evaluated. In vivo, about 20% of orally administered labeled amino or keto acids were oxidized in 6 h, after which time little further oxidation occurred. In perfused neonatal liver the amino acids were oxidized at only 5-10% the rate of the keto acids. The oxidation of the keto acids showed a saturable dependence on concentration. The decarboxylation of ketoisocaproate (KIC) had a maximal rate of 40.1 +/- 1.6 mumol/h/g liver with an apparent Km of 0.27 +/- 0.03 mM, and decarboxylation of ketoisovalerate (KIV) had a maximal rate of 37.9 +/- 1.9 mumol/h/g liver and an apparent Km of 0.28 +/- 0.04 mM. KIC was ketogenic, producing mainly acetoacetate at a maximal rate of 44.5 +/- 1.6 mumol/h/g liver with an apparent Km of 0.27 +/- 0.03 mM. On the other hand, KIV was not gluconeogenic, although the perfused neonatal liver was able to produce glucose from lactate. During liver perfusion, KIV did not produce measurable quantities of either propionic or beta-aminoisobutyric acids, which are possible end products of KIV metabolism. Decanoic acid inhibited the decarboxylation of both keto acids to the same extent with a maximal effect at 0.4 mM fatty acid. At saturating levels, KIC was less ketogenic than decanoate. Inhibition of endogenous fatty acid oxidation by 2-tetradecylglycidic acid had no effect on keto acid oxidation. These data suggest that branched-chain amino acids derived from milk proteins are probably not quantitatively significant sources of either ketone bodies or glucose in the neonatal rat.

  17. Antidepressive and BDNF effects of enriched environment treatment across ages in mice lacking BDNF expression through promoter IV

    PubMed Central

    Jha, S; Dong, B E; Xue, Y; Delotterie, D F; Vail, M G; Sakata, K

    2016-01-01

    Reduced promoter IV-driven expression of brain-derived neurotrophic factor (BDNF) is implicated in stress and major depression. We previously reported that defective promoter IV (KIV) caused depression-like behavior in young adult mice, which was reversed more effectively by enriched environment treatment (EET) than antidepressants. The effects of promoter IV-BDNF deficiency and EET over the life stages remain unknown. Since early-life development (ED) involves dynamic epigenetic processes, we hypothesized that EET during ED would provide maximum antidepressive effects that would persist later in life due to enhanced, long-lasting BDNF induction. We tested this hypothesis by determining EET effects across three life stages: ED (0–2 months), young adult (2–4 months), and old adult (12–14 months). KIV mice at all life stages showed depression-like behavior in the open-field and tail-suspension tests compared with wild-type mice. Two months of EET reduced depression-like behavior in ED and young adult, but not old adult mice, with the largest effect in ED KIV mice. This effect lasted for 1 month after discontinuance of EET only in ED mice. BDNF protein induction by EET in the hippocampus and frontal cortex was also the largest in ED mice and persisted only in the hippocampus of ED KIV mice after discontinuance of EET. No gender-specific effects were observed. The results suggest that defective promoter IV causes depression-like behavior, regardless of age and gender, and that EET during ED is particularly beneficial to individuals with promoter IV-BDNF deficiency, while additional treatment may be needed for older adults. PMID:27648918

  18. Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex.

    PubMed

    Sakata, Kazuko; Woo, Newton H; Martinowich, Keri; Greene, Joshua S; Schloesser, Robert J; Shen, Liya; Lu, Bai

    2009-04-07

    Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF.

  19. A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo.

    PubMed

    Jiao, Yuanyuan; Zhang, Zhi; Zhang, Chunzhao; Wang, Xinjun; Sakata, Kazuko; Lu, Bai; Sun, Qian-Quan

    2011-07-19

    Mechanisms underlying experience-dependent refinement of cortical connections, especially GABAergic inhibitory circuits, are unknown. By using a line of mutant mice that lack activity-dependent BDNF expression (bdnf-KIV), we show that experience regulation of cortical GABAergic network is mediated by activity-driven BDNF expression. Levels of endogenous BDNF protein in the barrel cortex are strongly regulated by sensory inputs from whiskers. There is a severe alteration of excitation and inhibition balance in the barrel cortex of bdnf-KIV mice as a result of reduced inhibitory but not excitatory conductance. Within the inhibitory circuits, the mutant barrel cortex exhibits significantly reduced levels of GABA release only from the parvalbumin-expressing fast-spiking (FS) interneurons, but not other interneuron subtypes. Postnatal deprivation of sensory inputs markedly decreased perisomatic inhibition selectively from FS cells in wild-type but not bdnf-KIV mice. These results suggest that postnatal experience, through activity-driven BDNF expression, controls cortical development by regulating FS cell-mediated perisomatic inhibition in vivo.

  20. Comparative assessment of native and heterologous 2-oxo acid decarboxylases for application in isobutanol production by Saccharomyces cerevisiae.

    PubMed

    Milne, N; van Maris, A J A; Pronk, J T; Daran, J M

    2015-01-01

    Decarboxylation of α-ketoisovalerate to isobutyraldehyde is a key reaction in metabolic engineering of Saccharomyces cerevisiae for isobutanol production with published studies relying on overexpression of either the native ARO10 gene or of the Lactococcus lactis kivD decarboxylase gene resulting in low enzymatic activities. Here, we compare relevant properties for isobutanol production of Aro10, KivD and an additional, less studied, L. lactis decarboxylase KdcA. To eliminate interference by native decarboxylases, each 2-oxo acid decarboxylase was overexpressed in a 'decarboxylase-negative' (pdc1Δ pdc5Δ pdc6Δ aro10Δ) S. cerevisiae background. Kinetic analyses in cell extracts revealed a superior V max/K m ratio of KdcA for α-ketoisovalerate and a wide range of linear and branched-chain 2-oxo acids. However, KdcA also showed the highest activity with pyruvate which, in engineered strains, can contribute to formation of ethanol as a by-product. Removal of native decarboxylase genes eliminated growth on valine as sole nitrogen source and subsequent complementation of this growth impairment by expression of each decarboxylase indicated that based on the increased growth rate, the in vivo activity of KdcA with α-ketoisovalerate was higher than that of KivD and Aro10. Moreover, during oxygen-limited incubation in the presence of glucose, strains expressing kdcA or kivD showed a ca. twofold higher in vivo rate of conversion of α-ketoisovalerate into isobutanol than an ARO10-expressing strain. Finally, cell extracts from cultures grown on different nitrogen sources revealed increased activity of constitutively expressed KdcA after growth on both valine and phenylalanine, while KivD and Aro10 activity was only increased after growth on phenylalanine suggesting a difference in the regulation of these enzymes. This study illustrates important differences in substrate specificity, enzyme kinetics and functional expression between different decarboxylases in the context

  1. Interpersonal violence, early life adversity, and suicidal behavior in hypersexual men

    PubMed Central

    Chatzittofis, Andreas; Savard, Josephine; Arver, Stefan; Öberg, Katarina Görts; Hallberg, Jonas; Nordström, Peter; Jokinen, Jussi

    2017-01-01

    Background and aims There are significant gaps in knowledge regarding the role of childhood adversity, interpersonal violence, and suicidal behavior in hypersexual disorder (HD). The aim of this study was to investigate interpersonal violence in hypersexual men compared with healthy volunteers and the experience of violence in relation to suicidal behavior. Methods This case–control study includes 67 male patients with HD and 40 healthy male volunteers. The Childhood Trauma Questionnaire – Short Form (CTQ-SF) and the Karolinska Interpersonal Violence Scale (KIVS) were used for assessing early life adversity and interpersonal violence in childhood and in adult life. Suicidal behavior (attempts and ideation) was assessed with the Mini-International Neuropsychiatric Interview (version 6.0) and the Montgomery–Åsberg Depression Rating Scale – Self-rating. Results Hypersexual men reported more exposure to violence in childhood and more violent behavior as adults compared with healthy volunteers. Suicide attempters (n = 8, 12%) reported higher KIVS total score, more used violence as a child, more exposure to violence as an adult as well as higher score on CTQ-SF subscale measuring sexual abuse (SA) compared with hypersexual men without suicide attempt. Discussion Hypersexuality was associated with interpersonal violence with higher total scores in patients with a history of suicide attempt. The KIVS subscale exposure to interpersonal violence as a child was validated using the CTQ-SF but can be complemented with questions focusing on SA for full assessment of early life adversity. Conclusion Childhood adversity is an important factor in HD and interpersonal violence might be related to suicidal behavior in hypersexual men. PMID:28467102

  2. Regulation of valine and. alpha. -ketoisocaproate metabolism in rat kidney mitochondria

    SciTech Connect

    Miller, R.H.; Harper, A.E. )

    1988-10-01

    Activities of branched-chain amino acid (BCAA) aminotransferase (BCAT) and {alpha}-keto acid dehydrogenase (BCKD) were assayed in mitochondria isolated from kidneys of rats. Rates of transamination of valine and oxidation of keto acids {alpha}-ketoisocaproate (KIC) or {alpha}-ketoisovalerate (KIV) were estimated using radioactive tracers of the appropriate substrate from amounts of {sup 14}C-labeled products formed. Because of the high mitochondrial BCAT activity, an amino acceptor for BCAT, {alpha}-ketoglutarate ({alpha}-KG) or KIC, was added to the assay medium when valine was the substrate. Rates of valine transamination and subsequent oxidation of the KIV formed were determined with 0.5 mM {alpha}-KG as the amino acceptor; these rates were 5- to 50-fold those without added {alpha}-KG. Rates of CO{sub 2} evolution from valine also increased when KIC was present; however, with KIC concentrations above 0.2 mM, rates of CO{sub 2} evolution from valine declined although rates of transamination continued to rise. When 0.05 mM KIC was added to the assay medium, oxidation of KIC was suppressed by inclusion of valine or glutamate in the medium. When valine was present KIC was not oxidized preferentially, presumably because it was also serving as an amino acceptor for BCAT. These results indicate that as the supply of amino acceptor, {alpha}-KG or KIC, is increased in mitochondria not only is the rate of valine transamination stimulated but also the rate of oxidation of the KIV formed from valine. Thus the rate of oxidation of BCAA can be controlled by factors that influence the rate and direction of BCAA transamination and, thereby, the supply of substrate for BCKD.

  3. The apolipoprotein(a) component of lipoprotein(a) mediates binding to laminin: contribution to selective retention of lipoprotein(a) in atherosclerotic lesions.

    PubMed

    D'Angelo, Angela; Geroldi, Diego; Hancock, Mark A; Valtulina, Viviana; Cornaglia, Antonia I; Spencer, Craig A; Emanuele, Enzo; Calligaro, Alberto; Koschinsky, Marlys L; Speziale, Pietro; Visai, Livia

    2005-02-21

    Lipoprotein(a) [Lp(a)] entrapment by vascular extracellular matrix may be important in atherogenesis. We sought to determine whether laminin, a major component of the basal membrane, may contribute to Lp(a) retention in the arterial wall. First, immunohistochemistry experiments were performed to examine the relative distribution of Lp(a) and laminin in human carotid artery specimens. There was a high degree of co-localization of Lp(a) and laminin in atherosclerotic specimens, but not in non-atherosclerotic sections. We then studied the binding interaction between Lp(a) and laminin in vitro. ELISA experiments showed that native Lp(a) particles and 17K and 12K recombinant apolipoprotein(a) [r-apo(a)] variants interacted strongly with laminin whereas LDL, apoB-100, and the truncated KIV(6-P), KIV(8-P), and KIV(9-P) r-apo(a) variants did not. Overall, the ELISA data demonstrated that Lp(a) binding to laminin is mediated by apo(a) and a combination of the lysine analogue epsilon-aminocaproic acid and salt effectively decreases apo(a) binding to laminin. Secondary binding analyses with 125I-labeled r-apo(a) revealed equilibrium dissociation constants (K(d)) of 180 and 360 nM for the 17K and 12K variants binding to laminin, respectively. Such similar K(d) values between these two r-apo(a) variants suggest that isoform size does not appear to influence apo(a) binding to laminin. In summary, our data suggest that laminin may bind to apo(a) in the atherosclerotic intima, thus contributing to the selective retention of Lp(a) in this milieu.

  4. Hypothalamic pituitary thyroid axis and exposure to interpersonal violence in childhood among women with borderline personality disorder

    PubMed Central

    Sinai, Cave; Hirvikoski, Tatja; Nordström, Anna-Lena; Nordström, Peter; Nilsonne, Åsa; Wilczek, Alexander; Åsberg, Marie; Jokinen, Jussi

    2014-01-01

    Background A relationship between exposure to sexual violence and thyroid hormone alterations has been observed among women with posttraumatic stress disorder (PTSD). Women with borderline personality disorder (BPD) report a high estimate of childhood trauma. Objective The aim of the present study was to assess relationships between thyroid hormone measures and exposure to violence in childhood in women with BPD. Method A total of 92 clinically euthyroid women with BPD (53% with comorbid PTSD) diagnosis and at least two prior suicide attempts were assessed with the Karolinska Interpersonal Violence Scales (KIVS). The KIVS contains four subscales with concrete examples of exposure to violence and expressed violent behavior in childhood (aged 6–14 years) and during adult life (15 years or older). Baseline thyroid function was evaluated by measuring plasma free and bound triiodothyronine (FT3 and T3), thyroxine (FT4 and T4), and thyroid-stimulating hormone (TSH) with immunoassays. The FT3/FT4 ratio was used to estimate peripheral deiodination. Plasma cortisol was also assessed. Results Sixty-seven percent of patients reported medium high or high level of exposure to interpersonal violence as a child. The FT3/FT4 ratio showed a significant negative correlation with exposure to violence as a child. Patients with PTSD had significantly higher plasma cortisol levels. An ad hoc analysis revealed that the correlation between KIVS exposure to interpersonal violence as a child and FT3/FT4 ratio was significant only in patients with comorbid PTSD. Altered thyroid activity, especially FT3/FT4, levels was associated with exposure to violence in childhood in women with BPD. Conclusion Severe childhood trauma-related stress may promote lasting altered thyroid levels and/or contribute to the development of psychopathology associated with BPD traits or PTSD. PMID:24959326

  5. Navy Network Dependability: Models, Metrics, and Tools

    DTIC Science & Technology

    2010-01-01

    surveillance; TCDL = Tactical Common Data Link; UHF = ultra high frequency; UFO = ultra-high-frequency follow-on; WGS = Wideband Gapfiller Satellite. RAND...VOICE (DMR VALUES) UFO OE-82 UHF LOS VOICE (DMR VALUES) UHF SATCOM VOICE DMR UHF LOS VOICE DMR TVs ADMS KIV-7 COMSEC ADNS SW ADNS II HW ISNS SW ISNS HW...Data Link; UHF = ultra high frequency; UFO = ultra-high-frequency follow-on; WGS = Wideband Gapfiller Satellite. RAND MG1003-1.1 4 Navy Network

  6. Non-Suicidal Self-Injury and Interpersonal Violence in Suicide Attempters.

    PubMed

    Sahlin, Hanna; Moberg, Tomas; Hirvikoski, Tatja; Jokinen, Jussi

    2015-01-01

    The current study compared characteristics of suicidal behavior and interpersonal violence in suicide attempters with and without a history of non-suicidal self-injury (NSSI). A total of 100 suicide attempters were assessed with Karolinska Interpersonal Violence Scale (KIVS) and Karolinska Suicide History Interview concerning interpersonal violence and NSSI. There was a high degree of comorbid NSSI in suicide attempters (44%). Suicide attempters with NSSI-history reported more interpersonal violence as adults and more severe suicidal behavior compared to suicide attempters without NSSI. Comorbid NSSI was related to severity of suicidal behavior in a gender specific manner. Comorbid NSSI in suicide attempters may increase suicide and violence risk.

  7. Direct Solutions of Large, Sparse Linear Systems

    DTIC Science & Technology

    1977-12-01

    kiV W 2 Z.J@ gi z1 " ~Z iO P- I-SrP--NX VAJ 0 S Ci 0-4q., 4g ’’ p..CD wi I X I-- X X( 0 a. CD "M=0 4 W- W4 M maCJ P.-~ 4 4 r^ = = = obb 0I’ P4IUP so. Cat...r ;•i glll ,•-~l .j- , I• UNCLASSI FIED SECURIT ’, CLASSIFICATION OF THIS PAGE("Whw Does En.o ,,d) The performance comparison involves a wide rang of

  8. Exploring the Prevalence of Ten Polyomaviruses and Two Herpes Viruses in Breast Cancer

    PubMed Central

    Rockett, Rebecca J.; Jacob, Kevin; Bennett, Ian C.; Sloots, Theo P.

    2012-01-01

    Several different viruses have been proposed to play a role in breast carcinogenesis. The aim of this study was to investigate the prevalence of a subset of viruses in breast cancer tissue. We investigated the prevalence of 12 DNA viruses: EBV and CMV from the Herpesviridae family and SV40, BKV, JCV, MCV, WUV, KIV, LPV, HPyV6, HPyV7, and TSV from the Polyomaviridae family in 54 fresh frozen breast tumour specimens. Relevant clinical data and basic lifestyle data were available for all patients. The tissue samples were DNA extracted and real-time PCR assays were used for viral detection. The highest prevalence, 10% (5/54), was found for EBV. MCV, HPyV6, and HPyV7 were detected in single patient samples (2% each), while WUV, KIV, JCV, BKV, LPV, SV40, TSV and CMV were not detected in the 54 breast cancer specimens analysed here. Further investigations are needed to elucidate the potential role of viruses, and particularly EBV, in breast carcinogenesis. PMID:22916092

  9. The characterization for the binding of calcium and terbium to Euplotes octocarinatus centrin

    NASA Astrophysics Data System (ADS)

    Yaqin, Zhao; Jiuying, Feng; Aihua, Liang; Binsheng, Yang

    2009-01-01

    Centrin is a member of the EF-hand superfamily that plays critical role in the centrosome duplication and separation. In the present paper, we characterized properties of metal ions binding to Euplotes octocarinatus centrin (EoCen) by fluorescence spectra and circular dichroism (CD) spectra. Changes of fluorescence spectra and α-helix contents of EoCen proved that Tb 3+ and Ca 2+ induced great conformational changes of EoCen resulting in exposing hydrophobic surfaces. At pH 7.4, Ca 2+ (and Tb 3+) bond with EoCen at the ratio of 4:1. Equilibrium experiment indicated that Ca 2+ and Tb 3+ exhibited different binding capabilities for C- and N-terminal domains of protein. C-terminal domain bond with Ca 2+ or Tb 3+ ˜ 100-fold more strongly than N-terminal. Aromatic residue-sensitized Tb 3+ energy transfer suggested that site IV bond to Tb 3+ or Ca 2+ more strongly than site III. Based on fluorescence titration curves, we reckoned the conditional binding constants of EoCen site IV quantitatively to be KIV = (1.23 ± 0.51) × 10 8 M -1 and KIV = (6.82 ± 0.33) × 10 5 M -1 with Tb 3+ and Ca 2+, respectively. Metal ions bond to EoCen in the order of IV > III > II, I.

  10. The characterization for the binding of calcium and terbium to Euplotes octocarinatus centrin.

    PubMed

    Yaqin, Zhao; Jiuying, Feng; Aihua, Liang; Binsheng, Yang

    2009-01-01

    Centrin is a member of the EF-hand superfamily that plays critical role in the centrosome duplication and separation. In the present paper, we characterized properties of metal ions binding to Euplotes octocarinatus centrin (EoCen) by fluorescence spectra and circular dichroism (CD) spectra. Changes of fluorescence spectra and alpha-helix contents of EoCen proved that Tb(3+) and Ca(2+) induced great conformational changes of EoCen resulting in exposing hydrophobic surfaces. At pH 7.4, Ca(2+) (and Tb(3+)) bond with EoCen at the ratio of 4:1. Equilibrium experiment indicated that Ca(2+) and Tb(3+) exhibited different binding capabilities for C- and N-terminal domains of protein. C-terminal domain bond with Ca(2+) or Tb(3+) approximately 100-fold more strongly than N-terminal. Aromatic residue-sensitized Tb(3+) energy transfer suggested that site IV bond to Tb(3+) or Ca(2+) more strongly than site III. Based on fluorescence titration curves, we reckoned the conditional binding constants of EoCen site IV quantitatively to be K(IV)=(1.23+/-0.51)x10(8)M(-1) and K(IV)=(6.82+/-0.33)x10(5)M(-1) with Tb(3+) and Ca(2+), respectively. Metal ions bond to EoCen in the order of IV>III>II, I.

  11. Interpersonal violence and the prediction of short-term risk of repeat suicide attempt

    PubMed Central

    Haglund, Axel; Lindh, Åsa U.; Lysell, Henrik; Renberg, Ellinor Salander; Jokinen, Jussi; Waern, Margda; Runeson, Bo

    2016-01-01

    In this multi-center cohort study, suicide attempters presenting to hospital (N = 355, 63% women) were interviewed using the Karolinska Interpersonal Violence Scale (KIVS) and followed-up by medical record review. Main outcome was non-fatal or fatal repeat suicide attempt within six months. Also, repeat attempt using a violent method was used as an additional outcome in separate analyses. Data were analyzed for the total group and for men and women separately. Repeat attempts were observed within six months in 78 persons (22%) and 21 (6%) of these used a violent method. KIVS total score of 6 or more was associated with repeat suicide attempt within six months (OR = 1.81, CI 1.08–3.02) and predicted new attempts with a sensitivity of 62% and a specificity of 53%. A three-fold increase in odds ratio was observed for repeat attempt using a violent method (OR = 3.40, CI 1.22–9.49). An association between exposure to violence in adulthood and violent reattempt was seen in women (OR = 1.38, CI 1.06–1.82). The overall conclusions are that information about interpersonal violence may help predict short-term risk for repeat suicide attempt, and that structured assessment of interpersonal violence may be of value in risk assessment after attempted suicide. PMID:27841333

  12. Thyroid hormones and adult interpersonal violence among women with borderline personality disorder.

    PubMed

    Sinai, Cave; Hirvikoski, Tatja; Nordström, Anna-Lena; Nordström, Peter; Nilsonne, Åsa; Wilczek, Alexander; Åsberg, Marie; Jokinen, Jussi

    2015-06-30

    Elevated T3 levels have been reported in men with antisocial behavior. The aim of the present study was to investigate the relationship between thyroid hormones and expressed adult interpersonal violence in female patients with borderline personality disorder (BPD). Furthermore, expressed adult interpersonal violence in female BPD patients was compared to healthy female controls. A total of 92 clinically euthyroid women with BPD and 57 healthy women were assessed with the Karolinska Interpersonal Violence Scales (KIVS). Baseline thyroid function was evaluated by measuring plasma free and bound triiodothyronine (FT3 and T3), thyroxine (FT4 and T4), and thyroid-stimulating hormone (TSH) with immunoassays in patients. Plasma cortisol was also measured. Among females with BPD, expressed interpersonal violence as an adult showed a significant positive correlation with the T3 levels. The mean expression of interpersonal violence as an adult was significantly higher in BPD patients as compared to healthy controls. The multiple regression model indicated that two independent predictors of KIVS expressed interpersonal violence as an adult: T3 and comorbid diagnosis of alcohol abuse. Association between T3 levels and violent/aggressive behavior earlier reported exclusively in male samples may be valid also in females with BPD.

  13. (1)H NMR-based metabolomic approach for understanding the fermentation behaviors of wine yeast strains.

    PubMed

    Son, Hong-Seok; Hwang, Geum-Sook; Kim, Ki Myong; Kim, Eun-Young; van den Berg, Frans; Park, Won-Mok; Lee, Cherl-Ho; Hong, Young-Shick

    2009-02-01

    (1)H NMR spectroscopy coupled with multivariate statistical analysis was used for the first time to investigate metabolic changes in musts during alcoholic fermentation and wines during aging. Three Saccharomyces cerevisiae yeast strains (RC-212, KIV-1116, and KUBY-501) were also evaluated for their impacts on the metabolic changes in must and wine. Pattern recognition (PR) methods, including PCA, PLS-DA, and OPLS-DA scores plots, showed clear differences for metabolites among musts or wines for each fermentation stage up to 6 months. Metabolites responsible for the differentiation were identified as valine, 2,3-butanediol (2,3-BD), pyruvate, succinate, proline, citrate, glycerol, malate, tartarate, glucose, N-methylnicotinic acid (NMNA), and polyphenol compounds. PCA scores plots showed continuous movements away from days 1 to 8 in all musts for all yeast strains, indicating continuous and active fermentation. During alcoholic fermentation, the highest levels of 2,3-BD, succinate, and glycerol were found in musts with the KIV-1116 strain, which showed the fastest fermentation or highest fermentative activity of the three strains, whereas the KUBY-501 strain showed the slowest fermentative activity. This study highlights the applicability of NMR-based metabolomics for monitoring wine fermentation and evaluating the fermentative characteristics of yeast strains.

  14. Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels.

    PubMed

    Lu, Wensheng; Cheng, Yu-Ching; Chen, Keping; Wang, Hong; Gerhard, Glenn S; Still, Christopher D; Chu, Xin; Yang, Rongze; Parihar, Ankita; O'Connell, Jeffrey R; Pollin, Toni I; Angles-Cano, Eduardo; Quon, Michael J; Mitchell, Braxton D; Shuldiner, Alan R; Fu, Mao

    2015-04-15

    Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation.

  15. Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels

    PubMed Central

    Lu, Wensheng; Cheng, Yu-Ching; Chen, Keping; Wang, Hong; Gerhard, Glenn S.; Still, Christopher D.; Chu, Xin; Yang, Rongze; Parihar, Ankita; O'Connell, Jeffrey R.; Pollin, Toni I.; Angles-Cano, Eduardo; Quon, Michael J.; Mitchell, Braxton D.; Shuldiner, Alan R.; Fu, Mao

    2015-01-01

    Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68–0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5–APOA4–APOC3–APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10−8 to 3.91 × 10−19) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10−14) and rs10455872 (P = 1.85 × 10−12). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10−9). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation. PMID:25575512

  16. Significant differentiation in the apolipoprotein(a)/lipoprotein(a) trait between chimpanzees from Western and Central Africa.

    PubMed

    Noureen, Asma; Ronke, Claudius; Khalifa, Mahmoud; Halbwax, Michel; Fischer, Anne; André, Claudine; Atencia, Rebeca; Garriga, Rosa; Mugisha, Lawrence; Ceglarek, Uta; Thiery, Joachim; Utermann, Gerd; Schmidt, Konrad

    2017-09-01

    Elevated Lipoprotein(a) (Lp(a)) plasma concentrations are a risk factor for cardiovascular disease in humans, largely controlled by the LPA gene encoding apolipoprotein(a) (apo(a)). Lp(a) is composed of low-density lipoprotein (LDL) and apo(a) and restricted to Catarrhini. A variable number of kringle IV (KIV) domains in LPA lead to a size polymorphism of apo(a) that is inversely correlated with Lp(a) concentrations. Smaller apo(a) isoforms and higher Lp(a) levels in central chimpanzees (Pan troglodytes troglodytes [PTT]) compared to humans from Europe had been reported. We studied apo(a) isoforms and Lp(a) concentrations in 75 western (Pan troglodytes verus [PTV]) and 112 central chimpanzees, and 12 bonobos (Pan paniscus [PPA]), all wild born and living in sanctuaries in Sierra Leone, Republic of the Congo, and DR Congo, respectively, and 116 humans from Gabon. Lp(a) levels were severalfold higher in western than in central chimpanzees (181.0 ± 6.7 mg/dl vs. 56.5 ± 4.3 mg/dl), whereas bonobos showed intermediate levels (134.8 ± 33.4 mg/dl). Apo(a) isoform sizes differed significantly between subspecies (means 20.9 ± 2.2, 22.9 ± 4.4, and 23.8 ± 3.8 KIV repeats in PTV, PTT, and PPA, respectively). However, far higher isoform-associated Lp(a) concentrations for all isoform sizes in western chimpanzees offered the main explanation for the higher overall Lp(a) levels in this subspecies. Human Lp(a) concentrations (mean 47.9 ± 2.8 mg/dl) were similar to those in central chimpanzees despite larger isoforms (mean 27.1 ± 4.9 KIV). Lp(a) and LDL, apoB-100, and total cholesterol levels only correlated in PTV. This remarkable differentiation between chimpanzees from different African habitats and the trait's similarity in humans and chimpanzees from Central Africa poses the question of a possible impact of an environmental factor that has shaped the genetic architecture of LPA. Overall, studies on the cholesterol

  17. Heme oxygenase is involved in cobalt chloride-induced lateral root development in tomato.

    PubMed

    Xu, Sheng; Zhang, Bo; Cao, Ze-Yu; Ling, Teng-Fang; Shen, Wen-Biao

    2011-04-01

    In animals, heme oxygenase (HO), a rate-limiting enzyme responsible for carbon monoxide (CO) production, was regarded as a protective system maintaining cellular homeostasis. It was also established that metal ions are powerful HO-inducing agents and cobalt chloride (CoCl(2)) was the first metal ion identified with an inducing property. Previous study suggests that CoCl(2) stimulates adventitious root formation in tomato and cucumber cuttings. In this test, we discover that both CoCl(2) and an inducer of HO-1, hemin, could lead to the promotion of lateral root development, as well as the induction of HO-1 protein expression, HO activity, or LeHO-1/2 transcripts, in lateral root initiation zone of tomato seedlings. The effect is specific for HO since the potent HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX) blocked the above actions of CoCl(2), and the inhibitory effect was reversed partially when 50% CO aqueous solution was added. However, the addition of ascorbic acid (AsA), a well-known antioxidant, exhibited no obvious effect on lateral root formation. Molecular evidence further showed that CoCl(2)-induced the up-regulation of target genes responsible for lateral root formation, including LeCDKA1, LeCYCA2;1, and LeCYCA3;1, was suppressed differentially by ZnPPIX. And these decreases were reversed further by the addition of CO. All together, these results suggest a novel role for HO in the CoCl(2)-induced tomato lateral root formation.

  18. Combining Task Execution and Background Knowledge for the Verification of Medical Guidelines

    NASA Astrophysics Data System (ADS)

    Hommersom, Arjen; Groot, Perry; Lucas, Peter; Balser, Michael; Schmitt, Jonathan

    The use of a medical guideline can be seen as the execution of computational tasks, sequentially or in parallel, in the face of patient data. It has been shown that many of such guidelines can be represented as a 'network of tasks', i.e., as a number of steps that have a specific function or goal. To investigate the quality of such guidelines we propose a formalization of criteria for good practice medicine a guideline should comply to. We use this theory in conjunction with medical background knowledge to verify the quality of a guideline dealing with diabetes mellitus type 2 using the interactive theorem prover KIV. Verification using task execution and background knowledge is a novel approach to quality checking of medical guidelines.

  19. Chromosome mapping of the owl monkey CSF1R and IL5 genes.

    PubMed

    Ma, N S; Lin, K C

    1992-08-01

    We mapped the owl monkey colony-stimulating factor 1 receptor (CSF1R) locus to the proximal region of chromosome 3q of karyotype VI(K-VI) and karyotype V(K-V) and the interleukin 5 (IL5) locus to the mid-region of chromosome 3q(K-VI) and 19q(K-IV) using a combination of Southern hybridization of somatic cells and in situ chromosomal hybridization methodologies. The findings support the proposed evolution of owl monkey chromosome 3(K-VI) from a fusion of two smaller structures, the homologs of chromosomes 6 and 19 (K-IV). The data also indicate genomic conservation of the HSA 5q23-q35 segment in the higher primates.

  20. RADIO ASTROMETRY OF THE CLOSE ACTIVE BINARY HR 5110

    SciTech Connect

    Abbuhl, E.; Mutel, R. L.; Lynch, C.; Güedel, M.

    2015-09-20

    The close active binary HR 5110 was observed at six epochs over 26 days using a global very long baseline interferometry array at 15.4 GHz. We used phase referencing to determine the position of the radio centroid at each epoch with an uncertainty significantly smaller than the component separation. After correcting for proper motion and parallax, we find that the centroid locations of all six epochs have barycenter separations consistent with an emission source located on the KIV secondary, and not in an interaction region between the stars or on the F primary. We used a homogeneous power-law gyrosynchrotron emission model to reproduce the observed flux densities and fractional circular polarization. The resulting ranges of mean magnetic field strength and relativistic electron densities are of the order of 10 G and 10{sup 5} cm{sup −3}, respectively, in the source region.

  1. Perioperative epidural or intravenous ketamine does not improve the effectiveness of thoracic epidural analgesia for acute and chronic pain after thoracotomy.

    PubMed

    Tena, Beatriz; Gomar, Carmen; Rios, Jose

    2014-06-01

    Persistent postsurgical pain (PPP) after thoracotomy effect 50% to 80%. Nerve damage and central sensitization involving NDMDAr activation may play an important role. This study evaluates the efficacy of adding intravenous (IV) or epidural ketamine to thoracic epidural analgesia (TEA) after thoracotomy. Double-blind randomized study on patients undergoing thoracotomy allocated to one of the following: group Kiv (IV racemic ketamine 0.5 mg/kg preincisional +0.25 mg/kg/h for 48 h), group Kep (epidural racemic ketamine 0.5 mg/kg preincisional +0.25 mg/kg/h for 48 h), or group S (saline). Postoperative analgesia was ensured by TEA with ropivacaine and fentanyl. Pain visual analog scales (VAS), Neuropathic Pain Symptom Inventory, Catastrophizing Scale, and Quantitative Sensory Testing, measuring both the peri-incisional and distant hyperalgesia area, were conducted preoperatively and postoperatively until 6 months. Plasma ketamine levels and stability of the analgesic solutions were analyzed. A total of 104 patients were included. PPP incidence was 20% at 6 months. Pain scores on coughing were significantly lower in Kiv and Kep than in S at 24 and 72 hours, but there were no differences afterwards. There were no significant differences in pain at rest, Neuropathic Pain Symptom Inventory, and Catastrophizing Scale, or in the area of mechanical allodynia at any time. Adverse effects were mild. Plasma ketamine levels did not differ significantly between groups. Analgesic solutions were stable. Adding epidural or IV racemic ketamine to TEA after thoracotomy did not lead to any reduction in PPP or allodynia. Epidural administration produced similar plasma ketamine levels to the IV route.

  2. Recombinant immunoglobulin variable domains generated from synthetic genes provide a system for in vitro characterization of light-chain amyloid proteins.

    PubMed Central

    Stevens, P. W.; Raffen, R.; Hanson, D. K.; Deng, Y. L.; Berrios-Hammond, M.; Westholm, F. A.; Murphy, C.; Eulitz, M.; Wetzel, R.; Solomon, A.

    1995-01-01

    The primary structural features that render human monoclonal light chains amyloidogenic are presently unknown. To gain further insight into the physical and biochemical factors that result in the pathologic deposition of these proteins as amyloid fibrils, we have selected for detailed study three closely homologous protein products of the light-chain variable-region single-gene family VkIV. Two of these proteins, REC and SMA, formed amyloid fibrils in vivo. The third protein, LEN, was excreted by the patient at levels of 50 g/day with no indication of amyloid deposits. Sequences of amyloidogenic proteins REC and SMA differed from the sequence of the nonpathogenic protein LEN at 14 and 8 amino acid positions, respectively, and these amino acid differences have been analyzed in terms of the three-dimensional structure of the LEN dimer. To provide a replenishable source of these human proteins, we constructed synthetic genes coding for the REC, SMA, and LEN variable domains and expressed these genes in Escherichia coli. Immunochemical and biophysical comparisons demonstrated that the recombinant VkIV products have tertiary structural features comparable to those of the patient-derived proteins. This well-defined set of three clinically characterized human kIV light chains, together with the capability to produce these kIV proteins recombinantly, provide a system for biophysical and structural comparisons of two different amyloidogenic light-chain proteins and a nonamyloidogenic protein of the same subgroup. This work lays the foundation for future investigations of the structural basis of light-chain amyloidogenicity. PMID:7795526

  3. RADIO ASTROMETRY OF THE TRIPLE SYSTEMS ALGOL AND UX ARIETIS

    SciTech Connect

    Peterson, W. M.; Mutel, R. L.; Lestrade, J.-F.; Guedel, M.; Goss, W. M.

    2011-08-20

    We have used multi-epoch long-baseline radio interferometry to determine the proper motion and orbital elements of Algol and UX Arietis, two radio-bright, close binary stellar systems with distant tertiary components. For Algol, we refine the proper motion and outer orbit solutions, confirming the recent result of Zavala et al. that the inner orbit is retrograde. The radio centroid closely tracks the motion of the KIV secondary. In addition, the radio morphology varies from double-lobed at low flux level to crescent-shaped during active periods. These results are most easily interpreted as synchrotron emission from a large, co-rotating meridional loop centered on the K star. If this is correct, it provides a radio-optical frame tie candidate with an uncertainty {+-}0.5 mas. For UX Arietis, we find an outer orbit solution that accounts for previous very long baseline interferometry observations of an acceleration term in the proper motion fit. The outer orbit solution is also consistent with previously published radial velocity curves and speckle observations of a third body. The derived tertiary mass, 0.75 solar masses, is consistent with the K1 main-sequence star detected spectroscopically. The inner orbit solution favors radio emission from the active K0IV primary only. The radio morphology, consisting of a single, partially resolved emission region, may be associated with the persistent polar spot observed using Doppler imaging.

  4. The 16th Werner Brandt Workshop on charged particle penetration phenomena

    SciTech Connect

    1996-05-01

    This report contains viewgraphs on the following topics: impact parameter dependence of charge transfer and energy loss; nonlinear dynamical response of the electron gas: comparison of some simple theories; stopping of ultrarelativistic ions in solids (33.2-TeV {sup 108}Pb); collective excitation in reduced dimensionality; collective states in atoms and cluster; plasmon coupling with external probes; atomic collisions with antiprotons; layer-number scaling in ultra-thin film stopping and energetics; atom-surface scattering under classical conditions; nonlinear effect of sweeping-out electrons in stopping power and electron emission in cluster impacts; electron emission from fast grazing collisions of ions with silicon surfaces; electron emission from ultra-thin carbon foils by kiV ions; Auger rates for highly charged ions in metals; Auger and plasmon assisted neutralization at surfaces; low energy (< 5eV) F{sup +} and F{sup -} ions transmission through condensed layers of water: enhancement and attenuation processes; charge transfer for H interacting with Al: atomic levels and linewidths; scattered projectile angular and charge state distributions for grazing collisions of multicharged ions with metal and insulator single crystal targets; the prolate hyperboloidat model in scanning probe microscopy; scanning probe microscopy of large biomolecules; microcantilever sensors; solution of the Fokker-Planck equation for electron transport using analytic spatial moments; and effective charge parametrization for z = 3-17 projectiles in composite targets.

  5. Suicide Risk Associated with Experience of Violence and Impulsivity in Alcohol Dependent Patients

    PubMed Central

    Khemiri, Lotfi; Jokinen, Jussi; Runeson, Bo; Jayaram-Lindström, Nitya

    2016-01-01

    Alcohol dependence (AD) and aggression-impulsivity are both associated with increased suicide risk. There is a need to evaluate clinical tools in order to improve suicide risk assessment of AD patients. The present study consisted of 95 individuals with a diagnosis of AD, consecutively admitted for addiction treatment, compared with 95 healthy controls. Suicidal risk was assessed together with exposure of violence and impulsivity. AD patients reported significantly higher rates of exposure to violence in childhood, as measured by the Karolinska Interpersonal Violence Scale (KIVS), compared to HC. Within the AD group, individuals with history of suicidal ideation and suicidal behavior reported higher levels of violence experience compared to AD individuals without such history. AD patients with previous suicidal ideation scored higher on self-reported impulsivity as assessed by the Barratt Impulsivity Scale (BIS). Our main finding was that experience of trauma and expression of violent behavior, coupled with increased impulsivity are associated with an elevated suicide risk in AD patients. Future longitudinal studies assessing these traits are needed to evaluate their potential role in identifying AD patients at risk of future suicide. PMID:26784730

  6. A large coronal loop in the Algol system.

    PubMed

    Peterson, W M; Mutel, R L; Güdel, M; Goss, W M

    2010-01-14

    The close binary Algol system contains a radio-bright KIV subgiant star in a very close (0.062 astronomical units) and rapid (2.86 day) orbit with a main sequence B8 star. Because the rotation periods of the two stars are tidally locked to the orbital period, the rapid rotation drives a magnetic dynamo. A large body of evidence points to the existence of an extended, complex coronal magnetosphere originating at the cooler K subgiant. The detailed morphology of the subgiant's corona and its possible interaction with its companion are unknown, though theory predicts that the coronal plasma should be confined in a magnetic loop structure, as seen on the Sun. Here we report multi-epoch radio imaging of the Algol system, in which we see a large, persistent coronal loop approximately one subgiant diameter in height, whose base is straddling the subgiant and whose apex is oriented towards the B8 star. This suggests that a persistent asymmetric magnetic field structure is aligned between the two stars. The loop is larger than anticipated theoretically, but the size may be the result of a magnetic interaction between the two stars.

  7. De Novo Biosynthesis of Glutarate via α-Keto Acid Carbon Chain Extension and Decarboxylation Pathway in Escherichia coli.

    PubMed

    Wang, Jian; Wu, Yifei; Sun, Xinxiao; Yuan, Qipeng; Yan, Yajun

    2017-06-23

    Microbial based bioplastics are promising alternatives to petroleum based synthetic plastics due to their renewability and economic feasibility. Glutarate is one of the most potential building blocks for bioplastics. The recent biosynthetic routes for glutarate were mostly based on the l-lysine degradation pathway from Pseudomonas putida that required lysine either by feeding or lysine overproduction via genetic manipulations. Herein, we established a novel glutarate biosynthetic pathway by incorporation of a "+1" carbon chain extension pathway from α-ketoglutarate (α-KG) in combination with α-keto acid decarboxylation pathway in Escherichia coli. Introduction of homocitrate synthase (HCS), homoaconitase (HA) and homoisocitrate dehydrogenase (HICDH) from Saccharomyces cerevisiae into E. coli enabled "+1" carbon extension from α-KG to α-ketoadipate (α-KA), which was subsequently converted into glutarate by a promiscuous α-keto acid decarboxylase (KivD) and a succinate semialdehyde dehydrogenase (GabD). The recombinant E. coli coexpressing all five genes produced 0.3 g/L glutarate from glucose. To further improve the titers, α-KG was rechanneled into carbon chain extension pathway via the clustered regularly interspersed palindromic repeats system mediated interference (CRISPRi) of essential genes sucA and sucB in tricarboxylic acid (TCA) cycle. The final strain could produce 0.42 g/L glutarate, which was increased by 40% compared with the parental strain.

  8. Engineering alternative isobutanol production platforms.

    PubMed

    Felpeto-Santero, Carmen; Rojas, Antonia; Tortajada, Marta; Galán, Beatriz; Ramón, Daniel; García, José L

    2015-12-01

    A synthetic inducible operon (IbPSO) expressing alsS, ilvC, ilvD and kivD genes encoding a pathway capable to transform pyruvate into 2-isobutyraldehyde has been designed and two recombinant plasmids named pIZIbPSO and p424IbPSO were constructed. The IbPSO containing plasmids can generate in a single transformation event new recombinant isobutanol producer strains and are useful for testing as suitable hosts wild type bacteria in different culture media. In this way we found that Shimwellia blattae (p424IbPSO) was able to produce in flasks up to 6 g l(-1) of isobutanol using glucose as carbon source. Moreover, for the first time, we have demonstrated that isobutanol can be produced from sucrose using Escherichia coli W (ATCC9367) transformed with pIZIbPSO. These robust recombinant strains were also able to produce isobutanol from a raw carbon source like hydrolysed lignocellulosic biomass.

  9. Isobutanol production from an engineered Shewanella oneidensis MR-1.

    PubMed

    Jeon, Jong-Min; Park, Hyojung; Seo, Hyung-Min; Kim, Jung-Ho; Bhatia, Shashi Kant; Sathiyanarayanan, Ganesan; Song, Hun-Suk; Park, Sung-Hee; Choi, Kwon-Young; Sang, Byoung-In; Yang, Yung-Hun

    2015-11-01

    Shewanella oneidensis MR-1 is one of the most well-known metal-reducing bacteria and it has been extensively studied for microbial fuel cell and bioremediation aspects. In this study, we have examined S. oneidensis MR-1 as an isobutanol-producing host by assessing three key factors such as isobutanol synthetic genes, carbon sources, and electron supply systems. Heterologous Ehrlich pathway genes, kivD encoding ketoisovalerate decarboxylase and adh encoding alcohol dehydrogenase, were constructed in S. oneidensis MR-1. Among the composition of carbon sources examined, 2% of N-acetylglucosamine, 1.5% of pyruvate and 2% of lactate were found to be the most optimal nutrients and resulted in 10.3 mg/L of isobutanol production with 48 h of microaerobic incubation. Finally, the effects of metal ions (electron acceptor) and direct electron transfer systems on isobutanol production were investigated, and Fe(2+) ions increased the isobutanol production up to 35%. Interestingly, deletion of mtrA and mtrB, genes responsible for membrane transport systems, did not have significant impact on isobutanol production. Finally, we applied engineered S. oneidensis to a bioelectrical reactor system to investigate the effect of a direct electron supply system on isobutanol production, and it resulted in an increased growth and isobutanol production (up to 19.3 mg/L). This report showed the feasibility of S. oneidensis MR-1 as a genetic host to produce valuable biochemicals and combine an electron-supplying system with biotechnological applications.

  10. Calmodulin-mediated suppression of 2-ketoisovalerate reductase in Beauveria bassiana beauvericin biosynthetic pathway.

    PubMed

    Kim, Jiyoung; Yoon, Deok-Hyo; Oh, Junsang; Hyun, Min-Woo; Han, Jae-Gu; Sung, Gi-Ho

    2016-11-01

    Ketoisovalerate reductase (KIVR, E.C. 1.2.7.7) mediates the specific reduction of 2-ketoisovalerate (2-Kiv) to d-hydroxyisovalerate (d-Hiv), a precursor for beauvericin biosynthesis. Beauvericin, a famous mycotoxin produced by many fungi, is a cyclooligomer depsipeptide, which has insecticidal, antimicrobial, antiviral, and cytotoxic activities. In this report, we demonstrated that Beauveria bassiana 2-ketoisovalerate reductase (BbKIVR) acts as a typical KIVR enzyme in the entomopathogenic fungus B. bassiana. In addition, we found that BbKIVR interacts with calmodulin (CaM) in vitro and in vivo. The functional role of CaM-binding to BbKIVR was to negatively regulate the BbKIVR activity in B. bassiana. Environmental stimuli such as light and salt stress suppressed BbKIVR activity in B. bassiana. Interestingly, this negative effect of BbKIVR activity by light and salt stress was recovered by CaM inhibitors, suggesting that the inhibitory mechanism is mediated through stimulation of CaM activity. Therefore, this work suggests that BbKIVR plays an important role in the beauvericin biosynthetic pathway mediated by environmental stimuli such as light and salt stress via the CaM signaling pathway.

  11. Automatic reconstruction of the muscle architecture from the superficial layer fibres data.

    PubMed

    Kohout, Josef; Cholt, David

    2017-10-01

    Physiological cross-sectional area (PCSA) of a muscle plays a significant role in determining the force contribution of muscle fascicles to skeletal movement. This parameter is typically calculated from the lengths of muscle fibres selectively sampled from the superficial layer of the muscle. However, recent studies have found that the length of fibres in the superficial layer often differs significantly (p < 0.5) from the length of fibres in the deep layer. As a result, PCSA estimation is inaccurate. In this paper, we propose a method to automatically reconstruct fibres in the whole volume of a muscle from those selectively sampled on the superficial layer. The method performs a centripetal Catmull-Rom interpolation of the input fibres within the volume of a muscle represented by its 3D surface model, automatically distributing the fibres among multiple heads of the muscle and shortening the deep fibres to support large attachment areas with extremely acute angles. Our C++ implementation runs in a couple of seconds on commodity hardware providing realistic results for both artificial and real data sets we tested. The fibres produced by the method can be used directly to determine the personalised mechanical muscle functioning. Our implementation is publicly available for the researchers at https://mi.kiv.zcu.cz/. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Geophysical imaging of karst features in Missouri

    NASA Astrophysics Data System (ADS)

    Obi, Jeremiah Chukwunonso

    Automated electrical resistivity tomography (ERT) supported with multichannel analysis of surface waves (MASW) and boring data were used to map karst related features in Missouri in order to understand karst processes better in Missouri. Previous works on karst in Missouri were mostly surficial mapping of bedrock outcrops and joints, which are not enough to define the internal structure of karst system, since most critical processes in karst occur underground. To understand these processes better, the density, placement and pattern of karst related features like solution-widened joints and voids, as well as top of bedrock were mapped. In the course of the study, six study sites were visited in Missouri. The sites were in Nixa, Gasconade River Bridge in Lebanon, Battlefield, Aurora, Protem and Richland. The case studies reflect to a large extent some of the problems inherent in karst terrain, ranging from environmental problems to structural problems especially sinkhole collapses. The result of the study showed that karst in Missouri is mostly formed as a result of piping of sediments through solution-widened joints, with a pattern showing that the joints/fractures are mostly filled with moist clay-sized materials of low resistivity values. The highest density of mapped solution-widened joints was one in every one hundred and fifty feet, and these areas are where intense dissolution is taking place, and bedrock pervasively fractured. The study also showed that interpreted solution-widened joints trend in different directions, and often times conform with known structural lineaments in the area. About 40% of sinkhole collapses in the study areas are anthropogenic. Karst in Missouri varies, and can be classified as a combination of kI (juvenile), kIII (mature) and kIV (complex) karsts.

  13. Engineering the leucine biosynthetic pathway for isoamyl alcohol overproduction in Saccharomyces cerevisiae.

    PubMed

    Yuan, Jifeng; Mishra, Pranjul; Ching, Chi Bun

    2017-01-01

    Isoamyl alcohol can be used not only as a biofuel, but also as a precursor for various chemicals. Saccharomyces cerevisiae inherently produces a small amount of isoamyl alcohol via the leucine degradation pathway, but the yield is very low. In the current study, several strategies were devised to overproduce isoamyl alcohol in budding yeast. The engineered yeast cells with the cytosolic isoamyl alcohol biosynthetic pathway produced significantly higher amounts of isobutanol over isoamyl alcohol, suggesting that the majority of the metabolic flux was diverted to the isobutanol biosynthesis due to the broad substrate specificity of Ehrlich pathway enzymes. To channel the key intermediate 2-ketosiovalerate (KIV) towards α-IPM biosynthesis, we introduced an artificial protein scaffold to pull dihydroxyacid dehydratase and α-IPM synthase into the close proximity, and the resulting strain yielded more than twofold improvement of isoamyl alcohol. The best isoamyl alcohol producer yielded 522.76 ± 38.88 mg/L isoamyl alcohol, together with 540.30 ± 48.26 mg/L isobutanol and 82.56 ± 8.22 mg/L 2-methyl-1-butanol. To our best knowledge, our work represents the first study to bypass the native compartmentalized α-IPM biosynthesis pathway for the isoamyl alcohol overproduction in budding yeast. More importantly, artificial protein scaffold based on the feature of quaternary structure of enzymes would be useful in improving the catalytic efficiency and the product specificity of other enzymatic reactions.

  14. Competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors, prenylated caged xanthones from Garcinia hanburyi and their inhibitory mechanism.

    PubMed

    Tan, Xue Fei; Uddin, Zia; Park, Chanin; Song, Yeong Hun; Son, Minky; Lee, Keun Woo; Park, Ki Hun

    2017-04-15

    Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC50s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC50=70.25µM) and methylbutenyl 8 (IC50>200µM) showed less activity. The most potent inhibitor, gambogic acid 1 (IC50=0.47µM) showed 30-fold more potency than ursolic acid (IC50=15.5µM), a positive control. In kinetic study, all isolated xanthones behaved as competitive inhibitors which were fully demonstrated with Km, Vmax and Kik/Kiv ratio. It was also proved that inhibitor 1 operated under the enzyme isomerization model having k5=0.0751µM(-)(1)S(-)(1), k6=0.0249µM(-)(1)S(-)(1) and Ki(app)=0.499µM. To develop a pharmacophore model, we explored the binding sites of compound 1 and 7 in PTP1B. These modeling results were in agreement with our findings, which revealed that the inhibitory activities are tightly related to caged motif and prenyl group in A ring.

  15. Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls.

    PubMed

    Bendix, Marie; Uvnäs-Moberg, Kerstin; Petersson, Maria; Kaldo, Viktor; Åsberg, Marie; Jokinen, Jussi

    2017-03-23

    Mental disorders and related behaviors such as suicidality and violence have been associated to dysregulation of e g carbohydrate metabolism. We hypothesized that patients after suicide attempt, compared to healthy controls, would have higher insulin and lower glucagon levels in plasma and cerebrospinal fluid and that these changes would be associated to violent behavior. Twenty-eight medication-free patients (10 women, 18 men), hospitalized after suicide attempt, and 19 healthy controls (7 women, 12 men) were recruited with the aim to study risk factors for suicidal behavior. Psychological/psychiatric assessment was performed with SCID I and II or the SCID interview for healthy volunteers respectively, the Karolinska Interpersonal Violence Scale (KIVS) for assessment of lifetime violence expression behavior, the Montgomery-Åsberg-Depression-Scale (MADRS) and the Comprehensive Psychological Rating Scale (CPRS) for symptomatic assessment of depression and appetite. Fasting levels of insulin and glucagon were measured in plasma (P) and cerebrospinal fluid (CSF). Suicide attempters had higher insulin- and lower glucagon-levels in plasma- and CSF compared to controls. Except for P-glucagon these associations remained significant after adjusting for age and/or BMI. Patients reported significantly more expressed interpersonal violence compared to healthy volunteers. Expressed violence was significantly positively correlated with P- and CSF-insulin and showed a significant negative correlation with P-glucagon in study participants. These findings confirm and extend prior reports that higher insulin and lower glucagon levels in plasma and cerebrospinal fluid are associated with suicidal behavior pointing towards a potential autonomic dysregulation in the control of insulin and glucagon secretion in suicidal patients.

  16. Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase.

    PubMed

    D'Antonio, Edward L; Deinema, Mason S; Kearns, Sean P; Frey, Tyler A; Tanghe, Scott; Perry, Kay; Roy, Timothy A; Gracz, Hanna S; Rodriguez, Ana; D'Antonio, Jennifer

    2015-12-01

    Glucokinase and hexokinase from pathogenic protozoa Trypanosoma cruzi are potential drug targets for antiparasitic chemotherapy of Chagas' disease. These glucose kinases phosphorylate d-glucose with co-substrate ATP and yield glucose 6-phosphate and are involved in essential metabolic pathways, such as glycolysis and the pentose phosphate pathway. An inhibitor class was conceived that is selective for T. cruzi glucokinase (TcGlcK) using structure-based drug design involving glucosamine having a linker from the C2 amino that terminates with a hydrophobic group either being phenyl, p-hydroxyphenyl, or dioxobenzo[b]thiophenyl groups. The synthesis and characterization for two of the four compounds are presented while the other two compounds were commercially available. Four high-resolution X-ray crystal structures of TcGlcK inhibitor complexes are reported along with enzyme inhibition constants (Ki) for TcGlcK and Homo sapiens hexokinase IV (HsHxKIV). These glucosamine analogue inhibitors include three strongly selective TcGlcK inhibitors and a fourth inhibitor, benzoyl glucosamine (BENZ-GlcN), which is a similar variant exhibiting a shorter linker. Carboxybenzyl glucosamine (CBZ-GlcN) was found to be the strongest glucokinase inhibitor known to date, having a Ki of 0.71±0.05μM. Also reported are two biologically active inhibitors against in vitro T. cruzi culture that were BENZ-GlcN and CBZ-GlcN, with intracellular amastigote growth inhibition IC50 values of 16.08±0.16μM and 48.73±0.69μM, respectively. These compounds revealed little to no toxicity against mammalian NIH-3T3 fibroblasts and provide a key starting point for further drug development with this class of compound. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Functional and structural specific roles of activity-driven BDNF within circuits formed by single spiny stellate neurons of the barrel cortex.

    PubMed

    Sun, Qian-Quan; Zhang, Zhi; Sun, June; Nair, Anand S; Petrus, Dan P; Zhang, Chunzhao

    2014-01-01

    Brain derived neurotrophic factor (BDNF) plays key roles in several neurodevelopmental disorders and actions of pharmacological treatments. However, it is unclear how specific BDNF's effects are on different circuit components. Current studies have largely focused on the role of BDNF in modification of synaptic development. The precise roles of BDNF in the refinement of a functional circuit in vivo remain unclear. Val66Met polymorphism of BDNF may be associated with increased risk for cognitive impairments and is mediated at least in part by activity-dependent trafficking and/or secretion of BDNF. Using mutant mice that lacked activity-driven BDNF expression (bdnf-KIV), we previously reported that experience regulation of the cortical GABAergic network is mediated by activity-driven BDNF expression. Here, we demonstrate that activity-driven BDNF's effects on circuits formed by the layer IV spiny stellate cells are highly specific. Structurally, dendritic but not axonal morphology was altered in the mutant. Physiologically, GABAergic but not glutamatergic synapses were severely affected. The effects on GABA transmission occurs via presynaptic alteration of calcium-dependent release probability. These results suggest that neuronal activity through activity-driven BDNF expression, can selectively regulate specific features of layer IV circuits in vivo. We postulate that the role of activity-dependent BDNF is to modulate the computational ability of circuits that relate to the gain control (i.e., feed-forward inhibition); whereas the basic wiring of circuits relevant to the sensory pathway is spared. Gain control modulation within cortical circuits has broad impact on cognitive processing and brain state-transitions. Cognitive behavior and mode is determined by brain states, thus the studying of circuit alteration by endogenous BDNF provides insights into the cellular and molecular mechanisms of diseases mediated by BDNF.

  18. Formate and Nitrate Utilization in Enterobacter aerogenes for Semi-Anaerobic Production of Isobutanol.

    PubMed

    Jung, Hwi-Min; Kim, Yong Hwan; Oh, Min-Kyu

    2017-07-21

    Anaerobic bioprocessing is preferred because of its economic advantages. However, low productivity and decreased growth of the host strain have limited the use of the anaerobic process. Anaerobic respiration can be applied to anoxic processing using formate and nitrate metabolism to improve the productivity of value-added metabolites. A isobutanol-producing strains is constructed using Enterobacter aerogenes as a host strain by metabolic engineering approaches. The byproduct pathway (ldhA, budA, and pflB) is knocked out, and heterologous keto-acid decarboxylase (kivD) and alcohol dehydrogenase (adhA) are expressed along with the L-valine synthesis pathway (ilvCD and budB). The pyruvate formate-lyase mutant shows decreased growth rates when cultivated in semi-anaerobic conditions, which results in a decline in productivity. When formate and nitrate are supplied in the culture medium, the growth rates and amount of isobutanol production is restored (4.4 g L(-1) , 0.23 g g(-1) glucose, 0.18 g L(-1)  h(-1) ). To determine the function of the formate and nitrate coupling reaction system, the mutant strains that could not utilize formate or nitrate is contructed. Decreased growth and productivity are observed in the nitrate reductase (narG) mutant strain. This is the first report of engineering isobutanol-producing E. aerogenes to increase strain fitness via augmentation of formate and nitrate metabolism during anaerobic cultivation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Low CSF oxytocin reflects high intent in suicide attempters.

    PubMed

    Jokinen, Jussi; Chatzittofis, Andreas; Hellström, Christer; Nordström, Peter; Uvnäs-Moberg, Kerstin; Asberg, Marie

    2012-04-01

    Data from animal studies suggest that oxytocin is an important modulating neuropeptide in regulation of social interaction. One human study has reported a negative correlation between CSF oxytocin levels, life history of aggression and suicidal behaviour. We hypothesized that CSF oxytocin levels would be related to suicidal behaviour, suicide intent, lifetime interpersonal violence and suicide risk. 28 medication free suicide attempters and 19 healthy volunteers participated in this cross sectional and longitudinal study. CSF and plasma morning basal levels of oxytocin were assessed with specific radio-immunoassays. The Beck Suicide Intent Scale (SIS), the Freeman scale and the Karolinska Interpersonal Violence Scale (KIVS) were used to assess suicide intent and lifetime violent behaviour. All patients were followed up for cause of death. The mean follow-up was 21 years. Suicide attempters had lower CSF oxytocin levels compared to healthy volunteers p=0.077. In suicide attempters CSF oxytocin showed a significant negative correlation with the planning subscale of SIS. CSF oxytocin showed a significant negative correlation with suicide intent, the planning subscale of SIS and Freeman interruption probability in male suicide attempters. Correlations between plasma oxytocin levels and the planning subscale of SIS and Freeman interruption probability were significant in male suicide attempters. Lifetime violent behaviour showed a trend to negative correlation with CSF oxytocin. In the regression analysis suicide intent remained a significant predictor of CSF oxytocin corrected for age and gender whereas lifetime violent behaviour showed a trend to be a predictor of CSF oxytocin. Oxytocin levels did not differ significantly in suicide victims compared to survivors. CSF oxytocin may be an important modulator of suicide intent and interpersonal violence in suicide attempters.

  20. Inhibition of the CaM-kinases augments cell death in response to oxygen radicals and oxygen radical inducing cancer therapies in MCF-7 human breast cancer cells.

    PubMed

    Rodriguez-Mora, Oswaldo G; Lahair, Michelle M; Evans, Mark J; Kovacs, Charles J; Allison, Ron R; Sibata, Claudio H; White, Kawana S; McCubrey, James A; Franklin, Richard A

    2006-08-01

    Many cancer treatments induce cell death through lethal oxidative stress. Oxidative stress also induces the activation of the calcium/calmodulin-dependent kinases (CaM-Ks), CaM-KII and CaM-KIV. In turn, the CaM-Ks are known to induce the activation of antiapoptotic signaling pathways, such as Akt, ERK, and NF-kappaB in many different cell types. The aim of this study was to determine the role of CaM-Kinases in resistance to hydrogen peroxide and three oxidative stress-inducing cancer therapies in MCF-7 breast cancer cells. We found that oxidative stress induced CaM-Kinase activity in MCF-7 breast cancer cells and that CaM-K inhibition increased hydrogen peroxide-induced cell death in MCF-7 human breast cancer cells. When MCF-7 cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy in the presence of a CaM-K inhibitor a greater level of cell killing was observed than when cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy alone. In support of this finding, CaM-K inhibition increased hydrogen peroxide-induced apoptosis in MCF-7 cells, as determined by increased number of apoptotic cells, DNA fragmentation, and PARP cleavage. Pharmacological and molecular inhibition indicated that CaM-KII was participating in hydrogen peroxide-induced ERK phosphorylation in breast cancer cells indicating a potential mechanism by which this sensitization occurs. This is the first time that CaM-K inhibition is reported to sensitize cancer cells to reactive oxygen intermediate inducing cancer treatments.

  1. Functional and structural specific roles of activity-driven BDNF within circuits formed by single spiny stellate neurons of the barrel cortex

    PubMed Central

    Sun, Qian-Quan; Zhang, Zhi; Sun, June; Nair, Anand S.; Petrus, Dan P.; Zhang, Chunzhao

    2014-01-01

    Brain derived neurotrophic factor (BDNF) plays key roles in several neurodevelopmental disorders and actions of pharmacological treatments. However, it is unclear how specific BDNF’s effects are on different circuit components. Current studies have largely focused on the role of BDNF in modification of synaptic development. The precise roles of BDNF in the refinement of a functional circuit in vivo remain unclear. Val66Met polymorphism of BDNF may be associated with increased risk for cognitive impairments and is mediated at least in part by activity-dependent trafficking and/or secretion of BDNF. Using mutant mice that lacked activity-driven BDNF expression (bdnf-KIV), we previously reported that experience regulation of the cortical GABAergic network is mediated by activity-driven BDNF expression. Here, we demonstrate that activity-driven BDNF’s effects on circuits formed by the layer IV spiny stellate cells are highly specific. Structurally, dendritic but not axonal morphology was altered in the mutant. Physiologically, GABAergic but not glutamatergic synapses were severely affected. The effects on GABA transmission occurs via presynaptic alteration of calcium-dependent release probability. These results suggest that neuronal activity through activity-driven BDNF expression, can selectively regulate specific features of layer IV circuits in vivo. We postulate that the role of activity-dependent BDNF is to modulate the computational ability of circuits that relate to the gain control (i.e., feed-forward inhibition); whereas the basic wiring of circuits relevant to the sensory pathway is spared. Gain control modulation within cortical circuits has broad impact on cognitive processing and brain state-transitions. Cognitive behavior and mode is determined by brain states, thus the studying of circuit alteration by endogenous BDNF provides insights into the cellular and molecular mechanisms of diseases mediated by BDNF. PMID:25414642

  2. Crustal and uppermost mantle structure in the Middle East: assessing constraints provided by jointly modelling Ps and Sp receiver functions and Rayleigh wave group velocity dispersion curves

    NASA Astrophysics Data System (ADS)

    Agrawal, Mohit; Pulliam, Jay; Sen, Mrinal K.; Dutta, Utpal; Pasyanos, Michael E.; Mellors, Robert

    2015-05-01

    Seismic velocity models are found, along with uncertainty estimates, for 11 sites in the Middle East by jointly modelling Ps and Sp receiver functions and surface (Rayleigh) wave group velocity dispersion. The approach performs a search for models that satisfy goodness-of-fit criteria guided by a variant of simulated annealing and uses statistical tools to assess these products of searches. These tools, a parameter correlation matrix and marginal posterior probability density (PPD) function, allow us to evaluate quantitatively the constraints that each data type imposes on model parameters and to identify portions of each model that are well-constrained relative to other portions. This joint modelling technique, which we call `multi-objective optimization for seismology', does not require a good starting solution, although such a model can be incorporated easily, if available, and can reduce the computation time significantly. Applying the process described above to broadband seismic data reveals that crustal thickness varies from 15 km beneath Djibouti (station ATD) to 45 km beneath Saudi Arabia (station RAYN). A pronounced low velocity zone for both Vp and Vs is present at a depth of ˜12 km beneath station KIV located in northern part of greater Caucasus, which may be due to the presence of a relatively young volcano. Similarly, we also noticed a 6-km-thick low velocity zone for Vp beginning at 20 km depth beneath seismic station AGIN, on the Anatolian plateau, while positive velocity gradients prevail elsewhere in eastern Turkey. Beneath station CSS, located in Cyprus, an anomalously slow layer is found in the uppermost mantle, which may indicate the presence of altered lithospheric material. Crustal P- and S-wave velocities beneath station D2, located in the northeastern portion of central Zagros, range between 5.2-6.2 and 3.2-3.8 km s-1, respectively. In Oman, we find a Moho depth of 34.0 ± 1.0 km and 25.0 ± 1.0 to 30.0 ± 1.0 km beneath stations S02 and S

  3. Characterization of recombinantly expressed dihydroxy-acid dehydratase from Sulfobus solfataricus-A key enzyme for the conversion of carbohydrates into chemicals.

    PubMed

    Carsten, Jörg M; Schmidt, Anja; Sieber, Volker

    2015-10-10

    Dihydroxyacid dehydratases (DHADs) are excellent biocatalysts for the defunctionalization of biomass. Here, we report on the recombinant production of DHAD from Sulfolobus solfataricus (SsDHAD) in E. coli and its characterization with special focus on activity toward non-natural substrates, thermo-stability, thermo-inactivation kinetics and activation capabilities and its application within multi-step cascades for chemicals production. Using a simple heat treatment of cell lysate as major purification step we achieved a specific activity of 4.4 units per gram cell mass toward the substrate d-gluconate. The optimal temperature and pH value for this reaction are 77°C and pH 6.2. The inhibitory concentration (IC50, 50% residual activity) of different alcohols was determined to be 15% (v/v) for ethanol, 4.5% (v/v) for butanol and 4% (v/v) for isobutanol. Besides d-gluconate and the natural substrate 2,3-dihydroxyisovalerate (DHIV) SsDHAD is able to convert the C3-sugar-acid d-glycerate to pyruvate, a reaction, which does not occur in natural metabolic pathways, with a specific activity of 10.7±0.4mU/mg. The specific activity of the enzyme can be increased 3-fold by incubation with 2-mercaptoethanol. The activation has no impact on temperature dependence, but modulates the thermo-inactivation tolerance at 50°C. The total turnover numbers for all of the three reactions was found to be 35.5×10(3)±1.0×10(3) for the conversion of d-gluconate to 2-keto-3-deoxygluconate (KDG), 28.2×10(3)±0.8×10(3) for DHIV to 2-ketovalerate (KIV) and 943±0.28×10(2) for d-glycerate to pyruvate. With activated SsDHAD these values could be further increased 5- and 4-fold for the d-gluconate and d-glycerate conversion, respectively. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. [Lipid-lowering therapy and patient adherence in the MULTI GAP 2013 trial].

    PubMed

    Simonyi, Gábor

    2014-04-27

    Bevezetés: A dyslipidaemia ismert cardiovascularis kockázati tényező. A lipidterápiában a célértékek elérésének fontos tényezője a megfelelő betegadherencia. Célkitűzés: A MULTI GAP (MULTI Goal Attainment Problem) 2013-as vizsgálatban atheroscleroticus betegségben szenvedő betegek esetében a statinterápia adherenciájának és perzisztenciájának felmérése, amely részben a vizsgálatban részt vevő orvosok becslésén, illetve 319, a megelőző évben elvégzett MULTI GAP vizsgálatban részt vett beteg esetében az Országos Egészségbiztosítási Pénztár vénykiváltási adatbázisán alapult. Módszer: A MULTI GAP 2013 vizsgálatban standard, strukturált kérdőívek segítségével 1519 beteg adatai kerültek feldolgozásra. Az elemzésben kiértékelésre kerültek az egyes ellátási szinteken elért lipidértékek, a kezelőorvos által vélt betegadherencia, a 319 beteg Országos Egészségbiztosítási Pénztár vénykiváltási adataira támaszkodó valós adherencia, a kezelőorvosok elégedettsége a statinterápia eredményeivel, illetve az adherencia és a lipideredmények összevetése. Eredmények: Az elmúlt 7 év felméréseinek adatait is figyelembe véve előtérbe kerültek a hatékonyabb statinok; az atorvastatin és rozuvastatin alkalmazásának összesített aránya 49%-ról 83%-ra, azaz mintegy 70%-kal nőtt. A betegadherencia vonatkozásában kimutatták, hogy a 2,5 mmol/l alatti LDL-koleszterin-értékeket elért betegeknél az 1 év alatt kiváltott receptek száma mintegy nyolc gyógyszertári beváltást jelentett. Ehhez képest a 2,5 mmol/l feletti LDL-koleszterin-értékű csoportban a gyógyszerkiváltás lényegesen alacsonyabb volt (5,3 és 6,3 közötti). Éves szinten a 10–12 és a 7–9 gyógyszerkiváltás szignifikánsan alacsonyabb LDL-koleszterin-szintet jelentett a semennyit (0), illetve az 1–3 receptet éves szinten kiváltók csoportjaihoz képest. A kezelőorvosok által 100%-os

  5. [Cognitive functions in type 1 and type 2 diabetes. Meta-analysis].

    PubMed

    Kálcza-Jánosi, Kinga; Lukács, Andrea; Barkai, László; Szamosközi, István

    2013-05-05

    Bevezetés: A cukorbetegséget különféle kognitív károsodásokkal társítják. Célkitűzés: A szerzők 1-es és 2-es típusú diabetesben a kognitív működés közötti különbségek pontosítását tűzték ki célul. Módszer: Metaanalízis a Medline, PubMed és ScienceDirect felhasználásával (három tanulmány az 1-es és hat tanulmány a 2-es típusú cukorbetegséggel kapcsolatban). Eredmények: Az 1-es típusú cukorbeteg felnőttek teljesítménye gyengébb volt a kontrollokhoz képest az összes mért területen. A hatásméret a pszichomotoros aktivitásnál volt a legmagasabb (D = –0,69). Kicsi volt a hatásméret a késleltetett verbális memória (D = –0,48), figyelem (D = –0,47), nyelv (D = –0,44), vizuális feldolgozás (D = –0,35), azonnali verbális memória (D = –0,30), munkamemória (D = –0,27) és a végrehajtó funkcióknál (D = –0,26). A felnőtt 2-es típusú cukorbetegek teljesítménye gyengébb volt, mint a kontrolloké a munkamemória kivételével (D = +0,03) az összes kognitív területen. Legmagasabb hatásméretet az azonnali verbális memória (D = –1,12), pszichomotoros aktivitás (D = –0,82) és a késleltetett verbális memória (D = –0,81) mutatott. Közepes volt a hatásméret az általános intellektuális képességek (D = –0,68) területén, míg kicsi volt a hatásméret az általános memória (D = –0,37), a figyelem (D = –0,35), nyelv (D = –0,35), vizuális feldolgozás (D = –0,33) és a végrehajtó funkciók (D = –0,33) terén. Következtetés: Mindkét típusú cukorbetegség csökkent teljesítménnyel társul számos kognitív területen. Orv. Hetil., 2013, 154, 694–699.

  6. [Mini-laparoscopic cholecystectomy as an innovative method in minimally invasive abdominal surgery].

    PubMed

    Andrási, László; Ábrahám, Szabolcs; Lázár, György

    2014-12-01

    Bevezetés: Vizsgálatunkban a minilaparoscopos módon (portok számának és méretének csökkentése révén) végzett laparoscopos cholecystectomiák (LC) eredményeit mutatjuk be. Elemeztük a mini-LC előnyeit és hátrányait a hagyományos LC-vel összehasonlítva. Betegek és módszerek: Mini-LC során összesen 3 portot (11, 5 és 3,5 mm) alkalmaztunk. Tíz esetben végzett mini-LC eredményeit hasonlítottuk össze 10 konvencionális LC eredményeivel. A betegválogatás alapját a nem, az életkor, a BMI és az ASA-beosztás képezte, amely mindkét vizsgált csoportot homogénné tett. Összehasonlítottuk a két eljárás átlagos műtéti időtartamát, a segédport szükségességét, a konverziós arányt, a postoperativ fájdalomcsillapító-igényt, a korai/késői szövődmények előfordulásának gyakoriságát és a kozmetikai eredményeket. Eredmények: A műtéti időtartam, vérveszteség, kórházi tartózkodás, szövődmények vonatkozásában nem észleltünk szignifikáns különbséget a két csoport között. A sebészi metszések összesített mérete mini-LC során 19,5 mm, míg az LC-csoportban 41 mm, a szöveti károsodás mértéke pedig 124,2 mm2 és 448,2 mm2 volt a két csoportban. Mindezek jelentősen javították a mini-LC kozmetikai eredményét. A hagyományos LC után a betegek szignifikánsan nagyobb arányban igényeltek postoperativ fájdalomcsillapítást. Következtetések: A mini-LC biztonságos, kiváló kozmetikai eredményeket adó eljárás, amely kisebb postoperativ fájdalomcsillapító-igénnyel jár. Válogatott esetekben ez a műtéti típus ajánlott eljárás lehet a konvencionális LC-vel szemben.

  7. [Use of hysteroscopy at the office in gynaecological practice].

    PubMed

    Török, Péter

    2014-10-05

    Bevezetés: Az office hiszteroszkópia a méhűri vizsgálatot gyorsabbá teszi, alacsonyabb költségigényű, a betegek számára pedig kevesebb megterheléssel jár. Célkitűzés: A szerző célja volt a vizsgálatok közben tapasztalt fájdalomérzetek elemzése, új eljárás kidolgozása a petevezető-átjárhatóság ambuláns vizsgálatára. Módszer: A vizsgálatok a Debreceni Egyetem, Szülészeti és Nőgyógyászati Klinikáján történtek, ambuláns körülmények között, anesztézia nélkül. A 400 vizsgálat eredményének elemzése a hagyományos módszernél ismert javallatok alapján készült. A szerző a vizsgálatokhoz 2,7 mm átmérőjű optikát használt diagnosztikus, illetve operatív hüvellyel, és a fájdalomérzet objektivizálására 70 betegnél VAS-t alkalmazott. A petevezető-átjárhatósági vizsgálat során 70 esetben hasonlította az új módszert a laparoszkópos változathoz. Eredmények: Az office hiszteroszkópia alkalmazható ambuláns körülmények között, anesztézia nélkül. A tapasztalt fájdalomértékek az alcsoportokban (nem szült, szült, posztmenopauza, diagnosztikus/operatív alcsoport) szignifikánsan nem különböztek, átlagértékük 3,5±1,01 volt (p=0,34). A szelektív pertubáció a laparoszkópos kromohidrotubációhoz viszonyítva 92,06% pontosságúnak bizonyult. Következtetések: Az office hiszteroszkópia gyorsasága, fájdalommentessége az új eljárás széles körű alkalmazását támasztja alá. Meddőségi kivizsgálásban kiválthatja a műtői körülményeket igénylő beavatkozásokat. Orv. Hetil., 2014, 155(40), 1589–1597.

  8. [Evaluation of the usefulness of the EOS 2D/3D system for the measurement of lower limbs anatomical and biomechanical parameters in children].

    PubMed

    Schlégl, Adám Tibor; Szuper, Kinga; Somoskeöy, Szabolcs; Than, Péter

    2014-10-26

    Bevezetés: Az alsó végtag anatómiai és biomechanikai paraméterei számos gyermekortopédiai betegség kulcstényezői, így pontos mérésük elengedhetetlen. Célkitűzés: A szerzők célja a rendelkezésükre álló 3D rekonstrukcióra képes képalkotó eszköz, az EOS 2D/3D System gyermekkori alkalmazhatóságának vizsgálata volt. Módszer: A 2–16 éves korcsoportba tartozó 523 egyén 3D modellezését végezték el, akiknél az alsó végtag biomechanikáját befolyásoló eltérés nem igazolódott. Az adatok statisztikai feldolgozásához intraclass korrelációs vizsgálatot, páros t-próbát, Spearman-korrelációt, illetve Welch-tesztet alkalmaztak. Eredmények: A megbízhatósági vizsgálat során az operátor minden paraméter esetében kiváló eredményt ért el. A képalkotás során alkalmazott előrelépett pozíció egyedül a sagittalis tibifemoralis szögnél okozott eltérést. A szerzők által vizsgált összes paraméter összefüggést mutatott a korral és a nemmel. Ezzel szemben a magassággal nem mutatott összefüggést a collodiaphysealis szög, a csípő-térd eltolódás és a femoralis és tibialis torzió. Következtetések: Az EOS-technológia alkalmas módszernek bizonyult az alsó végtag anatómiai paramétereinek mérésére gyermekkorban. Ezek változása összefügg a nemmel és a korral egyaránt. Orv., Hetil., 2014, 155(43), 1701–1711.

  9. [Connection between cancer- and alcohol-related mortality in a rural practice of a South-Hungarian village].

    PubMed

    Péter, Arpád

    2013-05-05

    Bevezetés: A több mint negyedszázada ugyanazon egykörzetes községben dolgozó szerző az 1987 és 1999 közötti vizsgálati periódusban a daganatos halálozásnak az alkohollal kapcsolatos halálozással összefüggő hányadát férfiak körében 50%-nak, nők körében 7,9%-nak találta. Célkitűzés: A szerző célként tűzte ki a halálozás e két meghatározó tényezőjének hosszabb távú nyomon követéséhez és elemzéséhez a halálozási mutatók ismételt felmérését a 2000 és 2011 közötti időszakra vonatkozóan. Módszer: Az elhunyt betegek valamennyi fontos előzményi adatát összefoglaló háziorvosi halotti epikrízisekbe tömörítette és a halálokok kiválasztásakor ezeket döntő súllyal vette figyelembe. Eredmények: A vizsgált 12 év alatt a szerző úgynevezett „tisztított praxislakossága” körében 326 ember halt meg (167 férfi, 159 nő). Bár a részeredményeket tekintve is jelentős átstruktúrálódás következett be a daganatos és alkoholos halálozási kategóriákon belül, és ezek összes halálozáson belüli aránya is megváltozott (az alkohollal kapcsolatos halálozásé számottevően csökkent, míg a daganatos halálozásé kisebb mértékben nőtt), az újabb vizsgálati periódusban a daganatos halálozásnak alkohollal kapcsolatos hányada mindkét nemben nőtt (a férfiak körében 60%-ra, a nők körében 9,1%-ra). Következtetés: Legfőbb epidemiológiai következtetésként megerősítést nyert, hogy a daganatos betegségek megelőzésének, különösen bizonyos lokalizációjú daganatok mint halálokok csökkentésének egyik kulcskérdése – megkülönböztetetten a férfiak körében – az alkoholabúzus visszaszorítása. Orv. Hetil., 2013, 154, 700–706.

  10. [Low persistence of simvastatin and ezetimibe fixed combination in the lipid lowering therapy].

    PubMed

    Simonyi, Gábor; Ferenci, Tamás

    2015-01-25

    Bevezetés: Jól ismert, hogy a magas koleszterinszint fontos módosítható cardiovascularis kockázati tényező. A lipidcsökkentő kezelés során a cardiovascularis kockázat csökkentése miatt fontos a betegek terápiahűsége. Célkitűzés: A szerzők célja a simvastatin/ezetimib szabad és fix kombinációk, illetve a leghatékonyabb statin, a rozuvastatin egyéves perzisztenciájának összehasonlítása volt. Módszer: Az Országos Egészségbiztosítási Pénztár vényforgalmi adataira támaszkodva 2012. október 1. és 2013. szeptember 30. között első alkalommal a simvastatin/ezetimib szabad és fix kombinációi és a rozuvastatinmonoterápia receptjeit kiváltó betegeket választották ki, akik az ezt megelőző egy évben hasonló hatóanyaggal végzett antilipaemiás terápiában nem részesültek. A perzisztenciagörbéket Kaplan–Meier-becsléssel határozták meg, 95%-os, log-skálán számolt pontonkénti konfidenciaintervallummal. Cenzoráltnak azokat a betegeket vették, akik a vizsgálat záró időpontjában is perzisztensek voltak. A görbék modellezéséhez félparaméteres eljárást, Cox-regressziót használtak, ahol az egyetlen – kategoriális – magyarázó változó a terápia volt; referenciacsoportnak a simvastatin/ezetimib fix kombinációt vették. Eredmények: A bevonási kritériumoknak összesen 204 699 beteg felelt meg. E betegek közül 10 030 beteg kezdett simvastatin/ezetimib szabad, 7613 beteg simvastatin/ezetimib fix, illetve 187 056 beteg rozuvastatinmonoterápiát. Az egyéves perzisztencia a simvastatin/ezetimib szabad kombináció esetében 10,97%, a simvastatin/ezetimib fix kombinációt szedőkben 24,35%, míg a rozuvastatinmonoterápián lévők esetében 30,47% volt. A simvastatin/ezetimib fix kombinációhoz képest a simvastatin/ezetimib szabad kombináció elhagyásának az esélye 73%-kal volt nagyobb (kockázatarány = 1,73 [95% konfidenciaintervallum: 1,61–1,85], p<0,0001), míg a

  11. [Treatment outcome in primary testicular non-Hodgkin lymphoma].

    PubMed

    Iványi, János László; Marton, Eva; Plander, Márk; Engert, Zoltán Vendel; Tóth, Csaba

    2013-10-20

    Bevezetés: A primer herelymphoma ritkán előforduló extranodalis non-Hodgkin-lymphoma-entitás. Legtöbbször idős férfiakban fordul elő, nagy malignitású szövettani képpel és kedvezőtlen kórlefolyással. Az érintett here eltávolítása után alkalmazott immunkemoterápia ellenére a betegek kezelési eredményei elmaradnak más extranodalis lymphomásokétól. Célkitűzés: Retrospektív felmérésben a szerzők célul tűzték ki 2000 és 2012 között kórismézett és kezelt herelymphomás betegeik klinikopatológiai és kezelési eredményeinek felmérését. Módszer: Ezen időszak alatt 334 agresszív non-Hodgkin-lymphomás betegből nyolc esetben (8/334, 2,39%) kórisméztek primer herelymphomát (diffúz nagysejtes B-sejtes hét esetben, Burkitt-típusú egy esetben). A betegek medián életkora 60 év (23 és 86 év között) volt. Korai I–IIE hét betegben, előrehaladott stádium egy betegben fordult elő. Egy beteg kivételével (csak radioterápia) minden beteg kemoterápiát kapott (rituximab+CHOP, hat–nyolc ciklus 21 vagy 28 naponként). Mindössze egy beteg részesült központi idegrendszeri kemoterápiás profilaxisban, preventív ellenoldali hereirradiációt nem alkalmaztak. Eredmények: Ötven hónapos medián követés alatt semicastratiót követő rituximab- és CHOP-kúra után hét beteg került komplett remisszióba, két beteg elhunyt (egy beteg a lymphoma progressziója következtében, a remisszióban levő másik beteg szekunder tüdőtumor miatt). Komplett remissziót a betegek 87,5%-ában értek el. A betegségmentes túlélés 13–152 hónap között (medián 38 hónap), az összesített túlélés 17–156 hónap között (medián 43 hónap), az ötéves betegségmentes és összesített túlélés pedig egyaránt 37,5% volt. Következtetések: A viszonylag kedvező kezelési eredmények hátterében a korai stádium túlsúlya, a lymphoma urológiai sebészi eltávolítása, az immunkemoterápia hat

  12. Petrochemical types of kimberlites and their diamond-bearing capacity

    NASA Astrophysics Data System (ADS)

    Kostrovitsky, Sergey

    2010-05-01

    kimberlites, varying in the rate of diamond capacity, are indistinguishable in the content of incompatible elements or differ slightly (Kostrovitsky et al, 2007). There is no correlation relationship between the microelement composition (from some incoherent elements) and diamond-bearing capacity of kimberlites. The efficiency of applying petrochemical and mineralogical criteria of diamond-bearing capacity is explained considering the genesis of kimberlite rock formation. It is assumed that the asthenosphere kimberlite-forming fluid-melt displayed capacity of fluid brecciation of rocks of lithosphere mantle. The composition of kimberlites and their diamond-bearing capacity also depend on the fact, which rocks of the mantle are largely brecciated and captured by the fluid melt. While kimberlite pipes Aikhal and International were formed, these were basically the rocks of high-Mg dunite-harzburgite diamondiferous paragenesis, which experienced brecciation. This predetermined both the petrochemical type of kimberlites and diamond-bearing capacity of these pipes. Thus, we suppose, that kimberlites, traditionally referred to group I, are not similar. Within this group it is feasible to recognize petrochemical types differing in mineralogical composition and the rate of potential diamond-bearing capacity. References Ilupin, I.P., Kaminsky, F.V., Frantsesson, E.V. (1978) Geochemistry of kimberlites [in Russian]. Nedra, Moscow. Khar'kiv, A.D., Zuenko, V.V., Zinchuk, N.N., Kryuchkov, A.I., Ukhanov, V.A. (1991). Petrochemistry of kimberlites [in Russian]. Nedra, Moscow. Kostrovitsky S.I., T. Morikiyo, I.V. Serov, D.A. Yakovlev, A.A. Amirzhanov. (2007) Isotope-geochemical systematics of kimberlites and related rocks from the Siberian Platform. Russian Geology and Geophysics. V. 48. P. 272-290. Krivonos V.F. (1999) Petrochemical criteria of diamond content in the kimberlites and lamproites. Geology and Geophysics. [in Russian] № 2. P. 187-200. Meyer, H.O.A. Chrome pyrope: an inclusion